Until recently, the long-standing standard of care for locally advanced cervical cancer was chemoradiation followed by brachytherapy boost. Though outcomes with this approach are reasonable, there is significant room for improvement particularly among patients with stage III-IV disease, who had a 5-year overall survival (OS) of just 49% on the EMBRACE trial. In the last year, the presentation and publication of the INTERLACE and KEYNOTE-A18 trials have made induction chemotherapy and concurrent+consolidative immunotherapy, respectively, standard treatment options. However, prior to their publication, other approaches intended to synergize with chemotherapy were under investigation.
At least 95% of cervical cancers are related to human papilloma virus (HPV). In theory, this could represent a potential therapeutic target specific to cancer cells. However, to date there are no Food and Drug Administration (FDA) approved HPV-specific immunotherapies available. Grippin et al. sought to address that possibility in their Phase II IMMUNOCERV trial (NCT04580771) that evaluated a vaccine (PDS0101) that contains peptide pools encoding E6/E7 antigens, which are known to be expressed on HPV-related cancers, in patients with locally advanced cervical cancer undergoing chemoradiation. As part of the study, PDS0101 was administered on days -10, 7, 28, and 49 (+/- 5 days) in relation to the start of chemoradiation.
The trial was designed to include 35 patients but was closed early after 17 patients were accrued due to the aforementioned change in standard of care. Overall, a not insignificant 47% of patients experienced acute grade 3+ toxicity. Notably this is consistent with rates of about 46% seen in other landmark trials in cervical cancer (Rose, NEJM 1999; Rose, JCO 2007; Keys, NEJM 1999; Morris, JCO 1999; Eifel, JCO 2004). However, when examining toxicities that were thought to be specific to PDS0101, the most common toxicity was injection site reactions in 71% of patients. There was limited high-grade toxicity with single incidences of Grade 3 urticarial allergic reaction and Grade 2 pain. At four-month follow-up, 58.8% of patients achieved a complete metabolic response (CMR) but notably 88.8% of the eight patients who received all five PDS1010 injections achieved a CMR. Remarkably, all eight of the patients were alive and disease-free at three-year follow-up. In the overall cohort, three-year OS and progression-free survival were 84.4% and 74.9% respectively.
Although this study is limited by its early closure, the results are certainly compelling and suggest there may be a benefit to adding HPV-directed treatment in cervical cancer, particularly in more advanced stage patients. Importantly, it also did not appear to add toxicity relative to historical controls. Per Adam Grippin, MD, PhD: “These encouraging outcomes in this very high-risk patient population support further investigation of HPV-directed therapy in patients with HPV-positive cervical cancer. Our future work will consider combinations of cancer vaccines with immune checkpoint blockade, which we hope will further improve outcomes for patients with advanced stage disease.” Indeed, future questions may seek to answer whether such a targeted immunotherapeutic approach may be preferable to pembrolizumab or induction chemotherapy from a toxicity standpoint if efficacy is equivalent. Alternatively, combined regimens including PDS0101 with induction chemotherapy, pembrolizumab, or both may have the potential to further enhance outcomes in high-risk patients. Regardless, it is encouraging that there is another promising therapeutic option that may be available to women with cervical cancer and harnessing targeted biologic methods appears to be an ideal way of maximizing efficacy while off-target limiting toxicity.
Abstract 298 - IMMUNOCERV Phase II Trial Combining the HPV-Specific T Cell Immunotherapy PDS0101 with Chemoradiation for Treatment of Locally Advanced Cervical Cancer was presented during the SS 34 - GYN 2: Strategies and Innovations of Clinical Trials in Gynecologic Cancers session of ASTRO’s 66th Annual Meeting.
