Despite the KEYNOTE-B96 trial showing a statistically significant survival benefit, the expert's enthusiasm for adding pembrolizumab in platinum-resistant ovarian cancer is only "neutral." This hesitation stems from challenges in sequencing it with other effective therapies and uncertainty about which patient subgroups truly benefit.
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The treatment landscape for platinum-resistant ovarian cancer has rapidly evolved into a biomarker-driven paradigm. Clinicians must now test for and choose between therapies targeting distinct markers like folate receptor alpha (mirvetuximab), HER2 (T-DXd), and PD-L1 (pembrolizumab), requiring a sophisticated sequencing strategy.
The B96 trial's potential approval for platinum-resistant ovarian cancer introduces a new treatment sequencing challenge. Clinicians must decide between this immunotherapy combination and the ADC mervituximab, which has a clear biomarker (foliate receptor alpha). The lack of a reliable biomarker for the B96 regimen complicates this decision-making process for patients.
The traditional six-month timeframe for defining platinum sensitivity is being challenged. A growing theory suggests that tumors progressing while on a PARP inhibitor have a distinct biology that responds poorly to subsequent platinum, indicating a potential need to move directly to therapies like ADCs.
Despite multiple clinical trials, adding checkpoint inhibitors to frontline therapy for ovarian cancer has not demonstrated a proven survival benefit. The role of immunotherapy in this setting remains confined to rare subsets like DMMR or TMB-high tumors, and it is not standard practice for the general population.
Real-world data shows that in platinum-sensitive ovarian cancer patients who have progressed on PARP inhibitors, subsequent platinum-based chemotherapy has a surprisingly low response rate of only 20%. This quantifies a significant opportunity for highly active ADCs to potentially replace platinum in this growing patient population.
The B96 trial's positive outcome in historically immunotherapy-resistant ovarian cancer is not just about adding pembrolizumab. The regimen's success is attributed to the thoughtful use of continuous weekly paclitaxel, a form of metronomic chemotherapy known to have favorable immunogenic effects, which was a deliberate, science-backed choice.
The ADC mirvetuximab is the first drug to demonstrate an overall survival benefit for platinum-resistant ovarian cancer. This groundbreaking result establishes a higher efficacy standard that subsequent therapies will likely need to meet for regulatory approval and clinical adoption, raising the bar for future drug development.
The future of GYN oncology immunotherapy is diverging. For responsive cancers like endometrial, the focus is on refining biomarkers and overcoming resistance. For historically resistant cancers like ovarian, the strategy shifts to using combinatorial approaches (e.g., CAR-NKs, vaccines) to fundamentally alter the tumor microenvironment itself, making it more receptive to an immune response.
While KEYNOTE-905 showed dramatic survival benefits with neoadjuvant plus adjuvant EV-pembrolizumab, its design makes it impossible to isolate the benefit of each phase. The high (57%) pathologic complete response after neoadjuvant therapy alone suggests many patients may be overtreated with adjuvant cycles, risking unnecessary long-term toxicity like neuropathy.
Historically, therapies for platinum-resistant ovarian cancer were so ineffective that the order of administration was irrelevant. With the advent of multiple active ADCs, the concept of treatment sequencing and potential cross-resistance based on payloads or targets has become a critical, and entirely new, clinical consideration for this disease.