The final overall survival analysis of the phase III PALOMA-2 trial has shown no significant benefit for palbociclib given with letrozole, vs letrozole and placebo, as a first-line treatment in hormone receptor–positive, HER2-negative metastatic breast cancer.1 The results were reported at the 2022 ASCO Annual Meeting by Richard Finn, MD, Professor of Medicine at the David Geffen School of Medicine, University of California, Los Angeles.
“Overall survival was numerically longer in the palbociclib-plus-letrozole arm, but the results were not statistically significant.”— Richard Finn, MD
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“Overall survival was numerically longer in the palbociclib-plus-letrozole arm, but the results were not statistically significant,” Dr. Finn announced. “The interpretation of overall survival is limited by the large and disproportionate percentage of patients with missing survival data [ie, lost to follow-up or censored] between the treatment arms.”
Final data were missing for 13% in the experimental arm vs 21% in the control arm. Also of note, after 7.5 years of follow-up, 10% of the combination arm vs 2% of placebo arm were still on study treatment at the time of the final analysis, he said.
“Median survival of over 50 months in this population represents a significant improvement in the natural history of hormone receptor–positive breast cancer,” Dr. Finn commented. “This is highlighted in the patients with disease-free intervals of more than 12 months and a median overall survival of 66 months.”
The PALOMA-2 population included 666 postmenopausal patients with hormone receptor–positive, HER2-negative metastatic breast cancer not previously treated for advanced disease. Patients were randomly assigned to receive the inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) palbociclib at 125 mg orally once daily for 3 of 4 weeks in repeated cycles in combination with letrozole (2.5 mg, once daily, continuously) vs letrozole and placebo.
Overall survival was a secondary endpoint. After a median follow-up of 90 months, median overall survival was 53.9 months with palbociclib/letrozole vs 51.2 months with letrozole alone (hazard ratio [HR] = 0.956; 95% confidence interval [CI] = 0.777–1.177).
The study previously met its primary endpoint of progression-free survival, which was improved with palbociclib and letrozole to a median of 24.8 months vs 14.5 months with letrozole alone (HR = 0.580; P > .001). These results were reported in TheNew England Journal of Medicine in 2016.2
Effect on Subgroups
Examining the outcomes in relevant subgroups, Dr. Finn commented: “By and large, the hazard ratios tend to hover around 1 for overall survival. Looking a little more closely at those subgroups, where there is balance between the amount of missing data, we can see the hazard ratios tend to favor palbociclib plus letrozole.” Those subgroups included patients with an Eastern Cooperative Oncology Group performance status of 1 or 2 (HR = 0.807), disease-free interval of more than 12 months (HR = 0.728), prior endocrine therapy (HR = 0.801), and bone-alone disease (HR = 0.712). He emphasized the median overall survival was 66 months for patients with a disease-free interval exceeding 12 months.
To demonstrate the impact of missing data, Dr. Finn showed a post hoc analysis excluding patients for whom survival data were not available. In that analysis, the median overall survival was 51.6 months with palbociclib/letrozole vs 44.6 months with letrozole alone (HR = 0.869; 95% CI = 0.706–1.069).
Regarding other outcomes that affected quality of life, Dr. Finn reported the median duration of treatment and the time to chemotherapy were prolonged with palbociclib plus letrozole. The median treatment duration was 22.0 months vs 13.8 months, and at each benchmark, more of the palbociclib arm were still on treatment. “At 6 years or longer, this was three times as many (16% vs 5%),” he noted.
The time to chemotherapy was 38.1 months with palbociclib/letrozole vs 29.8 months with letrozole alone (HR = 0.730; 95% CI = 0.607–0.879). Poststudy systemic therapy included a CDK4/6 inhibitor for 27% vs 12%, respectively.
Combined Analysis of PALOMA-2 and PALOMA-1
“Prespecified in the PALOMA-2 study was a combined analysis of PALOMA-13 and PALOMA-2, based on the fact that the populations being studied were very similar between these studies,” Dr. Finn said.
With a combined population of more than 800 patients, overall survival in the control arm was 46.8 months, increasing to 51.8 months with the combination (HR = 0.934; 95% CI = 0.780–1.120). For the largest subgroup of patients—those with a disease-free interval of more than 12 months—overall survival increased from 44.6 months in the control arm to 64.0 months with palbociclib/letrozole (HR = 0.736; 95% CI = 0.551–0.982). This subgroup analysis was not prespecified.
Dr. Finn further reported that, after 7.5 years of follow-up, “there were no new safety concerns…, and quality of life has been maintained.”
DISCLOSURE: Dr. Finn reported financial relationships with AstraZeneca, Bayer, Bristol Myers Squibb, CStone Pharmaceuticals, Eisai, Exelixis, Genentech/Roche, Hengrui Therapeutics, Lilly, Merck, Novartis, and Pfizer.
1. Finn RS, Rugo HS, Dieras VC, et al: Overall survival with first-line palbociclib plus letrozole versus placebo plus letrozole in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer: Analyses from PALOMA-2. 2022 ASCO Annual Meeting. Abstract LBA1003. Presented June 4, 2022.
2. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.
3. Finn RS, Boer K, Bondarenko I, et al: Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2– advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat 183:419-428, 2020.