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No benefit to adding ICI to chemo in triple-negative breast cancer: study
Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.
chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.
“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.
NeoTRIP results
Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.
“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.
At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.
In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.
A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.
Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.
At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076 for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.
Pathologic complete responses key
In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.
Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).
Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.
The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.
“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.
Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.
Why no benefit to the ICI?
Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.
For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.
In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.
“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.
Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.
The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.
Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.
chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.
“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.
NeoTRIP results
Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.
“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.
At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.
In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.
A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.
Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.
At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076 for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.
Pathologic complete responses key
In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.
Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).
Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.
The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.
“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.
Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.
Why no benefit to the ICI?
Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.
For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.
In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.
“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.
Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.
The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.
Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.
chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.
“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.
NeoTRIP results
Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.
“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.
At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.
In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.
A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.
Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.
At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076 for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.
Pathologic complete responses key
In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.
Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).
Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.
The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.
“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.
Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.
Why no benefit to the ICI?
Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.
For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.
In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.
“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.
Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.
The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.
FROM ESMO CONGRESS 2023
Remote symptom monitoring in advanced cancer improves quality of life
During treatment for metastatic cancer, remote monitoring of symptoms using electronic patient-reported outcomes (ePROs) reduced health care visits and improved patients’ physical function and quality of life, but did not impact overall survival, according to findings from the PRO-TECT trial.
said Ethan Basch, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, who presented the findings at the annual meeting of the European Society for Medical Oncology.
Jiyoung Ahn, PhD, professor of population health at NYU Langone Health and associate director of population science, NYU Langone Perlmutter Cancer Center, both in New York, said this study “provides exciting scientific evidence” supporting real-time, remote monitoring of PROs. Dr. Ahn was not involved with the PRO-TECT trial.
Symptoms among patients with advanced cancer receiving treatment are “exceedingly common,” Dr. Basch explained, but “unfortunately, evidence demonstrates that we as clinicians miss up to 50% of our patients’ symptoms with potential serious downstream consequences.”
Remote monitoring with ePROs can help clinicians detect patients’ symptoms early so they can intervene early.
In the PRO-TECT cluster-randomized trial, 52 oncology practices in the United States were randomly assigned (1:1) to remote monitoring with ePRO surveys or usual care. The cohort included 1,191 patients with metastatic cancer – with 593 patients at PRO practices and 598 patients at control practices. Participating practices could enroll up to 50 patients with any type of metastatic cancer, except for indolent lymphoma or acute leukemia, who were receiving systemic treatment.
Patients in the ePRO practices completed weekly surveys either online or using an automated telephone system for up to 1 year. The survey included questions related to nine common symptoms, performance status, and falls.
For symptoms that are severe or worsening, a real-time alert goes to the care team through the electronic health record or by an email, Dr. Basch explained. Similarly, reports highlighting the longitudinal trajectory of symptoms can be generated at patient visits and reviewed by clinicians, which can bring “the patient and the care team closer together by elevating those issues that are particularly salient to the patient’s experience,” he noted.
Patients completed over 91% of the electronic symptom surveys. After 24 months, the team observed no significant difference in the primary outcome of overall survival – 42.0 months with ePRO vs. 43.5 months with usual care (hazard ratio, 0.99; P = .86).
Dr. Basch and colleagues did, however, observe a 6% reduction in emergency or hospital admissions in the ePRO group, compared with usual care. The ePRO group also had a significantly longer time to first emergency admission (HR, 0.84; P = .03) and a decreased average number of admissions per patient over 1 year (1.48 vs. 1.81; P = .006).
At multiple time points, the team also observed “clinically meaningful and statistically significant” benefits in physical functioning, symptom control, and health-related quality of life, Dr. Basch reported. More patients in the ePRO than the usual-care group experienced benefits in fatigue (odds ratio, 1.77; P < .001), anorexia (OR, 1.32; P = .03), nausea/vomiting (OR, 1.40; P = .01), and sleep (OR, 1.73; P < .001).
Patients’ impressions of the ePRO symptom monitoring system were also “overwhelmingly” positive, Dr. Basch said. Most found the questions relevant and easy to understand and felt that their care team used the information, which made patients feel more in control of their care.
Nurses generally had a favorable impression of the system, with the majority stating that the information was helpful for electronic health record documentation and that it improved discussions with their patients and improved their efficiency.
However, about one-quarter of the nurses expressed reluctance about continuing to use the system, citing the “added work of the ePROs, particularly alerts that were triggered that prompted them to call their patients, particularly during the pandemic when nurses in the United States were pulled in many directions,” Dr. Basch said.
He noted that future ePRO implementations should aim to integrate ePROs into care processes and adjust nurse responsibilities to allow time for ePRO work.
It will also be important to offer a variety of ePRO platforms that are easily accessible for different patient groups. “Notably,” said Dr. Basch, about one-third of the patients selected the automated telephone option. These were largely patients living in rural areas of the United States with lower socioeconomic status and lower health literacy, “suggesting that we need to think about our technologies to meet patients where they are,” he said.
Despite the positive outcomes, there are “challenges to widespread adoption,” agreed NYU’s Dr. Ahn.
These challenges include the need for physician adaptation to new technologies, data security, and ensuring patient engagement and compliance with remote monitoring systems.
“Successfully addressing these challenges is crucial for optimizing the integration of ePROs into cancer care,” Dr. Ahn said.
ESMO’s invited discussant, Anne Letsch, MD, noted that “cancer therapies are getting more complex, and it’s important that patients are well informed and empowered to get together with the treatment teams throughout therapy.”
The high completion rate with ePRO symptom surveys was “quite remarkable,” said Dr. Letsch, head of the Cancer Center at the University Hospital Schleswig Holstein, Kiel, Germany.
But, Dr. Letsch said, it’s “a pity” that there was no overall survival benefit among patients in the ePRO group. Perhaps overall survival is not what matters most in this context, she said. Instead, she asked, “are other outcomes, like health-related quality of life, symptom control and treatment safety, much more important?”
Dr. Basch also questioned whether the survival differences between the two groups may have been blunted because a substantial portion of the trial was conducted during the COVID-19 pandemic, when medical resources and treatments were delayed and diverted.
Dr. Basch pointed to a 2017 study he and colleagues conducted at a single tertiary care medical center, in which patients monitored with ePROs did demonstrate an overall survival benefit, compared with usual care.
Overall, though, the study demonstrated that “symptom monitoring with ePROs is feasible during routine treatment for advanced cancers across diverse practices in the U.S.” and improved patients’ quality of life, Dr. Basch said.
Funding for the study was provided by a grant from the Patient-Centered Outcomes Research Institute. Dr. Basch has disclosed relationships with Resilience Health, Sivan Health, Navigating Cancer, and AstraZeneca. Dr. Letsch and Dr. Ahn report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
During treatment for metastatic cancer, remote monitoring of symptoms using electronic patient-reported outcomes (ePROs) reduced health care visits and improved patients’ physical function and quality of life, but did not impact overall survival, according to findings from the PRO-TECT trial.
said Ethan Basch, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, who presented the findings at the annual meeting of the European Society for Medical Oncology.
Jiyoung Ahn, PhD, professor of population health at NYU Langone Health and associate director of population science, NYU Langone Perlmutter Cancer Center, both in New York, said this study “provides exciting scientific evidence” supporting real-time, remote monitoring of PROs. Dr. Ahn was not involved with the PRO-TECT trial.
Symptoms among patients with advanced cancer receiving treatment are “exceedingly common,” Dr. Basch explained, but “unfortunately, evidence demonstrates that we as clinicians miss up to 50% of our patients’ symptoms with potential serious downstream consequences.”
Remote monitoring with ePROs can help clinicians detect patients’ symptoms early so they can intervene early.
In the PRO-TECT cluster-randomized trial, 52 oncology practices in the United States were randomly assigned (1:1) to remote monitoring with ePRO surveys or usual care. The cohort included 1,191 patients with metastatic cancer – with 593 patients at PRO practices and 598 patients at control practices. Participating practices could enroll up to 50 patients with any type of metastatic cancer, except for indolent lymphoma or acute leukemia, who were receiving systemic treatment.
Patients in the ePRO practices completed weekly surveys either online or using an automated telephone system for up to 1 year. The survey included questions related to nine common symptoms, performance status, and falls.
For symptoms that are severe or worsening, a real-time alert goes to the care team through the electronic health record or by an email, Dr. Basch explained. Similarly, reports highlighting the longitudinal trajectory of symptoms can be generated at patient visits and reviewed by clinicians, which can bring “the patient and the care team closer together by elevating those issues that are particularly salient to the patient’s experience,” he noted.
Patients completed over 91% of the electronic symptom surveys. After 24 months, the team observed no significant difference in the primary outcome of overall survival – 42.0 months with ePRO vs. 43.5 months with usual care (hazard ratio, 0.99; P = .86).
Dr. Basch and colleagues did, however, observe a 6% reduction in emergency or hospital admissions in the ePRO group, compared with usual care. The ePRO group also had a significantly longer time to first emergency admission (HR, 0.84; P = .03) and a decreased average number of admissions per patient over 1 year (1.48 vs. 1.81; P = .006).
At multiple time points, the team also observed “clinically meaningful and statistically significant” benefits in physical functioning, symptom control, and health-related quality of life, Dr. Basch reported. More patients in the ePRO than the usual-care group experienced benefits in fatigue (odds ratio, 1.77; P < .001), anorexia (OR, 1.32; P = .03), nausea/vomiting (OR, 1.40; P = .01), and sleep (OR, 1.73; P < .001).
Patients’ impressions of the ePRO symptom monitoring system were also “overwhelmingly” positive, Dr. Basch said. Most found the questions relevant and easy to understand and felt that their care team used the information, which made patients feel more in control of their care.
Nurses generally had a favorable impression of the system, with the majority stating that the information was helpful for electronic health record documentation and that it improved discussions with their patients and improved their efficiency.
However, about one-quarter of the nurses expressed reluctance about continuing to use the system, citing the “added work of the ePROs, particularly alerts that were triggered that prompted them to call their patients, particularly during the pandemic when nurses in the United States were pulled in many directions,” Dr. Basch said.
He noted that future ePRO implementations should aim to integrate ePROs into care processes and adjust nurse responsibilities to allow time for ePRO work.
It will also be important to offer a variety of ePRO platforms that are easily accessible for different patient groups. “Notably,” said Dr. Basch, about one-third of the patients selected the automated telephone option. These were largely patients living in rural areas of the United States with lower socioeconomic status and lower health literacy, “suggesting that we need to think about our technologies to meet patients where they are,” he said.
Despite the positive outcomes, there are “challenges to widespread adoption,” agreed NYU’s Dr. Ahn.
These challenges include the need for physician adaptation to new technologies, data security, and ensuring patient engagement and compliance with remote monitoring systems.
“Successfully addressing these challenges is crucial for optimizing the integration of ePROs into cancer care,” Dr. Ahn said.
ESMO’s invited discussant, Anne Letsch, MD, noted that “cancer therapies are getting more complex, and it’s important that patients are well informed and empowered to get together with the treatment teams throughout therapy.”
The high completion rate with ePRO symptom surveys was “quite remarkable,” said Dr. Letsch, head of the Cancer Center at the University Hospital Schleswig Holstein, Kiel, Germany.
But, Dr. Letsch said, it’s “a pity” that there was no overall survival benefit among patients in the ePRO group. Perhaps overall survival is not what matters most in this context, she said. Instead, she asked, “are other outcomes, like health-related quality of life, symptom control and treatment safety, much more important?”
Dr. Basch also questioned whether the survival differences between the two groups may have been blunted because a substantial portion of the trial was conducted during the COVID-19 pandemic, when medical resources and treatments were delayed and diverted.
Dr. Basch pointed to a 2017 study he and colleagues conducted at a single tertiary care medical center, in which patients monitored with ePROs did demonstrate an overall survival benefit, compared with usual care.
Overall, though, the study demonstrated that “symptom monitoring with ePROs is feasible during routine treatment for advanced cancers across diverse practices in the U.S.” and improved patients’ quality of life, Dr. Basch said.
Funding for the study was provided by a grant from the Patient-Centered Outcomes Research Institute. Dr. Basch has disclosed relationships with Resilience Health, Sivan Health, Navigating Cancer, and AstraZeneca. Dr. Letsch and Dr. Ahn report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
During treatment for metastatic cancer, remote monitoring of symptoms using electronic patient-reported outcomes (ePROs) reduced health care visits and improved patients’ physical function and quality of life, but did not impact overall survival, according to findings from the PRO-TECT trial.
said Ethan Basch, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, who presented the findings at the annual meeting of the European Society for Medical Oncology.
Jiyoung Ahn, PhD, professor of population health at NYU Langone Health and associate director of population science, NYU Langone Perlmutter Cancer Center, both in New York, said this study “provides exciting scientific evidence” supporting real-time, remote monitoring of PROs. Dr. Ahn was not involved with the PRO-TECT trial.
Symptoms among patients with advanced cancer receiving treatment are “exceedingly common,” Dr. Basch explained, but “unfortunately, evidence demonstrates that we as clinicians miss up to 50% of our patients’ symptoms with potential serious downstream consequences.”
Remote monitoring with ePROs can help clinicians detect patients’ symptoms early so they can intervene early.
In the PRO-TECT cluster-randomized trial, 52 oncology practices in the United States were randomly assigned (1:1) to remote monitoring with ePRO surveys or usual care. The cohort included 1,191 patients with metastatic cancer – with 593 patients at PRO practices and 598 patients at control practices. Participating practices could enroll up to 50 patients with any type of metastatic cancer, except for indolent lymphoma or acute leukemia, who were receiving systemic treatment.
Patients in the ePRO practices completed weekly surveys either online or using an automated telephone system for up to 1 year. The survey included questions related to nine common symptoms, performance status, and falls.
For symptoms that are severe or worsening, a real-time alert goes to the care team through the electronic health record or by an email, Dr. Basch explained. Similarly, reports highlighting the longitudinal trajectory of symptoms can be generated at patient visits and reviewed by clinicians, which can bring “the patient and the care team closer together by elevating those issues that are particularly salient to the patient’s experience,” he noted.
Patients completed over 91% of the electronic symptom surveys. After 24 months, the team observed no significant difference in the primary outcome of overall survival – 42.0 months with ePRO vs. 43.5 months with usual care (hazard ratio, 0.99; P = .86).
Dr. Basch and colleagues did, however, observe a 6% reduction in emergency or hospital admissions in the ePRO group, compared with usual care. The ePRO group also had a significantly longer time to first emergency admission (HR, 0.84; P = .03) and a decreased average number of admissions per patient over 1 year (1.48 vs. 1.81; P = .006).
At multiple time points, the team also observed “clinically meaningful and statistically significant” benefits in physical functioning, symptom control, and health-related quality of life, Dr. Basch reported. More patients in the ePRO than the usual-care group experienced benefits in fatigue (odds ratio, 1.77; P < .001), anorexia (OR, 1.32; P = .03), nausea/vomiting (OR, 1.40; P = .01), and sleep (OR, 1.73; P < .001).
Patients’ impressions of the ePRO symptom monitoring system were also “overwhelmingly” positive, Dr. Basch said. Most found the questions relevant and easy to understand and felt that their care team used the information, which made patients feel more in control of their care.
Nurses generally had a favorable impression of the system, with the majority stating that the information was helpful for electronic health record documentation and that it improved discussions with their patients and improved their efficiency.
However, about one-quarter of the nurses expressed reluctance about continuing to use the system, citing the “added work of the ePROs, particularly alerts that were triggered that prompted them to call their patients, particularly during the pandemic when nurses in the United States were pulled in many directions,” Dr. Basch said.
He noted that future ePRO implementations should aim to integrate ePROs into care processes and adjust nurse responsibilities to allow time for ePRO work.
It will also be important to offer a variety of ePRO platforms that are easily accessible for different patient groups. “Notably,” said Dr. Basch, about one-third of the patients selected the automated telephone option. These were largely patients living in rural areas of the United States with lower socioeconomic status and lower health literacy, “suggesting that we need to think about our technologies to meet patients where they are,” he said.
Despite the positive outcomes, there are “challenges to widespread adoption,” agreed NYU’s Dr. Ahn.
These challenges include the need for physician adaptation to new technologies, data security, and ensuring patient engagement and compliance with remote monitoring systems.
“Successfully addressing these challenges is crucial for optimizing the integration of ePROs into cancer care,” Dr. Ahn said.
ESMO’s invited discussant, Anne Letsch, MD, noted that “cancer therapies are getting more complex, and it’s important that patients are well informed and empowered to get together with the treatment teams throughout therapy.”
The high completion rate with ePRO symptom surveys was “quite remarkable,” said Dr. Letsch, head of the Cancer Center at the University Hospital Schleswig Holstein, Kiel, Germany.
But, Dr. Letsch said, it’s “a pity” that there was no overall survival benefit among patients in the ePRO group. Perhaps overall survival is not what matters most in this context, she said. Instead, she asked, “are other outcomes, like health-related quality of life, symptom control and treatment safety, much more important?”
Dr. Basch also questioned whether the survival differences between the two groups may have been blunted because a substantial portion of the trial was conducted during the COVID-19 pandemic, when medical resources and treatments were delayed and diverted.
Dr. Basch pointed to a 2017 study he and colleagues conducted at a single tertiary care medical center, in which patients monitored with ePROs did demonstrate an overall survival benefit, compared with usual care.
Overall, though, the study demonstrated that “symptom monitoring with ePROs is feasible during routine treatment for advanced cancers across diverse practices in the U.S.” and improved patients’ quality of life, Dr. Basch said.
Funding for the study was provided by a grant from the Patient-Centered Outcomes Research Institute. Dr. Basch has disclosed relationships with Resilience Health, Sivan Health, Navigating Cancer, and AstraZeneca. Dr. Letsch and Dr. Ahn report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ESMO CONGRESS 2023
Fasting during breast cancer chemo improves quality of life
Short-term fasting during chemotherapy enhances health-related quality of life in patients with early breast cancer, with no untoward effects, according to late-breaking research presented on day 1 of the annual meeting of the European Society for Medical Oncology.
“Strikingly,” fasting also appeared to prevent fatigue, something patients with breast cancer struggle with, Daniela A. Koppold, MD, Charité University Medicine Berlin, noted in her oral presentation.
The invited discussant, Jann Arends, MD, with Freiburg (Germany) University Medical Center, said that the findings fit “very well” with previous observations. “Short-term fasting in subjects not at risk for malnutrition is feasible, well tolerated, and appears to improve several parameters of quality of life,” Dr. Arends said.
Promising supportive therapy
The randomized controlled trial assessed the feasibility and impact of short-term fasting on health-related quality of life, compared with a plant-based, low-sugar diet (active comparator) in 106 women with early breast cancer.
The chemotherapy regimens in the trial included four cycles of doxorubicin or epirubicin, followed by taxane therapy. The interventions for both groups occurred about 2 days before chemotherapy plus 24 hours after each cycle ended (about 60-72 hours total).
For the fasting group, this meant about 200 kcal/day through vegetable juices and vegetable broths. In between chemotherapy sessions, both groups were advised to eat a more vegetarian-focused diet, but that was not mandatory.
Health-related quality of life assessments occurred at baseline and after each chemotherapy session (cycle four at day 7) as well as after 4 and 6 months.
The investigators assessed health-related quality of life using the 27-item Functional Assessment of Cancer Therapy-General (FACT-G) that measured the domains of physical, social/familial, emotional, and functional well-being.
At baseline, the two groups had similar FACT-G scores (fasting, 82.9 vs. plant diet, 81.9; P = .523). By day 7, the short-term–fasting group had a significantly better FACT-G score, compared with the plant-based–diet group (fasting, 78.3 vs. plant, 69.5; P = .021).
Although the two groups “started out from the same point, the fasting group had an incremental effect, which quite startled us,” Dr. Koppold told the audience. “Over the course of the chemotherapies, [fasting] had additive effects” and by cycle four of chemotherapy, the difference became statistically and clinically significant, indicating “much better” quality of life in the short-term–fasting group.
What was “even more striking,” said Dr. Koppold, was the impact fasting had on the secondary outcome of fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue).
“Short-term fasting not only had a protective effect on fatigue, compared to the control group, but the short-term–fasting group didn’t develop any clinically visible fatigue,” Dr. Koppold said. “They were in a normal range by cycle four while the control group developed fatigue as we would have expected.”
Importantly, she noted, fasting had no significant impact on weight. The study excluded women who were underweight or had a history of eating disorder or relevant psychopathology.
Summing up, Dr. Koppold said that short-term fasting represents a “promising” supportive therapy during breast cancer chemotherapy to enhance quality of life.
Commenting on the study, Rebecca Guterman, a registered dietitian at Perlmutter Cancer Center at NYU Langone Health, New York, said that it’s well known that a healthy diet plays “a key role during anticancer treatments.” Dietary changes can, for instance, help alleviate common chemotherapy side effects such as loss of appetite, nausea, fatigue, or diarrhea, she said.
These new findings support fasting for 60-72 hours around chemotherapy for some patients with breast cancer who may experience more rapid recovery and better quality of life, said Ms. Guterman.
However, she noted, the results should not be applied to patient populations outside of breast cancer or treatment regimens outside this study. And, she noted, “how the patient feels during the 60-72 hour fast also has to be considered.”
An individual’s “nutritional status must be considered. If a patient has poor appetite and loses weight between treatments, fasting should not be done before next treatment,” Ms. Guterman said.
The study was funded by a private sponsor (G. Müller, Munich, Germany) and a grant from the Günter and Regine KelmFoundation (Zurich). Dr. Koppold is a member of the steering board of ÄGHE e.V. (German-speaking Medical Association for Fasting and Nutrition); cofounder of the Academy for Integrative Fasting GbR; and consults for a mobile app on intermittent fasting (Fastic) as well as a company producing plant-based supplements (EVERYYIN). Dr. Arends has disclosed relationships with Baxter. Ms. Guterman has no relevant disclosures.
A version of this article first appeared on Medscape.com.
Short-term fasting during chemotherapy enhances health-related quality of life in patients with early breast cancer, with no untoward effects, according to late-breaking research presented on day 1 of the annual meeting of the European Society for Medical Oncology.
“Strikingly,” fasting also appeared to prevent fatigue, something patients with breast cancer struggle with, Daniela A. Koppold, MD, Charité University Medicine Berlin, noted in her oral presentation.
The invited discussant, Jann Arends, MD, with Freiburg (Germany) University Medical Center, said that the findings fit “very well” with previous observations. “Short-term fasting in subjects not at risk for malnutrition is feasible, well tolerated, and appears to improve several parameters of quality of life,” Dr. Arends said.
Promising supportive therapy
The randomized controlled trial assessed the feasibility and impact of short-term fasting on health-related quality of life, compared with a plant-based, low-sugar diet (active comparator) in 106 women with early breast cancer.
The chemotherapy regimens in the trial included four cycles of doxorubicin or epirubicin, followed by taxane therapy. The interventions for both groups occurred about 2 days before chemotherapy plus 24 hours after each cycle ended (about 60-72 hours total).
For the fasting group, this meant about 200 kcal/day through vegetable juices and vegetable broths. In between chemotherapy sessions, both groups were advised to eat a more vegetarian-focused diet, but that was not mandatory.
Health-related quality of life assessments occurred at baseline and after each chemotherapy session (cycle four at day 7) as well as after 4 and 6 months.
The investigators assessed health-related quality of life using the 27-item Functional Assessment of Cancer Therapy-General (FACT-G) that measured the domains of physical, social/familial, emotional, and functional well-being.
At baseline, the two groups had similar FACT-G scores (fasting, 82.9 vs. plant diet, 81.9; P = .523). By day 7, the short-term–fasting group had a significantly better FACT-G score, compared with the plant-based–diet group (fasting, 78.3 vs. plant, 69.5; P = .021).
Although the two groups “started out from the same point, the fasting group had an incremental effect, which quite startled us,” Dr. Koppold told the audience. “Over the course of the chemotherapies, [fasting] had additive effects” and by cycle four of chemotherapy, the difference became statistically and clinically significant, indicating “much better” quality of life in the short-term–fasting group.
What was “even more striking,” said Dr. Koppold, was the impact fasting had on the secondary outcome of fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue).
“Short-term fasting not only had a protective effect on fatigue, compared to the control group, but the short-term–fasting group didn’t develop any clinically visible fatigue,” Dr. Koppold said. “They were in a normal range by cycle four while the control group developed fatigue as we would have expected.”
Importantly, she noted, fasting had no significant impact on weight. The study excluded women who were underweight or had a history of eating disorder or relevant psychopathology.
Summing up, Dr. Koppold said that short-term fasting represents a “promising” supportive therapy during breast cancer chemotherapy to enhance quality of life.
Commenting on the study, Rebecca Guterman, a registered dietitian at Perlmutter Cancer Center at NYU Langone Health, New York, said that it’s well known that a healthy diet plays “a key role during anticancer treatments.” Dietary changes can, for instance, help alleviate common chemotherapy side effects such as loss of appetite, nausea, fatigue, or diarrhea, she said.
These new findings support fasting for 60-72 hours around chemotherapy for some patients with breast cancer who may experience more rapid recovery and better quality of life, said Ms. Guterman.
However, she noted, the results should not be applied to patient populations outside of breast cancer or treatment regimens outside this study. And, she noted, “how the patient feels during the 60-72 hour fast also has to be considered.”
An individual’s “nutritional status must be considered. If a patient has poor appetite and loses weight between treatments, fasting should not be done before next treatment,” Ms. Guterman said.
The study was funded by a private sponsor (G. Müller, Munich, Germany) and a grant from the Günter and Regine KelmFoundation (Zurich). Dr. Koppold is a member of the steering board of ÄGHE e.V. (German-speaking Medical Association for Fasting and Nutrition); cofounder of the Academy for Integrative Fasting GbR; and consults for a mobile app on intermittent fasting (Fastic) as well as a company producing plant-based supplements (EVERYYIN). Dr. Arends has disclosed relationships with Baxter. Ms. Guterman has no relevant disclosures.
A version of this article first appeared on Medscape.com.
Short-term fasting during chemotherapy enhances health-related quality of life in patients with early breast cancer, with no untoward effects, according to late-breaking research presented on day 1 of the annual meeting of the European Society for Medical Oncology.
“Strikingly,” fasting also appeared to prevent fatigue, something patients with breast cancer struggle with, Daniela A. Koppold, MD, Charité University Medicine Berlin, noted in her oral presentation.
The invited discussant, Jann Arends, MD, with Freiburg (Germany) University Medical Center, said that the findings fit “very well” with previous observations. “Short-term fasting in subjects not at risk for malnutrition is feasible, well tolerated, and appears to improve several parameters of quality of life,” Dr. Arends said.
Promising supportive therapy
The randomized controlled trial assessed the feasibility and impact of short-term fasting on health-related quality of life, compared with a plant-based, low-sugar diet (active comparator) in 106 women with early breast cancer.
The chemotherapy regimens in the trial included four cycles of doxorubicin or epirubicin, followed by taxane therapy. The interventions for both groups occurred about 2 days before chemotherapy plus 24 hours after each cycle ended (about 60-72 hours total).
For the fasting group, this meant about 200 kcal/day through vegetable juices and vegetable broths. In between chemotherapy sessions, both groups were advised to eat a more vegetarian-focused diet, but that was not mandatory.
Health-related quality of life assessments occurred at baseline and after each chemotherapy session (cycle four at day 7) as well as after 4 and 6 months.
The investigators assessed health-related quality of life using the 27-item Functional Assessment of Cancer Therapy-General (FACT-G) that measured the domains of physical, social/familial, emotional, and functional well-being.
At baseline, the two groups had similar FACT-G scores (fasting, 82.9 vs. plant diet, 81.9; P = .523). By day 7, the short-term–fasting group had a significantly better FACT-G score, compared with the plant-based–diet group (fasting, 78.3 vs. plant, 69.5; P = .021).
Although the two groups “started out from the same point, the fasting group had an incremental effect, which quite startled us,” Dr. Koppold told the audience. “Over the course of the chemotherapies, [fasting] had additive effects” and by cycle four of chemotherapy, the difference became statistically and clinically significant, indicating “much better” quality of life in the short-term–fasting group.
What was “even more striking,” said Dr. Koppold, was the impact fasting had on the secondary outcome of fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue).
“Short-term fasting not only had a protective effect on fatigue, compared to the control group, but the short-term–fasting group didn’t develop any clinically visible fatigue,” Dr. Koppold said. “They were in a normal range by cycle four while the control group developed fatigue as we would have expected.”
Importantly, she noted, fasting had no significant impact on weight. The study excluded women who were underweight or had a history of eating disorder or relevant psychopathology.
Summing up, Dr. Koppold said that short-term fasting represents a “promising” supportive therapy during breast cancer chemotherapy to enhance quality of life.
Commenting on the study, Rebecca Guterman, a registered dietitian at Perlmutter Cancer Center at NYU Langone Health, New York, said that it’s well known that a healthy diet plays “a key role during anticancer treatments.” Dietary changes can, for instance, help alleviate common chemotherapy side effects such as loss of appetite, nausea, fatigue, or diarrhea, she said.
These new findings support fasting for 60-72 hours around chemotherapy for some patients with breast cancer who may experience more rapid recovery and better quality of life, said Ms. Guterman.
However, she noted, the results should not be applied to patient populations outside of breast cancer or treatment regimens outside this study. And, she noted, “how the patient feels during the 60-72 hour fast also has to be considered.”
An individual’s “nutritional status must be considered. If a patient has poor appetite and loses weight between treatments, fasting should not be done before next treatment,” Ms. Guterman said.
The study was funded by a private sponsor (G. Müller, Munich, Germany) and a grant from the Günter and Regine KelmFoundation (Zurich). Dr. Koppold is a member of the steering board of ÄGHE e.V. (German-speaking Medical Association for Fasting and Nutrition); cofounder of the Academy for Integrative Fasting GbR; and consults for a mobile app on intermittent fasting (Fastic) as well as a company producing plant-based supplements (EVERYYIN). Dr. Arends has disclosed relationships with Baxter. Ms. Guterman has no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM ESMO CONGRESS 2023
Does first-line pembrolizumab add-on improve PFS in high-risk cervical cancer?
Pembrolizumab (Keytruda) improved progression-free survival when added to standard concurrent chemoradiotherapy in the first-line for newly diagnosed, locally advanced cervical cancer in the KEYNOTE-A18 trial, according to a study presented at the annual meeting of the European Society for Medical Oncology.
The study “supports pembrolizumab plus chemoradiotherapy as a new potential standard of care” in the first-line setting for high-risk, locally advanced cervical cancer, said lead investigator Domenica Lorusso, MD, PhD, a gynecologic oncologist at the Catholic University of Rome, who reported the findings at the meeting.
The results of the trial “are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years,” she said in a press release from pembrolizumab maker Merck.
Trial data are under review at the Food and Drug Administration as part of Merck’s application for a first-line indication for pembrolizumab added to concurrent chemoradiotherapy in newly diagnosed patients with high-risk, locally advanced cervical cancer; the agency’s decision is expected in Jan. 2024.
Pembrolizumab already carries indications for persistent, recurrent, or metastatic cervical cancer.
Women in the trial were new to treatment and had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease; almost 85% had squamous cell cancer. About half the women were White; 28% were Asian, and about 2% were Black. About 5% of subjects were PD-L1 negative.
Overall, 529 women were randomized to 200 mg pembrolizumab every 3 weeks for five cycles with concurrent chemoradiotherapy (CCRT); they then received pembrolizumab 400 mg every 6 weeks for 15 cycles; 531 were randomized to placebo with CCRT, followed by 15 6-week placebo cycles.
CCRT included five cycles of cisplatin 40 mg/m2 every week for 5-6 weeks plus external beam radiotherapy followed by brachytherapy.
Two-year progression-free survival was 57.3% with placebo but 67.8% with pembrolizumab add-on, a 30% reduction in the risk of progression (P = .002).
On subgroup analysis, pembrolizumab’s PFS benefit was not statistically significant for White women (hazard ratio, 0.83; 95% confidence interval, 0.59-1.15) and women with stage 1B2 to 2B disease (HR, 0.91; 95% CI, 0.63-1.31), among others.
Although OS is not yet mature, 80.8% of placebo subjects but 87.2% of pembrolizumab women were alive at 2 years, a 27% drop in the risk of death (95% CI, 0.49-1.07).
At the meeting, Bradley Monk, MD, a gynecologic oncologist at the University of Arizona, Phoenix, who was also the study discussant, noted that “the magnitude of the benefit here is difficult to interpret because 55% of the patients [were] still on treatment” in the interim analysis, but the difference “is substantial enough for us to have confidence.”
Rates of grade 3/4 treatment-related adverse events were 60.6% in the placebo group and 67% with pembrolizumab, with anemia, nausea, and diarrhea the most common.
Grade 3/4 immune-mediated adverse events occurred in 1.1% of placebo and 4.2% of pembrolizumab subjects; hypothyroidism was the most common with pembrolizumab.
Protocol amendments in the trial included a change from PFS assessment by blinded, independent, central review to investigator assessment.
In the press release, Dr. Monk, said the results “demonstrate that, by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”
The study was funded by Merck, maker of pembrolizumab. Investigators reported wide-ranging ties to the company, including Dr. Lorusso, who reported honoraria from Merck as well as ties to other companies. Dr. Monk also had deep industry ties, including being a speaker and consultant for Merck and reporting honoraria from the company.
Pembrolizumab (Keytruda) improved progression-free survival when added to standard concurrent chemoradiotherapy in the first-line for newly diagnosed, locally advanced cervical cancer in the KEYNOTE-A18 trial, according to a study presented at the annual meeting of the European Society for Medical Oncology.
The study “supports pembrolizumab plus chemoradiotherapy as a new potential standard of care” in the first-line setting for high-risk, locally advanced cervical cancer, said lead investigator Domenica Lorusso, MD, PhD, a gynecologic oncologist at the Catholic University of Rome, who reported the findings at the meeting.
The results of the trial “are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years,” she said in a press release from pembrolizumab maker Merck.
Trial data are under review at the Food and Drug Administration as part of Merck’s application for a first-line indication for pembrolizumab added to concurrent chemoradiotherapy in newly diagnosed patients with high-risk, locally advanced cervical cancer; the agency’s decision is expected in Jan. 2024.
Pembrolizumab already carries indications for persistent, recurrent, or metastatic cervical cancer.
Women in the trial were new to treatment and had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease; almost 85% had squamous cell cancer. About half the women were White; 28% were Asian, and about 2% were Black. About 5% of subjects were PD-L1 negative.
Overall, 529 women were randomized to 200 mg pembrolizumab every 3 weeks for five cycles with concurrent chemoradiotherapy (CCRT); they then received pembrolizumab 400 mg every 6 weeks for 15 cycles; 531 were randomized to placebo with CCRT, followed by 15 6-week placebo cycles.
CCRT included five cycles of cisplatin 40 mg/m2 every week for 5-6 weeks plus external beam radiotherapy followed by brachytherapy.
Two-year progression-free survival was 57.3% with placebo but 67.8% with pembrolizumab add-on, a 30% reduction in the risk of progression (P = .002).
On subgroup analysis, pembrolizumab’s PFS benefit was not statistically significant for White women (hazard ratio, 0.83; 95% confidence interval, 0.59-1.15) and women with stage 1B2 to 2B disease (HR, 0.91; 95% CI, 0.63-1.31), among others.
Although OS is not yet mature, 80.8% of placebo subjects but 87.2% of pembrolizumab women were alive at 2 years, a 27% drop in the risk of death (95% CI, 0.49-1.07).
At the meeting, Bradley Monk, MD, a gynecologic oncologist at the University of Arizona, Phoenix, who was also the study discussant, noted that “the magnitude of the benefit here is difficult to interpret because 55% of the patients [were] still on treatment” in the interim analysis, but the difference “is substantial enough for us to have confidence.”
Rates of grade 3/4 treatment-related adverse events were 60.6% in the placebo group and 67% with pembrolizumab, with anemia, nausea, and diarrhea the most common.
Grade 3/4 immune-mediated adverse events occurred in 1.1% of placebo and 4.2% of pembrolizumab subjects; hypothyroidism was the most common with pembrolizumab.
Protocol amendments in the trial included a change from PFS assessment by blinded, independent, central review to investigator assessment.
In the press release, Dr. Monk, said the results “demonstrate that, by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”
The study was funded by Merck, maker of pembrolizumab. Investigators reported wide-ranging ties to the company, including Dr. Lorusso, who reported honoraria from Merck as well as ties to other companies. Dr. Monk also had deep industry ties, including being a speaker and consultant for Merck and reporting honoraria from the company.
Pembrolizumab (Keytruda) improved progression-free survival when added to standard concurrent chemoradiotherapy in the first-line for newly diagnosed, locally advanced cervical cancer in the KEYNOTE-A18 trial, according to a study presented at the annual meeting of the European Society for Medical Oncology.
The study “supports pembrolizumab plus chemoradiotherapy as a new potential standard of care” in the first-line setting for high-risk, locally advanced cervical cancer, said lead investigator Domenica Lorusso, MD, PhD, a gynecologic oncologist at the Catholic University of Rome, who reported the findings at the meeting.
The results of the trial “are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years,” she said in a press release from pembrolizumab maker Merck.
Trial data are under review at the Food and Drug Administration as part of Merck’s application for a first-line indication for pembrolizumab added to concurrent chemoradiotherapy in newly diagnosed patients with high-risk, locally advanced cervical cancer; the agency’s decision is expected in Jan. 2024.
Pembrolizumab already carries indications for persistent, recurrent, or metastatic cervical cancer.
Women in the trial were new to treatment and had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease; almost 85% had squamous cell cancer. About half the women were White; 28% were Asian, and about 2% were Black. About 5% of subjects were PD-L1 negative.
Overall, 529 women were randomized to 200 mg pembrolizumab every 3 weeks for five cycles with concurrent chemoradiotherapy (CCRT); they then received pembrolizumab 400 mg every 6 weeks for 15 cycles; 531 were randomized to placebo with CCRT, followed by 15 6-week placebo cycles.
CCRT included five cycles of cisplatin 40 mg/m2 every week for 5-6 weeks plus external beam radiotherapy followed by brachytherapy.
Two-year progression-free survival was 57.3% with placebo but 67.8% with pembrolizumab add-on, a 30% reduction in the risk of progression (P = .002).
On subgroup analysis, pembrolizumab’s PFS benefit was not statistically significant for White women (hazard ratio, 0.83; 95% confidence interval, 0.59-1.15) and women with stage 1B2 to 2B disease (HR, 0.91; 95% CI, 0.63-1.31), among others.
Although OS is not yet mature, 80.8% of placebo subjects but 87.2% of pembrolizumab women were alive at 2 years, a 27% drop in the risk of death (95% CI, 0.49-1.07).
At the meeting, Bradley Monk, MD, a gynecologic oncologist at the University of Arizona, Phoenix, who was also the study discussant, noted that “the magnitude of the benefit here is difficult to interpret because 55% of the patients [were] still on treatment” in the interim analysis, but the difference “is substantial enough for us to have confidence.”
Rates of grade 3/4 treatment-related adverse events were 60.6% in the placebo group and 67% with pembrolizumab, with anemia, nausea, and diarrhea the most common.
Grade 3/4 immune-mediated adverse events occurred in 1.1% of placebo and 4.2% of pembrolizumab subjects; hypothyroidism was the most common with pembrolizumab.
Protocol amendments in the trial included a change from PFS assessment by blinded, independent, central review to investigator assessment.
In the press release, Dr. Monk, said the results “demonstrate that, by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”
The study was funded by Merck, maker of pembrolizumab. Investigators reported wide-ranging ties to the company, including Dr. Lorusso, who reported honoraria from Merck as well as ties to other companies. Dr. Monk also had deep industry ties, including being a speaker and consultant for Merck and reporting honoraria from the company.
FROM ESMO CONGRESS 2023
Can some patients with esophageal cancer avoid surgery?
MADRID – , findings from the Dutch SANO trial suggest.
After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery.
Overall, patients who underwent active surveillance had “noninferior overall survival at 2 years,” said Berend J. Van der Wilk, PhD candidate, Erasmus University, Rotterdam, the Netherlands, who presented the findings at the annual meeting of the European Society for Medical Oncology.
Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery, Mr. Van der Wilk said.
Magnus Nilsson, MD, PhD, the invited discussant, who was not involved in the research, said performing such a conceptually important and complex trial was a “huge achievement.” However, Dr. Nilsson highlighted some “major concerns” with the trial design, which could affect the generalizability of the findings.
Avoiding surgery?
Esophagectomy remains the “keystone of curative treatment for esophageal cancer,” Mr. Van der Wilks explained. However, this operation is a “major surgical procedure” that comes with a mortality rate of up to 5%. As many as 59% of patients experience complications.
The CROSS trial, which included more than 360 patients with esophageal or esophagogastric junction cancer, found that neoadjuvant chemoradiotherapy improved survival among patients with potentially curable disease; 29% of patients achieved a pathologic complete response.
Mr. Van der Wilk said those strong outcomes create some uncertainty as to whether all patients need standard surgery after chemoradiotherapy.
In other words, Mr. Van der Wilk asked, “Should we be willing to follow an active surveillance, organ-sparing strategy for patients with a clinical response?”
An active surveillance strategy, he said, would require frequent evaluations of the patient’s clinical response. Surgery would be performed only in cases of proven residual tumor in which there were no distant metastases. The potential pitfall of an active surveillance approach is that patients may develop unresectable tumor regrowths, “possibly resulting in inferior overall survival.”
To compare active surveillance with standard surgery, the team conducted a phase 3 noninferiority stepped-wedge cluster randomized trial involving patients with locally advanced esophageal cancer.
Patients received neoadjuvant chemoradiotherapy with carboplatin and paclitaxel for 5 weeks. Concurrent radiotherapy was delivered at 41.4 Gy in 23 fractions, 5 days per week, as in the CROSS trial.
More than 300 patients who achieved a complete clinical response 12 weeks after completing chemoradiotherapy were randomly assigned to undergo standard surgery or active surveillance. Surgery was performed for those with subsequent tumor regrowth.
Overall, 198 patients underwent active surveillance, and 111 patients underwent standard surgery. The two groups were well balanced in terms of median age, sex distribution, proportion of adenocarcinomas, and World Health Organization performance scores. At the last patient assessment, on July 6, 2023, the median follow-up was 38 months.
Overall, 101 of 111 patients in the standard surgery arm and 83 of 198 (42%) in the active surveillance group had surgery. The time to surgery in the active surveillance arm was 5.9 months, compared with 0.7 months with standard surgery. For both groups, the R0 resection rate was 98%.
Mr. Van der Wilk reported no significant difference in overall survival between the active surveillance and standard surgery groups (hazard ratio for death, 1.14; 95% confidence interval, 0.74-0.78; P = .55). Overall survival in the active surveillance group was noninferior to that in the standard surgery group at 2 years. Noninferiority was defined as an overall survival difference between the two arms of less than 15%.
Mr. Van der Wilk also reported no significant difference in disease-free survival between the active surveillance and the standard surgery groups – 35 months with active surveillance, and 49 months with surgery (HR, 1.35; P = .15). At 30 months following neoadjuvant chemoradiotherapy, 43% of patients on active surveillance and 34% with standard surgery developed distant metastases, but the difference was not significant (odds ratio, 1.45; P = .18).
Among the patients in the active surveillance arm who had a complete response, 35% (n = 69) had a persistent clinical response, while 17% (33 patients) developed distant metastases, and 48% (n = 96) experienced locoregional growth. The postoperative 90-day mortality was 4% in the active surveillance group and 5% in the surgery group.
Health-related quality of life was significantly better at 6 and 9 months in the active surveillance group, Mr. Van der Wilk noted.
Although Dr. Nilsson, the invited discussant, highlighted the importance of the trial, he also expressed concern over the trial design.
The intention-to-treat analysis was contaminated, Dr. Nilsson said, because the trial design allowed for one crossover, but patients in the trial crossed over at two time points – 35 patients who were initially assigned to standard surgery crossed over to the active surveillance arm, and later, seven patients from a preSANO trial were included in the active surveillance arm.
Dr. Nilsson also expressed concern about mixing squamous cell carcinoma and adenocarcinoma histologies in the study. If the authors had distinguished patients with squamous cell carcinoma and those with adenocarcinoma in each arm, there may have a difference in overall survival, given that squamous cell carcinoma is much easier to treat.
The study also included some patients who did not have a complete clinical response and whose surgery was delayed by more than 10 weeks – a practice that, Dr. Nilsson said, “does not really seem to be safe.” A recent study led by Dr. Nilsson found that delaying surgery for 10-12 weeks in comparison with 4-6 weeks did not improve histologic complete response or other pathologic endpoints and may have led to worse survival.
“I’m afraid it’s not really certain that it’s safe to prolong surgery more than 10 weeks or longer in the clinical noncomplete responders,” said Dr. Nilsson, from the department of clinical science, intervention, and technology, Karolinska Institute, Stockholm.
Overall, he said, the study “suggests that survival may be noninferior” among patients on active surveillance in comparison with those who undergo immediate surgery, but the findings need to be confirmed in a trial with a more stringent intention-to-treat analysis that is stratified by histologic subtypes.
The study was funded by the Dutch Cancer Society and the Netherlands Organisation for Health Research and Development (ZonMw). Mr. Van der Wilk has disclosed no relevant financial relationships. Dr. Nilsson has relationships with Medtronic, Intuitive Surgical, Bristol-Myers Squibb, and Merck Sharp & Dohme, from which he received no personal financial benefit.
A version of this article first appeared on Medscape.com.
MADRID – , findings from the Dutch SANO trial suggest.
After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery.
Overall, patients who underwent active surveillance had “noninferior overall survival at 2 years,” said Berend J. Van der Wilk, PhD candidate, Erasmus University, Rotterdam, the Netherlands, who presented the findings at the annual meeting of the European Society for Medical Oncology.
Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery, Mr. Van der Wilk said.
Magnus Nilsson, MD, PhD, the invited discussant, who was not involved in the research, said performing such a conceptually important and complex trial was a “huge achievement.” However, Dr. Nilsson highlighted some “major concerns” with the trial design, which could affect the generalizability of the findings.
Avoiding surgery?
Esophagectomy remains the “keystone of curative treatment for esophageal cancer,” Mr. Van der Wilks explained. However, this operation is a “major surgical procedure” that comes with a mortality rate of up to 5%. As many as 59% of patients experience complications.
The CROSS trial, which included more than 360 patients with esophageal or esophagogastric junction cancer, found that neoadjuvant chemoradiotherapy improved survival among patients with potentially curable disease; 29% of patients achieved a pathologic complete response.
Mr. Van der Wilk said those strong outcomes create some uncertainty as to whether all patients need standard surgery after chemoradiotherapy.
In other words, Mr. Van der Wilk asked, “Should we be willing to follow an active surveillance, organ-sparing strategy for patients with a clinical response?”
An active surveillance strategy, he said, would require frequent evaluations of the patient’s clinical response. Surgery would be performed only in cases of proven residual tumor in which there were no distant metastases. The potential pitfall of an active surveillance approach is that patients may develop unresectable tumor regrowths, “possibly resulting in inferior overall survival.”
To compare active surveillance with standard surgery, the team conducted a phase 3 noninferiority stepped-wedge cluster randomized trial involving patients with locally advanced esophageal cancer.
Patients received neoadjuvant chemoradiotherapy with carboplatin and paclitaxel for 5 weeks. Concurrent radiotherapy was delivered at 41.4 Gy in 23 fractions, 5 days per week, as in the CROSS trial.
More than 300 patients who achieved a complete clinical response 12 weeks after completing chemoradiotherapy were randomly assigned to undergo standard surgery or active surveillance. Surgery was performed for those with subsequent tumor regrowth.
Overall, 198 patients underwent active surveillance, and 111 patients underwent standard surgery. The two groups were well balanced in terms of median age, sex distribution, proportion of adenocarcinomas, and World Health Organization performance scores. At the last patient assessment, on July 6, 2023, the median follow-up was 38 months.
Overall, 101 of 111 patients in the standard surgery arm and 83 of 198 (42%) in the active surveillance group had surgery. The time to surgery in the active surveillance arm was 5.9 months, compared with 0.7 months with standard surgery. For both groups, the R0 resection rate was 98%.
Mr. Van der Wilk reported no significant difference in overall survival between the active surveillance and standard surgery groups (hazard ratio for death, 1.14; 95% confidence interval, 0.74-0.78; P = .55). Overall survival in the active surveillance group was noninferior to that in the standard surgery group at 2 years. Noninferiority was defined as an overall survival difference between the two arms of less than 15%.
Mr. Van der Wilk also reported no significant difference in disease-free survival between the active surveillance and the standard surgery groups – 35 months with active surveillance, and 49 months with surgery (HR, 1.35; P = .15). At 30 months following neoadjuvant chemoradiotherapy, 43% of patients on active surveillance and 34% with standard surgery developed distant metastases, but the difference was not significant (odds ratio, 1.45; P = .18).
Among the patients in the active surveillance arm who had a complete response, 35% (n = 69) had a persistent clinical response, while 17% (33 patients) developed distant metastases, and 48% (n = 96) experienced locoregional growth. The postoperative 90-day mortality was 4% in the active surveillance group and 5% in the surgery group.
Health-related quality of life was significantly better at 6 and 9 months in the active surveillance group, Mr. Van der Wilk noted.
Although Dr. Nilsson, the invited discussant, highlighted the importance of the trial, he also expressed concern over the trial design.
The intention-to-treat analysis was contaminated, Dr. Nilsson said, because the trial design allowed for one crossover, but patients in the trial crossed over at two time points – 35 patients who were initially assigned to standard surgery crossed over to the active surveillance arm, and later, seven patients from a preSANO trial were included in the active surveillance arm.
Dr. Nilsson also expressed concern about mixing squamous cell carcinoma and adenocarcinoma histologies in the study. If the authors had distinguished patients with squamous cell carcinoma and those with adenocarcinoma in each arm, there may have a difference in overall survival, given that squamous cell carcinoma is much easier to treat.
The study also included some patients who did not have a complete clinical response and whose surgery was delayed by more than 10 weeks – a practice that, Dr. Nilsson said, “does not really seem to be safe.” A recent study led by Dr. Nilsson found that delaying surgery for 10-12 weeks in comparison with 4-6 weeks did not improve histologic complete response or other pathologic endpoints and may have led to worse survival.
“I’m afraid it’s not really certain that it’s safe to prolong surgery more than 10 weeks or longer in the clinical noncomplete responders,” said Dr. Nilsson, from the department of clinical science, intervention, and technology, Karolinska Institute, Stockholm.
Overall, he said, the study “suggests that survival may be noninferior” among patients on active surveillance in comparison with those who undergo immediate surgery, but the findings need to be confirmed in a trial with a more stringent intention-to-treat analysis that is stratified by histologic subtypes.
The study was funded by the Dutch Cancer Society and the Netherlands Organisation for Health Research and Development (ZonMw). Mr. Van der Wilk has disclosed no relevant financial relationships. Dr. Nilsson has relationships with Medtronic, Intuitive Surgical, Bristol-Myers Squibb, and Merck Sharp & Dohme, from which he received no personal financial benefit.
A version of this article first appeared on Medscape.com.
MADRID – , findings from the Dutch SANO trial suggest.
After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery.
Overall, patients who underwent active surveillance had “noninferior overall survival at 2 years,” said Berend J. Van der Wilk, PhD candidate, Erasmus University, Rotterdam, the Netherlands, who presented the findings at the annual meeting of the European Society for Medical Oncology.
Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery, Mr. Van der Wilk said.
Magnus Nilsson, MD, PhD, the invited discussant, who was not involved in the research, said performing such a conceptually important and complex trial was a “huge achievement.” However, Dr. Nilsson highlighted some “major concerns” with the trial design, which could affect the generalizability of the findings.
Avoiding surgery?
Esophagectomy remains the “keystone of curative treatment for esophageal cancer,” Mr. Van der Wilks explained. However, this operation is a “major surgical procedure” that comes with a mortality rate of up to 5%. As many as 59% of patients experience complications.
The CROSS trial, which included more than 360 patients with esophageal or esophagogastric junction cancer, found that neoadjuvant chemoradiotherapy improved survival among patients with potentially curable disease; 29% of patients achieved a pathologic complete response.
Mr. Van der Wilk said those strong outcomes create some uncertainty as to whether all patients need standard surgery after chemoradiotherapy.
In other words, Mr. Van der Wilk asked, “Should we be willing to follow an active surveillance, organ-sparing strategy for patients with a clinical response?”
An active surveillance strategy, he said, would require frequent evaluations of the patient’s clinical response. Surgery would be performed only in cases of proven residual tumor in which there were no distant metastases. The potential pitfall of an active surveillance approach is that patients may develop unresectable tumor regrowths, “possibly resulting in inferior overall survival.”
To compare active surveillance with standard surgery, the team conducted a phase 3 noninferiority stepped-wedge cluster randomized trial involving patients with locally advanced esophageal cancer.
Patients received neoadjuvant chemoradiotherapy with carboplatin and paclitaxel for 5 weeks. Concurrent radiotherapy was delivered at 41.4 Gy in 23 fractions, 5 days per week, as in the CROSS trial.
More than 300 patients who achieved a complete clinical response 12 weeks after completing chemoradiotherapy were randomly assigned to undergo standard surgery or active surveillance. Surgery was performed for those with subsequent tumor regrowth.
Overall, 198 patients underwent active surveillance, and 111 patients underwent standard surgery. The two groups were well balanced in terms of median age, sex distribution, proportion of adenocarcinomas, and World Health Organization performance scores. At the last patient assessment, on July 6, 2023, the median follow-up was 38 months.
Overall, 101 of 111 patients in the standard surgery arm and 83 of 198 (42%) in the active surveillance group had surgery. The time to surgery in the active surveillance arm was 5.9 months, compared with 0.7 months with standard surgery. For both groups, the R0 resection rate was 98%.
Mr. Van der Wilk reported no significant difference in overall survival between the active surveillance and standard surgery groups (hazard ratio for death, 1.14; 95% confidence interval, 0.74-0.78; P = .55). Overall survival in the active surveillance group was noninferior to that in the standard surgery group at 2 years. Noninferiority was defined as an overall survival difference between the two arms of less than 15%.
Mr. Van der Wilk also reported no significant difference in disease-free survival between the active surveillance and the standard surgery groups – 35 months with active surveillance, and 49 months with surgery (HR, 1.35; P = .15). At 30 months following neoadjuvant chemoradiotherapy, 43% of patients on active surveillance and 34% with standard surgery developed distant metastases, but the difference was not significant (odds ratio, 1.45; P = .18).
Among the patients in the active surveillance arm who had a complete response, 35% (n = 69) had a persistent clinical response, while 17% (33 patients) developed distant metastases, and 48% (n = 96) experienced locoregional growth. The postoperative 90-day mortality was 4% in the active surveillance group and 5% in the surgery group.
Health-related quality of life was significantly better at 6 and 9 months in the active surveillance group, Mr. Van der Wilk noted.
Although Dr. Nilsson, the invited discussant, highlighted the importance of the trial, he also expressed concern over the trial design.
The intention-to-treat analysis was contaminated, Dr. Nilsson said, because the trial design allowed for one crossover, but patients in the trial crossed over at two time points – 35 patients who were initially assigned to standard surgery crossed over to the active surveillance arm, and later, seven patients from a preSANO trial were included in the active surveillance arm.
Dr. Nilsson also expressed concern about mixing squamous cell carcinoma and adenocarcinoma histologies in the study. If the authors had distinguished patients with squamous cell carcinoma and those with adenocarcinoma in each arm, there may have a difference in overall survival, given that squamous cell carcinoma is much easier to treat.
The study also included some patients who did not have a complete clinical response and whose surgery was delayed by more than 10 weeks – a practice that, Dr. Nilsson said, “does not really seem to be safe.” A recent study led by Dr. Nilsson found that delaying surgery for 10-12 weeks in comparison with 4-6 weeks did not improve histologic complete response or other pathologic endpoints and may have led to worse survival.
“I’m afraid it’s not really certain that it’s safe to prolong surgery more than 10 weeks or longer in the clinical noncomplete responders,” said Dr. Nilsson, from the department of clinical science, intervention, and technology, Karolinska Institute, Stockholm.
Overall, he said, the study “suggests that survival may be noninferior” among patients on active surveillance in comparison with those who undergo immediate surgery, but the findings need to be confirmed in a trial with a more stringent intention-to-treat analysis that is stratified by histologic subtypes.
The study was funded by the Dutch Cancer Society and the Netherlands Organisation for Health Research and Development (ZonMw). Mr. Van der Wilk has disclosed no relevant financial relationships. Dr. Nilsson has relationships with Medtronic, Intuitive Surgical, Bristol-Myers Squibb, and Merck Sharp & Dohme, from which he received no personal financial benefit.
A version of this article first appeared on Medscape.com.
Adjuvant abemaciclib-ET combo shows long-term benefit in high-risk early breast cancer
MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.
Results of a planned 5-year efficacy analysis of the monarchE trial showed that , reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.
“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
High recurrence risk
Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.
The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.
A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.
An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.
As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.
At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.
In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.
All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
Results
At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).
The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).
As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).
There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.
The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.
In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
Changing road map
Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”
To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.
In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.
To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.
“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.
Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.
The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.
MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.
Results of a planned 5-year efficacy analysis of the monarchE trial showed that , reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.
“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
High recurrence risk
Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.
The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.
A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.
An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.
As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.
At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.
In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.
All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
Results
At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).
The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).
As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).
There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.
The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.
In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
Changing road map
Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”
To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.
In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.
To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.
“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.
Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.
The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.
MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.
Results of a planned 5-year efficacy analysis of the monarchE trial showed that , reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.
“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
High recurrence risk
Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.
The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.
A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.
An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.
As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.
At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.
In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.
All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
Results
At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).
The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).
As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).
There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.
The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.
In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
Changing road map
Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”
To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.
In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.
To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.
“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.
Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.
The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.
FROM ESMO 2023