In a randomised, double-blind, multicentre, placebo-controlled phase III COMPASSION-16 study, adding cadonilimab, a bispecific antibody targeting PD1 and CTLA-4, to first-line standard chemotherapy with or without bevacizumab significantly and clinically meaningfully improved progression-free survival (PFS) and overall survival (OS) in patients advanced cervical cancer. The benefit of cadonilimab was generally consistent across protocol-specified subgroups.
COMPASSION-16 was conducted in China and is the largest first-line cervical cancer trial conducted in an Asian population to date. The safety profile was tolerable and manageable. The findings are reported by Prof. Xiaohua Wu of the Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center in Shanghai, China, and colleagues on 16 October 2024 in The Lancet.
More than half of all global cervical cancer cases are estimated to be in Asia, but previous clinical trials (GOG 240, KEYNOTE-826, and BEATcc) have included few or no Asian patients. For the past decade, the first-line standard-of-care for patients with persistent, recurrent, or metastatic cervical cancer has been platinum-based chemotherapy, with the option of adding bevacizumab.
The phase III KEYNOTE-826 study showed that pembrolizumab in combination with the existing standard treatment improved PFS and OS in patients with PD-L1 expression; however, this treatment regimen did not confer a survival benefit in patients with tumours with a PD-L1 combined positive score (CPS) less than 1. The phase III BEATcc study found that atezolizumab in combination with chemotherapy and bevacizumab statistically significantly improved PFS and OS compared with chemotherapy and bevacizumab.
The authors wrote in the background that anti-CTLA-4 and anti-PD1 have similar but non-redundant negative effects on T-cell activity, and the combination of CTLA-4 and PD1 blockers has shown enhanced efficacy and prolonged survival across different metastatic solid tumours. The co-administration of CTLA-4 and PD1 blockers showed promising antitumour effects in the second-line treatment of advanced cervical cancer but with high rates of adverse events.
Cadonilimab is a bispecific antibody that simultaneously blocks PD1 and CTLA-4 pathways. It has a higher binding avidity in a high-density PD1 and CTLA-4 setting (i.e. tumour microenvironment) than in a low-density PD1 setting (i.e. normal peripheral tissues), thus achieving lower toxicities and enhanced antitumour activity.
In the phase II COMPASSION-13 study, cadonilimab plus chemotherapy with or without bevacizumab as first-line treatment showed encouraging antitumour activity in patients with cervical cancer with an objective response rate of 79.3%, and 75.0% even in patients with PD-L1-negative tumours. In the phase III COMPASSION-16 study, the researchers evaluated the addition of cadonilimab to first-line standard chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer.
Women aged 18-75 years across 59 clinical sites in China with previously untreated persistent, recurrent, or metastatic cervical cancer were randomly assigned 1:1 in the COMPASSION-16 study to receive cadonilimab 10 mg/kg or placebo plus platinum-based chemotherapy with or without bevacizumab every 3 weeks for six cycles, followed by maintenance therapy every 3 weeks for up to 2 years.
Stratification factors were the use of bevacizumab (yes or no) and previous concurrent chemoradiotherapy (yes or no). The dual primary outcomes were PFS as assessed by blinded independent central review and OS in the full analysis set. This study has completed enrolment and is ongoing for treatment and follow-up.
A total, 445 eligible women were enrolled between 11 September 2021 and 23 June 2022. Median PFS was 12.7 months (95% confidence interval [CI] 11.6–16.1) in the cadonilimab group and 8.1 months (95% CI 7.7–9.6) in the placebo group with hazard ratio (HR) of 0.62 (95% CI 0.49–0.80, p < 0.0001). Median OS was not reached (95% CI 27.0 months to not estimable) versus 22.8 months (95% CI 17.6–29.0) with HR of 0.64 (95% CI 0.48–0.86, p = 0.0011).
The subgroup analysis showed that the addition of cadonilimab could improve PFS and OS regardless of the use of bevacizumab. In particular, the HR for PFS was 0.46 and the HR for OS was 0.50 in the subgroup without concomitant bevacizumab. The study investigators speculated that the efficacy shown in the subgroup without bevacizumab use could be attributable to the combined anti-PD1 and anti-CTLA-4 activity of cadonilimab. They stated that cadonilimab might offer a more suitable treatment option for individuals who are not eligible for bevacizumab.
The safety profiles of both regimens were as expected with no new safety signals emerged. The incidence of adverse events of any cause and treatment-related adverse events was similar in the cadonilimab group and placebo group; the incidence of adverse events and treatment-related adverse events of grade 3 or above was also similar in the two groups, suggesting that the addition of cadonilimab did not increase the toxicity of the regimen.
The common adverse events in both groups were known haematologic toxicity associated with chemotherapy, which were manageable. The most common grade 3 or higher adverse events were decreased neutrophil count, decreased white blood cell count, and anaemia. As anticipated, immune-related adverse events occurred in 46% of the patients in the cadonilimab group, the majority of which were grade 1 or 2. Grade 3–4 immune-related adverse events occurred in 10% of the patients in the cadonilimab group.
In an accompanied comment, Drs. Chaoyang Sun and Ding Ma of the Department of Gynecological Oncology and National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College and Huazhong University of Science and Technology in Wuhan, China wrote that cervical cancer is primarily driven by human papillomavirus infection, rendering it an immunogenic tumour type.
A substantial proportion of cervical cancers exhibit PD-L1 positivity. Therefore, the role of PD-L1 as a biomarker to predict cervical cancer sensitivity to immunotherapy, particularly in selecting individuals who would benefit most from such treatments, warrants serious attention. Whether to select target individuals based on PD-L1 status requires careful consideration of several factors, including treatment settings, therapeutic agents (PD-1 antibodies, PD-L1 antibodies, or bispecific antibodies), and the use of monotherapies or combination therapies (with chemotherapy or anti-angiogenic agents).
Concerning the contribution of bevacizumab when used alongside immunotherapy, the commentators wrote that although no definitive conclusions can be drawn, post-hoc analyses from COMPASSION-16 suggest that cadonilimab confers greater advantages for individuals not receiving concurrent bevacizumab than for those who do, with an HR of 0.46 versus 0.81 for PFS and 0.50 versus 0.84 for OS.
In contrast, KEYNOTE-826 indicated slightly higher HRs for pembrolizumab when added to chemotherapy without bevacizumab. Given that bevacizumab has shown a proven OS benefit when added to chemotherapy, it is recommended to administer bevacizumab alongside chemotherapy and immune checkpoint inhibitors whenever feasible. For individuals’ ineligible for bevacizumab, who might be more frail or have more comorbidities, cadonilimab might represent a more appropriate treatment option.
As the KEYNOTE-A18 study furthers the application of pembrolizumab in newly diagnosed, high-risk, locally advanced cervical cancer, it also prompts consideration for subsequent therapies in individuals progressing after anti-PD1 therapy, who might benefit from alternative pathways targeting PD-L1, bispecific antibodies, or novel immunotherapy strategies such as antibody–drug conjugates or cellular-based therapies.
The study was supported by Akeso Biopharma.
References
- Wu X, Sun Y, Yang H, et al. Cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer (COMPASSION-16): a randomised, double-blind, placebo-controlled phase 3 trial in China. The Lancet; Published online 16 October 2024. DOI: https://doi.org/10.1016/S0140-6736(24)02135-4
- Sun C, Ma D. Embracing more treatment choices for metastatic, recurrent, or persistent cervical cancer. The Lancet; Published online 16 October 2024. DOI: https://doi.org/10.1016/S0140-6736(24)02196-2