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Lead investigator Claudio Vernieri, MD, PhD, presented these findings of the PALMARES-2 study at the annual meeting of the American Society of Clinical Oncology.
“Along with different safety profiles, drug-drug interactions, and costs of the three available CDK4/6 inhibitor molecules, our efficacy data may help clinicians and patients in choosing the most appropriate CDK4/6 inhibitor in specific clinical contexts,” Dr. Vernieri, who is from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said during the meeting.
CDK4/6 inhibitors combined with ET, are the standard of care as first line treatment for this population, noted Dr. Vernieri. However, their efficacy has never been directly compared in a large clinical trial.
“Since these compounds have different pharmacokinetics, pharmacodynamics, safety profiles, costs, and drug-drug interactions, identifying which of the three CDK4/6 inhibitors may be more effective in specific clinical contexts is a highly clinically relevant issue,” he said. “Real-world data represent a key source to perform direct comparisons.”
The PALMARES-2 study was a retrospective, multicenter, population-based study, in 18 Italian cancer centers. Its two main objectives were to compare the real-world PFS of abemaciclib versus ribociclib versus palbociclib, in combination with ET, in the whole study cohort, as well as in various subgroups including patients with endocrine-resistant disease, luminal B-like disease, or in premenopausal women.
A total of 1,850 patients (median age, 63 years) were enrolled between January 1, 2016 and September 1, 2023, with 750 (40.6%) receiving palbociclib, and 676 (36.5%) and 424 (22.9%) receiving ribociclib and abemaciclib, respectively.
Baseline imbalance
Importantly, there were significant imbalances in baseline characteristics of the patients, with those receiving abemaciclib being more likely to have endocrine-resistant disease, low progesterone receptor expression, and liver metastasis, and less likely to have de novo metastatic disease, compared with other patients, said Dr. Vernieri.
The analysis showed that across the entire cohort, the median real-world PFS and overall survival (OS) were 34.7 months and 66.6 months, respectively, by a January 1, 2024, data cutoff date. “I believe that the overall survival data are still immature to make a definitive conclusion,” he commented, noting that at enrollment only about half of patients had undergone disease progression, and at the close of the study only about 25% had died.
After adjusting for clinically relevant patient- and tumor-related covariates, “we found that both abemaciclib and ribociclib were more effective than palbociclib, whereas we did not find statistically significant differences between abemaciclib and ribociclib,” he reported.
Specifically, the adjusted hazard ratio (aHR) for PFS was 0.71 for abemaciclib versus palbociclib (95% CI, 0.56-0.90; P = .005), 0.81 for ribociclib versus palbociclib (95% CI, 0.65-0.99; P = .048), and 0.91 for abemaciclib versus ribociclib (95% CI, 0.70-1.19; P = .505).
“Regarding subgroup analysis, we found that abemaciclib and ribociclib were more effective than palbociclib in patients with endocrine-resistant or luminal B-like disease, as well as in premenopausal women. Abemaciclib was superior to palbociclib in patients with poorer ECOG [Eastern Cooperative Oncology Group] performance status and to both palbociclib and ribociclib in patients with de novo metastatic disease. Both ribociclib and abemaciclib showed a trend toward higher efficacy in patients with liver metastases. However, this difference only reached statistical significance in patients treated with ribociclib. And finally, the three CDK4/6 inhibitors were similarly effective in patients who were older or at bone-only disease,” he concluded.
Justifying adjustment
Speaking during the audience question period Giuseppe Del Priore, MD, from Morehouse School of Medicine in Atlanta, Georgia, said he preferred unadjusted results when examining real-world data, “because that’s the benefit,” and he questioned why the researchers had adjusted their numbers.
Dr. Vernieri explained that the adjustments were made to account for the important imbalances in the baseline characteristics of the patients.
“When we plotted unadjusted curves, we did not find statistically significant differences between these three drugs, only a trend toward the direction that I showed you today,” he said. “However, as you saw from the tables showing the characteristics of patients, there were important imbalances in terms of important prognostic factors in the three patient cohorts. So, I think that, for this kind of data and based on this level of imbalance, adjustment is necessary.
“To reinforce our conclusions, what we did was also to perform a propensity score match–based analysis,” Dr. Vernieri continued. “I did not have the time to show the results today, but these data were fully in line with the study conclusions. And we also performed a backward selection of variables. So, we basically selected variables more likely to be associated with patient prognosis. And also those models confirm the study conclusion. So I think the conclusions are quite solid.”
Dr. Del Priore, an adjunct professor of obstetrics and gynecology with a specialty in oncology, on the other hand, said he was not convinced that any of the drugs might be better or worse in the actual population treated.
“I still maintain that unadjusted real-world data should be presented and then only a limited adjusted analysis performed using the most unbalanced variables,” he said. “To do more elaborate adjustments may falsely imply a difference in drug choice and outcomes which never should be the conclusion with observational studies. Instead, the conclusions should be that, with typical use, the following similarities in PFS and OS were observed. Then point out how drug choice and important prognostic variables might be linked, thus limiting the generalizable conclusions even further.
“I would conclude that prospective studies should balance for the variables used in the PALMARES-2 analyses, which actually may have been chosen for adjustment post hoc,” Dr. Del Priore said.
The study was funded by the Italian Association for Cancer Research, the European Research Council, the Ministero della Salute, the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori, Giuliani’s Foundation and Roche. Dr. Vernieri reported consulting or advisory roles with Daiichi Sankyo/Astra Zeneca, Novartis, and Pfizer; speakers’ bureau roles with Accademia Nazionale Di Medicina (ACCMED), Istituto Gentili, Lilly and Novartis; and research funding from Roche. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
Lead investigator Claudio Vernieri, MD, PhD, presented these findings of the PALMARES-2 study at the annual meeting of the American Society of Clinical Oncology.
“Along with different safety profiles, drug-drug interactions, and costs of the three available CDK4/6 inhibitor molecules, our efficacy data may help clinicians and patients in choosing the most appropriate CDK4/6 inhibitor in specific clinical contexts,” Dr. Vernieri, who is from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said during the meeting.
CDK4/6 inhibitors combined with ET, are the standard of care as first line treatment for this population, noted Dr. Vernieri. However, their efficacy has never been directly compared in a large clinical trial.
“Since these compounds have different pharmacokinetics, pharmacodynamics, safety profiles, costs, and drug-drug interactions, identifying which of the three CDK4/6 inhibitors may be more effective in specific clinical contexts is a highly clinically relevant issue,” he said. “Real-world data represent a key source to perform direct comparisons.”
The PALMARES-2 study was a retrospective, multicenter, population-based study, in 18 Italian cancer centers. Its two main objectives were to compare the real-world PFS of abemaciclib versus ribociclib versus palbociclib, in combination with ET, in the whole study cohort, as well as in various subgroups including patients with endocrine-resistant disease, luminal B-like disease, or in premenopausal women.
A total of 1,850 patients (median age, 63 years) were enrolled between January 1, 2016 and September 1, 2023, with 750 (40.6%) receiving palbociclib, and 676 (36.5%) and 424 (22.9%) receiving ribociclib and abemaciclib, respectively.
Baseline imbalance
Importantly, there were significant imbalances in baseline characteristics of the patients, with those receiving abemaciclib being more likely to have endocrine-resistant disease, low progesterone receptor expression, and liver metastasis, and less likely to have de novo metastatic disease, compared with other patients, said Dr. Vernieri.
The analysis showed that across the entire cohort, the median real-world PFS and overall survival (OS) were 34.7 months and 66.6 months, respectively, by a January 1, 2024, data cutoff date. “I believe that the overall survival data are still immature to make a definitive conclusion,” he commented, noting that at enrollment only about half of patients had undergone disease progression, and at the close of the study only about 25% had died.
After adjusting for clinically relevant patient- and tumor-related covariates, “we found that both abemaciclib and ribociclib were more effective than palbociclib, whereas we did not find statistically significant differences between abemaciclib and ribociclib,” he reported.
Specifically, the adjusted hazard ratio (aHR) for PFS was 0.71 for abemaciclib versus palbociclib (95% CI, 0.56-0.90; P = .005), 0.81 for ribociclib versus palbociclib (95% CI, 0.65-0.99; P = .048), and 0.91 for abemaciclib versus ribociclib (95% CI, 0.70-1.19; P = .505).
“Regarding subgroup analysis, we found that abemaciclib and ribociclib were more effective than palbociclib in patients with endocrine-resistant or luminal B-like disease, as well as in premenopausal women. Abemaciclib was superior to palbociclib in patients with poorer ECOG [Eastern Cooperative Oncology Group] performance status and to both palbociclib and ribociclib in patients with de novo metastatic disease. Both ribociclib and abemaciclib showed a trend toward higher efficacy in patients with liver metastases. However, this difference only reached statistical significance in patients treated with ribociclib. And finally, the three CDK4/6 inhibitors were similarly effective in patients who were older or at bone-only disease,” he concluded.
Justifying adjustment
Speaking during the audience question period Giuseppe Del Priore, MD, from Morehouse School of Medicine in Atlanta, Georgia, said he preferred unadjusted results when examining real-world data, “because that’s the benefit,” and he questioned why the researchers had adjusted their numbers.
Dr. Vernieri explained that the adjustments were made to account for the important imbalances in the baseline characteristics of the patients.
“When we plotted unadjusted curves, we did not find statistically significant differences between these three drugs, only a trend toward the direction that I showed you today,” he said. “However, as you saw from the tables showing the characteristics of patients, there were important imbalances in terms of important prognostic factors in the three patient cohorts. So, I think that, for this kind of data and based on this level of imbalance, adjustment is necessary.
“To reinforce our conclusions, what we did was also to perform a propensity score match–based analysis,” Dr. Vernieri continued. “I did not have the time to show the results today, but these data were fully in line with the study conclusions. And we also performed a backward selection of variables. So, we basically selected variables more likely to be associated with patient prognosis. And also those models confirm the study conclusion. So I think the conclusions are quite solid.”
Dr. Del Priore, an adjunct professor of obstetrics and gynecology with a specialty in oncology, on the other hand, said he was not convinced that any of the drugs might be better or worse in the actual population treated.
“I still maintain that unadjusted real-world data should be presented and then only a limited adjusted analysis performed using the most unbalanced variables,” he said. “To do more elaborate adjustments may falsely imply a difference in drug choice and outcomes which never should be the conclusion with observational studies. Instead, the conclusions should be that, with typical use, the following similarities in PFS and OS were observed. Then point out how drug choice and important prognostic variables might be linked, thus limiting the generalizable conclusions even further.
“I would conclude that prospective studies should balance for the variables used in the PALMARES-2 analyses, which actually may have been chosen for adjustment post hoc,” Dr. Del Priore said.
The study was funded by the Italian Association for Cancer Research, the European Research Council, the Ministero della Salute, the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori, Giuliani’s Foundation and Roche. Dr. Vernieri reported consulting or advisory roles with Daiichi Sankyo/Astra Zeneca, Novartis, and Pfizer; speakers’ bureau roles with Accademia Nazionale Di Medicina (ACCMED), Istituto Gentili, Lilly and Novartis; and research funding from Roche. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
Lead investigator Claudio Vernieri, MD, PhD, presented these findings of the PALMARES-2 study at the annual meeting of the American Society of Clinical Oncology.
“Along with different safety profiles, drug-drug interactions, and costs of the three available CDK4/6 inhibitor molecules, our efficacy data may help clinicians and patients in choosing the most appropriate CDK4/6 inhibitor in specific clinical contexts,” Dr. Vernieri, who is from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said during the meeting.
CDK4/6 inhibitors combined with ET, are the standard of care as first line treatment for this population, noted Dr. Vernieri. However, their efficacy has never been directly compared in a large clinical trial.
“Since these compounds have different pharmacokinetics, pharmacodynamics, safety profiles, costs, and drug-drug interactions, identifying which of the three CDK4/6 inhibitors may be more effective in specific clinical contexts is a highly clinically relevant issue,” he said. “Real-world data represent a key source to perform direct comparisons.”
The PALMARES-2 study was a retrospective, multicenter, population-based study, in 18 Italian cancer centers. Its two main objectives were to compare the real-world PFS of abemaciclib versus ribociclib versus palbociclib, in combination with ET, in the whole study cohort, as well as in various subgroups including patients with endocrine-resistant disease, luminal B-like disease, or in premenopausal women.
A total of 1,850 patients (median age, 63 years) were enrolled between January 1, 2016 and September 1, 2023, with 750 (40.6%) receiving palbociclib, and 676 (36.5%) and 424 (22.9%) receiving ribociclib and abemaciclib, respectively.
Baseline imbalance
Importantly, there were significant imbalances in baseline characteristics of the patients, with those receiving abemaciclib being more likely to have endocrine-resistant disease, low progesterone receptor expression, and liver metastasis, and less likely to have de novo metastatic disease, compared with other patients, said Dr. Vernieri.
The analysis showed that across the entire cohort, the median real-world PFS and overall survival (OS) were 34.7 months and 66.6 months, respectively, by a January 1, 2024, data cutoff date. “I believe that the overall survival data are still immature to make a definitive conclusion,” he commented, noting that at enrollment only about half of patients had undergone disease progression, and at the close of the study only about 25% had died.
After adjusting for clinically relevant patient- and tumor-related covariates, “we found that both abemaciclib and ribociclib were more effective than palbociclib, whereas we did not find statistically significant differences between abemaciclib and ribociclib,” he reported.
Specifically, the adjusted hazard ratio (aHR) for PFS was 0.71 for abemaciclib versus palbociclib (95% CI, 0.56-0.90; P = .005), 0.81 for ribociclib versus palbociclib (95% CI, 0.65-0.99; P = .048), and 0.91 for abemaciclib versus ribociclib (95% CI, 0.70-1.19; P = .505).
“Regarding subgroup analysis, we found that abemaciclib and ribociclib were more effective than palbociclib in patients with endocrine-resistant or luminal B-like disease, as well as in premenopausal women. Abemaciclib was superior to palbociclib in patients with poorer ECOG [Eastern Cooperative Oncology Group] performance status and to both palbociclib and ribociclib in patients with de novo metastatic disease. Both ribociclib and abemaciclib showed a trend toward higher efficacy in patients with liver metastases. However, this difference only reached statistical significance in patients treated with ribociclib. And finally, the three CDK4/6 inhibitors were similarly effective in patients who were older or at bone-only disease,” he concluded.
Justifying adjustment
Speaking during the audience question period Giuseppe Del Priore, MD, from Morehouse School of Medicine in Atlanta, Georgia, said he preferred unadjusted results when examining real-world data, “because that’s the benefit,” and he questioned why the researchers had adjusted their numbers.
Dr. Vernieri explained that the adjustments were made to account for the important imbalances in the baseline characteristics of the patients.
“When we plotted unadjusted curves, we did not find statistically significant differences between these three drugs, only a trend toward the direction that I showed you today,” he said. “However, as you saw from the tables showing the characteristics of patients, there were important imbalances in terms of important prognostic factors in the three patient cohorts. So, I think that, for this kind of data and based on this level of imbalance, adjustment is necessary.
“To reinforce our conclusions, what we did was also to perform a propensity score match–based analysis,” Dr. Vernieri continued. “I did not have the time to show the results today, but these data were fully in line with the study conclusions. And we also performed a backward selection of variables. So, we basically selected variables more likely to be associated with patient prognosis. And also those models confirm the study conclusion. So I think the conclusions are quite solid.”
Dr. Del Priore, an adjunct professor of obstetrics and gynecology with a specialty in oncology, on the other hand, said he was not convinced that any of the drugs might be better or worse in the actual population treated.
“I still maintain that unadjusted real-world data should be presented and then only a limited adjusted analysis performed using the most unbalanced variables,” he said. “To do more elaborate adjustments may falsely imply a difference in drug choice and outcomes which never should be the conclusion with observational studies. Instead, the conclusions should be that, with typical use, the following similarities in PFS and OS were observed. Then point out how drug choice and important prognostic variables might be linked, thus limiting the generalizable conclusions even further.
“I would conclude that prospective studies should balance for the variables used in the PALMARES-2 analyses, which actually may have been chosen for adjustment post hoc,” Dr. Del Priore said.
The study was funded by the Italian Association for Cancer Research, the European Research Council, the Ministero della Salute, the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori, Giuliani’s Foundation and Roche. Dr. Vernieri reported consulting or advisory roles with Daiichi Sankyo/Astra Zeneca, Novartis, and Pfizer; speakers’ bureau roles with Accademia Nazionale Di Medicina (ACCMED), Istituto Gentili, Lilly and Novartis; and research funding from Roche. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
FROM ASCO 2024