On October 20, 2018 Pfizer Inc.(NYSE:PFE) reported detailed overall survival (OS) data from the PALOMA-3 trial, which evaluated IBRANCE (palbociclib) in combination with fulvestrant compared to placebo plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer whose disease progressed on or after prior endocrine therapy (Press release, Pfizer, OCT 20, 2018, View Source [SID1234530013]). In the study, there was a numerical improvement in OS of nearly seven months with IBRANCE plus fulvestrant compared to placebo plus fulvestrant, although this difference did not reach the prespecified threshold for statistical significance (median OS: 34.9 months [95% CI: 28.8, 40.0] versus 28.0 months [95% CI: 23.6, 34.6]; HR=0.81 [95% CI: 0.64, 1.03], 1-sided p=0.0429). These data will be presented as a late-breaking oral abstract during the Presidential Symposium at the ESMO (Free ESMO Whitepaper) 2018 Congress (European Society for Medical Oncology) in Munich, Germany, and simultaneously published in The New England Journal of Medicine.

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The difference in median OS demonstrated in this analysis (6.9 months) is consistent with the improvement previously demonstrated for the primary endpoint of median progression-free survival (mPFS). In the updated PFS analysis for this study (non-prespecified), the combination of IBRANCE plus fulvestrant showed a statistically significant and clinically meaningful 6.6-month mPFS improvement compared to placebo plus fulvestrant (11.2 vs. 4.6 months; HR=0.50 [95% CI: 0.40-0.62], p<0.000001).1 Overall survival is a secondary endpoint of PALOMA-3, and the trial design was not optimized to detect a statistically significant difference in OS.

"It’s noteworthy that the magnitude of progression-free survival benefit observed in PALOMA-3 has translated to a similar difference of nearly seven months in overall survival, which is clinically meaningful. This is particularly significant given the challenges of demonstrating overall survival in this disease setting, where post-progression therapy is often substantially longer than time on study," said Massimo Cristofanilli, M.D., associate director for Translational Research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, as well as senior investigator of the PALOMA-3 trial. "The overall survival data, coupled with the previously demonstrated progression-free survival benefit, are encouraging for patients."

At the time of this analysis, follow-up was 44.8 months and approximately 60 percent (n=310) of events had occurred in the 521 patients enrolled. Patients on both arms received up to 10 lines (range 1-10) of post-progression treatment.

The trend toward OS favoring the IBRANCE plus fulvestrant arm was observed across most subgroups, with hazard ratios consistent with the overall population. In addition, for the overall population, the difference in OS was associated with prolonged time from randomization to first use of chemotherapy post-progression, an exploratory endpoint (HR=0.58 [95% CI: 0.47, 0.73], 1-sided p<0.000001). Median time to chemotherapy was 17.6 months (95% CI: 15.2, 19.7) for patients who received IBRANCE plus fulvestrant, twice that observed in patients who received placebo plus fulvestrant (8.8 months [95% CI: 7.3, 12.7]).

"Delaying the need for chemotherapy is a central goal of treatment for women with this disease. These new data from PALOMA-3 show that adding IBRANCE to fulvestrant led to a substantial improvement in this important area," said Nicholas Turner, M.D., Ph.D., professor of molecular oncology at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, as well as principal investigator of the PALOMA-3 trial. "The difference in overall survival and prolonged time to chemotherapy demonstrated in PALOMA-3 further support the role of IBRANCE in combination with endocrine therapy as a standard of care in HR+, HER2- metastatic breast cancer."

"Looking at the data from the PALOMA-3 trial and across the PALOMA program, IBRANCE has transformed the treatment landscape for this disease," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "We are proud of the compelling body of evidence supporting the use of IBRANCE in this setting, and the difference this medicine continues to make in the lives of patients."

The most common adverse reactions in PALOMA-3 included neutropenia, leukopenia, infections, fatigue and nausea. No new safety signals observed with longer follow-up were identified as part of this final OS analysis.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,2 which are key regulators of the cell cycle that trigger cellular progression.3,4 In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.

IBRANCE currently is approved in more than 85 countries and has been prescribed to more than 160,000 patients globally.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg. The pharmacokinetics of IBRANCE have not been studied in patients requiring hemodialysis.