Nykode Therapeutics has announced interim Phase II trial results for its novel therapeutic cancer vaccine VB10.16, in combination with Roche’s anti-PD-L1 Tecentriq (atezolizumab), for the treatment of advanced cervical cancer. VB10.16 is a therapeutic DNA vaccine against human papillomavirus (HPV) 16, designed to stimulate antigen presenting cells (APCs) to produce a long-lasting CD8+ killer T-cell response against cancer cells. Chronic infection with high-risk oncogenic subtypes of HPV is the main etiological factor in cervical carcinogenesis, with HPV detected in almost all cervical cancer cases. HPV 16 is the most common subtype detected in cervical cancer, leading to the development of VB10.16 to stimulate an immune response against the HPV-positive cancer cells.

In the Phase II VB C-02 trial, 39 heavily pretreated cervical cancer patients with HPV 16-positive disease were treated with the VB10.16 and Tecentriq combination. The combination has demonstrated an overall response rate (ORR) of 21%, with two complete responses (CRs) and six partial responses (PRs). A very high disease control rate (DCR) of 64% was also reported, with a median follow-up time of six months. Importantly, anti-tumor activity was reported for both patients with PD-L1-positive (ORR of 27% and DCR of 77%) and PD-L1-negative disease (ORR of 17% and DCR of 58%).

In 2018, Merck & Co.’s anti-PD-1, Keytruda (pembrolizumab), was the first checkpoint inhibitor to receive FDA approval for the second-line treatment of advanced cervical cancer, with an ORR of 14%. The approval was limited to patients with PD-L1 positive disease. Sanofi and Regeneron’s anti-PD-1, Libtayo (cemiplimab), and Agenus’ anti-PD-1, balstilimab, have since demonstrated very similar response rates in this disease setting. Key opinion leaders (KOLs) interviewed by GlobalData found these response rates disappointing and surprising, with the expectation that checkpoint inhibitors would perform well and unleash a strong immune response against the virally induced cancer. KOLs identified combining checkpoint inhibitors with an HPV vaccine as a very promising R&D approach to try to stimulate an anti-HPV-driven immune response. Although cross-trial comparisons must be made with caution, the addition of an HPV vaccine appears to be increasing the response rates beyond that previously reported for single-agent PD-1/PD-L1 inhibition.

While these first Phase II results show promise for the use of an HPV and checkpoint combination, there is stiff competition for patient share in the cervical cancer market. In 2021, a Keytruda plus Herceptin/trastuzumab and chemotherapy combination received FDA approval for first-line use in the PD-L1-positive advanced cervical cancer setting, after showing an OS benefit over Herceptin/trastuzumab and chemotherapy. This means that the majority of patients are likely to be checkpoint inhibitor-exposed in the first line, making them unsuitable candidates for this novel vaccine/PD-L1-inhibitor combination in the second line, with checkpoint inhibitor-exposed patients excluded from this trial.

Furthermore, there are multiple checkpoint inhibitor combinations currently in trials, including Agenus’ balstilimab and zalifrelimab (anti-CTLA-4), Roche’s Tecentriq and tiragolumab (anti-TIGIT), Bristol Myers Squibb’s (BMS’s) relatlimab (anti-LAG-3) and Opdivo (nivolumab, anti-PD-1), and Akeso’s AK104, a bispecific anti-PD-1/CTLA-4 tetrameric antibody. Both Agenus and Akeso have reported impressive response rates in Phase II trials, with an ORR of 32.8% for the balstilimab and zalifrelimab combination and an ORR of 43.8% for AK104. Therefore, it remains to be seen whether combination checkpoint inhibition or a combination of checkpoint inhibition and vaccination provides a superior clinical benefit in the cervical cancer setting.