MADRID – New data from three trials evaluating the bispecific antibody amivantamab (Rybrevant) in EGFR-mutated advanced non–small cell lung cancer (NSCLC) have revealed a clear benefit, experts said at the annual meeting of the European Society for Medical Oncology (ESMO).

The results of the three trials – PAPILLON, MARIPOSA, and MARIPOSA-2 – are “really exciting” for patients harboring EGFR mutations, said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland, and the ESMO 2023 scientific chair.

Presenting findings from PAPILLON, Nicolas Girard, MD, PhD, highlighted outcomes among patients with EGFR exon 20 insertion-mutated advanced NSCLC. These patients, who represent about 2%-3% of NSCLC cases, have “historically poor” outcomes, with a 5-year overall survival rate of just 8%.

Tumors harboring exon 20 insertions are largely insensitive to targeted and immune checkpoint therapies, explained Dr. Girard, from Curie-Montsouris Thorax Institute, Institut Curie, Paris. That leaves platinum-based chemotherapy as the standard of care, which has “limited efficacy,” he noted.

The FDA approved amivantamab in 2021 for EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy, but the PAPILLON trial explored whether combining the two therapies upfront would provide a more meaningful benefit.

In the trial, 308 treatment-naive patients with locally advanced or metastatic NSCLC and documented exon 20 insertions were randomly assigned to amivantamab plus chemotherapy or chemotherapy alone. The median age was about 62 years, approximately half were female, and just over 60% were Asian – a similar patient profile as MARIPOSA and MARIPOSA-2.

The results, simultaneously published in The New England Journal of Medicine, showed that amivantamab plus chemotherapy significantly increased progression-free survival (PFS). More specifically, after a median follow-up of 14.9 months, patients receiving the combination had a median PFS of 11.4 months vs. 5.7 months with chemotherapy alone (hazard ratio, 0.395; P < .0001). This benefit consistently occurred across predefined subgroups.

Amivantamab plus chemotherapy was associated with a lower risk of a second progression, with the median not reached vs. 17.2 months with chemotherapy alone (HR, 0.493; P = .001).

A higher proportion of patients receiving the combination had an objective response – 73% vs. 47% – and these patients had a longer duration of response as well – 9.7 months vs. 4.4 months.

The overall survival data were immature but showed a trend toward a reduced risk of death for those on the combination (HR, 0.675; P = .106).

The rates of grade ≥ 3 adverse events were 75% with amivantamab plus chemotherapy and 54% with chemotherapy alone, and adverse events leading to discontinuation of amivantamab occurred in 7% of patients. Pneumonitis/interstitial lung disease (ILD) was reported in 3% of patients in the combination therapy arm.

Dr. Girard concluded that, with a safety profile “consistent” with that seen for the individual agents, amivantamab plus chemotherapy “represents a new standard of care” for first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC.

Benjamin Besse, MD, PhD, who was not involved in the research, agreed that this combination is “definitely a new standard of care.”

The effect of giving amivantamab alongside chemotherapy “seems to be really additive,” said Dr. Besse, director of clinical research at the Gustave Roussy Institute and professor of medical oncology at Paris-Saclay University, both in Paris. But he noted that amivantamab is a “challenging drug in terms of toxicity.”
 

The MARIPOSA trials

The two MARIPOSA trials also demonstrated that amivantamab, in combination with other agents, improved PFS among patients with EGFR-mutated advanced NSCLC.

Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, South Korea, presented results from MARIPOSA, which focused on patients with any kind of EGFR mutation.

Although the EGFR tyrosine kinase inhibitor (TKI) osimertinib is the current standard of care in this first-line setting, “resistance and disease progression are nearly inevitable,” and secondary EGFR and MET mutations may account for up to 50% of tumor resistance, Dr. Cho noted.

Early clinical data suggest that combining amivantamab with the highly selective third-generation EGFR TKI lazertinib leads to clinical activity and durable responses.

For the phase 3 MARIPOSA trial, 1,074 patients with treatment-naive locally advanced or metastatic EGFR-mutant NSCLC were randomly assigned to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216).

After a median follow-up of 22 months, the median PFS among patients on the combination was 23.7 months vs. 16.6 months for those on osimertinib alone (HR, 0.70; P < .001) and 18.5 months for those on lazertinib alone.

The PFS benefit observed with amivantamab plus lazertinib occurred across subgroups, including among patients with brain metastases. The combination reduced the risk for extracranial progression or death by 32% and improved median PFS by 9 months, compared with osimertinib alone (HR, 0.68; P < .001).

The risk for a second progression was also lower with the combination (HR, 0.75).

Interim overall survival data suggested a benefit with the combination therapy, compared with osimertinib alone (HR, 0.80; P = .11).

Grade 3 or higher adverse events were more common among patients treated with the combination vs. osimertinib alone – 75% vs. 43%. Higher rates of treatment-related discontinuation of any agent were observed in the combination group – 35% vs. 14% – though rates of adverse events leading to death were similar between the groups – 8% and 7%, respectively.

As in PAPILLON, rates of ILD/pneumonitis were “low,” said Dr. Cho, at approximately 3% in both treatment arms. However, he noted, rates of venous thromboembolism were higher with the combination, with grade ≥ 3 events occurring in 11% vs. 3.7% of patients on osimertinib.

Based on the findings, amivantamab plus lazertinib “represents a new standard of care in first-line EGFR-mutant advanced NSCLC,” Dr. Cho said. “It has been a long way and we finally made it.”

Next up is MARIPOSA-2, which evaluated patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on or after osimertinib.

In this trial, 657 patients were randomly assigned to amivantamab plus lazertinib and chemotherapy (n = 263), amivantamab plus chemotherapy (n = 263), or chemotherapy alone (n = 131).

Given the increased risk for hematologic toxicities, the study protocol was adjusted in the triple therapy arm so that patients received lazertinib after completing carboplatin.

The findings, presented by study investigator Antonio Passaro, MD, PhD, were simultaneously published in Annals of Oncology.

After a median follow-up of 8.7 months, the triple therapy reduced the risk for progression or death by 56% (HR,0.44) and amivantamab plus chemotherapy reduced the risk for progression or death by 52% (HR, 0.48). Overall, the median PFS was 8.3 months in the triple combination arm, 6.3 months in the amivantamab plus chemotherapy arm, and 4.2 months in the chemotherapy arm.

This PFS benefit was observed across prespecified subgroups with both combination therapies. The combinations also reduced the risk for intracranial progression (HR, 0.58 in the triple therapy arm; HR, 0.55 in the amivantamab plus chemotherapy arm).

The current interim analysis did not show an overall survival benefit with either combination therapy vs. chemotherapy alone, although the survival curve hinted at a benefit in the amivantamab plus chemotherapy arm.

The median duration of response was 9.4 months for triple therapy, 6.9 months for the double combination, and 5.6 months for monotherapy.

Rates of grade ≥ 3 adverse events were notably higher in the combination groups – 92% of patients on triple therapy, 72% on double, and 48% on chemotherapy alone. But the treatment duration was longer in the combination groups and adverse events leading to death were low, as was discontinuation.

Amivantamab plus chemotherapy or plus lazertinib and chemotherapy are the “first regimens to demonstrate improved PFS vs. chemotherapy in EGFR-mutated NSCLC after disease progression on osimertinib,” concluded Dr. Passaro, from the European Institute of Oncology IRCCS, Milan, who presented the findings.

Dr. Passaro added that, given the consistent efficacy and more favorable safety profile, “we can say that amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib,” although more follow-up is required to understand its “real impact” in the clinic.

Zofia Piotrowska, MD, who was not involved in either MARIPOSA trial, said both “are really important” in the EGFR-mutant NSCLC space.

The studies “addressed two different questions,” but both were “positive, and I think clinically significantly,” said Dr. Piotrowska, a lung cancer specialist at Massachusetts General Hospital Cancer Center, Boston.

However, Dr. Piotrowska noted that a core question for the community will be “how we find that balance between the clinical benefits [and] the toxicities.”

“There’s not going to be one easy answer” and treatment selection will have to be made on a “patient-by-patient basis,” she said.

PAPILLON, MARIPOSA, and MARIPOSA-2 were funded by Janssen Pharmaceuticals. Dr. Girard declared relationships with AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and others. Dr. Cho declared relationships with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Onegene Biotechnology, Pfizer, Eli Lilly, and others. Dr. Passaro declared relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer-Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape, and eCancer. Dr. Besse declared institutional relationships with AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, and others. Dr. Piotrowska declared relationships with numerous companies including AstraZeneca, Novartis, and Takeda.

A version of this article first appeared on Medscape.com.

MADRID – New data from three trials evaluating the bispecific antibody amivantamab (Rybrevant) in EGFR-mutated advanced non–small cell lung cancer (NSCLC) have revealed a clear benefit, experts said at the annual meeting of the European Society for Medical Oncology (ESMO).

The results of the three trials – PAPILLON, MARIPOSA, and MARIPOSA-2 – are “really exciting” for patients harboring EGFR mutations, said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland, and the ESMO 2023 scientific chair.

Presenting findings from PAPILLON, Nicolas Girard, MD, PhD, highlighted outcomes among patients with EGFR exon 20 insertion-mutated advanced NSCLC. These patients, who represent about 2%-3% of NSCLC cases, have “historically poor” outcomes, with a 5-year overall survival rate of just 8%.

Tumors harboring exon 20 insertions are largely insensitive to targeted and immune checkpoint therapies, explained Dr. Girard, from Curie-Montsouris Thorax Institute, Institut Curie, Paris. That leaves platinum-based chemotherapy as the standard of care, which has “limited efficacy,” he noted.

The FDA approved amivantamab in 2021 for EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy, but the PAPILLON trial explored whether combining the two therapies upfront would provide a more meaningful benefit.

In the trial, 308 treatment-naive patients with locally advanced or metastatic NSCLC and documented exon 20 insertions were randomly assigned to amivantamab plus chemotherapy or chemotherapy alone. The median age was about 62 years, approximately half were female, and just over 60% were Asian – a similar patient profile as MARIPOSA and MARIPOSA-2.

The results, simultaneously published in The New England Journal of Medicine, showed that amivantamab plus chemotherapy significantly increased progression-free survival (PFS). More specifically, after a median follow-up of 14.9 months, patients receiving the combination had a median PFS of 11.4 months vs. 5.7 months with chemotherapy alone (hazard ratio, 0.395; P < .0001). This benefit consistently occurred across predefined subgroups.

Amivantamab plus chemotherapy was associated with a lower risk of a second progression, with the median not reached vs. 17.2 months with chemotherapy alone (HR, 0.493; P = .001).

A higher proportion of patients receiving the combination had an objective response – 73% vs. 47% – and these patients had a longer duration of response as well – 9.7 months vs. 4.4 months.

The overall survival data were immature but showed a trend toward a reduced risk of death for those on the combination (HR, 0.675; P = .106).

The rates of grade ≥ 3 adverse events were 75% with amivantamab plus chemotherapy and 54% with chemotherapy alone, and adverse events leading to discontinuation of amivantamab occurred in 7% of patients. Pneumonitis/interstitial lung disease (ILD) was reported in 3% of patients in the combination therapy arm.

Dr. Girard concluded that, with a safety profile “consistent” with that seen for the individual agents, amivantamab plus chemotherapy “represents a new standard of care” for first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC.

Benjamin Besse, MD, PhD, who was not involved in the research, agreed that this combination is “definitely a new standard of care.”

The effect of giving amivantamab alongside chemotherapy “seems to be really additive,” said Dr. Besse, director of clinical research at the Gustave Roussy Institute and professor of medical oncology at Paris-Saclay University, both in Paris. But he noted that amivantamab is a “challenging drug in terms of toxicity.”
 

The MARIPOSA trials

The two MARIPOSA trials also demonstrated that amivantamab, in combination with other agents, improved PFS among patients with EGFR-mutated advanced NSCLC.

Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, South Korea, presented results from MARIPOSA, which focused on patients with any kind of EGFR mutation.

Although the EGFR tyrosine kinase inhibitor (TKI) osimertinib is the current standard of care in this first-line setting, “resistance and disease progression are nearly inevitable,” and secondary EGFR and MET mutations may account for up to 50% of tumor resistance, Dr. Cho noted.

Early clinical data suggest that combining amivantamab with the highly selective third-generation EGFR TKI lazertinib leads to clinical activity and durable responses.

For the phase 3 MARIPOSA trial, 1,074 patients with treatment-naive locally advanced or metastatic EGFR-mutant NSCLC were randomly assigned to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216).

After a median follow-up of 22 months, the median PFS among patients on the combination was 23.7 months vs. 16.6 months for those on osimertinib alone (HR, 0.70; P < .001) and 18.5 months for those on lazertinib alone.

The PFS benefit observed with amivantamab plus lazertinib occurred across subgroups, including among patients with brain metastases. The combination reduced the risk for extracranial progression or death by 32% and improved median PFS by 9 months, compared with osimertinib alone (HR, 0.68; P < .001).

The risk for a second progression was also lower with the combination (HR, 0.75).

Interim overall survival data suggested a benefit with the combination therapy, compared with osimertinib alone (HR, 0.80; P = .11).

Grade 3 or higher adverse events were more common among patients treated with the combination vs. osimertinib alone – 75% vs. 43%. Higher rates of treatment-related discontinuation of any agent were observed in the combination group – 35% vs. 14% – though rates of adverse events leading to death were similar between the groups – 8% and 7%, respectively.

As in PAPILLON, rates of ILD/pneumonitis were “low,” said Dr. Cho, at approximately 3% in both treatment arms. However, he noted, rates of venous thromboembolism were higher with the combination, with grade ≥ 3 events occurring in 11% vs. 3.7% of patients on osimertinib.

Based on the findings, amivantamab plus lazertinib “represents a new standard of care in first-line EGFR-mutant advanced NSCLC,” Dr. Cho said. “It has been a long way and we finally made it.”

Next up is MARIPOSA-2, which evaluated patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on or after osimertinib.

In this trial, 657 patients were randomly assigned to amivantamab plus lazertinib and chemotherapy (n = 263), amivantamab plus chemotherapy (n = 263), or chemotherapy alone (n = 131).

Given the increased risk for hematologic toxicities, the study protocol was adjusted in the triple therapy arm so that patients received lazertinib after completing carboplatin.

The findings, presented by study investigator Antonio Passaro, MD, PhD, were simultaneously published in Annals of Oncology.

After a median follow-up of 8.7 months, the triple therapy reduced the risk for progression or death by 56% (HR,0.44) and amivantamab plus chemotherapy reduced the risk for progression or death by 52% (HR, 0.48). Overall, the median PFS was 8.3 months in the triple combination arm, 6.3 months in the amivantamab plus chemotherapy arm, and 4.2 months in the chemotherapy arm.

This PFS benefit was observed across prespecified subgroups with both combination therapies. The combinations also reduced the risk for intracranial progression (HR, 0.58 in the triple therapy arm; HR, 0.55 in the amivantamab plus chemotherapy arm).

The current interim analysis did not show an overall survival benefit with either combination therapy vs. chemotherapy alone, although the survival curve hinted at a benefit in the amivantamab plus chemotherapy arm.

The median duration of response was 9.4 months for triple therapy, 6.9 months for the double combination, and 5.6 months for monotherapy.

Rates of grade ≥ 3 adverse events were notably higher in the combination groups – 92% of patients on triple therapy, 72% on double, and 48% on chemotherapy alone. But the treatment duration was longer in the combination groups and adverse events leading to death were low, as was discontinuation.

Amivantamab plus chemotherapy or plus lazertinib and chemotherapy are the “first regimens to demonstrate improved PFS vs. chemotherapy in EGFR-mutated NSCLC after disease progression on osimertinib,” concluded Dr. Passaro, from the European Institute of Oncology IRCCS, Milan, who presented the findings.

Dr. Passaro added that, given the consistent efficacy and more favorable safety profile, “we can say that amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib,” although more follow-up is required to understand its “real impact” in the clinic.

Zofia Piotrowska, MD, who was not involved in either MARIPOSA trial, said both “are really important” in the EGFR-mutant NSCLC space.

The studies “addressed two different questions,” but both were “positive, and I think clinically significantly,” said Dr. Piotrowska, a lung cancer specialist at Massachusetts General Hospital Cancer Center, Boston.

However, Dr. Piotrowska noted that a core question for the community will be “how we find that balance between the clinical benefits [and] the toxicities.”

“There’s not going to be one easy answer” and treatment selection will have to be made on a “patient-by-patient basis,” she said.

PAPILLON, MARIPOSA, and MARIPOSA-2 were funded by Janssen Pharmaceuticals. Dr. Girard declared relationships with AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and others. Dr. Cho declared relationships with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Onegene Biotechnology, Pfizer, Eli Lilly, and others. Dr. Passaro declared relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer-Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape, and eCancer. Dr. Besse declared institutional relationships with AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, and others. Dr. Piotrowska declared relationships with numerous companies including AstraZeneca, Novartis, and Takeda.

A version of this article first appeared on Medscape.com.

MADRID – New data from three trials evaluating the bispecific antibody amivantamab (Rybrevant) in EGFR-mutated advanced non–small cell lung cancer (NSCLC) have revealed a clear benefit, experts said at the annual meeting of the European Society for Medical Oncology (ESMO).

The results of the three trials – PAPILLON, MARIPOSA, and MARIPOSA-2 – are “really exciting” for patients harboring EGFR mutations, said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland, and the ESMO 2023 scientific chair.

Presenting findings from PAPILLON, Nicolas Girard, MD, PhD, highlighted outcomes among patients with EGFR exon 20 insertion-mutated advanced NSCLC. These patients, who represent about 2%-3% of NSCLC cases, have “historically poor” outcomes, with a 5-year overall survival rate of just 8%.

Tumors harboring exon 20 insertions are largely insensitive to targeted and immune checkpoint therapies, explained Dr. Girard, from Curie-Montsouris Thorax Institute, Institut Curie, Paris. That leaves platinum-based chemotherapy as the standard of care, which has “limited efficacy,” he noted.

The FDA approved amivantamab in 2021 for EGFR exon 20 insertion-mutated advanced NSCLC after progression on platinum-based chemotherapy, but the PAPILLON trial explored whether combining the two therapies upfront would provide a more meaningful benefit.

In the trial, 308 treatment-naive patients with locally advanced or metastatic NSCLC and documented exon 20 insertions were randomly assigned to amivantamab plus chemotherapy or chemotherapy alone. The median age was about 62 years, approximately half were female, and just over 60% were Asian – a similar patient profile as MARIPOSA and MARIPOSA-2.

The results, simultaneously published in The New England Journal of Medicine, showed that amivantamab plus chemotherapy significantly increased progression-free survival (PFS). More specifically, after a median follow-up of 14.9 months, patients receiving the combination had a median PFS of 11.4 months vs. 5.7 months with chemotherapy alone (hazard ratio, 0.395; P < .0001). This benefit consistently occurred across predefined subgroups.

Amivantamab plus chemotherapy was associated with a lower risk of a second progression, with the median not reached vs. 17.2 months with chemotherapy alone (HR, 0.493; P = .001).

A higher proportion of patients receiving the combination had an objective response – 73% vs. 47% – and these patients had a longer duration of response as well – 9.7 months vs. 4.4 months.

The overall survival data were immature but showed a trend toward a reduced risk of death for those on the combination (HR, 0.675; P = .106).

The rates of grade ≥ 3 adverse events were 75% with amivantamab plus chemotherapy and 54% with chemotherapy alone, and adverse events leading to discontinuation of amivantamab occurred in 7% of patients. Pneumonitis/interstitial lung disease (ILD) was reported in 3% of patients in the combination therapy arm.

Dr. Girard concluded that, with a safety profile “consistent” with that seen for the individual agents, amivantamab plus chemotherapy “represents a new standard of care” for first-line treatment of EGFR exon 20 insertion-mutated advanced NSCLC.

Benjamin Besse, MD, PhD, who was not involved in the research, agreed that this combination is “definitely a new standard of care.”

The effect of giving amivantamab alongside chemotherapy “seems to be really additive,” said Dr. Besse, director of clinical research at the Gustave Roussy Institute and professor of medical oncology at Paris-Saclay University, both in Paris. But he noted that amivantamab is a “challenging drug in terms of toxicity.”
 

The MARIPOSA trials

The two MARIPOSA trials also demonstrated that amivantamab, in combination with other agents, improved PFS among patients with EGFR-mutated advanced NSCLC.

Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, South Korea, presented results from MARIPOSA, which focused on patients with any kind of EGFR mutation.

Although the EGFR tyrosine kinase inhibitor (TKI) osimertinib is the current standard of care in this first-line setting, “resistance and disease progression are nearly inevitable,” and secondary EGFR and MET mutations may account for up to 50% of tumor resistance, Dr. Cho noted.

Early clinical data suggest that combining amivantamab with the highly selective third-generation EGFR TKI lazertinib leads to clinical activity and durable responses.

For the phase 3 MARIPOSA trial, 1,074 patients with treatment-naive locally advanced or metastatic EGFR-mutant NSCLC were randomly assigned to amivantamab plus lazertinib (n = 429), osimertinib alone (n = 429), or lazertinib alone (n = 216).

After a median follow-up of 22 months, the median PFS among patients on the combination was 23.7 months vs. 16.6 months for those on osimertinib alone (HR, 0.70; P < .001) and 18.5 months for those on lazertinib alone.

The PFS benefit observed with amivantamab plus lazertinib occurred across subgroups, including among patients with brain metastases. The combination reduced the risk for extracranial progression or death by 32% and improved median PFS by 9 months, compared with osimertinib alone (HR, 0.68; P < .001).

The risk for a second progression was also lower with the combination (HR, 0.75).

Interim overall survival data suggested a benefit with the combination therapy, compared with osimertinib alone (HR, 0.80; P = .11).

Grade 3 or higher adverse events were more common among patients treated with the combination vs. osimertinib alone – 75% vs. 43%. Higher rates of treatment-related discontinuation of any agent were observed in the combination group – 35% vs. 14% – though rates of adverse events leading to death were similar between the groups – 8% and 7%, respectively.

As in PAPILLON, rates of ILD/pneumonitis were “low,” said Dr. Cho, at approximately 3% in both treatment arms. However, he noted, rates of venous thromboembolism were higher with the combination, with grade ≥ 3 events occurring in 11% vs. 3.7% of patients on osimertinib.

Based on the findings, amivantamab plus lazertinib “represents a new standard of care in first-line EGFR-mutant advanced NSCLC,” Dr. Cho said. “It has been a long way and we finally made it.”

Next up is MARIPOSA-2, which evaluated patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on or after osimertinib.

In this trial, 657 patients were randomly assigned to amivantamab plus lazertinib and chemotherapy (n = 263), amivantamab plus chemotherapy (n = 263), or chemotherapy alone (n = 131).

Given the increased risk for hematologic toxicities, the study protocol was adjusted in the triple therapy arm so that patients received lazertinib after completing carboplatin.

The findings, presented by study investigator Antonio Passaro, MD, PhD, were simultaneously published in Annals of Oncology.

After a median follow-up of 8.7 months, the triple therapy reduced the risk for progression or death by 56% (HR,0.44) and amivantamab plus chemotherapy reduced the risk for progression or death by 52% (HR, 0.48). Overall, the median PFS was 8.3 months in the triple combination arm, 6.3 months in the amivantamab plus chemotherapy arm, and 4.2 months in the chemotherapy arm.

This PFS benefit was observed across prespecified subgroups with both combination therapies. The combinations also reduced the risk for intracranial progression (HR, 0.58 in the triple therapy arm; HR, 0.55 in the amivantamab plus chemotherapy arm).

The current interim analysis did not show an overall survival benefit with either combination therapy vs. chemotherapy alone, although the survival curve hinted at a benefit in the amivantamab plus chemotherapy arm.

The median duration of response was 9.4 months for triple therapy, 6.9 months for the double combination, and 5.6 months for monotherapy.

Rates of grade ≥ 3 adverse events were notably higher in the combination groups – 92% of patients on triple therapy, 72% on double, and 48% on chemotherapy alone. But the treatment duration was longer in the combination groups and adverse events leading to death were low, as was discontinuation.

Amivantamab plus chemotherapy or plus lazertinib and chemotherapy are the “first regimens to demonstrate improved PFS vs. chemotherapy in EGFR-mutated NSCLC after disease progression on osimertinib,” concluded Dr. Passaro, from the European Institute of Oncology IRCCS, Milan, who presented the findings.

Dr. Passaro added that, given the consistent efficacy and more favorable safety profile, “we can say that amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib,” although more follow-up is required to understand its “real impact” in the clinic.

Zofia Piotrowska, MD, who was not involved in either MARIPOSA trial, said both “are really important” in the EGFR-mutant NSCLC space.

The studies “addressed two different questions,” but both were “positive, and I think clinically significantly,” said Dr. Piotrowska, a lung cancer specialist at Massachusetts General Hospital Cancer Center, Boston.

However, Dr. Piotrowska noted that a core question for the community will be “how we find that balance between the clinical benefits [and] the toxicities.”

“There’s not going to be one easy answer” and treatment selection will have to be made on a “patient-by-patient basis,” she said.

PAPILLON, MARIPOSA, and MARIPOSA-2 were funded by Janssen Pharmaceuticals. Dr. Girard declared relationships with AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and others. Dr. Cho declared relationships with Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Onegene Biotechnology, Pfizer, Eli Lilly, and others. Dr. Passaro declared relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer-Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, Medscape, and eCancer. Dr. Besse declared institutional relationships with AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, and others. Dr. Piotrowska declared relationships with numerous companies including AstraZeneca, Novartis, and Takeda.

A version of this article first appeared on Medscape.com.

Researchers reporting in Vancouver at the annual meeting of the American College of Gastroenterology have identified a higher risk of inflammatory bowel disease (IBD) among adults who consumed a diet rich in ultra-processed foods, suggesting another field for inquiry about the potential role of industrial-produced edible food products in IBD.

The study, which was a meta-analysis of four studies, found a 47% greater risk of IBD in adults who consumed high levels of ultra-processed foods, compared with adults in reference groups.

“Our data are also consistent with other observational studies that found increased consumption of junk food, along with reduced intakes of fresh fruit and vegetables, are associated with the development of IBD. Because Americans consume over 60% of their calories in the form of ultra-processed foods, reductions in this level of consumption could meaningfully decrease the incidence of IBD,” wrote authors who were led by Eric Hecht, MD, PhD, MPH, president and executive director of the nonprofit Institute of Etiological Research, Boca Raton, Fla.

The potential effect of poor diet on the gut is a critical public health question, he said. Diet may be just one possible contributor to inflammatory bowel disease. Other contributors include genetics and having a compromised immune system.

Dr. Hecht and colleagues began this study with a search on the PubMed database of published research on IBD that included details of diet. Of 10 relevant studies, 4 studies met the inclusion criteria for the analysis.

The four studies included 652,880 adults, 2,240 cases of IBD with a follow-up period ranging from 2.3 to 22.3 years. Statistically significant elevated risks for both Crohn’s disease and ulcerative colitis were documented in the studies. There was a relative risk of 1.47 (95% confidence interval, 1.29-1.66) for IBD; 1.94 (95% CI, 1.45-2.58) for Crohn’s disease, and 1.26 (95% CI, 1.10-1.45) for ulcerative colitis.

Findings from the 4 studies

Chen et al. reported, in the Journal of Crohn’s and Colitis, the results of a cross-sectional and prospective cohort study of 187,854 adults who were followed for an average of 10 years. They found that a higher intake of ultra-processed foods was associated with a higher incidence of Crohn’s disease but not ulcerative colitis. It also found that people who were already diagnosed with an IBD consumed more ultra-processed foods than did those without a diagnosis. The authors called for further studies to address the impact of UPF intake.

Vasseur et al. documented, in Inflammatory Bowel Diseases, research drawn from the NutriNet-Santé Study, a large French web-based prospective study. It did not find that ultra-processed foods were significantly associated with the risk of incident IBD. But the authors noted that certain types of food items or dietary patterns could partly explain the increase in the incidence of IBD observed in several countries, saying that further large-scale studies would be needed to support pathophysiological assumptions made about the dietary risk factors and IBD.

In September 2020 in Gastroenterology, Lo et al. used data from the Nurses’ Health Study (1984-2014), Nurses’ Health Study II (1991-2015), and Health Professionals Follow-up Study (1986-2012). The authors reported finding dietary patterns associated with high inflammatory potential to be associated with increased risk of Crohn’s disease but not ulcerative colitis.

In October 2021 in Gastroenterology, Narula et al. reported finding no significant association between certain dietary patterns and risk of ulcerative colitis. There was some signal for Crohn’s disease, in keeping with findings from earlier research. Longer term follow-up is needed to clarify whether the observed excess risk for Crohn’s disease becomes more evident as more cases accumulate.

However, in an email interview with GI & Hepatology News, Neeraj Narula, MD, MPH, of McMaster University, Hamilton, Ont., cited two of his other published works that did make a connection between diet and IBD. In July 2021 in BMJ, he and colleagues reported findings of a prospective cohort study that found that higher intake of ultra-processed food was positively associated with risk of IBD. Further studies are needed to identify the contributory factors within ultra-processed foods, they wrote. He and colleagues published a meta-analysis of 5 cohort studies which concluded that higher ultra-processed food and lower unprocessed/minimally processed food intakes were associated with higher risk of Crohn’s disease but not ulcerative colitis.
 

Study limitations

Aviva Musicus, ScD, the science director for the nonprofit Center for Science in the Public Interest (CSPI), said the Dr. Hecht et al. meta-analysis suggests there could be a signal in the association between higher ultra-processed food consumption and IBD, but there’s also a lot of “noise” in this presentation.

It’s not clear from these analyses presented what might be driving the relationship between IBD and ultra-processed food, she said. “Is it the nutrient content of these foods, given that many are high in added sugar, sodium, and saturated fat and low in dietary fiber (potential risk factors for IBD)? Is it the emulsifiers used in some of these foods, or other chemicals added during processing? Or, is it something else?” Dr. Musicus said.

She said further studies are needed on the issue of ultra-processed food and IBD.

“I wasn’t convinced by the conclusion of this research abstract. It’s not clear to me that general reductions in UPF (ultra-processed foods) consumption could meaningfully decrease the incidence of IBD, given that it may be a subset of these (somewhat heterogeneous) foods driving the associations, and people may not reduce their consumption of that specific subset upon hearing this news,” Dr. Musicus said.

“However, we already know that consumers can reduce chronic disease risk by eating more vegetables, fruits, whole grains, and legumes (good sources of dietary fiber) and limiting consumption of added sugars, sodium, and saturated fat,” she added.

Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at Cleveland Clinic, agreed with the need for further study. There are limitations with the methodology used in the research from Dr. Hecht and colleagues, he said.

“Meta-analyses aren’t perfect and I think we all acknowledge that,” he said, adding that the Hecht poster provides “a larger perspective on the topic.”

There’s widespread agreement that ultraprocessed foods are not healthy, raising heart and cancer risks, he said. In counseling his patients, Dr. Regueiro said he acknowledges the challenges many people face in trying to pursue a healthier diet. Ultraprocessed foods tend to be cheap and readily available, and many people need help in spotting them, such as learning to look at labels for unfamiliar terms.

“What I tell my own patients in the clinic is to really try to clean up the diet as much as possible and in a realistic way,” he said.

The authors of the ACG poster did not report any financial conflicts. Dr. Hecht said he founded the Institute for Etiological Research to pursue questions about public health. Its funders include the Bertarelli Foundation.

Researchers reporting in Vancouver at the annual meeting of the American College of Gastroenterology have identified a higher risk of inflammatory bowel disease (IBD) among adults who consumed a diet rich in ultra-processed foods, suggesting another field for inquiry about the potential role of industrial-produced edible food products in IBD.

The study, which was a meta-analysis of four studies, found a 47% greater risk of IBD in adults who consumed high levels of ultra-processed foods, compared with adults in reference groups.

“Our data are also consistent with other observational studies that found increased consumption of junk food, along with reduced intakes of fresh fruit and vegetables, are associated with the development of IBD. Because Americans consume over 60% of their calories in the form of ultra-processed foods, reductions in this level of consumption could meaningfully decrease the incidence of IBD,” wrote authors who were led by Eric Hecht, MD, PhD, MPH, president and executive director of the nonprofit Institute of Etiological Research, Boca Raton, Fla.

The potential effect of poor diet on the gut is a critical public health question, he said. Diet may be just one possible contributor to inflammatory bowel disease. Other contributors include genetics and having a compromised immune system.

Dr. Hecht and colleagues began this study with a search on the PubMed database of published research on IBD that included details of diet. Of 10 relevant studies, 4 studies met the inclusion criteria for the analysis.

The four studies included 652,880 adults, 2,240 cases of IBD with a follow-up period ranging from 2.3 to 22.3 years. Statistically significant elevated risks for both Crohn’s disease and ulcerative colitis were documented in the studies. There was a relative risk of 1.47 (95% confidence interval, 1.29-1.66) for IBD; 1.94 (95% CI, 1.45-2.58) for Crohn’s disease, and 1.26 (95% CI, 1.10-1.45) for ulcerative colitis.

Findings from the 4 studies

Chen et al. reported, in the Journal of Crohn’s and Colitis, the results of a cross-sectional and prospective cohort study of 187,854 adults who were followed for an average of 10 years. They found that a higher intake of ultra-processed foods was associated with a higher incidence of Crohn’s disease but not ulcerative colitis. It also found that people who were already diagnosed with an IBD consumed more ultra-processed foods than did those without a diagnosis. The authors called for further studies to address the impact of UPF intake.

Vasseur et al. documented, in Inflammatory Bowel Diseases, research drawn from the NutriNet-Santé Study, a large French web-based prospective study. It did not find that ultra-processed foods were significantly associated with the risk of incident IBD. But the authors noted that certain types of food items or dietary patterns could partly explain the increase in the incidence of IBD observed in several countries, saying that further large-scale studies would be needed to support pathophysiological assumptions made about the dietary risk factors and IBD.

In September 2020 in Gastroenterology, Lo et al. used data from the Nurses’ Health Study (1984-2014), Nurses’ Health Study II (1991-2015), and Health Professionals Follow-up Study (1986-2012). The authors reported finding dietary patterns associated with high inflammatory potential to be associated with increased risk of Crohn’s disease but not ulcerative colitis.

In October 2021 in Gastroenterology, Narula et al. reported finding no significant association between certain dietary patterns and risk of ulcerative colitis. There was some signal for Crohn’s disease, in keeping with findings from earlier research. Longer term follow-up is needed to clarify whether the observed excess risk for Crohn’s disease becomes more evident as more cases accumulate.

However, in an email interview with GI & Hepatology News, Neeraj Narula, MD, MPH, of McMaster University, Hamilton, Ont., cited two of his other published works that did make a connection between diet and IBD. In July 2021 in BMJ, he and colleagues reported findings of a prospective cohort study that found that higher intake of ultra-processed food was positively associated with risk of IBD. Further studies are needed to identify the contributory factors within ultra-processed foods, they wrote. He and colleagues published a meta-analysis of 5 cohort studies which concluded that higher ultra-processed food and lower unprocessed/minimally processed food intakes were associated with higher risk of Crohn’s disease but not ulcerative colitis.
 

Study limitations

Aviva Musicus, ScD, the science director for the nonprofit Center for Science in the Public Interest (CSPI), said the Dr. Hecht et al. meta-analysis suggests there could be a signal in the association between higher ultra-processed food consumption and IBD, but there’s also a lot of “noise” in this presentation.

It’s not clear from these analyses presented what might be driving the relationship between IBD and ultra-processed food, she said. “Is it the nutrient content of these foods, given that many are high in added sugar, sodium, and saturated fat and low in dietary fiber (potential risk factors for IBD)? Is it the emulsifiers used in some of these foods, or other chemicals added during processing? Or, is it something else?” Dr. Musicus said.

She said further studies are needed on the issue of ultra-processed food and IBD.

“I wasn’t convinced by the conclusion of this research abstract. It’s not clear to me that general reductions in UPF (ultra-processed foods) consumption could meaningfully decrease the incidence of IBD, given that it may be a subset of these (somewhat heterogeneous) foods driving the associations, and people may not reduce their consumption of that specific subset upon hearing this news,” Dr. Musicus said.

“However, we already know that consumers can reduce chronic disease risk by eating more vegetables, fruits, whole grains, and legumes (good sources of dietary fiber) and limiting consumption of added sugars, sodium, and saturated fat,” she added.

Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at Cleveland Clinic, agreed with the need for further study. There are limitations with the methodology used in the research from Dr. Hecht and colleagues, he said.

“Meta-analyses aren’t perfect and I think we all acknowledge that,” he said, adding that the Hecht poster provides “a larger perspective on the topic.”

There’s widespread agreement that ultraprocessed foods are not healthy, raising heart and cancer risks, he said. In counseling his patients, Dr. Regueiro said he acknowledges the challenges many people face in trying to pursue a healthier diet. Ultraprocessed foods tend to be cheap and readily available, and many people need help in spotting them, such as learning to look at labels for unfamiliar terms.

“What I tell my own patients in the clinic is to really try to clean up the diet as much as possible and in a realistic way,” he said.

The authors of the ACG poster did not report any financial conflicts. Dr. Hecht said he founded the Institute for Etiological Research to pursue questions about public health. Its funders include the Bertarelli Foundation.

Researchers reporting in Vancouver at the annual meeting of the American College of Gastroenterology have identified a higher risk of inflammatory bowel disease (IBD) among adults who consumed a diet rich in ultra-processed foods, suggesting another field for inquiry about the potential role of industrial-produced edible food products in IBD.

The study, which was a meta-analysis of four studies, found a 47% greater risk of IBD in adults who consumed high levels of ultra-processed foods, compared with adults in reference groups.

“Our data are also consistent with other observational studies that found increased consumption of junk food, along with reduced intakes of fresh fruit and vegetables, are associated with the development of IBD. Because Americans consume over 60% of their calories in the form of ultra-processed foods, reductions in this level of consumption could meaningfully decrease the incidence of IBD,” wrote authors who were led by Eric Hecht, MD, PhD, MPH, president and executive director of the nonprofit Institute of Etiological Research, Boca Raton, Fla.

The potential effect of poor diet on the gut is a critical public health question, he said. Diet may be just one possible contributor to inflammatory bowel disease. Other contributors include genetics and having a compromised immune system.

Dr. Hecht and colleagues began this study with a search on the PubMed database of published research on IBD that included details of diet. Of 10 relevant studies, 4 studies met the inclusion criteria for the analysis.

The four studies included 652,880 adults, 2,240 cases of IBD with a follow-up period ranging from 2.3 to 22.3 years. Statistically significant elevated risks for both Crohn’s disease and ulcerative colitis were documented in the studies. There was a relative risk of 1.47 (95% confidence interval, 1.29-1.66) for IBD; 1.94 (95% CI, 1.45-2.58) for Crohn’s disease, and 1.26 (95% CI, 1.10-1.45) for ulcerative colitis.

Findings from the 4 studies

Chen et al. reported, in the Journal of Crohn’s and Colitis, the results of a cross-sectional and prospective cohort study of 187,854 adults who were followed for an average of 10 years. They found that a higher intake of ultra-processed foods was associated with a higher incidence of Crohn’s disease but not ulcerative colitis. It also found that people who were already diagnosed with an IBD consumed more ultra-processed foods than did those without a diagnosis. The authors called for further studies to address the impact of UPF intake.

Vasseur et al. documented, in Inflammatory Bowel Diseases, research drawn from the NutriNet-Santé Study, a large French web-based prospective study. It did not find that ultra-processed foods were significantly associated with the risk of incident IBD. But the authors noted that certain types of food items or dietary patterns could partly explain the increase in the incidence of IBD observed in several countries, saying that further large-scale studies would be needed to support pathophysiological assumptions made about the dietary risk factors and IBD.

In September 2020 in Gastroenterology, Lo et al. used data from the Nurses’ Health Study (1984-2014), Nurses’ Health Study II (1991-2015), and Health Professionals Follow-up Study (1986-2012). The authors reported finding dietary patterns associated with high inflammatory potential to be associated with increased risk of Crohn’s disease but not ulcerative colitis.

In October 2021 in Gastroenterology, Narula et al. reported finding no significant association between certain dietary patterns and risk of ulcerative colitis. There was some signal for Crohn’s disease, in keeping with findings from earlier research. Longer term follow-up is needed to clarify whether the observed excess risk for Crohn’s disease becomes more evident as more cases accumulate.

However, in an email interview with GI & Hepatology News, Neeraj Narula, MD, MPH, of McMaster University, Hamilton, Ont., cited two of his other published works that did make a connection between diet and IBD. In July 2021 in BMJ, he and colleagues reported findings of a prospective cohort study that found that higher intake of ultra-processed food was positively associated with risk of IBD. Further studies are needed to identify the contributory factors within ultra-processed foods, they wrote. He and colleagues published a meta-analysis of 5 cohort studies which concluded that higher ultra-processed food and lower unprocessed/minimally processed food intakes were associated with higher risk of Crohn’s disease but not ulcerative colitis.
 

Study limitations

Aviva Musicus, ScD, the science director for the nonprofit Center for Science in the Public Interest (CSPI), said the Dr. Hecht et al. meta-analysis suggests there could be a signal in the association between higher ultra-processed food consumption and IBD, but there’s also a lot of “noise” in this presentation.

It’s not clear from these analyses presented what might be driving the relationship between IBD and ultra-processed food, she said. “Is it the nutrient content of these foods, given that many are high in added sugar, sodium, and saturated fat and low in dietary fiber (potential risk factors for IBD)? Is it the emulsifiers used in some of these foods, or other chemicals added during processing? Or, is it something else?” Dr. Musicus said.

She said further studies are needed on the issue of ultra-processed food and IBD.

“I wasn’t convinced by the conclusion of this research abstract. It’s not clear to me that general reductions in UPF (ultra-processed foods) consumption could meaningfully decrease the incidence of IBD, given that it may be a subset of these (somewhat heterogeneous) foods driving the associations, and people may not reduce their consumption of that specific subset upon hearing this news,” Dr. Musicus said.

“However, we already know that consumers can reduce chronic disease risk by eating more vegetables, fruits, whole grains, and legumes (good sources of dietary fiber) and limiting consumption of added sugars, sodium, and saturated fat,” she added.

Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at Cleveland Clinic, agreed with the need for further study. There are limitations with the methodology used in the research from Dr. Hecht and colleagues, he said.

“Meta-analyses aren’t perfect and I think we all acknowledge that,” he said, adding that the Hecht poster provides “a larger perspective on the topic.”

There’s widespread agreement that ultraprocessed foods are not healthy, raising heart and cancer risks, he said. In counseling his patients, Dr. Regueiro said he acknowledges the challenges many people face in trying to pursue a healthier diet. Ultraprocessed foods tend to be cheap and readily available, and many people need help in spotting them, such as learning to look at labels for unfamiliar terms.

“What I tell my own patients in the clinic is to really try to clean up the diet as much as possible and in a realistic way,” he said.

The authors of the ACG poster did not report any financial conflicts. Dr. Hecht said he founded the Institute for Etiological Research to pursue questions about public health. Its funders include the Bertarelli Foundation.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

Until a couple of weeks ago I considered myself a COVID virgin. I had navigated a full 36 months without a positive test, despite cohabiting with my wife in a 2,500-square-foot house during her bout with the SARS-CoV-2 virus last year. I have been reasonably careful, a situational mask wearer, and good about avoiding poorly ventilated crowded spaces. Of course I was fully vaccinated but was waiting until we had gotten closer to a December trip before getting the newest booster.

I had always been quietly smug about my good luck. And, I was pretty sure that luck had been the major contributor to my run of good health. Nonetheless, in my private moments I often wondered if I somehow had inherited or acquired an unusual defense against the virus that had been getting the best of my peers. One rather far-fetched explanation that kept popping out of my subconscious involved my profuse and persistent runny nose.

Like a fair number in my demographic, I have what I have self-diagnosed as vasomotor rhinitis. In the cooler months and particularly when I am active outdoors, my nose runs like a faucet. I half-jokingly told my wife after a particularly drippy bike ride on a frigid November afternoon that even the most robust virus couldn’t possibly have survived the swim upstream against torrent of mucus splashing onto the handlebars of my bike.

A recent study published in the journal Cell suggests that my off-the-wall explanation for my COVID resistance wasn’t quite so hair-brained. The investigators haven’t found that septuagenarian adults with high-volume runny noses are drowning the SARS-Co- 2 virus before it can do any damage. However, the researchers did discover that, in general, young children seem to be having fewer and milder COVID infections because “infants mount a robust mucosal response” in their noses. This first line of defense seems to be more effective than in adults, where the virus can more easily slip through into the bloodstream, sometimes with a dramatic release of circulating cytokines, which occasionally create problems of their own. Children also release cytokines, but this is predominantly in their nose, where it appears to be less damaging. Interestingly, in children this initial response persists for around 300 days while in adults the immune response experiences a much more rapid decline. I guess this means we have to chalk one more up for snotty nose kids.

However, the results of this study also suggest that we should be giving more attention to the development of nasal vaccines. I recall that nearly 3 years ago, at the beginning of the pandemic, scientists using a ferret model had developed an effective nasal vaccine. I’m not sure why this faded out of the picture, but it feels like it’s time to turn the spotlight on this line of research again.

I suspect that in addition to being more effective, a nasal vaccine may gain more support among the antivaxxer population, many of whom I suspect are really needle phobics hiding behind a smoke screen of anti-science double talk.

At any rate, I will continue to search for articles that support my contention that my high-flow rhinorrhea is protecting me. I have always been told that a cold nose was the sign of a healthy dog. I’m just trying to prove that the same is true for us old guys with clear runny noses.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Until a couple of weeks ago I considered myself a COVID virgin. I had navigated a full 36 months without a positive test, despite cohabiting with my wife in a 2,500-square-foot house during her bout with the SARS-CoV-2 virus last year. I have been reasonably careful, a situational mask wearer, and good about avoiding poorly ventilated crowded spaces. Of course I was fully vaccinated but was waiting until we had gotten closer to a December trip before getting the newest booster.

I had always been quietly smug about my good luck. And, I was pretty sure that luck had been the major contributor to my run of good health. Nonetheless, in my private moments I often wondered if I somehow had inherited or acquired an unusual defense against the virus that had been getting the best of my peers. One rather far-fetched explanation that kept popping out of my subconscious involved my profuse and persistent runny nose.

Like a fair number in my demographic, I have what I have self-diagnosed as vasomotor rhinitis. In the cooler months and particularly when I am active outdoors, my nose runs like a faucet. I half-jokingly told my wife after a particularly drippy bike ride on a frigid November afternoon that even the most robust virus couldn’t possibly have survived the swim upstream against torrent of mucus splashing onto the handlebars of my bike.

A recent study published in the journal Cell suggests that my off-the-wall explanation for my COVID resistance wasn’t quite so hair-brained. The investigators haven’t found that septuagenarian adults with high-volume runny noses are drowning the SARS-Co- 2 virus before it can do any damage. However, the researchers did discover that, in general, young children seem to be having fewer and milder COVID infections because “infants mount a robust mucosal response” in their noses. This first line of defense seems to be more effective than in adults, where the virus can more easily slip through into the bloodstream, sometimes with a dramatic release of circulating cytokines, which occasionally create problems of their own. Children also release cytokines, but this is predominantly in their nose, where it appears to be less damaging. Interestingly, in children this initial response persists for around 300 days while in adults the immune response experiences a much more rapid decline. I guess this means we have to chalk one more up for snotty nose kids.

However, the results of this study also suggest that we should be giving more attention to the development of nasal vaccines. I recall that nearly 3 years ago, at the beginning of the pandemic, scientists using a ferret model had developed an effective nasal vaccine. I’m not sure why this faded out of the picture, but it feels like it’s time to turn the spotlight on this line of research again.

I suspect that in addition to being more effective, a nasal vaccine may gain more support among the antivaxxer population, many of whom I suspect are really needle phobics hiding behind a smoke screen of anti-science double talk.

At any rate, I will continue to search for articles that support my contention that my high-flow rhinorrhea is protecting me. I have always been told that a cold nose was the sign of a healthy dog. I’m just trying to prove that the same is true for us old guys with clear runny noses.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Until a couple of weeks ago I considered myself a COVID virgin. I had navigated a full 36 months without a positive test, despite cohabiting with my wife in a 2,500-square-foot house during her bout with the SARS-CoV-2 virus last year. I have been reasonably careful, a situational mask wearer, and good about avoiding poorly ventilated crowded spaces. Of course I was fully vaccinated but was waiting until we had gotten closer to a December trip before getting the newest booster.

I had always been quietly smug about my good luck. And, I was pretty sure that luck had been the major contributor to my run of good health. Nonetheless, in my private moments I often wondered if I somehow had inherited or acquired an unusual defense against the virus that had been getting the best of my peers. One rather far-fetched explanation that kept popping out of my subconscious involved my profuse and persistent runny nose.

Like a fair number in my demographic, I have what I have self-diagnosed as vasomotor rhinitis. In the cooler months and particularly when I am active outdoors, my nose runs like a faucet. I half-jokingly told my wife after a particularly drippy bike ride on a frigid November afternoon that even the most robust virus couldn’t possibly have survived the swim upstream against torrent of mucus splashing onto the handlebars of my bike.

A recent study published in the journal Cell suggests that my off-the-wall explanation for my COVID resistance wasn’t quite so hair-brained. The investigators haven’t found that septuagenarian adults with high-volume runny noses are drowning the SARS-Co- 2 virus before it can do any damage. However, the researchers did discover that, in general, young children seem to be having fewer and milder COVID infections because “infants mount a robust mucosal response” in their noses. This first line of defense seems to be more effective than in adults, where the virus can more easily slip through into the bloodstream, sometimes with a dramatic release of circulating cytokines, which occasionally create problems of their own. Children also release cytokines, but this is predominantly in their nose, where it appears to be less damaging. Interestingly, in children this initial response persists for around 300 days while in adults the immune response experiences a much more rapid decline. I guess this means we have to chalk one more up for snotty nose kids.

However, the results of this study also suggest that we should be giving more attention to the development of nasal vaccines. I recall that nearly 3 years ago, at the beginning of the pandemic, scientists using a ferret model had developed an effective nasal vaccine. I’m not sure why this faded out of the picture, but it feels like it’s time to turn the spotlight on this line of research again.

I suspect that in addition to being more effective, a nasal vaccine may gain more support among the antivaxxer population, many of whom I suspect are really needle phobics hiding behind a smoke screen of anti-science double talk.

At any rate, I will continue to search for articles that support my contention that my high-flow rhinorrhea is protecting me. I have always been told that a cold nose was the sign of a healthy dog. I’m just trying to prove that the same is true for us old guys with clear runny noses.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Certain products marketed for arthritis and pain management could contain hidden ingredients that could be harmful to consumers, according to a warning by the U.S. Food and Drug Administration.
 

Some of these products contain active ingredients found in anti-inflammatory prescription medication.

“These products may cause potentially serious side effects and may interact with medications or dietary supplements a consumer is taking,” the FDA said in a statement. “It is clear from the results of our decade of testing that retailers and distributors, including online marketplaces, do not effectively prevent these types of potentially harmful products from being sold to consumers.”

Unlike prescription medication and over-the-counter drugs such as loratadine (Claritin) or acetaminophen (Tylenol), supplements do not need FDA approval before they can be sold. Only after a complaint is made or FDA testing reveals illegal or unsafe ingredients can the FDA get involved.

From August 2013 to September 2023, the FDA identified 22 arthritis and pain products with active ingredients not disclosed on the product label. The most common hidden ingredients detected in these supplements were prescription-only corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants, said Candy Tsourounis, PharmD, a professor in the department of clinical pharmacy at the University of California, San Francisco.

Kuka Flex Forte and Reumo Flex, both promoted for joint pain and arthritis, both contain the NSAID diclofenac. Tapee Tea, a product promoted for pain relief, contains dexamethasone and piroxicam. AK Forte, also sold for joint pain and arthritis, contains diclofenac, dexamethasone, and methocarbamol not disclosed on the label.

“It is interesting that these products have hidden ingredients that are used to reduce swelling and inflammation,” Dr. Tsourounis said. “I don’t know if this was intentional, but it seems suspicious that a product marketed to reduce joint pain and inflammation contains prescription-only ingredients that are used for this purpose.”

Certain products also contained antihistamines including cyproheptadine and chlorpheniramine.

These types of products are likely targeted toward underserved and immigrant communities, added Pieter Cohen, MD, a primary care physician and an assistant professor of medicine at Harvard Medical School, Boston, who studies dietary supplements. They might be sold in mom-and-pop shops or gas stations to individuals with limited access to health care or insurance, he noted.

The FDA warned that this list included “only a small fraction of the potentially dangerous products marketed to consumers online and in stores. Even if a product is not included in this list, consumers should exercise caution before using these types of arthritis and pain management products.”
 

Advising patients

Research suggests that most patients do not tell doctors about the supplements they are taking, and often, clinicians do not ask, said Dr. Cohen. “Most of the time it’s a total black box – we don’t know what’s going on,” he added.

He advised raising the subject of supplements in a very nonjudgmental way, particularly when treating patients in marginalized and immigrant communities. One approach he suggested was first mentioning that other patients in your care dealing with joint pain have bought remedies locally or have tried treatments that friends recommend. You can then ask a patient about their own use, framing it as a way to better help with treatment decisions.

Once a clinician understands what their patient is taking, they can then give advice and discuss if a product is safe to combine with prescription drugs, Dr. Cohen said. “If they come down too hard, I think the patients will just clam up and not talk about it anymore,” he said.

If a patient begins to experience side effects or gets sick, a clinician will already be informed of what their patient is taking and can ask that patient to bring the product or supplement in, so they can look over the product together, Dr. Cohen noted. Any side effects or other adverse events potentially related to the use of these products should then be reported to FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
 

Tips for safe shopping

To make sure supplements and other over-the-counter products are safe to use, Dr. Tsourounis recommends that consumers:

• Buy products from well-known retailers like Target or large pharmacies like CVS or Walgreens.
• Avoid buying products with labels in another language that you cannot read or products with no drug label.
• Be cautious of buying products online or from other countries.
• Look up suspicious products on the FDA’s health fraud database.
• Be wary of any product that offers miracle cures or relies on personal testimonies without evidence.

In general, do not base purchasing decisions on any health claims on a product label because companies selling supplements making these claims “don’t have to have any clinical data to back them up,” Dr. Cohen said.

Dr. Cohen also recommends sticking with individual ingredients. “If you want echinacea, buy echinacea. Don’t buy a complicated mix that is supposed to be good for arthritis with 10 different botanical [ingredients]. That’s more likely to run [you] into trouble,” he said.

Last, Dr. Cohen recommended buying supplements that are certified by NSF International or United States Pharmacopeia, both respected third-party testing organizations. “If it has an NSF International or USP stamp, that gives us more certainty that what’s in the bottle is going to be what’s listed on label,” he said.

Dr. Tsourounis noted that if you are skeptical of a product, you can also try calling the manufacturer number on the product label.

“I always encourage people to call that number to see if somebody answers,” she said. “Sometimes, you can tell a lot about that company just by calling that number.”

Dr. Cohen has received research support from the Consumers Union and PEW Charitable Trusts and royalties from UpToDate. He has collaborated in research with NSF International. Dr. Tsourounis disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Certain products marketed for arthritis and pain management could contain hidden ingredients that could be harmful to consumers, according to a warning by the U.S. Food and Drug Administration.
 

Some of these products contain active ingredients found in anti-inflammatory prescription medication.

“These products may cause potentially serious side effects and may interact with medications or dietary supplements a consumer is taking,” the FDA said in a statement. “It is clear from the results of our decade of testing that retailers and distributors, including online marketplaces, do not effectively prevent these types of potentially harmful products from being sold to consumers.”

Unlike prescription medication and over-the-counter drugs such as loratadine (Claritin) or acetaminophen (Tylenol), supplements do not need FDA approval before they can be sold. Only after a complaint is made or FDA testing reveals illegal or unsafe ingredients can the FDA get involved.

From August 2013 to September 2023, the FDA identified 22 arthritis and pain products with active ingredients not disclosed on the product label. The most common hidden ingredients detected in these supplements were prescription-only corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants, said Candy Tsourounis, PharmD, a professor in the department of clinical pharmacy at the University of California, San Francisco.

Kuka Flex Forte and Reumo Flex, both promoted for joint pain and arthritis, both contain the NSAID diclofenac. Tapee Tea, a product promoted for pain relief, contains dexamethasone and piroxicam. AK Forte, also sold for joint pain and arthritis, contains diclofenac, dexamethasone, and methocarbamol not disclosed on the label.

“It is interesting that these products have hidden ingredients that are used to reduce swelling and inflammation,” Dr. Tsourounis said. “I don’t know if this was intentional, but it seems suspicious that a product marketed to reduce joint pain and inflammation contains prescription-only ingredients that are used for this purpose.”

Certain products also contained antihistamines including cyproheptadine and chlorpheniramine.

These types of products are likely targeted toward underserved and immigrant communities, added Pieter Cohen, MD, a primary care physician and an assistant professor of medicine at Harvard Medical School, Boston, who studies dietary supplements. They might be sold in mom-and-pop shops or gas stations to individuals with limited access to health care or insurance, he noted.

The FDA warned that this list included “only a small fraction of the potentially dangerous products marketed to consumers online and in stores. Even if a product is not included in this list, consumers should exercise caution before using these types of arthritis and pain management products.”
 

Advising patients

Research suggests that most patients do not tell doctors about the supplements they are taking, and often, clinicians do not ask, said Dr. Cohen. “Most of the time it’s a total black box – we don’t know what’s going on,” he added.

He advised raising the subject of supplements in a very nonjudgmental way, particularly when treating patients in marginalized and immigrant communities. One approach he suggested was first mentioning that other patients in your care dealing with joint pain have bought remedies locally or have tried treatments that friends recommend. You can then ask a patient about their own use, framing it as a way to better help with treatment decisions.

Once a clinician understands what their patient is taking, they can then give advice and discuss if a product is safe to combine with prescription drugs, Dr. Cohen said. “If they come down too hard, I think the patients will just clam up and not talk about it anymore,” he said.

If a patient begins to experience side effects or gets sick, a clinician will already be informed of what their patient is taking and can ask that patient to bring the product or supplement in, so they can look over the product together, Dr. Cohen noted. Any side effects or other adverse events potentially related to the use of these products should then be reported to FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
 

Tips for safe shopping

To make sure supplements and other over-the-counter products are safe to use, Dr. Tsourounis recommends that consumers:

• Buy products from well-known retailers like Target or large pharmacies like CVS or Walgreens.
• Avoid buying products with labels in another language that you cannot read or products with no drug label.
• Be cautious of buying products online or from other countries.
• Look up suspicious products on the FDA’s health fraud database.
• Be wary of any product that offers miracle cures or relies on personal testimonies without evidence.

In general, do not base purchasing decisions on any health claims on a product label because companies selling supplements making these claims “don’t have to have any clinical data to back them up,” Dr. Cohen said.

Dr. Cohen also recommends sticking with individual ingredients. “If you want echinacea, buy echinacea. Don’t buy a complicated mix that is supposed to be good for arthritis with 10 different botanical [ingredients]. That’s more likely to run [you] into trouble,” he said.

Last, Dr. Cohen recommended buying supplements that are certified by NSF International or United States Pharmacopeia, both respected third-party testing organizations. “If it has an NSF International or USP stamp, that gives us more certainty that what’s in the bottle is going to be what’s listed on label,” he said.

Dr. Tsourounis noted that if you are skeptical of a product, you can also try calling the manufacturer number on the product label.

“I always encourage people to call that number to see if somebody answers,” she said. “Sometimes, you can tell a lot about that company just by calling that number.”

Dr. Cohen has received research support from the Consumers Union and PEW Charitable Trusts and royalties from UpToDate. He has collaborated in research with NSF International. Dr. Tsourounis disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Certain products marketed for arthritis and pain management could contain hidden ingredients that could be harmful to consumers, according to a warning by the U.S. Food and Drug Administration.
 

Some of these products contain active ingredients found in anti-inflammatory prescription medication.

“These products may cause potentially serious side effects and may interact with medications or dietary supplements a consumer is taking,” the FDA said in a statement. “It is clear from the results of our decade of testing that retailers and distributors, including online marketplaces, do not effectively prevent these types of potentially harmful products from being sold to consumers.”

Unlike prescription medication and over-the-counter drugs such as loratadine (Claritin) or acetaminophen (Tylenol), supplements do not need FDA approval before they can be sold. Only after a complaint is made or FDA testing reveals illegal or unsafe ingredients can the FDA get involved.

From August 2013 to September 2023, the FDA identified 22 arthritis and pain products with active ingredients not disclosed on the product label. The most common hidden ingredients detected in these supplements were prescription-only corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants, said Candy Tsourounis, PharmD, a professor in the department of clinical pharmacy at the University of California, San Francisco.

Kuka Flex Forte and Reumo Flex, both promoted for joint pain and arthritis, both contain the NSAID diclofenac. Tapee Tea, a product promoted for pain relief, contains dexamethasone and piroxicam. AK Forte, also sold for joint pain and arthritis, contains diclofenac, dexamethasone, and methocarbamol not disclosed on the label.

“It is interesting that these products have hidden ingredients that are used to reduce swelling and inflammation,” Dr. Tsourounis said. “I don’t know if this was intentional, but it seems suspicious that a product marketed to reduce joint pain and inflammation contains prescription-only ingredients that are used for this purpose.”

Certain products also contained antihistamines including cyproheptadine and chlorpheniramine.

These types of products are likely targeted toward underserved and immigrant communities, added Pieter Cohen, MD, a primary care physician and an assistant professor of medicine at Harvard Medical School, Boston, who studies dietary supplements. They might be sold in mom-and-pop shops or gas stations to individuals with limited access to health care or insurance, he noted.

The FDA warned that this list included “only a small fraction of the potentially dangerous products marketed to consumers online and in stores. Even if a product is not included in this list, consumers should exercise caution before using these types of arthritis and pain management products.”
 

Advising patients

Research suggests that most patients do not tell doctors about the supplements they are taking, and often, clinicians do not ask, said Dr. Cohen. “Most of the time it’s a total black box – we don’t know what’s going on,” he added.

He advised raising the subject of supplements in a very nonjudgmental way, particularly when treating patients in marginalized and immigrant communities. One approach he suggested was first mentioning that other patients in your care dealing with joint pain have bought remedies locally or have tried treatments that friends recommend. You can then ask a patient about their own use, framing it as a way to better help with treatment decisions.

Once a clinician understands what their patient is taking, they can then give advice and discuss if a product is safe to combine with prescription drugs, Dr. Cohen said. “If they come down too hard, I think the patients will just clam up and not talk about it anymore,” he said.

If a patient begins to experience side effects or gets sick, a clinician will already be informed of what their patient is taking and can ask that patient to bring the product or supplement in, so they can look over the product together, Dr. Cohen noted. Any side effects or other adverse events potentially related to the use of these products should then be reported to FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
 

Tips for safe shopping

To make sure supplements and other over-the-counter products are safe to use, Dr. Tsourounis recommends that consumers:

• Buy products from well-known retailers like Target or large pharmacies like CVS or Walgreens.
• Avoid buying products with labels in another language that you cannot read or products with no drug label.
• Be cautious of buying products online or from other countries.
• Look up suspicious products on the FDA’s health fraud database.
• Be wary of any product that offers miracle cures or relies on personal testimonies without evidence.

In general, do not base purchasing decisions on any health claims on a product label because companies selling supplements making these claims “don’t have to have any clinical data to back them up,” Dr. Cohen said.

Dr. Cohen also recommends sticking with individual ingredients. “If you want echinacea, buy echinacea. Don’t buy a complicated mix that is supposed to be good for arthritis with 10 different botanical [ingredients]. That’s more likely to run [you] into trouble,” he said.

Last, Dr. Cohen recommended buying supplements that are certified by NSF International or United States Pharmacopeia, both respected third-party testing organizations. “If it has an NSF International or USP stamp, that gives us more certainty that what’s in the bottle is going to be what’s listed on label,” he said.

Dr. Tsourounis noted that if you are skeptical of a product, you can also try calling the manufacturer number on the product label.

“I always encourage people to call that number to see if somebody answers,” she said. “Sometimes, you can tell a lot about that company just by calling that number.”

Dr. Cohen has received research support from the Consumers Union and PEW Charitable Trusts and royalties from UpToDate. He has collaborated in research with NSF International. Dr. Tsourounis disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MILAN – Subcutaneous administration of anti-CD20 monoclonal antibody therapy offers ongoing clinical efficacy in the management of patients with relapsing and primary progressive multiple sclerosis (MS), suggest results from two clinical trials.

For OCARINA II, more than 325 patients with MS were randomly assigned to either subcutaneous or intravenous treatment with the anti-CD20 monoclonal antibody ocrelizumab (Ocrevus).

After 24 weeks, the presence of lesions on imaging and the occurrence of clinical remissions were almost completely suppressed by both treatments albeit with a higher rate of mild to moderate injection reactions with subcutaneous administration.

The study “makes me feel pretty comfortable that regardless of where you’re delivering the therapy, IV or subcutaneously, it’s getting in there and doing the job that we want it to do,” said lead author Scott D. Newsome, DO, director, Stiff Person Syndrome Center, Johns Hopkins University, Baltimore.

The second study, OLIKOS, involved just over 100 patients with relapsing MS who had previously been treated with an anti-CD20 monoclonal antibody and were switched to subcutaneous therapy with another: ofatumumab (Arzerra).

Le H. Hua, MD, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, and colleagues report that the novel treatment maintained clinical efficacy in all patients, with no safety concerns and no changes in serum immunoglobulin levels.

The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
 

Anti-CD20–naive

OCARINA II involved patients aged 18-65 years with relapsing or primary progressive MS who had never received ocrelizumab or any other anti-CD20 therapy and had an Expanded Disability Status Scale (EDSS) score of 0.0-6.5.

They were randomly assigned to subcutaneous or IV ocrelizumab as a first dose. At week 24, all patients were scheduled to receive subcutaneous ocrelizumab every 24 weeks up to week 96.

In all, 326 patients were randomly assigned to the two treatment arms. They had a mean age of approximately 40 years, and 59.3%-65.3% were women. The mean time since symptom onset was 6.8-7.7 years, and the mean EDSS score at baseline was 2.5-3.0. The majority (89.8%-89.0%) had relapsing MS.

The results showed that subcutaneous and IV administration led to similar exposure to ocrelizumab, and both resulted in rapid reduction in CD19+ B-cell counts.

By week 24, the mean number of lesions on MRI reduced to zero, resulting in “near-complete suppression” of disease activity, the team says, which was reflected in 99% of patients have no clinical evidence of relapse.

The overall adverse event rate was higher with subcutaneous vs. IV administration of ocrelizumab, at 73.7% vs. 45.8%, driven by both local and systemic injection reactions, which were mild to moderate in nature.

However, a similar proportion of patients in the subcutaneous and IV arms experienced serious adverse events, at 2.5% and 3.4%, respectively.

Crucially, the patients were “overwhelmingly positive” about the subcutaneous administration, Dr. Newsome said, and at his institution, “all the patients want to continue, if and when this gets approved.”

He said that, overall, he would like to have both routes available “because, coming down to patient preference, some prefer to have IV over subcutaneous in general, and that could be for a variety of reasons, so I would love to have as many different routes of administration as possible to offer.”
 

Efficacy maintained

The OLIKOS trial included patients aged 18-60 years with relapsing MS who had received at least two consecutive courses of anti-CD20 therapy with either ocrelizumab or rituximab and who had an EDSS score ≤ 5.5 and were neurologically stable.

After an initial loading regimen of subcutaneous ofatumumab on days 1, 7, and 14, the patients continued open-label subcutaneous ofatumumab once a month for 12 months, with assessments carried out at baseline and at 1, 6, and 12 months.

Of 142 patients assessed, 102 received treatment and were evaluated. Their mean age was 43.5 years, and 67.6% were women. The mean baseline EDSS score was 2.9, and the mean disease duration since diagnosis was 9.4 years.

The vast majority of patients (99.0%) had previously received ocrelizumab for an average duration of 26.7 months.

At this interim analysis, 100% of the 77 patients with follow-up MRI met the primary endpoint at month 6 of no change or a reduction in the number of lesions.

The team says there were “no new safety signals,” with 75.5% of patients experiencing a treatment-emergent adverse event, but only 1.0% having a serious adverse event. Injection site reactions occurred in 7.8%; 15.7% had a systemic injection reaction.

They also report that there were no changes in IgG and IgM concentrations between baseline and follow-up, which remained within normal reference ranges.
 

Reassuring results

“It’s exciting to see reassuring results from clinical studies of two high-efficacy therapies for multiple sclerosis, especially given their route of administration,” commented Julie Fiol, LMSW, BSN, RN, MSCN, associate vice president of Clinical Innovation and Strategy for the U.S. National MS Society.

“Subcutaneous injections allow people with multiple sclerosis more flexibility when selecting a therapy that matches their lifestyle and preferences,” she said in an interview.

“Adherence to therapy is critical in multiple sclerosis, and additional options for route of administration and site of care enhance the likelihood that someone with multiple sclerosis will find a medication that effectively manages their disease and fits into their lifestyle,” Dr. Fiol explained.

“Subcutaneous injections also have the potential to be more affordable as they could be administered at home or over a shorter duration than an infused medication,” she noted.

In terms of these two particular studies, she added, “it’s reassuring to see that the safety and efficacy of subcutaneous ocrelizumab was similar to intravenous. It was also reassuring to see those who switched from ocrelizumab and rituximab to ofatumumab remained clinically stable.”

OCARINA II was supported by F. Hoffmann-La Roche. OLIKOS was supported by Novartis. Dr. Newsome declares relationships with Biogen, Genentech, Bristol-Myers Squibb, EMD Serono, Greenwich Biosciences, Horizon Therapeutics, Novartis, Roche, and TG Therapeutics and institutional relationships with Biogen, Lundbeck, Roche, Genentech, National MS Society, The Stiff Person Syndrome Research Foundation, Department of Defense, and the Patient-Centered Outcomes Research Institute. Dr. Hua declares relationships with Alexion, Biogen, Bristol-Meyers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Horizon Therapeutics, and Novartis. Other authors also declare relationships.

A version of this article first appeared on Medscape.com.

MILAN – Subcutaneous administration of anti-CD20 monoclonal antibody therapy offers ongoing clinical efficacy in the management of patients with relapsing and primary progressive multiple sclerosis (MS), suggest results from two clinical trials.

For OCARINA II, more than 325 patients with MS were randomly assigned to either subcutaneous or intravenous treatment with the anti-CD20 monoclonal antibody ocrelizumab (Ocrevus).

After 24 weeks, the presence of lesions on imaging and the occurrence of clinical remissions were almost completely suppressed by both treatments albeit with a higher rate of mild to moderate injection reactions with subcutaneous administration.

The study “makes me feel pretty comfortable that regardless of where you’re delivering the therapy, IV or subcutaneously, it’s getting in there and doing the job that we want it to do,” said lead author Scott D. Newsome, DO, director, Stiff Person Syndrome Center, Johns Hopkins University, Baltimore.

The second study, OLIKOS, involved just over 100 patients with relapsing MS who had previously been treated with an anti-CD20 monoclonal antibody and were switched to subcutaneous therapy with another: ofatumumab (Arzerra).

Le H. Hua, MD, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, and colleagues report that the novel treatment maintained clinical efficacy in all patients, with no safety concerns and no changes in serum immunoglobulin levels.

The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
 

Anti-CD20–naive

OCARINA II involved patients aged 18-65 years with relapsing or primary progressive MS who had never received ocrelizumab or any other anti-CD20 therapy and had an Expanded Disability Status Scale (EDSS) score of 0.0-6.5.

They were randomly assigned to subcutaneous or IV ocrelizumab as a first dose. At week 24, all patients were scheduled to receive subcutaneous ocrelizumab every 24 weeks up to week 96.

In all, 326 patients were randomly assigned to the two treatment arms. They had a mean age of approximately 40 years, and 59.3%-65.3% were women. The mean time since symptom onset was 6.8-7.7 years, and the mean EDSS score at baseline was 2.5-3.0. The majority (89.8%-89.0%) had relapsing MS.

The results showed that subcutaneous and IV administration led to similar exposure to ocrelizumab, and both resulted in rapid reduction in CD19+ B-cell counts.

By week 24, the mean number of lesions on MRI reduced to zero, resulting in “near-complete suppression” of disease activity, the team says, which was reflected in 99% of patients have no clinical evidence of relapse.

The overall adverse event rate was higher with subcutaneous vs. IV administration of ocrelizumab, at 73.7% vs. 45.8%, driven by both local and systemic injection reactions, which were mild to moderate in nature.

However, a similar proportion of patients in the subcutaneous and IV arms experienced serious adverse events, at 2.5% and 3.4%, respectively.

Crucially, the patients were “overwhelmingly positive” about the subcutaneous administration, Dr. Newsome said, and at his institution, “all the patients want to continue, if and when this gets approved.”

He said that, overall, he would like to have both routes available “because, coming down to patient preference, some prefer to have IV over subcutaneous in general, and that could be for a variety of reasons, so I would love to have as many different routes of administration as possible to offer.”
 

Efficacy maintained

The OLIKOS trial included patients aged 18-60 years with relapsing MS who had received at least two consecutive courses of anti-CD20 therapy with either ocrelizumab or rituximab and who had an EDSS score ≤ 5.5 and were neurologically stable.

After an initial loading regimen of subcutaneous ofatumumab on days 1, 7, and 14, the patients continued open-label subcutaneous ofatumumab once a month for 12 months, with assessments carried out at baseline and at 1, 6, and 12 months.

Of 142 patients assessed, 102 received treatment and were evaluated. Their mean age was 43.5 years, and 67.6% were women. The mean baseline EDSS score was 2.9, and the mean disease duration since diagnosis was 9.4 years.

The vast majority of patients (99.0%) had previously received ocrelizumab for an average duration of 26.7 months.

At this interim analysis, 100% of the 77 patients with follow-up MRI met the primary endpoint at month 6 of no change or a reduction in the number of lesions.

The team says there were “no new safety signals,” with 75.5% of patients experiencing a treatment-emergent adverse event, but only 1.0% having a serious adverse event. Injection site reactions occurred in 7.8%; 15.7% had a systemic injection reaction.

They also report that there were no changes in IgG and IgM concentrations between baseline and follow-up, which remained within normal reference ranges.
 

Reassuring results

“It’s exciting to see reassuring results from clinical studies of two high-efficacy therapies for multiple sclerosis, especially given their route of administration,” commented Julie Fiol, LMSW, BSN, RN, MSCN, associate vice president of Clinical Innovation and Strategy for the U.S. National MS Society.

“Subcutaneous injections allow people with multiple sclerosis more flexibility when selecting a therapy that matches their lifestyle and preferences,” she said in an interview.

“Adherence to therapy is critical in multiple sclerosis, and additional options for route of administration and site of care enhance the likelihood that someone with multiple sclerosis will find a medication that effectively manages their disease and fits into their lifestyle,” Dr. Fiol explained.

“Subcutaneous injections also have the potential to be more affordable as they could be administered at home or over a shorter duration than an infused medication,” she noted.

In terms of these two particular studies, she added, “it’s reassuring to see that the safety and efficacy of subcutaneous ocrelizumab was similar to intravenous. It was also reassuring to see those who switched from ocrelizumab and rituximab to ofatumumab remained clinically stable.”

OCARINA II was supported by F. Hoffmann-La Roche. OLIKOS was supported by Novartis. Dr. Newsome declares relationships with Biogen, Genentech, Bristol-Myers Squibb, EMD Serono, Greenwich Biosciences, Horizon Therapeutics, Novartis, Roche, and TG Therapeutics and institutional relationships with Biogen, Lundbeck, Roche, Genentech, National MS Society, The Stiff Person Syndrome Research Foundation, Department of Defense, and the Patient-Centered Outcomes Research Institute. Dr. Hua declares relationships with Alexion, Biogen, Bristol-Meyers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Horizon Therapeutics, and Novartis. Other authors also declare relationships.

A version of this article first appeared on Medscape.com.

MILAN – Subcutaneous administration of anti-CD20 monoclonal antibody therapy offers ongoing clinical efficacy in the management of patients with relapsing and primary progressive multiple sclerosis (MS), suggest results from two clinical trials.

For OCARINA II, more than 325 patients with MS were randomly assigned to either subcutaneous or intravenous treatment with the anti-CD20 monoclonal antibody ocrelizumab (Ocrevus).

After 24 weeks, the presence of lesions on imaging and the occurrence of clinical remissions were almost completely suppressed by both treatments albeit with a higher rate of mild to moderate injection reactions with subcutaneous administration.

The study “makes me feel pretty comfortable that regardless of where you’re delivering the therapy, IV or subcutaneously, it’s getting in there and doing the job that we want it to do,” said lead author Scott D. Newsome, DO, director, Stiff Person Syndrome Center, Johns Hopkins University, Baltimore.

The second study, OLIKOS, involved just over 100 patients with relapsing MS who had previously been treated with an anti-CD20 monoclonal antibody and were switched to subcutaneous therapy with another: ofatumumab (Arzerra).

Le H. Hua, MD, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, and colleagues report that the novel treatment maintained clinical efficacy in all patients, with no safety concerns and no changes in serum immunoglobulin levels.

The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
 

Anti-CD20–naive

OCARINA II involved patients aged 18-65 years with relapsing or primary progressive MS who had never received ocrelizumab or any other anti-CD20 therapy and had an Expanded Disability Status Scale (EDSS) score of 0.0-6.5.

They were randomly assigned to subcutaneous or IV ocrelizumab as a first dose. At week 24, all patients were scheduled to receive subcutaneous ocrelizumab every 24 weeks up to week 96.

In all, 326 patients were randomly assigned to the two treatment arms. They had a mean age of approximately 40 years, and 59.3%-65.3% were women. The mean time since symptom onset was 6.8-7.7 years, and the mean EDSS score at baseline was 2.5-3.0. The majority (89.8%-89.0%) had relapsing MS.

The results showed that subcutaneous and IV administration led to similar exposure to ocrelizumab, and both resulted in rapid reduction in CD19+ B-cell counts.

By week 24, the mean number of lesions on MRI reduced to zero, resulting in “near-complete suppression” of disease activity, the team says, which was reflected in 99% of patients have no clinical evidence of relapse.

The overall adverse event rate was higher with subcutaneous vs. IV administration of ocrelizumab, at 73.7% vs. 45.8%, driven by both local and systemic injection reactions, which were mild to moderate in nature.

However, a similar proportion of patients in the subcutaneous and IV arms experienced serious adverse events, at 2.5% and 3.4%, respectively.

Crucially, the patients were “overwhelmingly positive” about the subcutaneous administration, Dr. Newsome said, and at his institution, “all the patients want to continue, if and when this gets approved.”

He said that, overall, he would like to have both routes available “because, coming down to patient preference, some prefer to have IV over subcutaneous in general, and that could be for a variety of reasons, so I would love to have as many different routes of administration as possible to offer.”
 

Efficacy maintained

The OLIKOS trial included patients aged 18-60 years with relapsing MS who had received at least two consecutive courses of anti-CD20 therapy with either ocrelizumab or rituximab and who had an EDSS score ≤ 5.5 and were neurologically stable.

After an initial loading regimen of subcutaneous ofatumumab on days 1, 7, and 14, the patients continued open-label subcutaneous ofatumumab once a month for 12 months, with assessments carried out at baseline and at 1, 6, and 12 months.

Of 142 patients assessed, 102 received treatment and were evaluated. Their mean age was 43.5 years, and 67.6% were women. The mean baseline EDSS score was 2.9, and the mean disease duration since diagnosis was 9.4 years.

The vast majority of patients (99.0%) had previously received ocrelizumab for an average duration of 26.7 months.

At this interim analysis, 100% of the 77 patients with follow-up MRI met the primary endpoint at month 6 of no change or a reduction in the number of lesions.

The team says there were “no new safety signals,” with 75.5% of patients experiencing a treatment-emergent adverse event, but only 1.0% having a serious adverse event. Injection site reactions occurred in 7.8%; 15.7% had a systemic injection reaction.

They also report that there were no changes in IgG and IgM concentrations between baseline and follow-up, which remained within normal reference ranges.
 

Reassuring results

“It’s exciting to see reassuring results from clinical studies of two high-efficacy therapies for multiple sclerosis, especially given their route of administration,” commented Julie Fiol, LMSW, BSN, RN, MSCN, associate vice president of Clinical Innovation and Strategy for the U.S. National MS Society.

“Subcutaneous injections allow people with multiple sclerosis more flexibility when selecting a therapy that matches their lifestyle and preferences,” she said in an interview.

“Adherence to therapy is critical in multiple sclerosis, and additional options for route of administration and site of care enhance the likelihood that someone with multiple sclerosis will find a medication that effectively manages their disease and fits into their lifestyle,” Dr. Fiol explained.

“Subcutaneous injections also have the potential to be more affordable as they could be administered at home or over a shorter duration than an infused medication,” she noted.

In terms of these two particular studies, she added, “it’s reassuring to see that the safety and efficacy of subcutaneous ocrelizumab was similar to intravenous. It was also reassuring to see those who switched from ocrelizumab and rituximab to ofatumumab remained clinically stable.”

OCARINA II was supported by F. Hoffmann-La Roche. OLIKOS was supported by Novartis. Dr. Newsome declares relationships with Biogen, Genentech, Bristol-Myers Squibb, EMD Serono, Greenwich Biosciences, Horizon Therapeutics, Novartis, Roche, and TG Therapeutics and institutional relationships with Biogen, Lundbeck, Roche, Genentech, National MS Society, The Stiff Person Syndrome Research Foundation, Department of Defense, and the Patient-Centered Outcomes Research Institute. Dr. Hua declares relationships with Alexion, Biogen, Bristol-Meyers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Horizon Therapeutics, and Novartis. Other authors also declare relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Among the 3,188 people with type 2 diabetes who were adherent to their tirzepatide (Mounjaro, Lilly) regimen in four pivotal trials of the agent, a quarter achieved at least a 15% cut from their baseline body weight after 40-42 weeks of treatment, and researchers found seven baseline variables that were significantly linked with a higher incidence of this level of weight loss.

“These findings help inform which people with type 2 diabetes are most likely to achieve greater body weight reduction with improved cardiometabolic risk factors with tirzepatide,” say the authors.

METHODOLOGY:

• Investigators conducted a post hoc analysis of data collected from a total of 3,188 people with type 2 diabetes who had been adherent to their assigned tirzepatide regimen for 40-42 weeks in any one of four pivotal trials of the agent.
• The researchers aimed to identify predictors of a reduction in body weight of at least 15% with tirzepatide treatment at any of the three tested doses – 5 mg, 10 mg, or 15 mg – which were administered by subcutaneous injection once a week.
• All four trials that provided data prohibited concurrent therapy that would promote weight loss, and the people included in the analysis did not receive any rescue medications for controlling glycemia.
• The primary efficacy measure in all four studies was the ability of tirzepatide to improve glycemic control (measured by A1c level), compared with placebo, semaglutide (Ozempic) 1 mg SC once weekly, insulin degludec (Tresiba, Novo Nordisk), or insulin glargine (Basaglar, Lilly).

TAKEAWAY:

• Among the 3,188 people who remained adherent to their tirzepatide regimen for 40-42 weeks, 792 (25%) experienced a weight reduction of at least 15% from baseline.
• Multivariate analysis of baseline covariates showed that these seven factors were significantly linked with greater than or equal to 15% weight loss: higher tirzepatide dose, being female, being of White or Asian race, being of younger age, undergoing treatment with metformin, having better glycemic control (based on lower A1c and lower fasting serum glucose), and having lower non–high-density lipoprotein cholesterol level.
• During follow-up, achievement of at least a 15% cut in baseline body weight was significantly associated with greater reductions in A1c, fasting serum glucose level, waist circumference, blood pressure, serum triglyceride level, and serum level of the liver enzyme alanine transaminase.

IN PRACTICE:

“These findings may provide valuable information to clinicians and people with type 2 diabetes regarding the likelihood of achieving substantial body weight reduction with tirzepatide and also help to signal likely improvements to be seen in a range of cardiometabolic risk parameters with tirzepatide-induced weight loss,” the authors concluded in their report.

SOURCE:

The study was largely run by researchers who are employees of Lilly, the company that markets tirzepatide (Mounjaro). It was published in Diabetes Care.

LIMITATIONS:

• The analysis was post hoc.
• The follow-up was limited.
• The analysis focused entirely on baseline parameters as potential predictors of weight loss magnitude.

DISCLOSURES:

The study was funded by Eli Lilly, the company that markets tirzepatide (Mounjaro) and that sponsored the SURPASS trials. Six authors are employees of Lilly, one is a contractor for Lilly, and the two remaining authors have had financial relationships with Lilly and with several other companies.

A version of this article first appeared on Medscape.com.

TOPLINE:

Among the 3,188 people with type 2 diabetes who were adherent to their tirzepatide (Mounjaro, Lilly) regimen in four pivotal trials of the agent, a quarter achieved at least a 15% cut from their baseline body weight after 40-42 weeks of treatment, and researchers found seven baseline variables that were significantly linked with a higher incidence of this level of weight loss.

“These findings help inform which people with type 2 diabetes are most likely to achieve greater body weight reduction with improved cardiometabolic risk factors with tirzepatide,” say the authors.

METHODOLOGY:

• Investigators conducted a post hoc analysis of data collected from a total of 3,188 people with type 2 diabetes who had been adherent to their assigned tirzepatide regimen for 40-42 weeks in any one of four pivotal trials of the agent.
• The researchers aimed to identify predictors of a reduction in body weight of at least 15% with tirzepatide treatment at any of the three tested doses – 5 mg, 10 mg, or 15 mg – which were administered by subcutaneous injection once a week.
• All four trials that provided data prohibited concurrent therapy that would promote weight loss, and the people included in the analysis did not receive any rescue medications for controlling glycemia.
• The primary efficacy measure in all four studies was the ability of tirzepatide to improve glycemic control (measured by A1c level), compared with placebo, semaglutide (Ozempic) 1 mg SC once weekly, insulin degludec (Tresiba, Novo Nordisk), or insulin glargine (Basaglar, Lilly).

TAKEAWAY:

• Among the 3,188 people who remained adherent to their tirzepatide regimen for 40-42 weeks, 792 (25%) experienced a weight reduction of at least 15% from baseline.
• Multivariate analysis of baseline covariates showed that these seven factors were significantly linked with greater than or equal to 15% weight loss: higher tirzepatide dose, being female, being of White or Asian race, being of younger age, undergoing treatment with metformin, having better glycemic control (based on lower A1c and lower fasting serum glucose), and having lower non–high-density lipoprotein cholesterol level.
• During follow-up, achievement of at least a 15% cut in baseline body weight was significantly associated with greater reductions in A1c, fasting serum glucose level, waist circumference, blood pressure, serum triglyceride level, and serum level of the liver enzyme alanine transaminase.

IN PRACTICE:

“These findings may provide valuable information to clinicians and people with type 2 diabetes regarding the likelihood of achieving substantial body weight reduction with tirzepatide and also help to signal likely improvements to be seen in a range of cardiometabolic risk parameters with tirzepatide-induced weight loss,” the authors concluded in their report.

SOURCE:

The study was largely run by researchers who are employees of Lilly, the company that markets tirzepatide (Mounjaro). It was published in Diabetes Care.

LIMITATIONS:

• The analysis was post hoc.
• The follow-up was limited.
• The analysis focused entirely on baseline parameters as potential predictors of weight loss magnitude.

DISCLOSURES:

The study was funded by Eli Lilly, the company that markets tirzepatide (Mounjaro) and that sponsored the SURPASS trials. Six authors are employees of Lilly, one is a contractor for Lilly, and the two remaining authors have had financial relationships with Lilly and with several other companies.

A version of this article first appeared on Medscape.com.

TOPLINE:

Among the 3,188 people with type 2 diabetes who were adherent to their tirzepatide (Mounjaro, Lilly) regimen in four pivotal trials of the agent, a quarter achieved at least a 15% cut from their baseline body weight after 40-42 weeks of treatment, and researchers found seven baseline variables that were significantly linked with a higher incidence of this level of weight loss.

“These findings help inform which people with type 2 diabetes are most likely to achieve greater body weight reduction with improved cardiometabolic risk factors with tirzepatide,” say the authors.

METHODOLOGY:

• Investigators conducted a post hoc analysis of data collected from a total of 3,188 people with type 2 diabetes who had been adherent to their assigned tirzepatide regimen for 40-42 weeks in any one of four pivotal trials of the agent.
• The researchers aimed to identify predictors of a reduction in body weight of at least 15% with tirzepatide treatment at any of the three tested doses – 5 mg, 10 mg, or 15 mg – which were administered by subcutaneous injection once a week.
• All four trials that provided data prohibited concurrent therapy that would promote weight loss, and the people included in the analysis did not receive any rescue medications for controlling glycemia.
• The primary efficacy measure in all four studies was the ability of tirzepatide to improve glycemic control (measured by A1c level), compared with placebo, semaglutide (Ozempic) 1 mg SC once weekly, insulin degludec (Tresiba, Novo Nordisk), or insulin glargine (Basaglar, Lilly).

TAKEAWAY:

• Among the 3,188 people who remained adherent to their tirzepatide regimen for 40-42 weeks, 792 (25%) experienced a weight reduction of at least 15% from baseline.
• Multivariate analysis of baseline covariates showed that these seven factors were significantly linked with greater than or equal to 15% weight loss: higher tirzepatide dose, being female, being of White or Asian race, being of younger age, undergoing treatment with metformin, having better glycemic control (based on lower A1c and lower fasting serum glucose), and having lower non–high-density lipoprotein cholesterol level.
• During follow-up, achievement of at least a 15% cut in baseline body weight was significantly associated with greater reductions in A1c, fasting serum glucose level, waist circumference, blood pressure, serum triglyceride level, and serum level of the liver enzyme alanine transaminase.

IN PRACTICE:

“These findings may provide valuable information to clinicians and people with type 2 diabetes regarding the likelihood of achieving substantial body weight reduction with tirzepatide and also help to signal likely improvements to be seen in a range of cardiometabolic risk parameters with tirzepatide-induced weight loss,” the authors concluded in their report.

SOURCE:

The study was largely run by researchers who are employees of Lilly, the company that markets tirzepatide (Mounjaro). It was published in Diabetes Care.

LIMITATIONS:

• The analysis was post hoc.
• The follow-up was limited.
• The analysis focused entirely on baseline parameters as potential predictors of weight loss magnitude.

DISCLOSURES:

The study was funded by Eli Lilly, the company that markets tirzepatide (Mounjaro) and that sponsored the SURPASS trials. Six authors are employees of Lilly, one is a contractor for Lilly, and the two remaining authors have had financial relationships with Lilly and with several other companies.

A version of this article first appeared on Medscape.com.

TOPLINE:

Tongxinluo, a traditional Chinese medicine made from extracts of multiple plants and insects, significantly reduced myocardial infarction (MI), stroke, and related events when used alongside guideline-directed treatments in patients with ST-segment elevation myocardial infarction (STEMI), results of a large trial suggest.

METHODOLOGY:

• The double-blind China Tongxinluo Study for Myocardial Protection in Patients With Acute Myocardial Infarction (CTS-AMI) included 3,777 adult patients, mean age 61 years, 76.9% men, with STEMI at 124 centers in China.
• Researchers randomly assigned patients to receive oral Tongxinluo using a loading dose of eight capsules (2.08 g) followed by a maintenance dose of four capsules (1.04 g) or oral placebo three times a day for 12 months.
• Doctors were instructed to also provide STEMI guideline-directed treatments, which include dual antiplatelet therapy and coronary reperfusion (percutaneous coronary intervention or thrombolysis).
• The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 30 days, a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke.

TAKEAWAY:

• At 30 days, 3.4% in the Tongxinluo group and 5.2% in the placebo group had a MACCE (relative risk, 0.64; 95% confidence interval, 0.47-0.88; risk difference, –1.8%; 95% CI, –3.2% to –0.6%; P = .006).
• Individual components of MACCEs were also significantly lower in the Tongxinluo group, including 30-day cardiac death (3.0% vs. 4.2%; RR, 0.70; 95% CI, 0.50-0.99; P = .04) and myocardial reinfarction (0% vs. 0.5%; RR, 0.35; 95% CI, 0.13-0.99; P = .003), but there was no significant difference in 30-day stroke rate.
• At 1 year, the Tongxinluo group had a lower MACCE rate than did the placebo group (5.3% vs. 8.3%; hazard ratio, 0.64; 95% CI, 0.49-0.82; P = .001), an almost significant lower rate of all-cause death (5.1% vs. 6.6%; HR, 0.77; 95% CI, 0.59-1.01; P = .06), and lower rates of other outcomes.
• Rates of nonfatal serious adverse events were similar (2.2% in the Tongxinluo and 2.8% in the placebo groups; P = .25), but the Tongxinluo group had more adverse drug reactions (2.1% vs 1.1%; P = .02), which were mainly driven by symptoms in the digestive system such as stomach discomfort and nausea.

IN PRACTICE:

Unlike most traditional Chinese medicine research, the design of this study incorporated all key elements of randomized clinical trials, including placebo control and blinding in addition to randomization, so it “may serve as a model for future clinical trials to evaluate the safety and efficacy of traditional Chinese medicine,” the authors conclude.

In an accompanying editorial, Richard G. Bach, MD, cardiovascular division, Washington University School of Medicine, St. Louis, expressed skepticism about whether the benefits of Tongxinluo can be extrapolated to populations outside China that have distinct genetic backgrounds, lipid profiles, and diets. He also stressed that the active ingredients and mechanisms of action of Tongxinluo are unknown and noted reports suggesting that traditional Chinese medicines can contain undeclared material, heavy metals, and other adulterants associated with potentially toxic effects.

In an Editor’s Note, Gregory Curfman, MD, said in making a judgment about the validity of this research, “the editors were faced with the task of walking a fine line between skepticism and plausibility.” Though all patients should receive beta-blockers and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker after STEMI, use of these drugs was suboptimal in these patients. Still, the benefits of Chinese medicine are plausible, said Dr. Curfman, noting research on the malaria drug artemisinin, which was isolated from a traditional Chinese medicine, was awarded the Nobel Prize.

SOURCE:

The research was led by Yuejin Yang, MD, PhD, department of cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, and colleagues. It was published online on Oct. 24 in JAMA. The results were previously reported at the American Heart Association Scientific Sessions 2022.

LIMITATIONS:

Despite the demonstrated clinical benefit of Tongxinluo, its active ingredients and the exact mechanisms of action have not been established. Use of guideline-directed medical therapy was suboptimal, with only 64% of patients prescribed beta-blockers and 51%-52% prescribed an ACE inhibitor or ARB during hospitalization, which may have affected the magnitude of the benefit of Tongxinluo. As study patients were all Chinese, the generalizability to other populations, especially in countries with higher adherence to guideline-directed medical therapy, is unknown.

DISCLOSURES:

The study received funding from the National Key Research and Development Program of China and a research grant from Shijiazhuang Yiling Pharmaceutical. Yuejin Yang reported receiving grants from Shijiazhuang Yiling Pharmaceutical and the National Key Research and Development Program of China; in addition, he has a patent related to the mechanisms of Tongxinluo in alleviating rat myocardial reperfusion injury and a patent related to the mechanisms of Tongxinluo on enhancing the protective effects of exosomes derived from mesenchymal stem cells in rat acute myocardial infarction. See paper for disclosures of other authors.

A version of this article first appeared on Medscape.com.

TOPLINE:

Tongxinluo, a traditional Chinese medicine made from extracts of multiple plants and insects, significantly reduced myocardial infarction (MI), stroke, and related events when used alongside guideline-directed treatments in patients with ST-segment elevation myocardial infarction (STEMI), results of a large trial suggest.

METHODOLOGY:

• The double-blind China Tongxinluo Study for Myocardial Protection in Patients With Acute Myocardial Infarction (CTS-AMI) included 3,777 adult patients, mean age 61 years, 76.9% men, with STEMI at 124 centers in China.
• Researchers randomly assigned patients to receive oral Tongxinluo using a loading dose of eight capsules (2.08 g) followed by a maintenance dose of four capsules (1.04 g) or oral placebo three times a day for 12 months.
• Doctors were instructed to also provide STEMI guideline-directed treatments, which include dual antiplatelet therapy and coronary reperfusion (percutaneous coronary intervention or thrombolysis).
• The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 30 days, a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke.

TAKEAWAY:

• At 30 days, 3.4% in the Tongxinluo group and 5.2% in the placebo group had a MACCE (relative risk, 0.64; 95% confidence interval, 0.47-0.88; risk difference, –1.8%; 95% CI, –3.2% to –0.6%; P = .006).
• Individual components of MACCEs were also significantly lower in the Tongxinluo group, including 30-day cardiac death (3.0% vs. 4.2%; RR, 0.70; 95% CI, 0.50-0.99; P = .04) and myocardial reinfarction (0% vs. 0.5%; RR, 0.35; 95% CI, 0.13-0.99; P = .003), but there was no significant difference in 30-day stroke rate.
• At 1 year, the Tongxinluo group had a lower MACCE rate than did the placebo group (5.3% vs. 8.3%; hazard ratio, 0.64; 95% CI, 0.49-0.82; P = .001), an almost significant lower rate of all-cause death (5.1% vs. 6.6%; HR, 0.77; 95% CI, 0.59-1.01; P = .06), and lower rates of other outcomes.
• Rates of nonfatal serious adverse events were similar (2.2% in the Tongxinluo and 2.8% in the placebo groups; P = .25), but the Tongxinluo group had more adverse drug reactions (2.1% vs 1.1%; P = .02), which were mainly driven by symptoms in the digestive system such as stomach discomfort and nausea.

IN PRACTICE:

Unlike most traditional Chinese medicine research, the design of this study incorporated all key elements of randomized clinical trials, including placebo control and blinding in addition to randomization, so it “may serve as a model for future clinical trials to evaluate the safety and efficacy of traditional Chinese medicine,” the authors conclude.

In an accompanying editorial, Richard G. Bach, MD, cardiovascular division, Washington University School of Medicine, St. Louis, expressed skepticism about whether the benefits of Tongxinluo can be extrapolated to populations outside China that have distinct genetic backgrounds, lipid profiles, and diets. He also stressed that the active ingredients and mechanisms of action of Tongxinluo are unknown and noted reports suggesting that traditional Chinese medicines can contain undeclared material, heavy metals, and other adulterants associated with potentially toxic effects.

In an Editor’s Note, Gregory Curfman, MD, said in making a judgment about the validity of this research, “the editors were faced with the task of walking a fine line between skepticism and plausibility.” Though all patients should receive beta-blockers and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker after STEMI, use of these drugs was suboptimal in these patients. Still, the benefits of Chinese medicine are plausible, said Dr. Curfman, noting research on the malaria drug artemisinin, which was isolated from a traditional Chinese medicine, was awarded the Nobel Prize.

SOURCE:

The research was led by Yuejin Yang, MD, PhD, department of cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, and colleagues. It was published online on Oct. 24 in JAMA. The results were previously reported at the American Heart Association Scientific Sessions 2022.

LIMITATIONS:

Despite the demonstrated clinical benefit of Tongxinluo, its active ingredients and the exact mechanisms of action have not been established. Use of guideline-directed medical therapy was suboptimal, with only 64% of patients prescribed beta-blockers and 51%-52% prescribed an ACE inhibitor or ARB during hospitalization, which may have affected the magnitude of the benefit of Tongxinluo. As study patients were all Chinese, the generalizability to other populations, especially in countries with higher adherence to guideline-directed medical therapy, is unknown.

DISCLOSURES:

The study received funding from the National Key Research and Development Program of China and a research grant from Shijiazhuang Yiling Pharmaceutical. Yuejin Yang reported receiving grants from Shijiazhuang Yiling Pharmaceutical and the National Key Research and Development Program of China; in addition, he has a patent related to the mechanisms of Tongxinluo in alleviating rat myocardial reperfusion injury and a patent related to the mechanisms of Tongxinluo on enhancing the protective effects of exosomes derived from mesenchymal stem cells in rat acute myocardial infarction. See paper for disclosures of other authors.

A version of this article first appeared on Medscape.com.

TOPLINE:

Tongxinluo, a traditional Chinese medicine made from extracts of multiple plants and insects, significantly reduced myocardial infarction (MI), stroke, and related events when used alongside guideline-directed treatments in patients with ST-segment elevation myocardial infarction (STEMI), results of a large trial suggest.

METHODOLOGY:

• The double-blind China Tongxinluo Study for Myocardial Protection in Patients With Acute Myocardial Infarction (CTS-AMI) included 3,777 adult patients, mean age 61 years, 76.9% men, with STEMI at 124 centers in China.
• Researchers randomly assigned patients to receive oral Tongxinluo using a loading dose of eight capsules (2.08 g) followed by a maintenance dose of four capsules (1.04 g) or oral placebo three times a day for 12 months.
• Doctors were instructed to also provide STEMI guideline-directed treatments, which include dual antiplatelet therapy and coronary reperfusion (percutaneous coronary intervention or thrombolysis).
• The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 30 days, a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke.

TAKEAWAY:

• At 30 days, 3.4% in the Tongxinluo group and 5.2% in the placebo group had a MACCE (relative risk, 0.64; 95% confidence interval, 0.47-0.88; risk difference, –1.8%; 95% CI, –3.2% to –0.6%; P = .006).
• Individual components of MACCEs were also significantly lower in the Tongxinluo group, including 30-day cardiac death (3.0% vs. 4.2%; RR, 0.70; 95% CI, 0.50-0.99; P = .04) and myocardial reinfarction (0% vs. 0.5%; RR, 0.35; 95% CI, 0.13-0.99; P = .003), but there was no significant difference in 30-day stroke rate.
• At 1 year, the Tongxinluo group had a lower MACCE rate than did the placebo group (5.3% vs. 8.3%; hazard ratio, 0.64; 95% CI, 0.49-0.82; P = .001), an almost significant lower rate of all-cause death (5.1% vs. 6.6%; HR, 0.77; 95% CI, 0.59-1.01; P = .06), and lower rates of other outcomes.
• Rates of nonfatal serious adverse events were similar (2.2% in the Tongxinluo and 2.8% in the placebo groups; P = .25), but the Tongxinluo group had more adverse drug reactions (2.1% vs 1.1%; P = .02), which were mainly driven by symptoms in the digestive system such as stomach discomfort and nausea.

IN PRACTICE:

Unlike most traditional Chinese medicine research, the design of this study incorporated all key elements of randomized clinical trials, including placebo control and blinding in addition to randomization, so it “may serve as a model for future clinical trials to evaluate the safety and efficacy of traditional Chinese medicine,” the authors conclude.

In an accompanying editorial, Richard G. Bach, MD, cardiovascular division, Washington University School of Medicine, St. Louis, expressed skepticism about whether the benefits of Tongxinluo can be extrapolated to populations outside China that have distinct genetic backgrounds, lipid profiles, and diets. He also stressed that the active ingredients and mechanisms of action of Tongxinluo are unknown and noted reports suggesting that traditional Chinese medicines can contain undeclared material, heavy metals, and other adulterants associated with potentially toxic effects.

In an Editor’s Note, Gregory Curfman, MD, said in making a judgment about the validity of this research, “the editors were faced with the task of walking a fine line between skepticism and plausibility.” Though all patients should receive beta-blockers and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker after STEMI, use of these drugs was suboptimal in these patients. Still, the benefits of Chinese medicine are plausible, said Dr. Curfman, noting research on the malaria drug artemisinin, which was isolated from a traditional Chinese medicine, was awarded the Nobel Prize.

SOURCE:

The research was led by Yuejin Yang, MD, PhD, department of cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, and colleagues. It was published online on Oct. 24 in JAMA. The results were previously reported at the American Heart Association Scientific Sessions 2022.

LIMITATIONS:

Despite the demonstrated clinical benefit of Tongxinluo, its active ingredients and the exact mechanisms of action have not been established. Use of guideline-directed medical therapy was suboptimal, with only 64% of patients prescribed beta-blockers and 51%-52% prescribed an ACE inhibitor or ARB during hospitalization, which may have affected the magnitude of the benefit of Tongxinluo. As study patients were all Chinese, the generalizability to other populations, especially in countries with higher adherence to guideline-directed medical therapy, is unknown.

DISCLOSURES:

The study received funding from the National Key Research and Development Program of China and a research grant from Shijiazhuang Yiling Pharmaceutical. Yuejin Yang reported receiving grants from Shijiazhuang Yiling Pharmaceutical and the National Key Research and Development Program of China; in addition, he has a patent related to the mechanisms of Tongxinluo in alleviating rat myocardial reperfusion injury and a patent related to the mechanisms of Tongxinluo on enhancing the protective effects of exosomes derived from mesenchymal stem cells in rat acute myocardial infarction. See paper for disclosures of other authors.

A version of this article first appeared on Medscape.com.

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.