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January 28, 2022

Cervical cancer: dual checkpoint inhibition is the future of immunotherapy

Pharmaceutical companies are assessing the use of combination immune checkpoint inhibition to improve response rates in the cervical cancer setting.

By GlobalData Healthcare

In 2018, Merck’s Keytruda (pembrolizumab) was the first programmed cell death protein 1 (PD-1) checkpoint inhibitor to receive FDA approval for the second-line treatment of programmed death-ligand 1 (PD-L1)-positive tumours in the persistent, recurrent, or metastatic cervical cancer setting. The approval was based on a 14% response rate reported from the KEYNOTE-158 trial. The EMPOWER-Cervical-1 trial investigated Sanofi and Regeneron’s PD-1 inhibitor Libtayo (cemiplimab), in the same disease setting, and reported a similar response rate of 16% in patients with PD-L1-positive tumours.

Pharmaceutical companies are assessing the use of combination immune checkpoint inhibition to improve response rates in the cervical cancer setting. Checkpoint inhibitors under investigation in the second-line include antibodies against CTLA-4, TIGIT, and LAG 3, in combination with an anti-PD-1 or anti-PD-L1 antibody. Agenus has announced a response rate of 32.8% for its zalifrelimab (anti-CTLA-4) and balstilimab (anti-PD-1) combination therapy in patients with PD-L1-positive tumours treated in the RaPiDs Phase II trial, with the combination receiving fast track designation from the FDA in 2020. Akeso Biopharma’s AK104 (cadonilimab) is a bispecific checkpoint inhibitor targeting PD-1 and CTLA-4, with the company reporting a response rate of 43.8% for PD-L1-positive tumours in the second line, further demonstrating the superior efficacy of dual checkpoint inhibition. AK104 has received FDA orphan drug and breakthrough therapy designation for the treatment of cervical cancer.

Roche’s tiragolumab (anti-TIGIT) is being investigated in the Phase II SKYSCRAPER-04 trial, in combination with Roche’s Tecentriq (atezolizumab) (anti-PD-L1) as a second-line cervical cancer therapeutic. Bristol Myers Squibb’s (BMS’s) anti-LAG 3 antibody, relatlimab, is being trialled in combination with Opdivo (nivolumab) (anti-PD-1) in a Phase I/II trial in cervical cancer patients, with the combination achieving positive results in melanoma patients. The combination of BMS’s Opdivo and Yervoy (ipilimumab) (anti-CTLA-4) is being investigated in the Phase I/II CheckMate-358 study. While there were initial concerns over the toxicity of dual checkpoint inhibition, Agenus and Akseo Biopharma have both reported acceptable toxicity and tolerability profiles for combined PD-1 and CTLA-4 inhibition in cervical cancer patients.

In October 2021, the FDA approved the movement of Keytruda into the first line, in combination with the standard of care, Roche’s Avastin (bevacizumab), and chemotherapy. The addition of Keytruda improved the response rate of first-line therapy from 48% to 66% in PD-L1-positive patients, and increased progression-free survival by 2.2 months. However, Akeso Biopharma believes that this response rate can be improved further with dual checkpoint inhibition, and has reported an initial response rate of close to 77% for the first 13 patients enrolled in its Phase III trial of AK104, in combination with Avastin and chemotherapy. It remains to be seen whether this impressive response rate will be maintained on trial completion. Akeso Biopharma has also announced a planned Phase III trial of AK104, in combination with chemoradiation in the locally advanced disease setting. Akeso expects this agent to outperform Keytruda and AstraZeneca’s Imfinzi (durvalumab), which are currently undergoing trials in this patient population.

Current trials for combination checkpoint inhibition have been conducted in checkpoint-naïve patients. With the approval of Keytruda in the first line, the number of checkpoint-naïve patients in the second-line setting is expected to be small. For combination checkpoint inhibition to achieve a substantial patient share in the cervical cancer setting, the combination would need to outperform checkpoint inhibitor monotherapy in the locally advanced or first-line setting. Alternatively, key opinion leaders interviewed by GlobalData have suggested that combination checkpoint inhibition may be feasible as a second-line treatment option in patients who have received prior checkpoint inhibition monotherapy. However, clinical trials would be required in this population to demonstrate efficacy.

Combination checkpoint inhibition is an exciting strategy in the cervical cancer setting, with evidence of improved efficacy, compared to checkpoint inhibitor monotherapy. This strategy will prove to be highly lucrative if approval can be gained in the locally advanced or first-line setting, or in patients with prior checkpoint exposure. GlobalData expects global annual sales for combination checkpoint inhibition to exceed $300 million by 2030.

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