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Breast Cancer
Ibrance® (palbociclib): New Hope in Advanced Breast Cancer Treatment
Palbociclib: First in Class CDK4/6 Inhibitor
At the American Association for Cancer Research, 2014 annual meeting (AACR) Richard Finn presented the results of the PALOMA-1 study with Ibrance® (palbociclib), an oral inhibitor of cyclin-dependent kinase 4/6 (CDK4/6). Based on the results of this Phase 2 study, palbociclib was recently approved by the United States Drug and Food Administration (U.S. FDA). What is the current level of evidence on palbociclib in approved indications?
The PALOMA-1 Study
The PALOMA-1 study investigated 165 post-menopausal women with metastatic hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer. 84 patients received daily Femara® (letrozole) 2.5 mg plus daily palbociclib 125 mg orally in a ‘three weeks on, one week off’ schedule. The remainder 81 patients received daily letrozole 2.5 mg alone. Median follow-up was 29.6 months in the palbociclib plus letrozole group, and 27.9 months in the letrozole alone group. 41 and 59 progression-free survival (PFS) events respectively occurred.
The PFS in the palbociclib plus letrozole group was 20.2 months (95% CI, 13.8–27.5). In the letrozole group, this was 10.2 months (95% CI, 5.7–12.6). Women treated with letrozole alone were 51% more likely to progress (HR 0.488; 95% CI, 0.319–0.748; one-sided P=0.0004) (Figure 1).
Figure 1: PALOMA-1 Profression Free Survival Kaplan-Meier Curve. Courtesy of Finn et al. Lancet Oncol 2015, Jan;16(1):25-35.
PALOMA-1 Biomarkers
A note should be made on the 66 patients who formed a biomarker-selected cohort in the trial. Patients participating in this group were selected for Cyclin D1 (CCND1) overexpression and loss of P16. The results in this cohort did not show improved outcome in biomarker-positive patients. Median PFS was 5.7 months (95% CI, 2.6–10.5) in letrozole-treated women vs. 26.1 months (95% CI, 11.2–not estimable) in palbociclib plus letrozole-treated women (HR 0.299; 95% CI, 0.156–0.572; one-sided P<0.0001).
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Palbociclib Side Effects in the PALOMA-1
Among the side-effects Grade 3-4 neutropenia was of the most concern. In the patients treated with palbociclib plus letrozole, neutropenia occurred in 45 (54%) patients. 16 (19%) patients on the combination treatment had leucopenia. For patients treated with letrozole alone, these numbers were 1 (1%) and none respectively. Febrile neutropenia or related infections did not occur during the study.
Palbociclib Plus Fulvestrant
At the American Society of Clinical Oncology (ASCO) annual meeting 2015, Turner et al. presented the results of the Phase 3 PALOMA-3 trial. Based on this study, US FDA granted approval for the use of concurrent palbociclib and fulvestrant in advanced endocrine-resistant breast cancer.
Women with hormone receptor-positive, HER2-negative advanced breast cancer who had previously relapsed on endocrine therapy were randomised in a 2:1 ratio. 347 subject received palbociclib 125 mg/d orally at a ‘three weeks on, one week off’ schedule plus Faslodex® (fulvestrant) 500 mg per standard of care. The remainder 174 subjects received fulvestrant 500 mg per standard-of-care plus matching placebo for palbociclib. Pre- and perimenopausal patients received additional treatment with Zoladex® (goserelin). Patients who had previously received more than one line of chemotherapy for metastatic disease were excluded from the study.
Figure 2: Kaplan-Meier estimate of PFS in the PALOMA-3 trial. Courtesy of Turner et al. N Engl J Med 2015, Jul 16;373(3):209-19.
Results of the PALOMA-3
521 women were randomised 2:1. 347 received palbociclib a fulvestrant and 174 fulvestrant plus placebo. 79% of participants were post-menopausal. 60% of patients had baseline visceral metastasis. Sensitivity to prior endocrine therapy was reported for 79% of patients. 33% of participants had received prior chemotherapy for advanced disease. At the time of the first pre-planned interim analysis, set for 195 PFS events, the study had met its primary endpoint. Median PFS was 9.2 vs. 3.8 months respectively for palbociclib plus fulvestrant vs. fulvestrant plus placebo.
This translates into a 57% risk reduction (HR 0.422; 95% CI, 0.318 to 0.560; P<0.000001) for subjects treated in the experimental arm. This benefit was consistent in both pre- and post-menopausal women.
Palbociclib Side Effects in the PALOMA-3 Study
The most common grade 3/4 adverse event reported in >10% of subjects in the PALOMA-3 study was neutropenia. It occurred in 62% of subjects in the combination arm vs. 0.6% of subjects in the control arm. The other adverse event reported in over 10% of patients was grade 3/4 leukopenia. It occurred in 25.2% vs. 0.6% of patients treated with palbociclib plus fulvestrant vs. fulvestrant plus placebo respectively. Unlike the PALOMA-1 study, febrile neutropenia occurred in 0.6% of subjects in both arms. The discontinuation rate due to adverse events was equal in both arms.
The Future of CDK4/6 Inhibition
Palbociclib represents the first-in-class CDK4/6 inhibitor with promising efficacy in endocrine-resistant patients. Ongoing studies in different settings will investigate if palbociclib is useful in other selected groups of patients or diseases. Furthermore, several other drugs with similar mode of action (ribociclib & abemaciclib) are currently under investigation for breast cancer and other diseases.
References
Disclaimer
This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).
© 2016 MediPaper Medical Communications Ltd.- Palbociclib: First in Class CDK4/6 Inhibitor
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© 2016 MediPaper Medical Communications Ltd.- Palbociclib: First in Class CDK4/6 Inhibitor
Novartis today announced positive results of the landmark MonaLeesa-2 study. The study was halted early per recommendation of the Independent Data-Monitoring Committee (IDMC) after pre-planned interim data review.
MonaLEEsa-2 investigated ribociclib, an inhibitor of the cyclin-dependent kinase 4 & 6 (CDK4/6) in combination with letrozole vs letrozole alone in first-line for post-menopausal women with advanced hormone-sensitive HER-2 negative breast-cancer.
At pre-planned interim analysis, the IDMC recommended closure of the study as the combination of ribociclib plus letrozole significantly improved progression free survival (PFS). PFS was the primaryendpoint of the study.
Data will be presented at a large medical congress. The positive results are thought to lead to the registration of the second CDK4/6 inhibitor, after approval last year of palbociclib (Pfizer).