Confirmation or Transformation? The Case of Palbociclib in Hormone Receptor–Positive Metastatic Breast Cancer

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Women with hormone receptor–positive metastatic breast cancer are witnessing an unprecedented time of success in the battle against their disease. Just in the past 12 months, a number of prospective, randomized, phase III studies were reported, with positive results indicating the value of fulvestrant (Faslodex) as a single agent in endocrine-naive cases but most important establishing a completely new standard of care in the management of advanced breast cancer. A new class of drugs, the cyclin-dependent kinase (CDK) 4/6 inhibitors, demonstrated in every large prospective study a significant superiority in comparison to single-agent endocrine therapy, and this benefit was associated with relatively minimal and tolerable toxicity. The most recent and significant study, PALOMA-2 was published by Finn et al in the November issue of The New England Journal of Medicine1 and is reviewed in this issue of The ASCO Post.

Study Findings

The PALOMA-2 trial was a prospective, randomized, placebo-controlled phase III study comparing a combination of letrozole and palbociclib (Ibrance) with standard monotherapy with letrozole. The study enrolled postmenopausal women who had not received any systemic therapy for their advanced disease but allowed patients who had received prior adjuvant endocrine therapy. Those patients could have been treated with adjuvant letrozole or other aromatase inhibitors or tamoxifen, provided the treatment was completed 12 months or more before recurrence, and included patients who were considered endocrine-sensitive by clinical criteria.

A total of 666 patients were assigned to treatment based on a 2:1 randomization, and the population included women with de novo stage IV disease (approximately 35% of cases). The majority of patients had a history of stage I or II disease (41%) and had received adjuvant or preoperative chemotherapy (48%), and more than half had been exposed to endocrine therapy. A large proportion of patients had more than one site of recurrence, and 48% of cases had visceral metastases. The primary objective of the study was investigator-assessed progression-free survival; secondary objectives included overall response rate, clinical benefit rate, patient-reported outcome, and overall survival.

Patients treated with the combination of letrozole and palbociclib experienced a significantly improved progression-free survival compared with the standard-treatment arm: 24.8 months (95% confidence interval [CI] = 22.1 months to not estimable) vs 14.8 months (95% CI = 12.9–17.1 months, with a hazard ratio of 0.58 (95% CI = 0.46–0.72). The subgroup analysis confirmed that the improvement was consistently seen across various disease groups, with a slightly more favorable trend for patients with bone-only, nonmeasurable disease and lobular histology. Patients treated with the combination also experienced an improved overall response rate and clinical benefit rate (84.9 % vs 70.3 %, P ≤ .001).

Toxicity Profile

The study confirmed the toxicity profile of palbociclib consisting primarily of hematologic toxicity; neutropenia of any grade occurred in 79.5% of patients, including grade 3/4 in 66%. Such events were managed according to recommendations resulting in dose interruptions in 67%, initially without dose reductions. Eventually, a dose reduction was required in approximately one-third of cases, and the median time to such an event was 90 days (range, 28–785 days). Febrile neutropenia was reported in 1.6% of patients treated with palbociclib, and otherwise serious adverse events were reported in < 1%. Nonhematologic toxicity was mild and consisted primarily of fatigue and gastrointestinal symptoms.

Discussion and Implications

The results of PALOMA-2 strongly suggest that the use of palbociclib in the first-line treatment of hormone receptor–positive postmenopausal metastatic breast cancer is associated with such a magnitude of benefit to recommend a mandatory use in this indication. No identified subset seemed to be better served with monotherapy. Furthermore, palbociclib is well tolerated, with no evidence of chronic toxicity, and can be used for long periods with minor dose adjustments. In addition, more recent analysis suggests that the use of palbociclib in this setting does not seem to compromise the benefit of additional endocrine therapies or other treatment modalities at the time of disease ­progression.

The results of PALOMA-2 strongly suggest that the use of palbociclib in the first-line treatment of hormone receptor–positive postmenopausal metastatic breast cancer is associated with such a magnitude of benefit to recommend a mandatory use in this indication. No identified subset seemed to be better served with monotherapy.
— Massimo Cristofanilli, MD, FACP

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In other subtypes of breast cancer disease (eg, HER2-negative and triple-negative breast cancers), the increment benefit with each combination, if any, has been generally more modest, and this indicates that “luminal breast cancers” are far more biologically heterogeneous. The clinical parameters used to define “endocrine sensitivities” are antiquated and unable to define the complex molecular features of the disease. The “first-line treatment” is simply a clinical condition that has not been treated in the metastatic setting but likely exposed to a number of endocrine agents in the adjuvant setting, sometimes for longer than 5 years. Moreover, the subset of “de novo stage IV” now constitutes a precious clinical subset, because it appears to be the only endocrine-naive condition to which we should dedicate resources to truly understand endocrine sensitivity beyond what any preclinical model can tell us. Nevertheless, we can assume the existence of an intrinsic resistance, even in these cases based on the benefit observed in these patients in the PALOMA-2 trial.

The use of molecular testing should be a more appropriate tool to define an endocrine-dependent disease likely to benefit from monotherapy, removing empiricism and clinical judgment from making one of the most important treatment decisions for these women. Several observations suggest that the detection of specific genomic abnormalities such as those involving the PI3KCA/akt/mTOR pathway using either tissue- or blood-based diagnostics identifies endocrine resistance in the advanced setting. Moreover, ESR1-acquired mutations are a recent discovery in patients exposed to endocrine (adjuvant) therapy, primarily aromatase inhibitors, and may contribute to endocrine resistance. In conclusion, future prospective trials should incorporate diagnostic tools and use such molecular stratification for selecting and monitoring disease with the potential of truly impacting survival in women with hormone receptor–positive metastatic breast cancer and introducing a model for the “complete transformation of patient care.” ■

Disclosure: Dr. Cristofanilli has received honoraria from Pfizer.

Dr. Cristofanilli is Professor of Medicine and Associate Director of Translational Research and Precision Medicine, Department of Medicine, Division of Hematology & Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago.


1. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.

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