Abstract
Background In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. Methods In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients—ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0–1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy—were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Findings Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8·9 months (IQR 8·7–9·2). Median progression-free survival was 9·5 months (95% CI 9·2–11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5–5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36–0·59, p<0·0001). Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response. Interpretation Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy. Funding Pfizer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 425-439 |
| Number of pages | 15 |
| Journal | The Lancet Oncology |
| Volume | 17 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2016 |
Funding
In our study, progression-free survival improved significantly in patients with hormone-receptor-positive, HER2-negative metastatic breast cancer whose disease had progressed on previous endocrine therapy who received fulvestrant plus palbociclib compared with those who received fulvestrant plus placebo in the overall population and in most subgroups. Our findings confirm the important observation that endocrine monotherapy has limited efficacy in patients with disease progression after previous exposure to endocrine therapy, irrespective of clinical or molecularly defined endocrine sensitivity, suggesting a need for the routine use of more effective combination regimens. 19,24,25 We showed that the combination of fulvestrant plus palbociclib is associated with significant improvement in objective response, clinical benefit, and progression-free survival. The efficacy of fulvestrant plus palbociclib was noted irrespective of the number of previous endocrine therapies, reported sensitivity to previously received endocrine therapy, and biomarkers that affect sensitivity to endocrine therapy, such as the level of expression of oestrogen and progesterone receptors. The combination treatment was also efficacious in patients in whom two lines of previous endocrine therapy were unsuccessful. Patients in this population are generally thought to be endocrine-refractory, and are traditionally given single-drug cytotoxic chemotherapy (eg, taxane, capecitabine, eribulin), which is often of limited benefit, rarely produces meaningful objective responses, and frequently resulted in increased toxicity and reduced quality of life. 26 In patients given fulvestrant plus palbociclib, a confirmed objective response was noted in 66 (25%) of 268 patients with measurable disease, which compares favourably with historical data for cytotoxic chemotherapy. 27 Responses to fulvestrant plus palbociclib were slow to manifest, with a median time to response of almost 4 months. The combination might also offer a more favourable safety profile than chemotherapy, although trials are needed to show this. Moreover, chemotherapy is still advisable in patients at risk for visceral crisis, 28 a setting in which the combination of fulvestrant plus palbociclib has not been assessed. Biomarker and tumour biology can substantially change from the original primary tumour. To our knowledge, PALOMA-3 is the first study in which protocol-mandated biopsy samples were taken from patients who have relapsed with advanced disease, which allowed assessment of hormone sensitivity at the time of disease recurrence, rather than reliance on data derived at the time of initial diagnosis. The results of previous studies suggest that expression level of hormone receptors is directly correlated with benefit from endocrine therapy. 2 In our study, the effect of fulvestrant plus palbociclib in metastatic breast cancer was not significantly affected by oestrogen-receptor expression or related to clinical sensitivity to previous endocrine therapy. The finding that the beneficial effects might be independent of hormone-receptor expression level in this setting strongly suggests that the mechanism of action of CDK4/CDK6 inhibitors could be unrelated to established oestrogen-receptor-associated resistance pathways; rather, perhaps palbociclib targets a dependence of the luminal subtype breast cancer on CDK4 and CDK6, thus introducing a novel molecular target in patients with endocrine-positive disease. 2,12,14 In primary breast cancer, PIK3CA mutations are associated with a lower rate of nodal and distant metastasis. 29,30 Preclinical assays suggest that these mutations confer a gain of function as measured by kinase activity, supporting the clinical development of drugs targeting the related pathways. 29 In an attempt to exploit this observation, several PI3K inhibitors are in clinical development for hormone-receptor-positive breast cancer, but the results so far have been disappointing. 31 A retrospective, exploratory analysis 32 of a subset of patients from the BOLERO-2 study showed no association between PIK3CA mutations and benefit from everolimus treatment. The conclusions of the authors were hampered by their use of archival tissue, mostly from primary disease (mastectomy or lumpectomy), which might not have been representative of the molecular features of advanced disease. The PALOMA-3 study is the largest reported cohort of PIK3CA mutation analysis in plasma DNA in patients whose disease progressed on endocrine therapy. We detected PIK3CA mutations at a frequency similar to that reported in other published work. PIK3CA mutation status was independent of treatment effects. There was no significant difference in progression-free survival or objective response between patients with or without a PIK3CA mutation. After median follow-up of 8·9 months the safety profile of fulvestrant plus palbociclib remained consistent with previous results and also provided assurance with respect to the stability of the safety profile. Neutropenia was frequently observed in the fulvestrant plus palbociclib group, but the rate of febrile neutropenia was similarly low in both groups. Discontinuation because of adverse effects was low (14 patients [4%] in the palbociclib group), which is lower than that associated with other therapies approved for this population. A possible limitation of this study is that fulvestrant might not be considered a standard of care for either premenopausal or postmenopausal women; however, there is no recognised standard treatment for these patients, except several minimally effective options. We conclude that targeting of CDK4 and CDK6 represents a novel, efficacious, and safe therapeutic approach for the treatment of patients with metastatic breast cancer, irrespective of the degree of endocrine sensitivity, levels of expression of oestrogen and progesterone receptors, and PI3K mutational status. This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on March 29, 2016. Further corrections made on June 28, 2016 Contributors MCr, NCT, JR, AD, SL, HI, NH, KZ, YJ, CHB, and MK designed the study. NH was a steering committee member involved in all aspects of the trial and provided oversight. JR, MCo, and DS contributed to recruitment, MCr and AD to enrolment, and KPT to study conduct. IB, JR, S-AI, NM, SL, SV, HI, NH, KZ, KPT, YJ, and DS gathered the data, and YJ contributed to data generation. JR, SL, SV, KZ, KPT, and CHB analysed data, which were reviewed by NM and DS and interpreted by MCr, NCT, IB, JR, S-AI, NM, AD, SL, SV, HI, NH, KZ, KPT, CHB, MK, and DS. MCr, NCT, S-AI, NM, MCo, AD, SL, SV, NH, KZ, KPT, YJ, CHB, and DS wrote the Article, CHB contributed to figures and tables, and JR, NH, KPT, and MK contributed to revisions. All authors reviewed the report and approved the final submitted version. Declaration of interests NCT has received advisory board honoraria and research funding from Pfizer . S-AI has advisory roles with AstraZeneca, Roche, and Novartis, and has received grants from AstraZeneca . NM has received personal fees from AstraZeneca, Chugai, Kyowa-Hakko Kirin, Sanofi, and Eisai. AD reports grants and other support from Pfizer , outside the submitted work. SV reports an advisory role at Amgen, BMS, Pfizer, AstraZeneca, Roche, Eli Lilly, Novartis, Eisai, and Merck. HI has received grants from AstraZeneca , Chugai , Eli Lilly , GSK , Daiichi-Sankyo , Pfizer , and Novartis , and personal fees from AstraZeneca and Eisai. NH reports personal fees from Pfizer, Novartis, Celgene, Genomic Health, Nanostring, and Roche. KZ, KPT, YJ, CHB, and MK are Pfizer employees. KZ reports personal fees from Pfizer during the study and personal fees from Pfizer outside the submitted work. YJ reports other support from Pfizer outside the submitted work. MK and DS are stockholders of Pfizer. MCr, IB, JR, MCo, and SL declare no competing interests. Acknowledgments This study was sponsored by Pfizer . Fulvestrant was provided by AstraZeneca. DS has received funding for the preclinical work on CDK4/CDK6 inhibition that generated translational concepts from the US Department of Defense Breast Cancer Innovator Award , the Revlon/University of California, Los Angeles Women's Cancer Research Program , and the Peter and Denise Wittich Breast Cancer Program . We thank the patients who participated and the investigators, study nurses, and site staff for their support. We also acknowledge Alexandra Thiele and Carla Giorgetti (full-time employees of Pfizer) for their role in study design and protocol development, Patricia English (a full-time employee of Pfizer) for analysis of PIK3CA mutation data, and Kevin O'Regan and Susan Reinwald (Complete Healthcare Communications) for editorial assistance, which was funded by Pfizer.
ASJC Scopus subject areas
- Oncology
