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FDA Approves Pfizer’s Hympavzi for Hemophilia A, B
The once-weekly subcutaneous injection targets an anticoagulation protein called tissue factor pathway inhibitor (TFPI). Reducing TFPI’s amount and activity in the blood subsequently increases the amount of thrombin, a pro-clotting enzyme, in circulation.
“Today’s approval of Hympavzi provides patients with hemophilia a new treatment option that is the first of its kind to work by targeting a protein in the blood clotting process,” Ann Farrell, MD, director of FDA’s Division of Non-Malignant Hematology, said in an agency press release.
Hympavzi is the first non-factor, once-weekly treatment for hemophilia B in the United States. The subcutaneous injection emicizumab (Hemlibra, Genentech), which works by a different mechanism, is already on the market for hemophilia A.
The current approval was based on the open-label BASIS trial in 116 men and boys with either severe hemophilia A or B without factor inhibitors.
During the trial’s first 6 months, patients received standard treatment with clotting factor replacement either on-demand (33 patients) or prophylactically (83 patients). Patients were then switched to Hympavzi prophylaxis for a year.
Among patients receiving on-demand standard treatment during the first 6 months, the annualized bleeding rate was 38 episodes. That rate fell to 3.2 episodes during treatment with Hympavzi.
Among patients receiving prophylactic standard treatment during the first 6 months, the estimated annualized bleeding rate was 7.85 episodes, which then fell to 5.08 during the year of Hympavzi prophylaxis, FDA said.
Injection-site reactions, headaches, and itching were the most common side effects with marstacimab, occurring in 3% or more of patients. Labeling warns of the potential for circulating blood clots, hypersensitivity, and embryofetal toxicity. Marstacimab is supplied in prefilled syringes.
Marstacimab is Pfizer’s second hemophilia approval in 2024. FDA approved the company’s hemophilia B gene therapy fidanacogene elaparvovec (Beqvez) in April.
Pfizer noted in a press release that results for another arm of the BASIS trial in patients with clotting factor inhibitors are expected in 2025.
A version of this article first appeared on Medscape.com.
The once-weekly subcutaneous injection targets an anticoagulation protein called tissue factor pathway inhibitor (TFPI). Reducing TFPI’s amount and activity in the blood subsequently increases the amount of thrombin, a pro-clotting enzyme, in circulation.
“Today’s approval of Hympavzi provides patients with hemophilia a new treatment option that is the first of its kind to work by targeting a protein in the blood clotting process,” Ann Farrell, MD, director of FDA’s Division of Non-Malignant Hematology, said in an agency press release.
Hympavzi is the first non-factor, once-weekly treatment for hemophilia B in the United States. The subcutaneous injection emicizumab (Hemlibra, Genentech), which works by a different mechanism, is already on the market for hemophilia A.
The current approval was based on the open-label BASIS trial in 116 men and boys with either severe hemophilia A or B without factor inhibitors.
During the trial’s first 6 months, patients received standard treatment with clotting factor replacement either on-demand (33 patients) or prophylactically (83 patients). Patients were then switched to Hympavzi prophylaxis for a year.
Among patients receiving on-demand standard treatment during the first 6 months, the annualized bleeding rate was 38 episodes. That rate fell to 3.2 episodes during treatment with Hympavzi.
Among patients receiving prophylactic standard treatment during the first 6 months, the estimated annualized bleeding rate was 7.85 episodes, which then fell to 5.08 during the year of Hympavzi prophylaxis, FDA said.
Injection-site reactions, headaches, and itching were the most common side effects with marstacimab, occurring in 3% or more of patients. Labeling warns of the potential for circulating blood clots, hypersensitivity, and embryofetal toxicity. Marstacimab is supplied in prefilled syringes.
Marstacimab is Pfizer’s second hemophilia approval in 2024. FDA approved the company’s hemophilia B gene therapy fidanacogene elaparvovec (Beqvez) in April.
Pfizer noted in a press release that results for another arm of the BASIS trial in patients with clotting factor inhibitors are expected in 2025.
A version of this article first appeared on Medscape.com.
The once-weekly subcutaneous injection targets an anticoagulation protein called tissue factor pathway inhibitor (TFPI). Reducing TFPI’s amount and activity in the blood subsequently increases the amount of thrombin, a pro-clotting enzyme, in circulation.
“Today’s approval of Hympavzi provides patients with hemophilia a new treatment option that is the first of its kind to work by targeting a protein in the blood clotting process,” Ann Farrell, MD, director of FDA’s Division of Non-Malignant Hematology, said in an agency press release.
Hympavzi is the first non-factor, once-weekly treatment for hemophilia B in the United States. The subcutaneous injection emicizumab (Hemlibra, Genentech), which works by a different mechanism, is already on the market for hemophilia A.
The current approval was based on the open-label BASIS trial in 116 men and boys with either severe hemophilia A or B without factor inhibitors.
During the trial’s first 6 months, patients received standard treatment with clotting factor replacement either on-demand (33 patients) or prophylactically (83 patients). Patients were then switched to Hympavzi prophylaxis for a year.
Among patients receiving on-demand standard treatment during the first 6 months, the annualized bleeding rate was 38 episodes. That rate fell to 3.2 episodes during treatment with Hympavzi.
Among patients receiving prophylactic standard treatment during the first 6 months, the estimated annualized bleeding rate was 7.85 episodes, which then fell to 5.08 during the year of Hympavzi prophylaxis, FDA said.
Injection-site reactions, headaches, and itching were the most common side effects with marstacimab, occurring in 3% or more of patients. Labeling warns of the potential for circulating blood clots, hypersensitivity, and embryofetal toxicity. Marstacimab is supplied in prefilled syringes.
Marstacimab is Pfizer’s second hemophilia approval in 2024. FDA approved the company’s hemophilia B gene therapy fidanacogene elaparvovec (Beqvez) in April.
Pfizer noted in a press release that results for another arm of the BASIS trial in patients with clotting factor inhibitors are expected in 2025.
A version of this article first appeared on Medscape.com.
FDA Panel Votes for Limits on Gastric, Esophageal Cancer Immunotherapy
During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher.
The agency usually follows the ODAC’s advice.
The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.
Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.
These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.
In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.
Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.
In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.
The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.
Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.
Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.
In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.
The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.
ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.
In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.
FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.
Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.
Still, one panelist said, it’s likely “the best dataset we will get.”
The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.
If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.
BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
A version of this article first appeared on Medscape.com.
During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher.
The agency usually follows the ODAC’s advice.
The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.
Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.
These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.
In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.
Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.
In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.
The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.
Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.
Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.
In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.
The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.
ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.
In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.
FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.
Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.
Still, one panelist said, it’s likely “the best dataset we will get.”
The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.
If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.
BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
A version of this article first appeared on Medscape.com.
During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher.
The agency usually follows the ODAC’s advice.
The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.
Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.
These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.
In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.
Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.
In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.
The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.
Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.
Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.
In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.
The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.
ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.
In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.
FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.
Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.
Still, one panelist said, it’s likely “the best dataset we will get.”
The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.
If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.
BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
A version of this article first appeared on Medscape.com.
FDA OKs Adjuvant Ribociclib in Earlier Stage Breast Cancer
FDA also approved ribociclib and the aromatase inhibitor letrozole packaged together (Kisqali Femara Co-Pack, Novartis) for the same indication.
A rival cyclin-dependent kinase 4/6 (CDK4/6) inhibitor abemaciclib (Verzenio, Eli Lilly) carries a similar adjuvant indication, but use of this agent requires patients to be lymph node–positive.
There’s no such restriction for the new ribociclib indication, which “allows us to offer treatment with a CDK4/6 inhibitor to a significantly broader group of people,” lead investigator Dennis J. Slamon, MD, breast oncologist at the University of California Los Angeless, said in a Novartis press release.
The new indication joins ribociclib’s previous approval for advanced or metastatic HR-positive, HER2-negative breast cancer in combination with an aromatase inhibitor or fulvestrant.
The current approval was based on data from the NATALEE trial. NATALEE randomized 5101 patients with early-stage HR-positive, HER2-negative disease to either 400 mg ribociclib with an aromatase inhibitor or to an aromatase inhibitor alone following surgery.
Invasive disease-free survival at 36 months was 90.7% in the ribociclib arm vs 87.6% with aromatase inhibitor monotherapy (hazard ratio [HR], 0.749; P = .0006). The trial included patients with and without lymph node involvement.
At 4 years (well beyond NATALEE’s 3-year treatment window), the ribociclib group continued to do better, with an invasive disease-free survival rate of 88.5% vs 83.6% in the control arm.
Overall survival data remain immature but with a trend towards improved survival in the ribociclib arm (HR, 0.715; P < .0001), according to a recent report from the 2024 European Society for Medical Oncology Congress.
There were no new safety signals in the trial. Adverse events in the ribociclib group included neutropenia (62.5% overall; 44.3% grade 3/4), liver-related events (26.4% overall; 8.6% grade 3/4), QT prolongation (5.3% overall; 1.0% grade 3/4), and interstitial lung disease/pneumonitis (1.5% overall; 0.0% grade 3/4), according to Novartis.
Ribociclib dosing for the adjuvant indication is lower than for metastatic disease, but patients are on the same schedule — two 200 mg tablets once daily for 21 days followed by 7 days off in 28-day cycles. Treatment continues for 3 years.
Forty-two 200 mg tablets cost about $15,000, according to drugs.com. A patient assistance program is available through Novartis.
A version of this article appeared on Medscape.com.
FDA also approved ribociclib and the aromatase inhibitor letrozole packaged together (Kisqali Femara Co-Pack, Novartis) for the same indication.
A rival cyclin-dependent kinase 4/6 (CDK4/6) inhibitor abemaciclib (Verzenio, Eli Lilly) carries a similar adjuvant indication, but use of this agent requires patients to be lymph node–positive.
There’s no such restriction for the new ribociclib indication, which “allows us to offer treatment with a CDK4/6 inhibitor to a significantly broader group of people,” lead investigator Dennis J. Slamon, MD, breast oncologist at the University of California Los Angeless, said in a Novartis press release.
The new indication joins ribociclib’s previous approval for advanced or metastatic HR-positive, HER2-negative breast cancer in combination with an aromatase inhibitor or fulvestrant.
The current approval was based on data from the NATALEE trial. NATALEE randomized 5101 patients with early-stage HR-positive, HER2-negative disease to either 400 mg ribociclib with an aromatase inhibitor or to an aromatase inhibitor alone following surgery.
Invasive disease-free survival at 36 months was 90.7% in the ribociclib arm vs 87.6% with aromatase inhibitor monotherapy (hazard ratio [HR], 0.749; P = .0006). The trial included patients with and without lymph node involvement.
At 4 years (well beyond NATALEE’s 3-year treatment window), the ribociclib group continued to do better, with an invasive disease-free survival rate of 88.5% vs 83.6% in the control arm.
Overall survival data remain immature but with a trend towards improved survival in the ribociclib arm (HR, 0.715; P < .0001), according to a recent report from the 2024 European Society for Medical Oncology Congress.
There were no new safety signals in the trial. Adverse events in the ribociclib group included neutropenia (62.5% overall; 44.3% grade 3/4), liver-related events (26.4% overall; 8.6% grade 3/4), QT prolongation (5.3% overall; 1.0% grade 3/4), and interstitial lung disease/pneumonitis (1.5% overall; 0.0% grade 3/4), according to Novartis.
Ribociclib dosing for the adjuvant indication is lower than for metastatic disease, but patients are on the same schedule — two 200 mg tablets once daily for 21 days followed by 7 days off in 28-day cycles. Treatment continues for 3 years.
Forty-two 200 mg tablets cost about $15,000, according to drugs.com. A patient assistance program is available through Novartis.
A version of this article appeared on Medscape.com.
FDA also approved ribociclib and the aromatase inhibitor letrozole packaged together (Kisqali Femara Co-Pack, Novartis) for the same indication.
A rival cyclin-dependent kinase 4/6 (CDK4/6) inhibitor abemaciclib (Verzenio, Eli Lilly) carries a similar adjuvant indication, but use of this agent requires patients to be lymph node–positive.
There’s no such restriction for the new ribociclib indication, which “allows us to offer treatment with a CDK4/6 inhibitor to a significantly broader group of people,” lead investigator Dennis J. Slamon, MD, breast oncologist at the University of California Los Angeless, said in a Novartis press release.
The new indication joins ribociclib’s previous approval for advanced or metastatic HR-positive, HER2-negative breast cancer in combination with an aromatase inhibitor or fulvestrant.
The current approval was based on data from the NATALEE trial. NATALEE randomized 5101 patients with early-stage HR-positive, HER2-negative disease to either 400 mg ribociclib with an aromatase inhibitor or to an aromatase inhibitor alone following surgery.
Invasive disease-free survival at 36 months was 90.7% in the ribociclib arm vs 87.6% with aromatase inhibitor monotherapy (hazard ratio [HR], 0.749; P = .0006). The trial included patients with and without lymph node involvement.
At 4 years (well beyond NATALEE’s 3-year treatment window), the ribociclib group continued to do better, with an invasive disease-free survival rate of 88.5% vs 83.6% in the control arm.
Overall survival data remain immature but with a trend towards improved survival in the ribociclib arm (HR, 0.715; P < .0001), according to a recent report from the 2024 European Society for Medical Oncology Congress.
There were no new safety signals in the trial. Adverse events in the ribociclib group included neutropenia (62.5% overall; 44.3% grade 3/4), liver-related events (26.4% overall; 8.6% grade 3/4), QT prolongation (5.3% overall; 1.0% grade 3/4), and interstitial lung disease/pneumonitis (1.5% overall; 0.0% grade 3/4), according to Novartis.
Ribociclib dosing for the adjuvant indication is lower than for metastatic disease, but patients are on the same schedule — two 200 mg tablets once daily for 21 days followed by 7 days off in 28-day cycles. Treatment continues for 3 years.
Forty-two 200 mg tablets cost about $15,000, according to drugs.com. A patient assistance program is available through Novartis.
A version of this article appeared on Medscape.com.
Isatuximab Approved First-Line for Transplant-Ineligible MM
The new first-line indication joins two previous approvals of the CD38 antibody for later-line indications, one for relapsed disease with carfilzomib and dexamethasone, the other with pomalidomide and dexamethasone after at least two prior regimens that include lenalidomide and a proteasome inhibitor.
In addition to other MM indications, isatuximab’s anti-CD38 competitor on the US market, daratumumab (Darzalex — Johnson & Johnson), also carries a first-line indication for transplant-ineligible MM in combination with either lenalidomide and dexamethasone or bortezomib, melphalan, and prednisone.
Isatuximab’s new approval is based on the open-label IMROZ trial in 446 patients randomized 3:2 to either isatuximab or placebo on a background of bortezomib, lenalidomide, and dexamethasone.
At a median follow-up of 59.7 months, estimated progression-free survival (PFS) was 63.2% with isatuximab add-on vs 45.2% in the placebo arm. Median PFS was not reached in the isatuximab group but 54.3 months with placebo (hazard ratio, 0.60; 98.5% CI, 0.41-0.88; P < .001).
In a press release announcing the results, Sanofi said “IMROZ is the first global phase 3 study of an anti-CD38 monoclonal antibody” to show benefit in combination with bortezomib, lenalidomide, and dexamethasone, the current standard of care for transplant-ineligible MM.
Upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19 were the most common adverse events in the isatuximab arm of IMROZ, occurring in 20% or more of subjects.
Eleven percent of isatuximab patients died during treatment vs 5.5% in the placebo group, driven primarily by infections.
The recommended dose of isatuximab is 10 mg/kg every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity.
The cost is approximately $843 for 5 mL of the 20 mg/mL intravenous solution, according to Drugs.com.
A version of this article appeared on Medscape.com.
The new first-line indication joins two previous approvals of the CD38 antibody for later-line indications, one for relapsed disease with carfilzomib and dexamethasone, the other with pomalidomide and dexamethasone after at least two prior regimens that include lenalidomide and a proteasome inhibitor.
In addition to other MM indications, isatuximab’s anti-CD38 competitor on the US market, daratumumab (Darzalex — Johnson & Johnson), also carries a first-line indication for transplant-ineligible MM in combination with either lenalidomide and dexamethasone or bortezomib, melphalan, and prednisone.
Isatuximab’s new approval is based on the open-label IMROZ trial in 446 patients randomized 3:2 to either isatuximab or placebo on a background of bortezomib, lenalidomide, and dexamethasone.
At a median follow-up of 59.7 months, estimated progression-free survival (PFS) was 63.2% with isatuximab add-on vs 45.2% in the placebo arm. Median PFS was not reached in the isatuximab group but 54.3 months with placebo (hazard ratio, 0.60; 98.5% CI, 0.41-0.88; P < .001).
In a press release announcing the results, Sanofi said “IMROZ is the first global phase 3 study of an anti-CD38 monoclonal antibody” to show benefit in combination with bortezomib, lenalidomide, and dexamethasone, the current standard of care for transplant-ineligible MM.
Upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19 were the most common adverse events in the isatuximab arm of IMROZ, occurring in 20% or more of subjects.
Eleven percent of isatuximab patients died during treatment vs 5.5% in the placebo group, driven primarily by infections.
The recommended dose of isatuximab is 10 mg/kg every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity.
The cost is approximately $843 for 5 mL of the 20 mg/mL intravenous solution, according to Drugs.com.
A version of this article appeared on Medscape.com.
The new first-line indication joins two previous approvals of the CD38 antibody for later-line indications, one for relapsed disease with carfilzomib and dexamethasone, the other with pomalidomide and dexamethasone after at least two prior regimens that include lenalidomide and a proteasome inhibitor.
In addition to other MM indications, isatuximab’s anti-CD38 competitor on the US market, daratumumab (Darzalex — Johnson & Johnson), also carries a first-line indication for transplant-ineligible MM in combination with either lenalidomide and dexamethasone or bortezomib, melphalan, and prednisone.
Isatuximab’s new approval is based on the open-label IMROZ trial in 446 patients randomized 3:2 to either isatuximab or placebo on a background of bortezomib, lenalidomide, and dexamethasone.
At a median follow-up of 59.7 months, estimated progression-free survival (PFS) was 63.2% with isatuximab add-on vs 45.2% in the placebo arm. Median PFS was not reached in the isatuximab group but 54.3 months with placebo (hazard ratio, 0.60; 98.5% CI, 0.41-0.88; P < .001).
In a press release announcing the results, Sanofi said “IMROZ is the first global phase 3 study of an anti-CD38 monoclonal antibody” to show benefit in combination with bortezomib, lenalidomide, and dexamethasone, the current standard of care for transplant-ineligible MM.
Upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19 were the most common adverse events in the isatuximab arm of IMROZ, occurring in 20% or more of subjects.
Eleven percent of isatuximab patients died during treatment vs 5.5% in the placebo group, driven primarily by infections.
The recommended dose of isatuximab is 10 mg/kg every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity.
The cost is approximately $843 for 5 mL of the 20 mg/mL intravenous solution, according to Drugs.com.
A version of this article appeared on Medscape.com.
KRAS Inhibitors in Pancreatic Cancer: Hope on the Horizon?
Finding effective treatments for the disease continues to be a challenge.
No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.
Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.”
Until recently.
In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers.
A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.
“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
A Challenging Cancer
Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.
But it’s still early days on the evidence front.
The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far.
The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.
Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.
And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.
For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.
In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations.
At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.
Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks.
Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%.
Revolution Medicines is now planning a phase 3 trial.
Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.
While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said.
Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained.
In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.
Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes.
Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing.
“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.”
Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.
But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?”
Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy.
Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.
Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”
Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.
A version of this article first appeared on Medscape.com.
Finding effective treatments for the disease continues to be a challenge.
No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.
Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.”
Until recently.
In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers.
A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.
“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
A Challenging Cancer
Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.
But it’s still early days on the evidence front.
The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far.
The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.
Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.
And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.
For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.
In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations.
At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.
Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks.
Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%.
Revolution Medicines is now planning a phase 3 trial.
Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.
While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said.
Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained.
In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.
Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes.
Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing.
“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.”
Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.
But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?”
Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy.
Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.
Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”
Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.
A version of this article first appeared on Medscape.com.
Finding effective treatments for the disease continues to be a challenge.
No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.
Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.”
Until recently.
In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers.
A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.
“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
A Challenging Cancer
Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.
But it’s still early days on the evidence front.
The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far.
The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.
Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.
And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.
For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.
In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations.
At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.
Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks.
Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%.
Revolution Medicines is now planning a phase 3 trial.
Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.
While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said.
Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained.
In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.
Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes.
Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing.
“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.”
Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.
But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?”
Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy.
Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.
Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”
Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.
A version of this article first appeared on Medscape.com.
FDA Issues Complete Response Letter for Myeloma Drug
On August 20, Regeneron announced that it had received a complete response letter from the FDA regarding its Biologics License Application for linvoseltamab, citing issues at a third-party manufacturer.
More specifically, Regeneron said in a company press release that the FDA issued the complete response letter based on findings from “a preapproval inspection at a third-party fill/finish manufacturer for another company’s product candidate.”
The third-party manufacturer told Regeneron it believes that the issues have been resolved, Regeneron said, and that facility is now awaiting a follow-up FDA inspection in the “coming months.”
Regeneron noted that this “anticipated outcome” from the FDA preapproval inspection had been disclosed previously during a company earnings call on August 1.
On that call, Regeneron had discussed the FDA’s concerns about the third-party manufacturer and anticipated that “any potential FDA approval for linvoseltamab is likely to be delayed beyond the August 22 PDUFA date.”
Regeneron had initially filed a Biologics License Application for its bispecific antibody in 2023, based on findings from the phase 1/2 single arm LINKER-MM1 trial.
In the latest published trial findings, investigators reported that, at a median follow-up of about 14 months, 71% of the 117 patients receiving 200 mg of linvoseltamab achieved an overall response, with 50% achieving a complete response. The probability of survival at 12 months was 75.3%.
This would have been the first approval for linvoseltamab, which would have joined two agents already on the US market for relapsed/refractory multiple myeloma: teclistamab (Tecvayli, Janssen) and elranatamab (Elrexfio, Pfizer).
Pricing information for linvoseltamab is not yet available, but its competitors teclistamab and elranatamab are reported to cost around $40,000 per month.
A version of this article appeared on Medscape.com.
On August 20, Regeneron announced that it had received a complete response letter from the FDA regarding its Biologics License Application for linvoseltamab, citing issues at a third-party manufacturer.
More specifically, Regeneron said in a company press release that the FDA issued the complete response letter based on findings from “a preapproval inspection at a third-party fill/finish manufacturer for another company’s product candidate.”
The third-party manufacturer told Regeneron it believes that the issues have been resolved, Regeneron said, and that facility is now awaiting a follow-up FDA inspection in the “coming months.”
Regeneron noted that this “anticipated outcome” from the FDA preapproval inspection had been disclosed previously during a company earnings call on August 1.
On that call, Regeneron had discussed the FDA’s concerns about the third-party manufacturer and anticipated that “any potential FDA approval for linvoseltamab is likely to be delayed beyond the August 22 PDUFA date.”
Regeneron had initially filed a Biologics License Application for its bispecific antibody in 2023, based on findings from the phase 1/2 single arm LINKER-MM1 trial.
In the latest published trial findings, investigators reported that, at a median follow-up of about 14 months, 71% of the 117 patients receiving 200 mg of linvoseltamab achieved an overall response, with 50% achieving a complete response. The probability of survival at 12 months was 75.3%.
This would have been the first approval for linvoseltamab, which would have joined two agents already on the US market for relapsed/refractory multiple myeloma: teclistamab (Tecvayli, Janssen) and elranatamab (Elrexfio, Pfizer).
Pricing information for linvoseltamab is not yet available, but its competitors teclistamab and elranatamab are reported to cost around $40,000 per month.
A version of this article appeared on Medscape.com.
On August 20, Regeneron announced that it had received a complete response letter from the FDA regarding its Biologics License Application for linvoseltamab, citing issues at a third-party manufacturer.
More specifically, Regeneron said in a company press release that the FDA issued the complete response letter based on findings from “a preapproval inspection at a third-party fill/finish manufacturer for another company’s product candidate.”
The third-party manufacturer told Regeneron it believes that the issues have been resolved, Regeneron said, and that facility is now awaiting a follow-up FDA inspection in the “coming months.”
Regeneron noted that this “anticipated outcome” from the FDA preapproval inspection had been disclosed previously during a company earnings call on August 1.
On that call, Regeneron had discussed the FDA’s concerns about the third-party manufacturer and anticipated that “any potential FDA approval for linvoseltamab is likely to be delayed beyond the August 22 PDUFA date.”
Regeneron had initially filed a Biologics License Application for its bispecific antibody in 2023, based on findings from the phase 1/2 single arm LINKER-MM1 trial.
In the latest published trial findings, investigators reported that, at a median follow-up of about 14 months, 71% of the 117 patients receiving 200 mg of linvoseltamab achieved an overall response, with 50% achieving a complete response. The probability of survival at 12 months was 75.3%.
This would have been the first approval for linvoseltamab, which would have joined two agents already on the US market for relapsed/refractory multiple myeloma: teclistamab (Tecvayli, Janssen) and elranatamab (Elrexfio, Pfizer).
Pricing information for linvoseltamab is not yet available, but its competitors teclistamab and elranatamab are reported to cost around $40,000 per month.
A version of this article appeared on Medscape.com.
Clinical Controversy: Watch-and-Wait or Surgery in Rectal Cancer Near Complete Responders?
Having an ostomy is a dreaded prospect for many patients with rectal cancer.
To defer, and potentially avoid, this life-altering surgery,
About 80% of these patients who have a complete clinical response — a perfectly healed scar where the tumor used to be and other favorable features — can forgo total mesorectal excision and preserve their rectum.
The success of watch-and-wait among complete responders has led some centers to offer the approach in patients with near-complete responses to neoadjuvant chemoradiation.
But watch-and-wait for near-complete clinical responders “is very controversial,” Alan P. Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco (UCSF), told this news organization.
“You sure as hell don’t want to miss a chance to cure a patient,” Dr. Venook said.
A near-complete clinical response essentially means there is no sign of the tumor 8 weeks after total neoadjuvant therapy, but the tumor bed hasn’t completely healed.
The goal of watch-and-wait in this scenario is to give near-complete response lesions time to become complete responses.
But there’s no clear way to predict which tumors will evolve into a clinical complete response.
Recent studies evaluating the conversion rate have reported that anywhere from 39% to about 90% of near-complete responders became complete responders. Some of the variation likely comes down to differences in the clinical stage of patients evaluated in each study as well as the limited number of patients who achieve a near-complete response overall.
Other concerns have emerged that waiting for near-complete responses to become complete leaves extra time for some tumors to metastasize and that tumor regrowth is much higher compared with complete responders.
A recent study found that 13% of near-complete responders who preserved their rectum on watch-and-wait developed distant metastases vs about 5% of long-term complete responders. The study also found that just over half of near-complete responders have tumor regrowth compared with about one in five complete responders.
But even with regrowth, “surgery is still curative,” explained Julio Garcia-Aguilar, MD, PhD, a pioneer of watch-and-wait for rectal cancer.
And overall, around 50%-60% of patients with a near-complete response can avoid surgery and preserve their rectum.
Selecting Patients for Watch-and-Wait
The key to deciding which patients are right for watch-and-wait is to understand how a near-complete clinical response was defined in the OPRA trial, a landmark randomized trial led by Dr. Garcia-Aguilar that helped establish watch-and-wait as an option in rectal cancer.
OPRA defined a near-complete response as no visible tumor but, in the tumor bed, mild erythema, superficial ulceration, minor mucosal abnormality or small nodules, and an irregular mucosa. The criteria also included no palpable tumor with smooth induration or a minor mucosal abnormality on the digital rectal exam.
The National Comprehensive Cancer Network mirrored the definition when, for the first time, it recommended watch-and-wait as an option for near-complete response in its 2023 rectal cancer guidelines. The group also added a few MRI requirements.
UCSF offers the watch-and-wait option to some patients with near-complete responses, but each decision is made on a case-by-case basis by a tumor board considering numerous measures of tumor aggressiveness.
Even then, “we have, in many cases, struggled to figure out what the right choices are,” Dr. Venook said.
For those chosen for watch-and-wait, Dr. Venook noted that UCSF has top-notch surgeons, radiation oncologists, medical oncologists, and pathologists who have the resources to follow patients closely.
For community practices without the resources of a major cancer center, watch-and-wait for near-complete response to rectal cancer “is really asking a lot,” Dr. Venook said.
Dr. Garcia-Aguilar, a colorectal surgeon at Memorial Sloan Kettering Cancer Center in New York City, explained that after years of studying the issue, he is comfortable with watch-and-wait in near-complete responders as long as it’s done carefully and in patients who will comply with ongoing surveillance.
Dr. Garcia-Aguilar explained that, after diagnosing a near-complete response 8 weeks following total neoadjuvant therapy, the patient needs to come back 6 weeks later. At that point, it’s time to assess whether that near-complete response is evolving into a complete response or not evolving into a complete response.
If it’s evolving into a complete response, surveillance continues about every 8 weeks, but if the tumor has stopped responding, “you take [the patient] to the operating room,” Dr. Garcia-Aguilar said.
As for the bigger safety concern — that near clinical complete response tumors will metastasize — Dr. Garcia-Aguilar’s opinion is that micrometastases are probably already there when the rectal cancer is first diagnosed and will manifest themselves “no matter what happens to the primary tumor.”
Because of that, he noted, “I don’t think the risk is very high” when surgery is delayed a few months to give near-complete response patients a chance to keep their rectum.
The way to answer the metastasis question is to do a randomized trial pitting surgery against watch-and-wait in patients with near-clinical complete response rectal cancer.
However, Dr. Garcia-Aguilar doesn’t think that trial will ever happen. Patients won’t allow themselves to be randomized to surgery once they find out they might be able to avoid a permanent ostomy, he said.
Dr. Venook had no disclosures. Dr. Garcia-Aguilar reported personal fees from Medtronic, Johnson & Johnson, and Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Having an ostomy is a dreaded prospect for many patients with rectal cancer.
To defer, and potentially avoid, this life-altering surgery,
About 80% of these patients who have a complete clinical response — a perfectly healed scar where the tumor used to be and other favorable features — can forgo total mesorectal excision and preserve their rectum.
The success of watch-and-wait among complete responders has led some centers to offer the approach in patients with near-complete responses to neoadjuvant chemoradiation.
But watch-and-wait for near-complete clinical responders “is very controversial,” Alan P. Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco (UCSF), told this news organization.
“You sure as hell don’t want to miss a chance to cure a patient,” Dr. Venook said.
A near-complete clinical response essentially means there is no sign of the tumor 8 weeks after total neoadjuvant therapy, but the tumor bed hasn’t completely healed.
The goal of watch-and-wait in this scenario is to give near-complete response lesions time to become complete responses.
But there’s no clear way to predict which tumors will evolve into a clinical complete response.
Recent studies evaluating the conversion rate have reported that anywhere from 39% to about 90% of near-complete responders became complete responders. Some of the variation likely comes down to differences in the clinical stage of patients evaluated in each study as well as the limited number of patients who achieve a near-complete response overall.
Other concerns have emerged that waiting for near-complete responses to become complete leaves extra time for some tumors to metastasize and that tumor regrowth is much higher compared with complete responders.
A recent study found that 13% of near-complete responders who preserved their rectum on watch-and-wait developed distant metastases vs about 5% of long-term complete responders. The study also found that just over half of near-complete responders have tumor regrowth compared with about one in five complete responders.
But even with regrowth, “surgery is still curative,” explained Julio Garcia-Aguilar, MD, PhD, a pioneer of watch-and-wait for rectal cancer.
And overall, around 50%-60% of patients with a near-complete response can avoid surgery and preserve their rectum.
Selecting Patients for Watch-and-Wait
The key to deciding which patients are right for watch-and-wait is to understand how a near-complete clinical response was defined in the OPRA trial, a landmark randomized trial led by Dr. Garcia-Aguilar that helped establish watch-and-wait as an option in rectal cancer.
OPRA defined a near-complete response as no visible tumor but, in the tumor bed, mild erythema, superficial ulceration, minor mucosal abnormality or small nodules, and an irregular mucosa. The criteria also included no palpable tumor with smooth induration or a minor mucosal abnormality on the digital rectal exam.
The National Comprehensive Cancer Network mirrored the definition when, for the first time, it recommended watch-and-wait as an option for near-complete response in its 2023 rectal cancer guidelines. The group also added a few MRI requirements.
UCSF offers the watch-and-wait option to some patients with near-complete responses, but each decision is made on a case-by-case basis by a tumor board considering numerous measures of tumor aggressiveness.
Even then, “we have, in many cases, struggled to figure out what the right choices are,” Dr. Venook said.
For those chosen for watch-and-wait, Dr. Venook noted that UCSF has top-notch surgeons, radiation oncologists, medical oncologists, and pathologists who have the resources to follow patients closely.
For community practices without the resources of a major cancer center, watch-and-wait for near-complete response to rectal cancer “is really asking a lot,” Dr. Venook said.
Dr. Garcia-Aguilar, a colorectal surgeon at Memorial Sloan Kettering Cancer Center in New York City, explained that after years of studying the issue, he is comfortable with watch-and-wait in near-complete responders as long as it’s done carefully and in patients who will comply with ongoing surveillance.
Dr. Garcia-Aguilar explained that, after diagnosing a near-complete response 8 weeks following total neoadjuvant therapy, the patient needs to come back 6 weeks later. At that point, it’s time to assess whether that near-complete response is evolving into a complete response or not evolving into a complete response.
If it’s evolving into a complete response, surveillance continues about every 8 weeks, but if the tumor has stopped responding, “you take [the patient] to the operating room,” Dr. Garcia-Aguilar said.
As for the bigger safety concern — that near clinical complete response tumors will metastasize — Dr. Garcia-Aguilar’s opinion is that micrometastases are probably already there when the rectal cancer is first diagnosed and will manifest themselves “no matter what happens to the primary tumor.”
Because of that, he noted, “I don’t think the risk is very high” when surgery is delayed a few months to give near-complete response patients a chance to keep their rectum.
The way to answer the metastasis question is to do a randomized trial pitting surgery against watch-and-wait in patients with near-clinical complete response rectal cancer.
However, Dr. Garcia-Aguilar doesn’t think that trial will ever happen. Patients won’t allow themselves to be randomized to surgery once they find out they might be able to avoid a permanent ostomy, he said.
Dr. Venook had no disclosures. Dr. Garcia-Aguilar reported personal fees from Medtronic, Johnson & Johnson, and Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Having an ostomy is a dreaded prospect for many patients with rectal cancer.
To defer, and potentially avoid, this life-altering surgery,
About 80% of these patients who have a complete clinical response — a perfectly healed scar where the tumor used to be and other favorable features — can forgo total mesorectal excision and preserve their rectum.
The success of watch-and-wait among complete responders has led some centers to offer the approach in patients with near-complete responses to neoadjuvant chemoradiation.
But watch-and-wait for near-complete clinical responders “is very controversial,” Alan P. Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco (UCSF), told this news organization.
“You sure as hell don’t want to miss a chance to cure a patient,” Dr. Venook said.
A near-complete clinical response essentially means there is no sign of the tumor 8 weeks after total neoadjuvant therapy, but the tumor bed hasn’t completely healed.
The goal of watch-and-wait in this scenario is to give near-complete response lesions time to become complete responses.
But there’s no clear way to predict which tumors will evolve into a clinical complete response.
Recent studies evaluating the conversion rate have reported that anywhere from 39% to about 90% of near-complete responders became complete responders. Some of the variation likely comes down to differences in the clinical stage of patients evaluated in each study as well as the limited number of patients who achieve a near-complete response overall.
Other concerns have emerged that waiting for near-complete responses to become complete leaves extra time for some tumors to metastasize and that tumor regrowth is much higher compared with complete responders.
A recent study found that 13% of near-complete responders who preserved their rectum on watch-and-wait developed distant metastases vs about 5% of long-term complete responders. The study also found that just over half of near-complete responders have tumor regrowth compared with about one in five complete responders.
But even with regrowth, “surgery is still curative,” explained Julio Garcia-Aguilar, MD, PhD, a pioneer of watch-and-wait for rectal cancer.
And overall, around 50%-60% of patients with a near-complete response can avoid surgery and preserve their rectum.
Selecting Patients for Watch-and-Wait
The key to deciding which patients are right for watch-and-wait is to understand how a near-complete clinical response was defined in the OPRA trial, a landmark randomized trial led by Dr. Garcia-Aguilar that helped establish watch-and-wait as an option in rectal cancer.
OPRA defined a near-complete response as no visible tumor but, in the tumor bed, mild erythema, superficial ulceration, minor mucosal abnormality or small nodules, and an irregular mucosa. The criteria also included no palpable tumor with smooth induration or a minor mucosal abnormality on the digital rectal exam.
The National Comprehensive Cancer Network mirrored the definition when, for the first time, it recommended watch-and-wait as an option for near-complete response in its 2023 rectal cancer guidelines. The group also added a few MRI requirements.
UCSF offers the watch-and-wait option to some patients with near-complete responses, but each decision is made on a case-by-case basis by a tumor board considering numerous measures of tumor aggressiveness.
Even then, “we have, in many cases, struggled to figure out what the right choices are,” Dr. Venook said.
For those chosen for watch-and-wait, Dr. Venook noted that UCSF has top-notch surgeons, radiation oncologists, medical oncologists, and pathologists who have the resources to follow patients closely.
For community practices without the resources of a major cancer center, watch-and-wait for near-complete response to rectal cancer “is really asking a lot,” Dr. Venook said.
Dr. Garcia-Aguilar, a colorectal surgeon at Memorial Sloan Kettering Cancer Center in New York City, explained that after years of studying the issue, he is comfortable with watch-and-wait in near-complete responders as long as it’s done carefully and in patients who will comply with ongoing surveillance.
Dr. Garcia-Aguilar explained that, after diagnosing a near-complete response 8 weeks following total neoadjuvant therapy, the patient needs to come back 6 weeks later. At that point, it’s time to assess whether that near-complete response is evolving into a complete response or not evolving into a complete response.
If it’s evolving into a complete response, surveillance continues about every 8 weeks, but if the tumor has stopped responding, “you take [the patient] to the operating room,” Dr. Garcia-Aguilar said.
As for the bigger safety concern — that near clinical complete response tumors will metastasize — Dr. Garcia-Aguilar’s opinion is that micrometastases are probably already there when the rectal cancer is first diagnosed and will manifest themselves “no matter what happens to the primary tumor.”
Because of that, he noted, “I don’t think the risk is very high” when surgery is delayed a few months to give near-complete response patients a chance to keep their rectum.
The way to answer the metastasis question is to do a randomized trial pitting surgery against watch-and-wait in patients with near-clinical complete response rectal cancer.
However, Dr. Garcia-Aguilar doesn’t think that trial will ever happen. Patients won’t allow themselves to be randomized to surgery once they find out they might be able to avoid a permanent ostomy, he said.
Dr. Venook had no disclosures. Dr. Garcia-Aguilar reported personal fees from Medtronic, Johnson & Johnson, and Intuitive Surgical.
A version of this article first appeared on Medscape.com.
FDA Approves Neoadjuvant/Adjuvant Durvalumab for NSCLC
The agency approved durvalumab alongside platinum-containing chemotherapy in the neoadjuvant setting and as monotherapy in the adjuvant setting.
The approval comes shortly after a meeting of FDA’s Oncology Drug Advisory Committee, where agency personnel took AstraZeneca to task for not following its request to include an arm in the approval study, AEGEAN, to clarify whether or not treatment after surgery was necessary.
Even so, advisers at the July 25 meeting voted “yes” to approving the neoadjuvant/adjuvant indication to give patients another immunotherapy option in NSCLC. However, the committee voted unanimously that, going forward, the agency should require — instead of simply request — that companies seeking combined neoadjuvant/adjuvant NSCLC indications show that patients actually need treatment after surgery.
The new approval is durvalumab’s first indication for resectable NSCLC. The agent has been previously approved for unresectable or metastatic disease as well as extensive-stage small cell lung cancer, locally advanced or metastatic biliary tract cancer, unresectable hepatocellular carcinoma, and advanced or recurrent endometrial cancer.
AEGEAN included 802 patients with previously untreated and resectable stage IIA-IIIB squamous or nonsquamous NSCLC. Patients were randomly assigned to receive either durvalumab (400 patients) or placebo (402 patients) on a background of platinum-based chemotherapy every 3 weeks for four cycles then, following surgery, durvalumab or placebo once a month for a year.
The pathologic complete response rate was 17% in the durvalumab arm vs 4.3% in the placebo arm. At 12 months, event-free survival was 73.4% with durvalumab vs 64.5% with placebo. Overall survival differences have not been tested for statistical significance, but there was “no clear detriment” with durvalumab, FDA said in a press release.
Adverse reactions in 20% or more of durvalumab recipients included anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash; 1.7% of durvalumab recipients and 1% of placebo recipients could not have surgery because of side effects during neoadjuvant treatment.
The dosage for patients weighing > 30 kg is 1500 mg every 3 weeks before surgery and every 4 weeks afterward. For patients who weigh less than that, the recommended dosage is 20 mg/kg.
Durvalumab costs around $1,053 for 120 mg, according to drugs.com.
A version of this article appeared on Medscape.com.
The agency approved durvalumab alongside platinum-containing chemotherapy in the neoadjuvant setting and as monotherapy in the adjuvant setting.
The approval comes shortly after a meeting of FDA’s Oncology Drug Advisory Committee, where agency personnel took AstraZeneca to task for not following its request to include an arm in the approval study, AEGEAN, to clarify whether or not treatment after surgery was necessary.
Even so, advisers at the July 25 meeting voted “yes” to approving the neoadjuvant/adjuvant indication to give patients another immunotherapy option in NSCLC. However, the committee voted unanimously that, going forward, the agency should require — instead of simply request — that companies seeking combined neoadjuvant/adjuvant NSCLC indications show that patients actually need treatment after surgery.
The new approval is durvalumab’s first indication for resectable NSCLC. The agent has been previously approved for unresectable or metastatic disease as well as extensive-stage small cell lung cancer, locally advanced or metastatic biliary tract cancer, unresectable hepatocellular carcinoma, and advanced or recurrent endometrial cancer.
AEGEAN included 802 patients with previously untreated and resectable stage IIA-IIIB squamous or nonsquamous NSCLC. Patients were randomly assigned to receive either durvalumab (400 patients) or placebo (402 patients) on a background of platinum-based chemotherapy every 3 weeks for four cycles then, following surgery, durvalumab or placebo once a month for a year.
The pathologic complete response rate was 17% in the durvalumab arm vs 4.3% in the placebo arm. At 12 months, event-free survival was 73.4% with durvalumab vs 64.5% with placebo. Overall survival differences have not been tested for statistical significance, but there was “no clear detriment” with durvalumab, FDA said in a press release.
Adverse reactions in 20% or more of durvalumab recipients included anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash; 1.7% of durvalumab recipients and 1% of placebo recipients could not have surgery because of side effects during neoadjuvant treatment.
The dosage for patients weighing > 30 kg is 1500 mg every 3 weeks before surgery and every 4 weeks afterward. For patients who weigh less than that, the recommended dosage is 20 mg/kg.
Durvalumab costs around $1,053 for 120 mg, according to drugs.com.
A version of this article appeared on Medscape.com.
The agency approved durvalumab alongside platinum-containing chemotherapy in the neoadjuvant setting and as monotherapy in the adjuvant setting.
The approval comes shortly after a meeting of FDA’s Oncology Drug Advisory Committee, where agency personnel took AstraZeneca to task for not following its request to include an arm in the approval study, AEGEAN, to clarify whether or not treatment after surgery was necessary.
Even so, advisers at the July 25 meeting voted “yes” to approving the neoadjuvant/adjuvant indication to give patients another immunotherapy option in NSCLC. However, the committee voted unanimously that, going forward, the agency should require — instead of simply request — that companies seeking combined neoadjuvant/adjuvant NSCLC indications show that patients actually need treatment after surgery.
The new approval is durvalumab’s first indication for resectable NSCLC. The agent has been previously approved for unresectable or metastatic disease as well as extensive-stage small cell lung cancer, locally advanced or metastatic biliary tract cancer, unresectable hepatocellular carcinoma, and advanced or recurrent endometrial cancer.
AEGEAN included 802 patients with previously untreated and resectable stage IIA-IIIB squamous or nonsquamous NSCLC. Patients were randomly assigned to receive either durvalumab (400 patients) or placebo (402 patients) on a background of platinum-based chemotherapy every 3 weeks for four cycles then, following surgery, durvalumab or placebo once a month for a year.
The pathologic complete response rate was 17% in the durvalumab arm vs 4.3% in the placebo arm. At 12 months, event-free survival was 73.4% with durvalumab vs 64.5% with placebo. Overall survival differences have not been tested for statistical significance, but there was “no clear detriment” with durvalumab, FDA said in a press release.
Adverse reactions in 20% or more of durvalumab recipients included anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash; 1.7% of durvalumab recipients and 1% of placebo recipients could not have surgery because of side effects during neoadjuvant treatment.
The dosage for patients weighing > 30 kg is 1500 mg every 3 weeks before surgery and every 4 weeks afterward. For patients who weigh less than that, the recommended dosage is 20 mg/kg.
Durvalumab costs around $1,053 for 120 mg, according to drugs.com.
A version of this article appeared on Medscape.com.
Immunotherapy May Be Overused in Dying Patients With Cancer
Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.
Immunotherapy, however, has been taking its place.
This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.
What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
The N-of-1 Patient
With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.
He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.
The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.
Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”
At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”
This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
Back to Earth
The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.
Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.
Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.
She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.
Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.
Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.
And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.
In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
Prescribing Decisions
Recent research highlights the growing use of immunotherapy at the end of life.
Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.
Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.
Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.
Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.
Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.
More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.
The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.
Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.
To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”
While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.
As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.
Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.
“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.
“Just because something can be done doesn’t always mean it should be done,” he said.
At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.
Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”
Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.
“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”
Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.
Immunotherapy, however, has been taking its place.
This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.
What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
The N-of-1 Patient
With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.
He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.
The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.
Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”
At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”
This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
Back to Earth
The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.
Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.
Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.
She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.
Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.
Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.
And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.
In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
Prescribing Decisions
Recent research highlights the growing use of immunotherapy at the end of life.
Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.
Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.
Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.
Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.
Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.
More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.
The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.
Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.
To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”
While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.
As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.
Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.
“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.
“Just because something can be done doesn’t always mean it should be done,” he said.
At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.
Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”
Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.
“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”
Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.
Immunotherapy, however, has been taking its place.
This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.
What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
The N-of-1 Patient
With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.
He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.
The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.
Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”
At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”
This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
Back to Earth
The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.
Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.
Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.
She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.
Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.
Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.
And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.
In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
Prescribing Decisions
Recent research highlights the growing use of immunotherapy at the end of life.
Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.
Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.
Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.
Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.
Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.
More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.
The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.
Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.
To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”
While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.
As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.
Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.
“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.
“Just because something can be done doesn’t always mean it should be done,” he said.
At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.
Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”
Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.
“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”
Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FDA Approves First Engineered Cell Therapy for a Solid Tumor
Afami-cel — the first engineered cell therapy for a solid tumor — is indicated specifically for adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are positive for several human leukocyte antigens (HLAs), and whose tumors express melanoma-associated antigen A4, as determined by FDA-authorized companion diagnostic devices.
The single-dose treatment targets solid tumors expressing melanoma-associated antigen A4, a protein highly expressed in synovial sarcoma.
Synovial sarcoma is a rare form of cancer, which affects about 1000 people in the US each year. Malignant cells develop and form a tumor in soft tissues, often in the extremities.
“Adults with metastatic synovial sarcoma, a life-threatening form of cancer, often face limited treatment options in addition to the risk of cancer spread or recurrence,” Nicole Verdun, MD, director of the Office of Therapeutic Products in the FDA’s Center for Biologics Evaluation and Research, said in the agency press release announcing the approval. “Today’s approval represents a significant milestone in the development of an innovative, safe and effective therapy for patients with this rare but potentially fatal disease.”
T-cell receptor therapy, like chimeric antigen receptor (CAR) T-cell (CAR-T) therapy, involves altering patient T cells to fight cancer. While CAR-T therapy inserts an artificial receptor to target a specific surface protein on cancer cells, the T-cell receptor therapy modifies existing receptors to recognize an array of antigens on the surface of cancer cells — a promising strategy for targeting solid tumors.
The accelerated approval of afami-cel was based on the phase 2 SPEARHEAD-1 trial in 44 patients with synovial sarcoma who received a single infusion of the therapy. The trial had enrolled 52 patients, but 8 did not receive afami-cel, including 3 who died and 1 who withdrew.
According to the FDA announcement, the overall response rate was 43.2%, with a median time to response of 4.9 weeks. The median duration of response was 6 months (95% CI, 4.6 months to not reached). Among patients who responded, 39% had a duration of response of 12 months or longer.
“These results suggest that a one-time treatment with afami-cel has the potential to extend life while allowing responders to go off chemotherapy,” said lead investigator Sandra D’Angelo, MD, a sarcoma specialist at Memorial Sloan Kettering Cancer Center in New York City, in a company press release.
The prescribing information includes a boxed warning for serious or fatal cytokine release syndrome.
The most common nonlaboratory adverse reactions, occurring in at least 20% of patients, included cytokine release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, tachycardia, hypotension, diarrhea, and edema. The most common grade 3 or 4 laboratory abnormalities, occurring in at least 20% of patients, included decreased lymphocyte count, neutrophil count, white cell blood count, red blood cell, and platelet count.
The recommended dose is between 2.68x109 to 10x109 MAGE-A4 T-cell receptor–positive T-cells. The FDA notice specifies not using a leukodepleting filter or prophylactic systemic corticosteroids.
The list price for the one-time therapy is $727,000, according to Fierce Pharma.
A version of this article first appeared on Medscape.com.
Afami-cel — the first engineered cell therapy for a solid tumor — is indicated specifically for adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are positive for several human leukocyte antigens (HLAs), and whose tumors express melanoma-associated antigen A4, as determined by FDA-authorized companion diagnostic devices.
The single-dose treatment targets solid tumors expressing melanoma-associated antigen A4, a protein highly expressed in synovial sarcoma.
Synovial sarcoma is a rare form of cancer, which affects about 1000 people in the US each year. Malignant cells develop and form a tumor in soft tissues, often in the extremities.
“Adults with metastatic synovial sarcoma, a life-threatening form of cancer, often face limited treatment options in addition to the risk of cancer spread or recurrence,” Nicole Verdun, MD, director of the Office of Therapeutic Products in the FDA’s Center for Biologics Evaluation and Research, said in the agency press release announcing the approval. “Today’s approval represents a significant milestone in the development of an innovative, safe and effective therapy for patients with this rare but potentially fatal disease.”
T-cell receptor therapy, like chimeric antigen receptor (CAR) T-cell (CAR-T) therapy, involves altering patient T cells to fight cancer. While CAR-T therapy inserts an artificial receptor to target a specific surface protein on cancer cells, the T-cell receptor therapy modifies existing receptors to recognize an array of antigens on the surface of cancer cells — a promising strategy for targeting solid tumors.
The accelerated approval of afami-cel was based on the phase 2 SPEARHEAD-1 trial in 44 patients with synovial sarcoma who received a single infusion of the therapy. The trial had enrolled 52 patients, but 8 did not receive afami-cel, including 3 who died and 1 who withdrew.
According to the FDA announcement, the overall response rate was 43.2%, with a median time to response of 4.9 weeks. The median duration of response was 6 months (95% CI, 4.6 months to not reached). Among patients who responded, 39% had a duration of response of 12 months or longer.
“These results suggest that a one-time treatment with afami-cel has the potential to extend life while allowing responders to go off chemotherapy,” said lead investigator Sandra D’Angelo, MD, a sarcoma specialist at Memorial Sloan Kettering Cancer Center in New York City, in a company press release.
The prescribing information includes a boxed warning for serious or fatal cytokine release syndrome.
The most common nonlaboratory adverse reactions, occurring in at least 20% of patients, included cytokine release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, tachycardia, hypotension, diarrhea, and edema. The most common grade 3 or 4 laboratory abnormalities, occurring in at least 20% of patients, included decreased lymphocyte count, neutrophil count, white cell blood count, red blood cell, and platelet count.
The recommended dose is between 2.68x109 to 10x109 MAGE-A4 T-cell receptor–positive T-cells. The FDA notice specifies not using a leukodepleting filter or prophylactic systemic corticosteroids.
The list price for the one-time therapy is $727,000, according to Fierce Pharma.
A version of this article first appeared on Medscape.com.
Afami-cel — the first engineered cell therapy for a solid tumor — is indicated specifically for adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are positive for several human leukocyte antigens (HLAs), and whose tumors express melanoma-associated antigen A4, as determined by FDA-authorized companion diagnostic devices.
The single-dose treatment targets solid tumors expressing melanoma-associated antigen A4, a protein highly expressed in synovial sarcoma.
Synovial sarcoma is a rare form of cancer, which affects about 1000 people in the US each year. Malignant cells develop and form a tumor in soft tissues, often in the extremities.
“Adults with metastatic synovial sarcoma, a life-threatening form of cancer, often face limited treatment options in addition to the risk of cancer spread or recurrence,” Nicole Verdun, MD, director of the Office of Therapeutic Products in the FDA’s Center for Biologics Evaluation and Research, said in the agency press release announcing the approval. “Today’s approval represents a significant milestone in the development of an innovative, safe and effective therapy for patients with this rare but potentially fatal disease.”
T-cell receptor therapy, like chimeric antigen receptor (CAR) T-cell (CAR-T) therapy, involves altering patient T cells to fight cancer. While CAR-T therapy inserts an artificial receptor to target a specific surface protein on cancer cells, the T-cell receptor therapy modifies existing receptors to recognize an array of antigens on the surface of cancer cells — a promising strategy for targeting solid tumors.
The accelerated approval of afami-cel was based on the phase 2 SPEARHEAD-1 trial in 44 patients with synovial sarcoma who received a single infusion of the therapy. The trial had enrolled 52 patients, but 8 did not receive afami-cel, including 3 who died and 1 who withdrew.
According to the FDA announcement, the overall response rate was 43.2%, with a median time to response of 4.9 weeks. The median duration of response was 6 months (95% CI, 4.6 months to not reached). Among patients who responded, 39% had a duration of response of 12 months or longer.
“These results suggest that a one-time treatment with afami-cel has the potential to extend life while allowing responders to go off chemotherapy,” said lead investigator Sandra D’Angelo, MD, a sarcoma specialist at Memorial Sloan Kettering Cancer Center in New York City, in a company press release.
The prescribing information includes a boxed warning for serious or fatal cytokine release syndrome.
The most common nonlaboratory adverse reactions, occurring in at least 20% of patients, included cytokine release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, tachycardia, hypotension, diarrhea, and edema. The most common grade 3 or 4 laboratory abnormalities, occurring in at least 20% of patients, included decreased lymphocyte count, neutrophil count, white cell blood count, red blood cell, and platelet count.
The recommended dose is between 2.68x109 to 10x109 MAGE-A4 T-cell receptor–positive T-cells. The FDA notice specifies not using a leukodepleting filter or prophylactic systemic corticosteroids.
The list price for the one-time therapy is $727,000, according to Fierce Pharma.
A version of this article first appeared on Medscape.com.