On 3 June 2017, the results of the overall survival analysis from the PALOMA-1 randomised phase II study were presented at the American Society of Clinical Oncology (ASCO) conference. Pfizer’s Ibrance (palbociclib) combined with an aromatase inhibitor in first line metastatic breast cancer patients did not improve significantly the overall survival (OS) endpoint.
Cyclin D kinase 4/6 (CDK4/6) inhibitors such as Ibrance were previously approved based on an improvement in progression-free survival (PFS), which is associated with delay in symptomatic disease allowing postponement of the use of toxic chemotherapy but is not necessarily correlated with a survival gain.
Considering that the cost of therapy for CDK4/6 inhibitors can reach $150,000 per patient in the US, a benefit in survival could be warranted, especially in increasingly cost-conscious markets. The UK drugs watchdog NICE has already refused to reimburse Ibrance due to the lack of reported long-term benefit of the CDK4/6 inhibitor. Pfizer chose to offer the drug for free to UK patients to cement its first-to-market status and therefore, only a benefit in overall survival could justify the adoption of this premium-priced agent.
During the question and answer session at the ASCO conference, principal investigator of the study Dr. Richard S. Finn highlighted that the PALOMA-1 trial was not powered to show a benefit in survival and that the PALOMA-2 Phase III trial will be a more adequate study to evaluate the impact of CDK4/6 inhibitors on overall survival when used in the first-line metastatic setting. Other challenges remain to show a benefit in survival including the variation in the use of subsequent treatments in metastatic breast cancer patients receiving often more than five lines of subsequent therapies.
As reported in the poster (Abstract #1001), the OS analysis of the PALOMA-1 was based on 116 events and showed a non-significant median OS difference of 37.5 months for Ibrance + letrozole versus 34.5 months for letrozole only (HR = 0.897; P= 0.281). Interestingly, the same trial led to the accelerated approval by the US Food and Drug Administration (FDA) based on an improvement in PFS, which almost doubled in the Ibrance + letrozole arm, and a similar primary endpoint outcome was reached in the PALOMA 2 Phase III trial, confirming the large benefit of Ibrance + letrozole in terms of PFS over endocrine therapy monotherapy.
GlobalData has interviewed several key opinion leaders who were concerned that the clinical exploration of CDK4/6 inhibitors could possibly recreate what was seen for Afinitor (everolimus) in breast cancer. Based on randomised trials, Afinitor failed to provide any benefit in terms of OS despite a significant gain in PFS. However, CDK4/6 inhibitors and mTOR inhibitors are very different drug classes both in terms of efficacy and safety outcome. In particular, the well-tolerated toxicity profile ofCDK4/6 inhibitors enables offering this new class of therapy to a large proportion of breast cancer patients. Nevertheless, physicians interviewed by GlobalData commented that the lack of survival clinical data for CDK4/6 inhibitors does not correlate with their high cost of therapy. In conclusion, the future survival data for CDK4/6 inhibitors could impact both their adoption and price tag.