Versamune HPV Could Bolster Long-Term Efficacy With Pembrolizumab in HPV16-Driven HNSCC

The growing incidence of head and neck squamous cell carcinoma (HNSCC) worldwide, driven by rising human papillomavirus (HPV)–related cases, is raising concerns about the increasing burden of this disease in the next decade.¹

“In recent times, we’ve seen a change in the demographic of who presents with HNSCC, particularly in terms of its etiology, with HPV-related cancers becoming more and more common in the developed world and also now increasingly throughout the globe,” Kevin Harrington, BSc, MBBS, PhD, MRCP, FRCP, FRCR, stated in an interview with OncologyLive.“It’s likely to lead to an increase in the overall number of patients diagnosed with HNSCC in the coming decade.” Harrington is a professor in Biological Cancer Therapies at The Institute of Cancer Research as well as a consultant clinical oncologist and joint head of the Division of Radiotherapy and Imaging at The Royal Marsden NHS Foundation in Chelsea, England.

“There are a lot of reasons for HPV vaccination hesitancy or lack of uptake, and that’s a complicated, multifactorial issue, “Katharine Price, MD, an associate professor of oncology and consultant at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, noted in a concurrent interview. “Certainly, health care access plays a role in that, [as does] health care delivery to more rural areas, or less understanding of the real reason for HPV vaccination. When we look at access to care for somebody who has cancer, we know that rural areas are more challenging, and we see differences in outcomes.”

This delay in, or lack of access to, vaccination coverage means that, despite improvements in cure rates for HNSCC and overall good prognosis, the expanding pool of patients with HPV-driven cancer and the risk for disease progression or recurrence after receiving initial curative treatments is becoming a more pressing challenge, underscoring the need for effective first-line therapies and potentially novel treatment combinations.

“[Unmet needs] are a bit lost in some of the conversation these days about HPV-driven HNSCC,” Jared Weiss, MD, told OncologyLive. “The big story here is that these cancers are easier to cure, if you look at the landscape of locally advanced disease…at first glance, there wouldn’t seem to be an unmet need in the recurrent metastatic setting. The problem is that, because of slow uptake of preventive vaccination in pediatric populations, the epidemic of HPV-driven HNSCC will not peak until sometime in the 2030s. Although we may cure a larger proportion of patients, the denominator of patients at risk for [progressing on curative therapies] is rapidly rising.” Weiss is a professor of medicine in the Division of Oncology, Department of Medicine at and section chief of Thoracic and Head/Neck Oncology at the University of North Carolina (UNC) School of Medicine in Chapel Hill.

Researchers Double Down on Vaccine Development to Boost Immunotherapy Outcomes Amid Rising Incidence of HPV16-Driven HNSCC

Pembrolizumab (Keytruda) with or without chemotherapy, has become a cornerstone in the first-line treatment of patients with unresectable recurrent or metastatic HNSCC.² This shift in the standard of care (SOC) followed data from the phase 3 KEYNOTE-048 trial (NCT02358031), which demonstrated the efficacy of pembrolizumab both as monotherapy and in combination with chemotherapy.³ Subsequent data from the phase 4 KEYNOTE-B10 trial (NCT04489888) confirmed the safety and efficacy of pembrolizumab with carboplatin and paclitaxel, validating chemoimmunotherapy’s role in the upfront treatment landscape for recurrent or metastatic HNSCC.⁴

“When I was trained in HNSCC, I was taught that the cure rate for recurrent metastatic disease was essentially zero” Weiss said. “That was happily violated with KEYNOTE-048, where we saw that we could provide durable control [with pembrolizumab]. Now, 10 years after phase 1, we can use the word ‘cure’ for a small but non-zero portion of the population. Ever since, the field of oncology research in general has been desperately seeking to raise that tail to provide a cure, or something that looks as close as possible to cure, to a greater proportion of patients.”

Despite this, standard chemotherapy or immuno-oncology regimens alone often fall short in achieving long-term disease control for those with HPV16-positive disease.³ Furthermore, nearly half of these patients may not proceed to second-line therapy, highlighting the need for optimal first-line approaches that extend survival, reduce toxicity, and improve quality of life.

“At the present time, neither single-agent pembrolizumab nor the pembrolizumab chemotherapy combination delivers results which are sufficiently good for this patient group, and we have still a significant unmet need both in terms of response rates, duration of response, and overall survival [OS],” Harrington reiterated.

Emerging therapeutic vaccines like the investigational immunotherapy Versamune HPV (formerly PDS0101) could provide a novel solution to the issue of long-term response and survival in this growing patient subset. Harrington explained that Versamune stimulates the uptake of HPV16 E6 and E7 antigens by dendritic cells, resulting in the production of HPV16-specific CD8 and CD4 T cells, which will attack and destroy tumor cells. The subsequent administration of an immune checkpoint inhibitor (ICI), such as pembrolizumab, could potentially restore pre-existing T-cell responses.²

Interim data from the phase 2 VERSATILE-002 trial (NCT04260126) suggest that the addition of Versamune HPV to other agents, such as the PD-1 inhibitor pembrolizumab could promote sustained disease control while maintaining a favorable safety profile without significant additional toxicity.⁵ This unique profile positions PDS0101 as a viable option to address the unmet needs of patients with HPV16-positive HNSCC in the first line, particularly for ICI-naive patients with limited therapeutic alternatives.

Initial Readouts From VERSATILE-002 Study Show Early Efficacy in ICI-Naive Population

VERSATILE-002 was designed to address the pressing need for novel therapeutic options in the subset of patients with HPV16-positive HNSCC, particularly those naive to immunotherapy. The open-label, multicenter, non-randomized, single-arm study evaluated pembrolizumab plus Versamune HPV in 2 patient cohorts of ICI-naive or -pretreated patients, respectively.⁶

Patients were required to have a histologically confirmed diagnosis of recurrent or metastatic HNSCC, confirmed HPV16 infection, and a PD-L1 combined positive score (CPS) of at least 1. Eligible patients were at least 18 years old, with an ECOG performance status (PS) of 0 or 1, and demonstrated adequate organ function.

In the ICI-naive cohort, patients could not have received prior immunotherapy for metastatic disease. In the pretreated cohort, patients must have previously received ICIs either as monotherapy or in combination, with a minimum of 6 weeks or 2 doses of treatment documented. Both cohorts also adhered to RECIST 1.1 criteria to confirm recurrent or metastatic disease, and patients were required to be free from major toxicities from prior treatments.

Upon enrollment, patients received 200 mg of pembrolizumab intravenously (IV) every 3 weeks in combination with Versamune HPV. Versamune HPV was administered subcutaneously (SC) as two 0.5 mL injections in cycles 1 through 4 and again in cycle 12.

The primary end point of the trial was best overall response (BOR) per RECIST 1.1 criteria. Secondary end points included progression-free survival (PFS), OS, safety, duration of response (DOR), and immune responses targeting HPV16 E6 and E7 antigens.

The first findings from a prespecified interim analysis of the ICI-naive cohort of VERSATILE-002 were presented at the2022 ASCO Annual Meeting, and showed that the combination met its primary efficacy end point by producing at least 4 objective responses.⁷ Among the 17 patients naive to checkpoint inhibition with a PD-L1 CPS of 1 or higher, the overall response rate (ORR) was 41.2%. This included 2 complete responses (CRs) and 5 partial responses. The regimen also demonstrated a favorable safety profile.

These data supported the FDA’s decision to grant fast track designation to Versamune HPV plus pembrolizumabin June 2022.⁸

Data presented the following year at the 2023 ASCO Annual Meeting further underscored the combination’s efficacy in the intention-to-treat (ITT) population (n = 48) of patients with ICI-naive disease.⁹ Although the median OS had not been reached, the 12-month OS rate was 87.1%. The modified ITT population (n = 34), comprising patients who underwent imaging post-treatment, experienced a median PFS of 10.4 months (95% CI, 4.2-15.3).

2024 Updates and Expanded Efficacy Data Support Phase 3 Investigation of Pembrolizumab Plus Versamune HPV

In May 2024, PDS Biotechnology, the developer of Versamune HPV, reported a BOR rate of 34% in the ICI-naive cohort (n = 53) with a PD-L1 CPS of 1 or higher.¹⁰ In patients with a higher PD-L1 CPS (20 or above), BOR increased to 48%. Additionally, the median PFS was 6.3 months for patients with a CPS of at least 1, extending to 14.1 months in those with a CPS of 20 or higher.

Following this update, OS data, which had previously been immature, were presented alongside updated safety and efficacy end points at the 2024 ESMO Congress.² At a data cutoff date of May 17, 2024, and a median follow-up of 16 months, patients with a CPS of 1 or higher (n = 53) reached a median OS of 30 months.¹¹ The ORR in this population was 35.8%, with CRs in 9.4% of patients, and a disease control rate (DCR) of 77.4%.² Notably, 21% of patients demonstrated significant tumor shrinkage between 90% and 100%. Out of those initially enrolled, 27 patients continue to be followed for survival outcomes, with 10 patients still receiving study treatment.

“Clearly, we have to recognize the fact that this is a phase 2 study in a relatively smaller number of patients, but nonetheless, these data are seen as extremely promising,” Harrison commented, adding that, “Even more promising is the fact that a number of patients were able to achieve CR.”

As of the most recent data cutoff, the combination of Versamune HPV and pembrolizumab has maintained favorable tolerability. Any-grade treatment-related adverse effects (TRAEs) were reported in 88.7% of patients, while 12.9% experienced grade 3 or higher TRAEs. Grade 4 TRAEs were rare, reported in only 1.6% of patients, and no grade 5 TRAEs occurred. The most common TRAE was injection site reactions (71%), all of which were low grade. Non-injection site TRAEs observed in over 10% of patients included fatigue, headache, pruritus, and diarrhea.

“The treatment was extremely well tolerated. Most AEs were of relatively low grade, and none were sufficient [enough] to significantly impact the ability to deliver the therapy in patients. Overall, this is a safe and apparently quite effective therapy, which is certainly worthy of further investigation,” Harrington commented.

“If that holds up in the phase 3 setting, it’s an important thing to think about when you have patients that might not be as robust and develop recurrent metastatic disease, or if they develop it early and they’re still recovering from their curative intent treatment,” Price said regarding the implications regimen’s toxicity profile. “There are definitely clinical scenarios where it’d be very helpful to know that there’s a treatment that’s not going to be too toxic.”

Enrollment in VERSATILE-002 is now complete. These data support the continued evaluation of Versamune HPV plus pembrolizumab in the confirmatory phase 3 VERSATILE-003 study, which will compare the regimen with pembrolizumab alone as first-line therapy in patients with recurrent or metastatic HPV16-positive HNSCC with a CPS of 1 or higher.

“I’m very optimistic that we will see activity of a vaccine-based approach in patients with HPV-related HNSCC, and I think the data from VERSATILE-002 give us cause for great positivity, that this agent will achieve a positive phase 3 [result],” Harrington stated.

“One exciting thing about the data presented here was that the survival improvement was not just in the median; the tail of the [OS] curve was substantially raised,” Weiss added. “If that is confirmed in the phase 3 study, it would change the SOC for recurrent metastatic disease and introduce a conversation about cure rate in this previously incurable [disease].”

VERSATILE-003 Overview

VERSATILE-003 is a global, randomized, active comparator-controlled study enrolling patients at least 18 years of age or older with a histologically- or cytologically-confirmed diagnosis of HNSCC and no prior exposure to ICIs.^3,5 Unresectable recurrent or metastatic disease with confirmation of at least 1 lesion that is considered a target lesion per RECIST 1.1 criteria by blinded independent central review (BICR); HPV16 positivity; tumor PD-L1 expression defined as a CPS of 1 or greater; and an ECOG PS of 0 or 1 are also required.³

Upon enrollment, patients will be randomly assigned 2:1 to receive 1 mL of subcutaneous Versamune with or without 200 mg of IV pembrolizumab every 3 weeks. In the Versamune HPV arm, patients will receive the combination from cycles 1 to 4 and during cycle 12; pembrolizumab alone will be administered during cycles 5 to 11 and 13 to 35.

The study’s primary efficacy end point is OS. Secondary objectives include PFS per RECIST 1.1 criteria by BICR; ORR per RECIST 1.1 criteria by BICR; DOR per RECIST 1.1 criteria by BICR; changes in patient-reported outcomes (PROs); time to deterioration in PRO scores; and safety.

The study is expected to be conducted across 90 to 100 clinical sites globally.

“VERSATILE-003 is not restricting to [a CPS] of 20 or higher, but it does restrict to 1 or more,” Price noted. “[We must balance] targeting the patients who are likely have the most benefit vs having something to offer to more people. In VERSATILE-002, the [CPS] cutoff was 1 or higher, and we did see responses in people that had a CPS less than 20. The data will ultimately unfold, and it may be that we end up with approval or indications that are more restrictive. I [also] suspect that if we see an approval in the future, it’ll probably be in the first-line, recurrent/metastatic setting in combination with immunotherapy. So there’s still going to be a treatment void for PD-L1–negative, CPS-negative patients,” she speculated.

As data from VERSATILE-002, reflecting increases in patient size and the duration of patient follow-up, continue to read out, minor modifications to the study design of VERSATILE-003 have been made since its first announcement.¹¹ These include an adjustment in anticipated enrollment to approximately 350 patients and the potential for earlier interim readouts and study completion.

An investigational new drug application reflecting these changes will be submitted to the FDA in November. PDS Biotechnology anticipates the FDA clearance decision by mid-December, which would allow for site activation during the first quarter of 2025.

“This is potentially a highly efficacious and well-tolerated treatment approach which offers patients a realistic chance of benefit and improved outcomes for HPV-related HNSCC. Within my own practice, this is a study which we are prioritizing, and I would hope that referrers in other centers will take a similar view and consider offering this as an option for their patients to try to deliver the best outcomes for this group with unmet needs,” Harrington concluded.

References

1. Lechner M, Liu J, Masterson L, Fenton TR. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol. 2022;19(5):306-327. doi:10.1038/s41571-022-00603-7
2. Weiss J, Kaczmar J, Harrington KJ, et al. VERSATILE-002: survival with first-line treatment with PDS0101 therapeutic vaccine and pembrolizumab in HPV16-positive recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Ann Oncol. 2024;35(suppl 2):S628. doi:10.1016/j.annonc.2024.08.940
3. PDS0101 in HPV16+ head and neck cancer KOL roundtable. PDS Biotechnology Corporation. October 3, 2023. Accessed November 13, 2024. https://www.pdsbiotech.com/images/pdf/presentation/2023/PDS0101_in_HPV16_Head_and_Neck_Cancer_KOL_Roundtable_KOL_Roundtable_Presentation_FINAL_100223.pdf
4. Dzienis M, Cundom J, Fuentes CS, et al. Pembrolizumab plus carboplatin and paclitaxel as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-B10): a single-arm phase IV trial. J Clin Oncol. 2024;42(25):2989-2999. doi:10.1200/JCO.23.02625
5. PDS Biotech announces submission of phase 3 protocol to FDA to initiate VERSATILE-003 trial. News release. PDS Biotechnology Corporation. August 14, 2023. Accessed November 13, 2024. https://www.pdsbiotech.com/index.php/investors/news-center/press-releases/press-releases1/125-2023-news/854-iotechnnouncesubmissionofhase3rotocolto20230814#:~:text=The%20Phase%203%20trial%2C%20named,or%20metastatic%20HPV16%2Dpositive%20HNSCC.
6. Study of PDS0101 and pembrolizumab combination I/​O in subjects with HPV16 + recurrent and/​or metastatic HNSCC (VERSATILE002). ClinicalTrials.gov. Updated May 21, 2024. Accessed November 13, 2024. https://clinicaltrials.gov/study/NCT04260126
7. Weiss J, Chintakuntlawar AV, Price KAR, et al. PDS0101 a novel type I interferon and CD8 T-cell activating immunotherapy, in combination with pembrolizumab in subjects with recurrent/metastatic HPV16-positive head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2022;40(suppl 16):6041. doi:10.1200/JCO.2022.40.16_suppl.6041
8. PDS Biotechnology granted FDA fast track designation for lead candidate PDS0101. News release. PDS Biotechnology Corporation. June 2, 2022. Accessed November 13, 2024. https://pdsbiotech.com/index.php/investors/news-center/press-releases/press-releases1/118-2022-news/616-iotechnologyrantedastrackesignationfore20220602
9. Price KAR, Kaczmar JM, Worden FP, et al. Safety and efficacy of immune checkpoint inhibitor (ICI) naïve cohort from study of PDS0101 and pembrolizumab in HPV16-positive head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2023;41(suppl 16):6012. doi:10.1200/JCO.2023.41.16_suppl.6012
10. PDS Biotech VERSATILE-002 phase 2 clinical trial meets primary study endpoints in first line recurrent/metastatic HPV16-positive head and neck cancer. News release. PDS Biotechnology. May 9, 2024. Accessed November 14, 2024. https://pdsbiotech.com/index.php/investors/news-center/press-releases/press-releases1/131-2024-news/918-iotech002hase2linicalrialeetsrim20240509/Study of PDS0101 and pembrolizumab combination
11. PDS Biotech provides clinical programs update and reports third quarter 2024 financial results. News release. PDS Biotechnology Corporation. November 14, 2024. Accessed November 14, 2024. https://pdsbiotech.com/index.php/investors/news-center/press-releases/press-releases1/131-2024-news/957-iotechrovideslinicalrogramspdateandeports20241114