Clinical trial summary
Real-world evidence complements data from randomized clinical trials. It is important to understand both the randomized clinical trial results and the limitations of this observational retrospective real-world study.
PALOMA-2 randomized clinical trial
2:1 randomized, double-blind, Phase 3 trial studying IBRANCE + letrozole vs placebo + letrozole in postmenopausal women receiving first-line treatment for estrogen receptor-positive (ER+)/HER2- mBC (N=666)†
Investigator-assessed progression-free survival (PFS)
24.8 months of mPFS with IBRANCE + letrozole (n=444; 95% CI: 22.1-not estimable [NE]) vs 14.5 months with placebo + letrozole (n=222; 95% CI: 12.9-17.1); HR=0.58 (95% CI: 0.46-0.72); P<0.0001
Number of PFS events: 194 (43.7%) in the IBRANCE + letrozole arm and 137 (61.7%) in the placebo + letrozole arm
IBRANCE + letrozole reduced the risk of disease progression or death by 42% vs placebo + letrozole
Overall response rate (ORR)‡: 55.3% (95% CI: 49.9-60.7) of patients with measurable disease achieved an objective response with IBRANCE + letrozole vs 44.4% (95% CI: 36.9-52.2) with placebo + letrozole (IBRANCE + letrozole n=338; placebo + letrozole n=171)
Overall survival (OS): With a median follow-up of 7.5 years, median OS was 53.9 months (95% CI: 49.8-60.8) in the IBRANCE + letrozole arm vs 51.2 months (95% CI: 43.7-58.9) in the placebo + letrozole arm (HR=0.96; 95% CI: 0.78-1.18; P=0.3378; 405 events [61% of trial population]). The result did not meet the secondary endpoint§
27.6 months of mPFS with IBRANCE + letrozole (n=444; 95% CI: 22.4-30.3) vs 14.5 months with placebo + letrozole (n=222; 95% CI: 12.3-17.1); HR=0.56 (95% CI: 0.46-0.69).5
Number of PFS events: 245 (55.2%) in the IBRANCE + letrozole arm and 160 (72.1%) in the placebo + letrozole arm3
The most common selected AEs (≥10%, all causality)‡‡ of any grade reported in an updated non-prespecified analysis of PALOMA-2 for IBRANCE + letrozole vs placebo + letrozole were neutropenia (82% vs 6%), infections (63% vs 45%), leukopenia (40% vs 2%), fatigue (40% vs 28%), nausea (37% vs 27%), alopecia (34% vs 16%), stomatitis (32% vs 15%), diarrhea (28% vs 21%), anemia (26% vs 10%), rash (20% vs 13%), thrombocytopenia (20% vs 1%), asthenia (18% vs 12%), decreased appetite (17% vs 9%), vomiting (17% vs 17%), dry skin (13% vs 7%), pyrexia (13% vs 9%), alanine aminotransferase (ALT) increased (13% vs 6%), aspartate aminotransferase (AST) increased (12% vs 6%), and dysgeusia (10% vs 5%).
The most common selected adverse events (≥10%, all causality)‡‡ of any grade reported in the final OS analysis of PALOMA-2 for IBRANCE + letrozole vs placebo + letrozole were neutropenia (82% vs 6%), infections (64% vs 46%), leukopenia (43% vs 3%), fatigue (41% vs 29%), nausea (38% vs 27%), alopecia (34% vs 16%), stomatitis (33% vs 15%), diarrhea (30% vs 23%), anemia (28% vs 10%), rash (22% vs 13%), thrombocytopenia (21% vs 2%), asthenia (19% vs 12%), decreased appetite (20% vs 10%), vomiting (18% vs 18%), dry skin (15% vs 7%), pyrexia (15% vs 9%), alanine aminotransferase increased (15% vs 6%), aspartate aminotransferase increased (14% vs 6%), and dysgeusia (NR vs NR).
In an updated non-prespecified PFS analysis and the final OS analysis no new safety signals were observed.3-5
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The FDA-approved Prescribing Information for IBRANCE includes data from the PALOMA trials. However, some data reported in this publication may be different from, or are not included in, the IBRANCE Prescribing Information. Please review results from PALOMA-2 provided on this page. The study met its primary endpoint of progression-free survival but did not meet the secondary endpoint of overall survival.
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.
Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with CDK4/6 inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g., hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis.
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 to consider sperm preservation before taking IBRANCE. 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.
Please see full Prescribing Information for IBRANCE capsules and tablets.