How PDS Biotech Approached FDA Meetings For Its Phase 3 Cancer Trial
A conversation with PDS Biotech Chief Medical Officer Kirk Shepard, MD
It can’t be overstated that talking with the FDA early and often during the trial design process is a must-do for clinical-stage drug companies. In this Q&A, PDS Biotech CMO Kirk Shepard shares his team’s interactions with the FDA as it sought to begin its Phase 3 trial for Versamune® HPV (formerly PDS0101) + pembrolizumab for HPV-positive recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the first quarter of 2025.
PDS Biotech and the FDA discussed data from the VERSATILE-002 study of Versamune® HPV + pembrolizumab for the Phase 3 VERSATILE-003 trial of Versamune® HPV + pembrolizumab. What was the type of meeting called, and what was its purpose?
The FDA granted PDS Biotech Fast Track designation for the development of Versamune® HPV + pembrolizumab for HPV-positive R/M HNSCC, also referred to as head and neck cancer. Hence, we had multiple discussions with the FDA. We initially had a Type B End of Phase 2 (EOP2) meeting on August 29, 2022, to discuss the interim results of the VERSATILE-002 trial and potential Phase 3 design. A Type B meeting is a formal milestone meeting held at the end of a phase, such as Phase 1 or 2 or before Phase 3. We had a more recent Type D meeting on September 28, 2023, in which we discussed the key details of the current Phase 3 design. A Type D meeting is focused on a defined set of one to two issues that include feedback after a formal meeting on new issues or follow-up questions and clarifications to support a program. Subsequently we have revised the Phase 3 protocol based on FDA feedback and submitted the protocol as final to the FDA.
How did you prepare for these meetings with the FDA?
We always prepare for such meetings with full team meetings involving regulatory, legal, medical, clinical operations, R&D and chemistry, manufacturing, and controls (CMC). The goal is to ensure that our questions address the critical areas where we need FDA guidance and that we are clear in our presentation of the background data, CMC, and clinical plan. We also try to anticipate any potential outcomes of the questions that may lead to additional questions from PDS Biotech and exactly how the questions should be presented to enable PDS Biotech to obtain the necessary information. We also decided on the PDS Biotech meeting attendees, including those who will facilitate the interactions with the FDA. This is most often our head of regulatory affairs and our chief medical officer.
What were the outcomes?
The outcome from each meeting was clear guidance on study design, including patient population, clinical endpoints, statistical approach, and ultimately, alignment between FDA and PDS Biotech on the path forward. For our pivotal phase 3 VERSATILE-003, median overall survival was the recommended primary endpoint from the FDA. It has become apparent to most investigators and the FDA that increased Objective Response Rate (ORR) and Progression Free Survival (PFS) have not resulted in improved patient overall survival or OS in many clinical trials, especially in R/M HNSCC. Historically, in two large competitor drug major trials in R/M HNSCC, KEYNOTE-048 and LEAP-010, the increased ORR and PFS in the EGFR-chemotherapy and lenvatinib-pembrolizumab combination arms did not result in increased OS over pembrolizumab alone. The FDA has made it very clear to us that the approval will be based on OS. The FDA also provided guidance on the timing of our interim data readout and designing our trial with OS as the main interim endpoint allowing for consideration of an accelerated approval.
Reflecting on the meeting, what did you learn from it (perhaps something that went well or something that could have gone better) to prepare you for “next time”?
We have found that our meetings with the FDA always have been constructive. With the right preparation, we obtain relevant feedback to guide our clinical development plan. If anything, we have learned that cross-functional input at PDS Biotech is critical to this preparation process so that we provide the FDA with a comprehensive list of questions as well as critical background information for them to consider.
In a recent release, PDS Biotech indicated that “The FDA supported the strategy and development of the double and triple combinations.” What does that support look like?
Both the combination of Versamune® HPV and pembrolizumab and the triple combination of Versamune® HPV, PDS01ADC, and pembrolizumab have provided encouraging survival of 30 months and >43 months, respectively. The best survival reported to date is 17.9 months. PDS Biotech engaged the FDA in a Type C meeting on July 1, 2024, to discuss our plans for a three-arm Phase 3 trial including the double and triple combinations vs. pembrolizumab control. The FDA agreed with us that the combination of Versamune® HPV + pembrolizumab vs. pembrolizumab presents the most efficient and optimal regulatory pathway for the Phase 3 trial, and that agreement was recorded in the meeting minutes.
The same release also indicated that “[t]o avoid potential delays in initiating the randomized trial, the FDA agreed that the dose optimization should be done separately and the registrational trial of the revised 2-arm double combination trial, VERSATILE-003, should proceed.” How will the dose optimization be run separately? And given its independence from the revised 2-arm double combination trial, what is the benefit of doing so?
At the July 1, 2024 meeting, PDS Biotech and the FDA discussed the dose optimization study of PDS01ADC in the context of the triple combination as the first part of the Phase 3 trial since this would be the first time these three agents would be used together. The FDA agreed that dose optimization of PDS01ADC would be required before evaluating the triple combination in the controlled portion of the suggested pivotal trial. As explained above, PDS Biotech decided to proceed with Phase 3 for the double combination of Versamune® HPV + pembrolizumab, which would be the fastest path to approval for Versamune® HPV. While this study is being conducted, PDS Biotech can perform the triple combination dose optimization to advance that program. Of note, initial approval of Versamune® HPV would also expedite the regulatory pathway for the triple combination as then PDS01ADC would be an investigational agent combined with two approved agents.
The release also mentioned talks with a CRO have begun. What criteria did you use to identify the best CRO for this trial? Will you retain your previous CRO from VERSATILE-002? Why/why not?
Our standard operating procedure is to conduct a request for proposal process in which we ask potential CROs to provide detailed information about their company, the processes, and people that would be used to conduct the study, and the estimated cost. Just because a CRO has been used in Phase 2 doesn’t mean that they should be a shoe-in for the Phase 3 trials. Some CROs because of their size, international reach, or skills may not transition well into the role of a Phase 3 pivotal international trial. Other considerations should be the CRO’s performance in past trials (either with you or other companies), the specific team or talents that will be dedicated to your trial (with the assurance that that those team members will remain dedicated to your study and not switched to another company’s study), and of course the consistency of unit costs. For our Phase 3 trial, there were three finalists. We selected a midsize CRO with deep oncology experience and expertise in performing global trials and working with emerging biotech companies like PDS Biotech.
Finally, and ultimately, what will this trial design help accomplish? And what does that mean for patients?
Incidences of HNSCC have been reported to be on a steep rise. This increase in incidence is driven almost exclusively by HPV16. This design has the potential to demonstrate the safety and efficacy of Versamune® HPV plus pembrolizumab when compared to pembrolizumab in treating HPV16-positive recurrent/metastatic HNSCC. The HPV16-positive disease is reported to be the most prevalent type of oropharyngeal head and neck cancer in the U.S. and EU. Of note, HPV-positive HNSCC is pathologically distinct from HPV- negative disease, with a different prognosis and response to treatment. Acknowledging this, several treatments in development are focusing on HPV-negative disease, which leaves a gap for new treatments for HPV-positive HNSCC, which constitutes a growing unmet medical need. Versamune® HPV provides a targeted cancer therapy specifically targeting HPV16. If our study is positive, Versamune® HPV would be a novel option for patients with HPV16-positive recurrent/metastatic HNSCC that may more effectively shrink tumors and may provide enhanced patient survival with good quality of life benefit.
About The Author:
Kirk Shepard, MD is the chief medical officer at PDS Biotechnology. Dr. Shepard is a US board-certified medical oncologist and hematologist physician, who received his fellowship oncology and hematology training at the University of Chicago Medical Center and then was on the hematology-oncology staff at the Cleveland Clinic Foundation before transitioning to the pharmaceutical industry. Dr. Shepard has served in leadership positions for over 30 years in the pharmaceutical industry at companies that have included Boehringer Ingelheim, Takeda, Baxter, and Baxalta. Before PDS, he was CMO and head of GMA at Eisai OBG. He is a co-founder of the Medical Affairs Professional Society (MAPS), which currently has over 13,000 members worldwide, and in 2016-17 he was president of MAPS. He received his BA from Cornell University in Ithaca, NY.