Regulatory Decision Summary for IBRANCE

The primary source of data supporting the proposed indication was one randomized Phase 1/2 study (PALOMA-1) performed in the target population, with additional safety data from clinical studies of Ibrance in ongoing trials and in other indications.

The Phase 2 portion of the study was comprised of two cohorts of patients: Phase 2 Part 1 (Ph2P1), a biomarker-unselected patient population, and Phase 2 Part 2 (Ph2P2), where patients had genomic amplification of cyclin D1 and/or loss of p16 (biomarker-selected patient population). A randomized Phase 3 study (PALOMA-2), in women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in the first line setting is currently ongoing. PALOMA-2 mirrors the Phase 2 study in eligibility, primary endpoint, and comparator, with the main differences being that it is double blinded and enrolled a biomarker-unselected patient population.

The Phase 2 portion of PALOMA-1 suggested a 10 month improvement in the primary efficacy endpoint, investigator-assessed progression-free survival (PFS) in patients treated with Ibrance plus letrozole compared to patients treated with letrozole alone (20.2 months versus 10.2 months, respectively; Hazard Ratio [HR] = 0.49). This improvement of PFS appears to be relatively large, and would be considered to confer a clinically meaningful benefit in a well-designed and well-conducted study;however, study design limitations precluded statistical inference, and internal inconsistencies within the study results suggested possible investigator bias favouring the Ibrance (palbociclib) arm. The magnitude of benefit may differ in the ongoing placebo-controlled Phase 3 study.

Significantly, there were multiple data-driven protocol amendments which limited the statistical analyses and conclusions of the data resulting from the PALOMA-1 Study. The protocol amendments affected which patients were to be enrolled in the study, and which patients were to comprise the final analysis population. No statistical methods can take into account clinical and operational aspects of these amendments, therefore the reported p-values and 95% confidence intervals are not meaningful or reliable. The results of the data analyses also suggested that bias (favouring the experimental treatment arm) likely was present in this open-label trial, evidenced by the fact that blinded central review did not confirm the investigator-assessed data, with the largest discrepancy in the biomarker unselected (Ph2P1) patient population. This appears to be due to informative censoring in Blinded Independent Central Review (BICR) data, where there was a much larger percentage of patients in the control arm compared to the Ibrance (palbociclib) arm who discontinued due to relapse that was not confirmed by BICR. Pre-specified and ad hoc sensitivity analyses were performed on the full Phase 2 population to partially address these imbalances; however, the analyses included Cohort 1, despite the highly likely presence of investigator bias in this population, and are therefore not reliable. Uncertainty remains regarding the impact of these imbalances on the reported efficacy of Ibrance. There is limited clinical evidence that Ibrance provides a clinical benefit in a biomarker-negative patient population.

The assessment of the safety profile demonstrated that the addition of Ibrance to letrozole treatment increased the reports of cytopenias (especially neutropenia), infections, diarrhea, nausea, eye disorders, and pulmonary embolisms. Neutropenia was the most frequently reported treatment-emergent adverse event in both phases of the PALOMA-1 study, reported by 91.7% of patients in the Phase 1 portion and 75.9% of patients in the Phase 2 portion of the study, compared to 5.2% in the letrozole-alone arm. There were also more reports of infections in the Ibrance plus letrozole treatment arm compared to letrozole alone. There were no reports of febrile neutropenia or neutropenic sepsis in either treatment arm in PALOMA-1, although there were two reports of febrile neutropenia in Ibrance-treated patients from other studies in the Ibrance clinical trial safety database.

Pulmonary embolism was the most significant serious adverse event, reported more frequently in the combination arm than in letrozole only patients; however, 80% (4/5) of the reported cases detected through imaging only and were asymptomatic in the affected patients.

There were more patients who permanently discontinued study treatment in the Ibrance plus letrozole treatment arm (15%) compared to the letrozole-alone treatment arm (3%). The only adverse event that led to discontinuation in more than one patient was neutropenia, which led to permanent discontinuation in 5 patients (6.0%), all in the Ibrance plus letrozole treatment arm. There were 32 patients (39%) who had their Ibrance dose reduced due to adverse events, and 42 (51%) who required temporary drug discontinuation. These results suggest that dose modifications were frequently sufficient in managing adverse events.

Of note, an additional clinical trial has been reported in the medical literature to have shown that palbociclib combined with fulvestrant resulted in longer PFS than fulvestrant alone among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, providing further evidence of its activity in breast cancer patients.

The Product Monograph is the primary risk management strategy to manage the risks associated with Ibrance. It clearly states the limitations of the study and summarizes the data that supported the authorization of Ibrance under the Notice of Compliance with Conditions (NOC/c) Guidance. The Product Monograph provides warnings pertaining to the significant adverse events reported in clinical trials, and recommendations to the prescriber regarding dose modifications/interruptions that may be required to manage adverse events. Recommendations for monitoring are also provided.

Overall, there were many sources of uncertainty in the PALOMA-1 study, including the likely presence of bias and the implementation of data-driven protocol amendments. A statistically significant benefit of Ibrance plus letrozole (over letrozole alone) has not been demonstrated; however, the safety profile of this treatment combination appears manageable, with no major concerns identified from the currently available data. Furthermore, patients who are administered the Ibrance plus letrozole combination are also receiving a standard of care (letrozole) for their disease. It is considered that the point estimate of benefit (PFS) reported in PALOMA-1 provides promising evidence of clinical efficacy in the target patient population. Given the serious nature of the disease and the medical need to prolong first-line PFS in order to prolong life and delay disease progression, the data provided in this submission and evidence available in the medical literature are considered sufficient to conclude that Ibrance, in combination with letrozole, has the potential to provide a significant increase in efficacy such that the overall benefit/risk profile is improved over the existing therapy letrozole. As such, Ibrance was issued a Notice of Compliance under the NOC/c Guidance for use in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. Continued approval for this indication is contingent upon verification and description of clinical benefit in the currently ongoing confirmatory Phase 3 trial (PALOMA-2).

For more information on Health Canadas decision, please view the Summary Basis of Decision.