A randomized phase 2 clinical trial recently investigated the efficacy and safety of combination versus sequential immune checkpoint inhibitor therapy in patients with recurrent platinum-resistant high-grade serous ovarian cancer (HGSOC). The study, published in Cancer on October 19, 2023, was conducted at The University of Texas MD Anderson Cancer Center and funded by AstraZeneca and the National Institutes of Health.
The trial aimed to compare the progression-free survival (PFS) of patients receiving either sequential or combination therapy with tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-L1). This study is particularly noteworthy as single-agent immune checkpoint inhibitors have shown limited responses in recurrent ovarian cancer, although 30-40% of patients achieve stable disease. By exploring different administration strategies, the researchers hoped to identify a more effective approach for this challenging patient population.
The study enrolled 61 patients with platinum-resistant HGSOC, who were randomized to either a sequential arm (n=38) or a combination arm (n=23). In the sequential arm, patients received tremelimumab followed by durvalumab upon disease progression. The combination arm received tremelimumab plus durvalumab concurrently, followed by durvalumab maintenance. The trial utilized a Bayesian adaptive design, which allowed for more patients to be randomized to the more effective arm as the study progressed.
Inclusion criteria required patients to have platinum-resistant or refractory disease, defined as a platinum-free interval of less than 6 months or progression on platinum-based therapy. There were no limitations on the number of prior treatment regimens, reflecting a heavily pretreated population. Patients were required to have measurable disease according to modified RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Exclusion criteria included prior treatment with adoptive T-cell therapy, PD-1/PD-L1 inhibitors, or anti-CTLA-4 therapy.
The demographic data showed a median age of 60 years, with the majority of patients being White (78.7%) and having an ECOG score of 0 (77.0%). Patients had received a median of four prior lines of cytotoxic chemotherapy, ranging from 1 to 10 lines. This highlights the advanced nature of the disease in this cohort and the limited treatment options available for these patients.
The primary endpoint of the study was immune-related PFS (irPFS). Secondary objectives included assessment of treatment-related toxicity, overall survival (OS), objective response rate, and clinical benefit rate. The researchers also incorporated patient-reported outcomes (PROs) to better understand the impact of treatment on quality of life.
Results of the trial showed no significant difference in PFS between the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) and the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p=0.402). Similarly, there was no difference in median OS between the two arms (10.61 months vs. 7.26 months, p=0.810). The objective response rate was low in both arms, with no responses observed in the sequential arm and only two partial responses (8.7%) in the combination arm.
Interestingly, the clinical benefit rate, which included stable disease, was higher in the sequential arm. Twelve patients (31.6%) in this arm achieved stable disease with a median duration of 3.65 months. This finding supports the initial hypothesis that sequential administration of immune checkpoint inhibitors may serve as an alternative strategy to improve disease control in this cohort.
The safety profile was consistent with previous reports of immune checkpoint inhibitors. Grade 3 or greater immune-related adverse events occurred in 23.7% of patients in the sequential arm and 30.4% in the combination arm. The most common adverse events were elevations in hepatic and pancreatic enzymes, followed by colitis. No treatment-related deaths were reported.
Patient-reported outcomes were similar between both arms, with no statistically significant differences in mean scores. However, the researchers noted that PRO signals often preceded grade 3 adverse events, suggesting that PROs could be valuable tools for early detection and management of treatment-related toxicities in future trials.
The study has several limitations that should be considered when interpreting the results. First, the sample size was relatively small, which may have limited the power to detect significant differences between the arms. Second, only 34.2% of patients in the sequential arm actually received durvalumab, primarily due to rapid disease progression or changes in therapy. This makes it challenging to fully assess the impact of the sequential strategy as originally designed.
The authors concluded that there was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in this heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit as has been previously described in other studies.
The potential clinical impact of this study is multifaceted. While the results do not support the routine use of combination or sequential immune checkpoint inhibitor therapy in unselected patients with platinum-resistant HGSOC, they do provide valuable insights for future research directions. The higher rate of stable disease observed in the sequential arm suggests that this approach may warrant further investigation, potentially in combination with other treatment modalities or in specific subgroups of patients.
Furthermore, the integration of PROs in this trial highlights the importance of considering patient experience and quality of life in the development of new treatment strategies. The finding that PRO signals often preceded grade 3 adverse events could inform future trial designs and clinical practice, potentially allowing for earlier intervention and improved management of treatment-related toxicities.
In conclusion, this study adds to the growing body of evidence on the use of immune checkpoint inhibitors in ovarian cancer. While the results were not as promising as hoped, they provide important data to guide future research efforts. The field continues to evolve, and ongoing studies exploring combinations with other agents, such as antiangiogenic therapies or targeted agents, may yet reveal more effective strategies for this challenging patient population. As always, careful patient selection and consideration of individual risk-benefit profiles will be crucial in determining the most appropriate treatment approach for patients with recurrent platinum-resistant ovarian cancer.
References
Hinchcliff EM, Knisely A, Adjei N, et al. Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer. Cancer. 2024;130(7):1061-1071. doi:10.1002/cncr.35126
