Novel Combination Immunotherapy and Clinical Activity in Patients With HPV-Associated Cancers: A Nonrandomized Clinical Trial
Mené sur 50 patients atteints d'un cancer de stade avancé ou métastatique associé au papillomavirus humain (HPV) (âge médian : 56 ans ; durée médiane de suivi : 37,7 mois), cet essai de phase 1/2 évalue l'activité antitumorale, du point de vue du taux de réponse objective, et la toxicité d'un traitement combinant un vaccin ciblant le HPV de type 16, un conjugué anticorps-médicament ciblant l'interleukine IL-12 et un anticorps ciblant à la fois PD-L1 et TGF-bêta
IMPORTANCE : Patients who experience progression of advanced human papillomavirus (HPV)–associated cancers and who have previously received first-line systemic treatment have a poor prognosis and limited therapeutic options.
OBJECTIVE : To assess the clinical activity of the combination of the HPV type 16 therapeutic vaccine PDS0101, the tumor-targeting interleukin 12 antibody-drug conjugate PDS01ADC, and the bifunctional anti–programmed cell death ligand 1 (PD-L1)/transforming growth factor
β (TGF-β) bintrafusp alfa in advanced HPV-associated cancers.
DESIGN
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Setting, and Participants This nonrandomized clinical trial was phase 1/2 and investigator initiated, and was conducted at a single US cancer research center between June 2020 and July 2022. Patients with advanced or metastatic HPV-associated cancers were eligible, including patients who were both immune checkpoint blockade (ICB) naive and ICB resistant. The cutoff date for data analysis was May 13, 2024.
INTERVENTION
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Patients received 1 mL of PDS0101 subcutaneously every 4 weeks for 6 doses then every 12 weeks for 2 additional doses, PDS01ADC, 16.8
µg/kg, subcutaneously every 4 weeks or PDS01ADC, 8 µg/kg, subcutaneously every 2 weeks, and bintrafusp alfa, 1200 mg, intravenously every 2 weeks.
MAIN OUTCOMES AND MEASURES : Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 in ICB-naive patients.
RESULTS : Of the 50 eligible patients, 26 (52%) were men and the median age was 56 years (range, 28-80 years). The median (IQR) follow-up was 37.7 (30.6-42.0) months. Fourteen patients (28%) were ICB naive, with an ORR of 35.7% (95% CI, 12.8%-64.9%), and median overall survival (OS) 42.4 months (95% CI, 8.3 months-not estimable); in ICB-resistant patients, the ORR was 16.7% (6 of 36 patients; 95% CI, 6.4%-32.8%) and median OS was 15.8 months (95% CI, 9.0-21.3 months). Among patients with HPV-16–positive tumors (37 patients [74%]), in the ICB-naive group (8 patients [21.6%]) the ORR was 62.5% (95% CI, 24.5%-91.5%) and a median OS measure was not reached. Grade 3 and 4 treatment-related adverse events occurred in 26 of 50 patients (52%). There were no treatment-related deaths.
CONCLUSIONS AND RELEVANCE : In this trial, the combination of PDS0101, PDS01ADC, and bintrafusp alfa showed an acceptable safety profile and promising antitumor activity and improved OS in patients with HPV-16–positive cancers, in both ICB-naive and ICB-resistant patients, warranting further evaluation of the combination of PDS0101 and PDS01ADC with simultaneous PD-L1/TGF-
β inhibition in these populations.
Trial Registration
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ClinicalTrials.gov Identifier: NCT04287868
JAMA Oncology 2024