In November 2023, PDS Biotech announced that the results of the Phase II VERSATILE-002 trial dictate the initiation of a registrational Phase III trial for its immunotherapy asset PDS0101 in human papillomavirus (HPV)-16-positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Previously, the Phase III KEYNOTE-048 study established Merck & Co (MSD)’s Keytruda (pembrolizumab) as the standard of care (SOC) in this patient population with or without chemotherapy, dethroning Eli Lilly’s Erbitux (cetuximab). In KEYNOTE-048, the median overall survival (OS) for patients with a PD-L1 combined positive score (CPS) ≥1 was 12.3 months with Keytruda monotherapy and 13.6 months for Keytruda + chemotherapy.

PDS0101 is a liposomal multi-peptide vaccine against HPV-16, and it has been shown to activate T-cells that mediate tumour cytotoxicity in HPV-related cancers, including HNSCC and cervical cancer. The VERSATILE-002 trial enrolled 54 recurrent or metastatic HNSCC patients with CPS ≥1 who were treated with Keytruda + PDS0101. The progression-free survival (PFS) was 8.1 months, which compares favourably to the historic result of five months for Keytruda + chemotherapy. However, the most interesting result is that the 24-month OS for these patients was 74%. This is substantially higher than Keytruda + chemotherapy’s OS of 30.8% and allows enough room for error in the cross-trial comparison. Furthermore, the addition of PDS0101 did not substantially increase high-grade adverse events, as is expected from the traditionally safe class of peptide vaccines. These results allow PDS Biotech to initiate a Phase III randomised trial of PDS0101 + Keytruda in Q1 2024. The control arm has been announced to be Keytruda monotherapy, an appropriate comparison given the current SOC, with OS as the primary endpoint. The hidden risk for PDS, however, is that historically, HPV+ HNSCC patients have had more favourable outcomes. Crucially, the KEYNOTE-048 study enrolled 471 HPV-negative patients and only 130 HPV-positive patients. Thus, it is very likely that the benefit of Keytruda with or without chemotherapy was much higher for HPV-positive patients in KEYNOTE-048 but was diluted by over three times as many HPV-negative patients (no HPV subgroup OS analysis was performed). A 2014 analysis of the Radiation Therapy Oncology Group showed that patients with HPV-16-positive disease had a roughly double two-year OS (54.6%) versus 27.6% for HPV-16-negative patients after progression on systemic chemotherapy.

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Another promising asset in development by PDS Biotech, PDS0301, is an interleukin (IL)-12-targeting antibody-drug conjugate (ADC). PDS Biotech collaborated with the National Cancer Institute (NCI) to conduct the single-arm Phase II NCT04287868 study evaluating the triplet combination of PDS0101 + PDS0301 + the bispecific fusion protein, Merck KGaA’s bintrafusp alfa (TGF-β Receptor/PD-L1). in HPV-positive solid tumours. The trial included both immune checkpoint inhibitor (ICI)-naïve and ICI-resistant patients. While the ICI-resistant data was promising, the real surprise came from the ICI-naïve cohort. The triplet combination allowed 75% of patients to remain alive at three years (N=8), which compares very favourably to historic results with an expected less than 30% 3-year OS for ICI-treated patients. However, the very low number of evaluated patients dictates a larger trial in order to draw conclusions. A key factor for the success of the triplet combination is finding an acceptable toxicity-to-efficacy balance. Both the IL-12 component of PDS0301 and the transforming growth factor-β (TGF-β)-targeting part of bintrafusp alfa will certainly lead to some toxicity and treatment discontinuations based on past experience with drugs that have a similar mechanism, as well as data from the NCT04287868 study (48% Grade 3 or higher adverse events).

PDS0101 has gained an FDA fast-track designation, which makes a swift market entry over the next few years more likely. While there is a strong case to be made for the clinical success of this immunotherapy, the limiting factor towards commercial sales will be HPV positivity. A 2005 meta-analysis by the International Agency for Research on Cancer (IARC) suggests that 25.9% of all HNSCC cases are HPV-positive and that the majority of these have HPV-16. As such, if approved, PDS0101 would have a four times smaller total addressable market compared to Keytruda.

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