Novel combinations in gynaecologic cancer

Prof Dr Christine Gennigens, a medical oncologist at the University Hospital of CHU de Liège, Belgium, summarised the “Stronger Together: Novel Combinations Across the Gynaecological Cancer Spectrum” session at ASCO 2024.

The session featured three abstracts focusing on various drug combinations for cervical, endometrial, and ovarian cancers. These combinations aim to overcome drug resistance, provide additive or synergistic effects, and target multiple components of major pathways or both primary and compensatory pathways, ultimately improving clinical outcomes.

The TORCH-2 study is a Phase I/II open-label, dose-escalation, expansion study in solid tumours, investigating onotasertib (a next-generation mTOR inhibitor) and toripalimab (a PD-1 inhibitor). The study included 31 cervical cancer patients who had undergone at least one prior systemic treatment, with most having SCC and about 40% showing PD-L1 overexpression by TPS score. The ORR was approximately 53%, with a DCR of 86%, regardless of PD-L1 expression. Safety data indicated that 40% of patients experienced grade 3 or higher treatment-related adverse events, primarily rash and decreased lymphocyte and platelet counts. This study is the first to test a combination of mTORC1/2 and PD-L1 inhibitors, showing impressive ORR. However, no data on activity or biomarkers beyond PD-L1 have been identified related to this response.

The CAPRI study is a Phase I/II trial involving dose expansion and dose escalation of ceralasertib combined with olaparib in patients with high-grade serous ovarian cancer. Earlier data from cohort C, consisting of platinum-sensitive, HRD-positive patients who progressed on prior PARP inhibitors, were presented at ASCO 2021. The current results are from cohort A, including 37 patients with platinum-sensitive recurrence and no progression on a PARP inhibitor. Most patients did not have germline mutations, and 60% were HRD-negative. The ORR was 49%, irrespective of HRD status. The toxicity profile showed about 40% of patients experienced grade 3 adverse events, mainly anaemia and diarrhoea, consistent with findings from olaparib monotherapy.

In a phase 2, open-label, single-arm trial, the combination of fulvestrant with abemaciclib was evaluated in patients with hormone receptor-positive advanced or recurrent endometrial cancer. The trial included 27 patients, predominantly with endometrioid cancer. Approximately 40% had received prior hormonal therapy, with 96% showing estrogen receptor expression and 70% progesterone receptor positivity. The ORR was 44%, slightly higher in patients without previous hormonal therapy, with a DOR of 15 months. This combination was well-tolerated, and molecular analysis indicated better results in the copy-number low and non-molecular-specific groups. However, the trial’s small size and non-randomized nature are limitations. In the EMBER trial, imlunestrant, another selective estrogen receptor degrader, is tested in combination with abemaciclib.