Discussion
cancers, HPV-associated anogenital cancers, pembrolizumab, tumor, toxicity, cancer, immune-suppressed tumor, HPV-associated cancers, HPV-associated malignancies, anal cancer, penile cancer
CANCERS, TUMOR, CANCER, DISEASE, CERVICAL CANCER, ANAL CANCER, ANAL CANCERS, PENILE CANCER
While the benefit of combination immunotherapy has yet to be demonstrated in patients with previously treated, advanced HPV-associated anogenital cancers, we present here intriguing pilot data that demonstrates prolonged disease control in multiple participants following treatment with durvalumab and the HPV-16/18 E6/E7 DNA vaccine MEDI0457. Here, durable responses occurred in persons with cervical cancer, anal cancer, and penile cancer alike. Overall, this treatment combination appeared safe and well-tolerated, with no DLTs observed and no suggestion of unacceptable toxicity.Anti-PD-1 antibodies as monotherapy have yielded modest response rates for treatment of incurable HPV-positive cancers. For example, in patients with advanced cervical and anal cancers, pembrolizumab demonstrated response rates of 12% and 10%, respectively.In our study, the overall response rate of durvalumab and MEDI0457 demonstrated an ORR of 21%. Notably, the cervical cancer and non-cervical cohorts were conducted independently in parallel, and responses were observed in 10% and 33% of participants, respectively. While the response rate in the initial stage did surpass the prespecified boundary for expansion in the non-cervical (anal/penile) cancer group, these criteria were not satisfied in the cohort of patients with cervical cancer, with a response noted only in 1 patient. Because the required response rate was not satisfied in all cohorts, further expansion for additional patients with advanced HPV-associated cancers to receive durvalumab and MEDI0457 was not pursued.Median progression-free survival for the entire study population was 4.6 months and similar for both cohorts. Those participants were able to experience durable disease control suggests that some patients with HPV-associated malignancies may derive clinical benefits with stimulation by a therapeutic vaccine targeting HPV-specific antigens. In a separate study of patients with advanced HPV-16 head/neck, cervical, and anal cancers, treatment with nivolumab and an HPV-16 specific synthetic peptide achieved an overall response rate of 33% and generated an increase in HPV-16 T cells within the tumor microenvironment.We recognize limitations associated with generalizing our trial findings. Many patients received 3 or more lines of prior systemic therapy, which has been shown in other cancers to promote an immune-suppressed tumor microenvironment that may blunt responses to immunotherapy. Nonetheless, we are encouraged that some participants in our study were able to achieve extended clinical benefits with the combination of durvalumab and MEDI0457 beyond what has historically been reported with anti-PD-(L)1 antibodies as monotherapy in patients with advanced HPV-associated cancers. Based on our findings, we support continued investigation of novel strategies in combination with immune checkpoint blockade that prime the tumor microenvironment for rationally designed immune-mediated attack.