Weiss, Jared

Importance The incidence of human papillomavirus type 16 (HPV16–positive) recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is rising. Approved therapies offer a durable response to a minority of patients. Objective To determine the efficacy and safety of a therapeutic HPV16-targeted immunotherapy, PDS0101, in combination with pembrolizumab in participants with HPV16-positive R/M HNSCC, with separate evaluation of immune checkpoint inhibitor (ICI)–naive and ICI-resistant cohorts. Design, Setting, and Participants VERSATILE-002 was a phase 2, open-label, multicenter nonrandomized clinical trial conducted at 26 oncology centers from March 29, 2021, to May 15, 2025, across the US, UK, and Ireland using the Simon 2-stage optimal design. Efficacy analyses were performed on modified intent-to-treat (mITT) population; safety analyses included all participants who received 1 or more doses. Eighty-eight participants with histologically confirmed R/M HPV16-positive HNSCC were enrolled, of whom 87 (98.9%) received treatment and composed the safety population. Seventy five (85.2%) were in the mITT population used for efficacy analyses, of whom 53 (70.7%) were ICI-naive with a programmed cell death ligand 1 combined positive score of 1 or greater and 22 (29.3%) were ICI-resistant. Exposures Pembrolizumab (200 mg, intravenously, every 3 weeks for up to 35 cycles) plus subcutaneous PDS0101 (5 scheduled doses per protocol). Main Outcomes and Measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors , version 1.1, by a masked independent central reviewer. Secondary end points included progression-free survival (PFS), median overall survival (mOS), and safety, with exploratory end points of duration of response, disease control rate, and response rates by programmed cell death ligand 1 status. Results Of the 75 patients in the mITT population, the mean (SD) age was 64.0 (8.3) years; 4 individuals (5%) were female and 71 (95%) were male; and 2 individuals (3%) were Asian, 1 (1%) was Black, 5 (7%) were Hispanic, and 71 (95%) were White. Among 53 ICI-naive participants in the mITT cohort, ORR by the central reviewer was 34.0%, median PFS was 5.3 months (95% CI, 2.10-9.00), and mOS was 39.3 months (95% CI, 23.90 to not evaluable). Among 22 ICI-resistant patients in the mITT cohort, no objective responses were observed and the primary end point (ORR by central reviewer) was not met, but mOS was 14.8 months (95% CI, 8.50-26.00). The treatment was well tolerated, with 13.8% experiencing grade 3 or higher treatment-related adverse events. Conclusions and Relevance The results of this nonrandomized clinical trial suggest that PDS0101 plus pembrolizumab showed antitumor activity in ICI-naive HPV16-positive R/M HNSCC, with favorable safety, response rates, and survival outcomes. The findings support further evaluation in a first-line setting. Trial Registration ClinicalTrials.gov Identifier: NCT04260126

4173 Background: [ 212 Pb]VMT-α-NET is an alpha-particle radiation-delivering agent targeted to somatostatin receptor type 2 (SSTR2)-expressing tumors. Here, we present safety and efficacy results from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: This phase 1/2a dose-escalation study uses a Bayesian algorithm to identify an optimal dose of [ 212 Pb]VMT-α-NET for participants with advanced, well-differentiated NETs expressing SSTR2. Eligible participants must have unresectable or metastatic disease, documented radiologic progression following at least one prior systemic treatment, and evidence of SSTR2 expression (Krenning Score ³2) in ≥1 lesion confirmed on an FDA-approved somatostatin receptor PET scan. Patients previously treated with systemic peptide receptor radionuclide therapy (PRRT) are excluded from enrollment. During the dose-finding phase, participants may receive up to four administrations of [ 212 Pb]VMT-α-NET at their assigned dose level, and they are monitored for dose-limiting toxicities (DLTs) for 42 days and safety throughout the study. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Dosimetry is included as a supportive analysis. Results: As of the 10-Dec-2025 data cut-off (DCO), 56 participants had been enrolled across Cohorts 1, 2, and 3 and received at least one dose of [ 212 Pb]VMT-α-NET: 2 participants in Cohort 1 (2.5 mCi), 46 in Cohort 2 (5 mCi), and 8 in Cohort 3 (6 mCi). No dose-limiting toxicities, grade 5 adverse events, treatment-related discontinuations, serious renal events, dysphagia, or clinically meaningful treatment-related myelosuppression were observed. The median follow-up for all treated participants was 40 weeks (range 6–97). Efficacy has been summarized in this abstract for 25 participants (2 in Cohort 1 and 23 in Cohort 2). Nineteen of these 25 participants remained progression-free at the time of the DCO, with a median efficacy follow-up of 49 weeks (range 6–97). In Cohort 2, investigators observed RECIST v1.1 objective responses in 9 of 23 participants (39%), including 8 confirmed responses. Both participants in Cohort 1 continued to exhibit stable disease after two years of follow-up. Updated safety for all participants and updated efficacy for participants with sufficient maturity beyond the 25 summarized here will be presented at the congress. Conclusions: Treatment with [ 212 Pb]VMT-α-NET continues to demonstrate a favorable safety profile across all treated participants (n = 56) and shows signs of sustained efficacy at the 2.5 mCi and 5 mCi dose levels. The therapy has been well-tolerated with no observed dose-limiting toxicities or serious treatment-related adverse outcomes. Based on these encouraging safety and efficacy findings, the study is ongoing, and enrollment into Cohort 3 (6 mCi) remains active. Clinical trial information: NCT05636618 .

Importance Standard treatment for human papillomavirus (HPV)–associated oropharyngeal carcinoma (OPC) often includes 7 weeks of intensive chemoradiotherapy with substantial toxic effects. Lowering the radiation dose to gross disease may maintain cancer control with fewer toxic effects. Objective To evaluate long-term oncologic outcomes among patients with HPV-associated OPC treated with definitive deintensified (chemo)radiotherapy. Design, Setting, and Participants This cohort study evaluated consecutive patients treated with (chemo)radiotherapy between September 2014 and August 2022 at multiple institutions under one academic hospital system. Eligible patients had p16-positive OPC with a clinical stage from T0 to T3 and N0 to N2c (according to the American Joint Committee on Cancer [AJCC] Staging Manual, seventh edition ) and favorable smoking history. Data were analyzed between August 2023 and October 2025. Interventions Treatment was 60-Gy intensity-modulated radiotherapy with first-choice concurrent chemotherapy of weekly cisplatin, 30 mg/m 2 , or weekly cisplatin, 40 mg/m 2 . Patients with OPC with a clinical stage from T0 to T2 and N0 to N1 (according to AJCC, seventh edition ) were recommended 60-Gy radiotherapy alone. Main Outcomes and Measures Evaluation of locoregional recurrence was the primary outcome. Distant recurrence, progression-free survival (PFS), and overall survival (OS) were secondary outcomes. Results A total of 240 patients received definitive deintensified (chemo)radiotherapy (207 receiving prospective protocol-adherent treatment and 33 receiving non–protocol-adherent treatment). Mean (SD) patient age was 60.3 (9.9) years (range, 33.0-84.0 years); 206 (85.8%) were male, and 34 (14.2%) were female. The cohort included 139 never smokers (57.9%) and 101 former smokers (42.1%) (median smoking history, 9.0 pack-years [range, 0.25-50.0 pack-years]). Concurrent chemotherapy was prescribed for 205 patients (85.4%), with 185 (77.1%) receiving cisplatin, and 165 (68.8%) receiving weekly cisplatin, 30 mg/m 2 . Median follow-up for surviving patients was 6.5 years (range, 0.44-11.0 years; 208 of 210 [99.0%] with minimum 2-year follow-up). Outcomes were as follows: 2-year OS was 97.9% (95% CI, 96.1%-99.7%), and 5-year OS, 92.4% (95% CI, 89.0%-96.0%); 2-year PFS, 94.1% (95% CI, 91.2%-97.2%), and 5-year PFS, 86.5% (95% CI, 82.1%-91.0%); 2-year locoregional recurrence, 1.3% (95% CI, −0.2% to 2.7%), and 5-year locoregional recurrence, 3.4% (95% CI, 1.1%-5.8%); 2-year distant recurrence, 4.6% (95% CI, 1.9%-7.3%), and 5-year distant recurrence, 7.3% (95% CI, 3.9%-10.7%). The median time to progression events was 1.9 years (range, 0.3-5.1 years); 12 of 26 recurrences (46.2%) occurred after 2 years. Thirty-three patients with low-risk disease (clinical stage T0-T2, N0-N1, according to AJCC, seventh edition ) received radiotherapy alone, which resulted in a 5-year PFS of 93.8%, with no patients experiencing a locoregional recurrence. Conclusions and Relevance In this cohort study, modest dose deintensification of 60-Gy radiotherapy in patients with HPV-associated OPC shows favorable rates of locoregional control. These findings provide support for ongoing investigations of deintensified radiotherapy.

Abstract Background: [212Pb]VMT-a-NET is a novel, next generation alpha therapy agent for advanced somatostatin receptor 2 positive (SSTR2+) neuroendocrine tumors (NETs). Here, we present safety and efficacy update from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: Adults with well-differentiated unresectable or metastatic NETs, who were peptide receptor radionuclide therapy-naïve, showed progressive disease after at least one prior line of systemic therapy and demonstrated SSTR2-expression on PET images were treated with up to four cycles of study therapy at the assigned dose level. Participants were followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy was evaluated by investigators according to RECIST criteria v1.1. Results: As of 10-Dec-2025 (data cut-off [DCO]) a total of 56 participants were enrolled into Cohorts 1, 2 and 3, and received at least 1 dose of [212Pb]VMT-a-NET (n=2 in Cohort 1, n=46 in Cohort 2, and n=8 in Cohort 3 at a dose level of 2.5 mCi, 5 mCi, and 6 mCi, respectively). For data analysis purposes, participants were categorized into two different groups: a safety group and an efficacy group. The safety group included all participants treated by the DCO (n=56), while the efficacy group included only the Cohort 1 participants (n=2) and the first half of participants treated in Cohort 2 (n=23). Among all participants treated with at least 1 dose of [212Pb]VMT-a-NET (n=56), no DLTs, no grade 5 adverse events (AEs), no treatment-related discontinuations, no serious renal complications, no dysphagia and no clinically significant treatment-related myelosuppression were observed. Median follow-up time for all patients treated was 40 weeks (range: 6-97). Among the 25 participants followed for efficacy (n=2 in Cohort 1 and n=23 in Cohort 2), 19 out of 25 were with no progression as of the DCO. Median follow-up time for participants included in the efficacy group was 49 weeks (range: 6-97). Investigator-assessed RECIST v1.1 objective responses were observed in 9 out of 23 participants (39%) enrolled in the first half of Cohort 2 (8 confirmed). The 2 patients enrolled in Cohort 1 at 2.5 mCi still have stable disease after 2 years of follow up. Updated safety outcomes for all participants along with updated efficacy findings for participants in Cohorts 1 and 2 with sufficient maturity will be presented during the congress. Conclusions: Treatment with [212Pb]VMT-α-NET continues to be well-tolerated among all patients treated (n=56), and to show promising efficacy at the dose levels of 2.5 mCi and 5 mCi. The study is ongoing with Cohort 3 (6 mCi) currently open for enrollment. Citation Format: Thorvardur R. Halfdanarson, Richard L. Wahl, Vineeth Sukrithan, Brandon R. Mancini, Seyed A. Mosallaie, Savitha Balaraman, Gregory S. Sibley, Jason Starr, Lowell B. Anthony, Chih Y. Liao, Samuel H. Mehr, Jared Weiss, Robert A. Ramirez, Lucia Baratto, Wenjing Yang, Alaa Hanna, Stephen M. Keefe, Markus Puhlmann, Vikas Prasad. [212Pb]VMT-a-NET in advanced SSTR2+ neuroendocrine tumors: safety and preliminary efficacy results from dose-finding cohorts 1,2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT088.

635 Background: [ 212 Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Here, we report the results of a prospective, open-label, Phase I/IIa trial (NCT05636618), assessing safety, tolerability, pharmacokinetics, and preliminary efficacy of [ 212 Pb]VMT-a-NET in patients with advanced neuroendocrine tumors (NETs). Methods: Adults with well-differentiated unresectable or metastatic SSTR2-expressing NETs, who are peptide receptor radionuclide therapy (PRRT) naïve, and who progressed on at least one prior line of systemic therapy, are eligible. Participants can receive up to four cycles of [ 212 Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Results: As of 16-Aug-2025 (data cut-off [DCO]) a total of 48 participants were enrolled into cohorts 1 and 2 and received at least one dose of [ 212 Pb]VMT-a-NET (n=2 in Cohort 1, and n=46 in Cohort 2 at a dose level of 92.5 MBq and 185 MBq, respectively). Among all participants treated with at least one dose of [ 212 Pb]VMT-a-NET (n=48), no DLTs, no grade 4 or 5 adverse events (AEs), and no treatment-related discontinuations, were observed. Median follow-up time was 28 weeks (range: 6-93). Nine participants were followed for DLT observation (n=2 in cohort 1 and n=7 in cohort 2).Seven of these patients were with no progression as of the DCO. Three out of the seven participants enrolled at the dose level of 185 MBq achieved a confirmed partial response (PR). Median follow-up time for participants included in the efficacy group was 72 weeks (range: 6-93). Cohort 3, at a dose level of 222 MBq, has recently been opened for enrollment. At the DCO, 4 participants were enrolled in this cohort. Updated safety outcome for all participants along with updated efficacy findings for participants in Cohort 1 and 2 with sufficient maturity, will be presented during the congress. Conclusions: [ 212 Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose levels of 92.5 MBq and 185 MBq. The study is ongoing with Cohort 3 (222 MBq) currently open for enrollment. Clinical trial information: NCT05636618 .

6037 Background: The incidence of HPV-associated head and neck squamous cell carcinoma (HNSCC) continues to rise with over 90% of cases being driven by HPV16. Median overall survival (OS) with pembrolizumab in first-line recurrent/metastatic (R/M) HNSCC is 12.3 months in subjects with CPS ≥1, 10.8 months for CPS ≥1-19, and 14.9 months for CPS ≥20. There is an urgent need to improve survival rates in the growing population of HPV16-positive R/M HNSCC. PDS0101 (Versamune HPV) is an investigational T cell stimulating immunotherapy that unleashes a potent, durable attack against HPV16-positive cancers and is being studied in combination with pembrolizumab. Preliminary results were presented at ASCO 2023. (Price KAR, et al. ASCO 2023. Abstract 6012). Methods: VERSATILE-002 is a single-arm phase 2 study evaluating PDS0101 and pembrolizumab for first-line HPV16-positive R/M HNSCC with CPS ≥1. Subjects received pembrolizumab 200 mg IV Q3W with PDS0101 1 mL SC administered concurrently during Cycles 1, 2, 3, 4, and 12 and pembrolizumab alone for all other Cycles up to Cycle 35 (approx. 2 years). The primary study endpoint is confirmed objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free survival (PFS), OS, and safety. Results: The median follow-up is 18.4 months (range 0.2-42.7 months). The efficacy population consists of 53 subjects: 32 (60%) with CPS ≥1-19 and 21 (40%) with CPS ≥20. The median OS for subjects with CPS ≥1 is 30 months (95% CI 23.9, NE). For the CPS ≥1-19 subgroup, the median OS is 29.5 months (95% CI 15.3, NE). For the CPS ≥20 subgroup, the median OS is 39.3 months (95% CI 18.4, NE). Confirmed response rates by investigator assessment are shown in the Table. Twenty-three subjects are still on study: 3 on treatment and 20 in long-term follow-up. No new safety signals have emerged. The most common TRAEs are injection site reactions, fatigue, headache, and pruritus. Only 19% of subjects experienced Grade ≥3 TRAEs. No subject had a Grade 5 TRAE. Conclusions: These data represent one of the most extended follow-up periods to date of subjects receiving an HPV16-targeted therapy for HPV16-positive R/M HNSCC. The PDS0101 and pembrolizumab combination is well tolerated and has demonstrated deep and durable clinical responses. Median OS is promising in light of historic expectations, both overall and relative to PD-L1 subgroup, and remains durable with continued follow up. The results support further evaluation in a randomized phase 3 study with OS as the primary endpoint. Clinical trial information: NCT04260126 . Summary of results. CPS ≥1-19 (N=32) CPS ≥20 (N=21) CPS ≥1 (N=53) ORR, % 28.1 47.6 35.8 DCR, % 75.0 81.0 77.4 Median DOR, months (95 % CI) 21.8 (4.2, NE) NE (5.6, NE) 21.8 (11.5, NE) Median PFS, months (95% CI) 5.1 (2.4, 8.1) 14.1 (2.1, NE) 6.3 (3.5, 9.0) Median OS, months (95% CI) 29.5 (15.3, NE) 39.3 (18.4, NE) 30.0 (23.9, NE)

6041 Background: Human papillomavirus (HPV) E6/E7 oncoproteins mediate immune evasion by down-regulating Type 1 interferons, TLR9, MHC Class I/II as well as other mechanisms, resulting in persistent infection and initiation of ̃5% of all cancers globally. Similarly, established cancers evade immune surveillance utilizing parallel mechanisms including the expression of checkpoint proteins. PDS0101 is a molecularly targeted immunotherapeutic based on an enantiospecific cationic lipid nanoparticle platform containing HPV16 neoantigens that exhibits anti-tumor activity with checkpoint inhibitors (CPIs) by upregulating Type I interferons and promoting antigen processing and cross presentation. This allows generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in treatment of CPI naïve and refractory patients with recurrent or metastatic HPV16-related HNSCC. Herein, we report preliminary safety and efficacy data for CPI naïve patients at a prespecified interim analysis. Methods: Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of Cycles1-4 and Cycle12; pembrolizumab continues up until 35 cycles, disease progression or intolerance to therapy. Results: Eighteen CPI naïve subjects with confirmed HPV16 tumors and a CPS score > = 1, median age 62 yrs (range 46-71), all male, 17 (94%) of whom were White and 16 (88.9%) not Hispanic or Latino, received at least one cycle of combination therapy. At the time of analysis, 17 (94%) subjects had received > = 4 doses of PDS0101 (median 4, range 1-5) and pembrolizumab (median 7, range 1-14). There were no Grade 3 or greater treatment-related toxicities and no drug discontinuation related to toxicity or immune-related AEs. Clinical activity (CR+PR+SD) was seen in 13 (72.2%) of 18 subjects, with best overall reponse per RECIST1.1 documenting: OR in 7 (38.9%; 2 CR, 5PR); stable disease (SD) in 6 (33.3%) and progressive disease in 3 (16.7%); 2 subjects had missing data. Tumor reduction was seen in 4 of 6 (67%) subjects with SD. Nine-month PFS and OS rates (95% CI) were 52% (22.5, 74.7) and 81% (37.8, 95.5) respectively; median PFS and OS have not been reached. Conclusions: The combination of PDS0101 and pembrolizumab demonstrates an excellent safety profile with preliminary evidence of clinical activity in the majority of CPI naïve patients with HPV-related HNSCC. Clinical trial information: NCT04260126.

6012 Background: Up to 70% of oropharyngeal cancers in the US are reported to be HPV-mediated with most caused by HPV16 infection. First line treatment for patients with unresectable, recurrent or metastatic (R/M) disease is pembrolizumab with or without chemotherapy, but most patients eventually experience disease progression. PDS0101 is a novel, investigational HPV16-targeted immunotherapy that stimulates a potent, targeted T cell attack against HPV16-positive cancers. Methods: VERSATILE-002 (NCT04260126) is an open-label, non-randomized, Simon 2-stage study evaluating the combination of PDS0101 and pembrolizumab in subjects with HPV16-positive R/M HNSCC in 2 cohorts: ICI-naïve and ICI-refractory. All subjects receive pembrolizumab IV Q3W with PDS0101 SC administered concurrently during Cycles 1, 2, 3, 4, and 12 (max 5 doses). The primary endpoint of the study is confirmed Best Overall Response per RECIST 1.1. Herein we update the safety, PFS, and OS data for the ICI-naïve subjects. Results: Forty-eight subjects who received at least one cycle of combination therapy (safety population) had a median age of 62.5 (range 45 – 83), were 93.8% male, 93.8% White, and 62.5% ECOG 0. Among this population, the median overall treatment duration in months was 3.5 (range 0.0 – 19.5). The median number of PDS0101 doses was 4 (range 1 – 5); 56.3% received 4 doses and 22.9% received 5 doses. The median number of pembrolizumab doses was 5 (range 1 – 29); 27.1% received ≥10 doses. Efficacy was evaluated in 34 subjects (47.1% with CPS ≥20) who had assessment of tumor response following treatment (efficacy population). Tumor reduction (maximum percent change from baseline) was seen in 23 (67.6%) subjects. Nine subjects (26.5%) had confirmed response including 1 CR and 8 PR, 15 subjects had SD (44.1%), and 9 subjects had PD (26.5%). One subject was not evaluable (2.9%). The median PFS was 10.4 months (95% CI 4.2, 15.3). Among the safety population, median overall survival was non-estimable due to the ongoing survival status of study subjects. The estimated 12-month OS rate was 87.1%. Thirty-three (68.5%) subjects had mild or moderate (Grade 1 or 2) PDS0101-related TEAE (TRAE); the most common were fatigue and injection site reactions (ISRs). Only 3 subjects (6.3%) had Grade 3 TRAEs: fatigue, ISR, blood alkaline phosphatase increased, and hyperglycemia. No subjects had Grade 4 or 5 TRAE. No subject came off study due to toxicity. Conclusions: PDS0101 with pembrolizumab is well tolerated in this ICI naïve R/M HPV-associated HNSCC population. Median PFS was 10.4 months which compares favorably to published median PFS of 2-3 months for approved ICIs when used as monotherapy in patients with similar PD-L1 levels. The estimated 12-month OS of 87.1% is promising compared to published results of about 36-50%. These results justify a confirmatory randomized, controlled study. Clinical trial information: NCT04260126 .