Phase II evaluation of the combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16+ malignancies.
Authors: Strauss Julius , Floudas Charalampos S. , Pastor Danielle M. , Manu Michell , Lamping Elizabeth , Francis Deneise C. , Cordes Lisa M. , Marte Jenn , Donahue Renee Nicole , Jochems Caroline , Norberg Scott , Redman Jason , Karzai Fatima , Madan Ravi Amrit , Schlom Jeffrey , Gulley James L. 
Published: June 2022

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Background: More than 630,000 cases of HPV related cancer occur worldwide annually. About 15-20% of cases respond to PD-(L)1 inhibitors and about 30% respond to dual PD-L1/TGF-β blockade including 10% of checkpoint refractory pts, but for the majority of pts with checkpoint refractory disease there is no effective standard therapy. Preclinical studies show that the combination of PDS0101, a therapeutic vaccine targeting HPV 16 E6/E7, M9241, a tumor-targeting IL-12 immunocytokine, and bintrafusp alfa (BA), a bifunctional fusion protein targeting TGF-β and PD-L1, resulted in maximum T cell infiltration and tumor reduction compared to any 1 or 2 of these agents alone. Prior clinical data suggests that the combination is preferentially active in HPV 16+ disease. Methods: 30 pts with advanced HPV 16+ cancer were treated with PDS0101, M9241 and BA (NCT04287868). Pts received BA at 1200 mg IV q2wks, M9241 at 16.8 mcg/kg SC q4wks or 8 mcg/kg SC q2wks, and PDS0101 as two 0.5 ml SC injections q4wks. Dose reductions or skipped doses for toxicities of BA and M9241 were allowed. 5 pts had surgical resection of tumor for disease control and were censored for PD but not survival. Results: 30 pts (9 cervical, 2 vaginal/vulvar, 6 anal, 13 oropharyngeal) were treated. 13/30 had grade 3 treatment related AEs including grade 3 anemia in 9 pts associated with grade 3 hematuria in 3 pts and grade 3 GI bleeding in 3 pts. 2 pts had grade 3 AST/ALT elevation. Grade 3 flu like symptoms and grade 3 hemophagocytic lymphohistiocytosis were each seen in 1 pt. One pt had grade 3 lymphopenia/leukopenia plus grade 4 neutropenia and one pt had grade 4 AST/ALT elevation. There were no grade 5 treatment related AEs. 7/8 (88%) pts with checkpoint naïve disease had objective responses (OR) including 1 delayed response after initial PD with 4/7 (57%) responses ongoing (median 17 months follow up). 10/22 (45%) with checkpoint refractory disease have had disease reduction including 6/22 (27%) with OR and 4/6 (67%) responses ongoing (median 12 months follow up). 6/8 (75%) pts with checkpoint naïve disease and 17/22 (77%) pts with checkpoint refractory disease are alive after a median of 17 and 12 months follow up respectively. For checkpoint refractory pts, M9241 dosing appears to affect response rates. 5/8 (63%) pts receiving M9241 at 16.8 mcg/kg had an OR compared to 1/14 (7%) who received M9241 at 8 mcg/kg with an OR. However, despite differences in response rates with higher vs lower M9241 dose, survival outcomes were similar irrespective of M9241 dose (p = 0.99 by Kaplan Meier analysis). Conclusions: The combination of PDS0101, M9241 and BA appears to have a manageable safety profile along with early evidence of clinical activity for pts with checkpoint naïve and refractory advanced HPV 16+ cancer. Moreover, growing data suggest that all 3 drugs in the combination contribute to the encouraging outcomes being observed. Clinical trial information: NCT04287868.