The Food and Drug Administration (FDA) has approved a new combination therapy for adults with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, offering a potential new treatment option for a challenging cancer. The approval, , includes pembrolizumab (Keytruda, marketed by Merck) in combination with paclitaxel, with or without bevacizumab (Avastin). A companion diagnostic test, PD-L1 IHC 22C3 pharmDx, is also approved to identify patients most likely to benefit from the treatment.
This approval marks a significant step forward for patients whose cancers have stopped responding to initial platinum-based chemotherapy. Platinum-resistant disease is notoriously difficult to treat, and new options are urgently needed. The KEYNOTE-B96 trial, a phase 3, randomized, double-blind study, demonstrated clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) with the pembrolizumab combination.
Understanding the KEYNOTE-B96 Trial
The KEYNOTE-B96 trial enrolled 643 patients with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who had previously received at least one line of platinum-based chemotherapy and experienced disease progression within six months. Patients were randomly assigned to receive either pembrolizumab plus paclitaxel, with or without bevacizumab, or placebo plus paclitaxel, with or without bevacizumab.
The primary endpoint of the study was progression-free survival, which measures the length of time patients live without their cancer growing or spreading. Secondary endpoints included overall survival, which measures the length of time patients live overall.
Efficacy in PD-L1 Positive Tumors
The most substantial benefit was observed in the subgroup of patients whose tumors expressed PD-L1 (Combined Positive Score ≥1). PD-L1 is a protein that can help cancer cells evade the immune system. In this population of 466 patients, the median PFS was 8.3 months with the pembrolizumab combination, compared to 7.2 months with placebo (HR, 0.72; 95% CI, 0.58–0.89; P = .0014). This represents a 28% reduction in the risk of disease progression.
the pembrolizumab combination demonstrated a statistically significant improvement in overall survival. The median OS was 18.2 months in the pembrolizumab arm versus 14.0 months in the placebo arm (HR, 0.76; 95% CI, 0.61–0.94; P = .0053), indicating a 24% reduction in the risk of death. These findings suggest that pembrolizumab can help patients live longer without their cancer progressing and potentially extend their overall lifespan.
How the Treatment Works and Dosing Information
Pembrolizumab is an immunotherapy drug that works by blocking the PD-1 protein on immune cells, allowing the immune system to recognize and attack cancer cells. Combining it with paclitaxel, a standard chemotherapy drug, and optionally bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, aims to enhance the anti-cancer effect.
Pembrolizumab can be administered intravenously (IV) at a dose of 400 mg every 6 weeks, or 200 mg every 3 weeks, for up to 24 months. A subcutaneous formulation, Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph), is also approved and can be administered at a dose of 395 mg/4800 units every 3 weeks or 790 mg/9600 units every 6 weeks. When administered on the same day, pembrolizumab or Keytruda Qlex should be given before paclitaxel, with or without bevacizumab.
Safety Profile
The safety profile of pembrolizumab in combination with paclitaxel, with or without bevacizumab, appears to be manageable and consistent with previous studies of pembrolizumab. No new or unexpected adverse events were reported in the KEYNOTE-B96 trial. However, as with any immunotherapy, there is a risk of immune-mediated adverse reactions, and healthcare providers should monitor patients closely for any signs or symptoms.
Prescribing information includes warnings regarding immune-mediated adverse reactions, infusion-related reactions, complications related to stem cell transplantation, and potential risks to developing fetuses.
The Importance of PD-L1 Testing
The FDA approval is contingent on PD-L1 expression in tumor cells, as determined by the PD-L1 IHC 22C3 pharmDx companion diagnostic. This test identifies patients whose tumors have a combined positive score (CPS) of 1 or greater, indicating a higher likelihood of responding to pembrolizumab. This targeted approach ensures that the treatment is used in patients who are most likely to benefit, maximizing its effectiveness and minimizing unnecessary exposure to potential side effects.
This approval provides a valuable new treatment option for patients with platinum-resistant ovarian cancer, offering hope for improved outcomes and a better quality of life. Further research will continue to refine our understanding of how to best utilize immunotherapy in the fight against this challenging disease.
