Phase II study evaluating the efficacy of niraparib and dostarlimab (TSR-042) in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients.

person Olga Zamulko University of Cincinnati Medical Center, Cincinnati, OH info_outline Olga Zamulko, Vidhya Karivedu, Muhammad Kashif Riaz, Ilaina Monroe, Audrey Romano, Rachel Mulanda, Nicky Kurtzweil, Allison Forsythe, Casey Allen, Nusrat Harun, Trisha M. Wise-Draper

Authors person Olga Zamulko University of Cincinnati Medical Center, Cincinnati, OH info_outline Olga Zamulko, Vidhya Karivedu, Muhammad Kashif Riaz, Ilaina Monroe, Audrey Romano, Rachel Mulanda, Nicky Kurtzweil, Allison Forsythe, Casey Allen, Nusrat Harun, Trisha M. Wise-Draper Organizations University of Cincinnati Medical Center, Cincinnati, OH, Mid-Florida Hematology Oncology, Orange City, FL, University of Cincinnati/University of Cincinnati Medical Center, Cincinnati, OH, University of Cincinnati, Cincinnati, OH, University of Cincinnati Cancer Institute, Cincinnati, OH, Cincinnati Children's Hospital Medical Center, Cincinnati, OH Abstract Disclosures Research Funding Other GSK provided funding for this trial, Tesaro Background: Patients with recurrent and/or metastatic (R/M) HNSCC have poor overall survival. Immune checkpoint inhibitors (ICIs), specifically programmed death-1 (PD-1) inhibitors, result in durable responses in R/M HNSCC but <20% benefit. Tumor mutational burden (TMB) correlates with ICI response. DNA pathway repair mutations have been reported in 17% of sporadic HNSCC and are associated with higher rates of TMB. Poly (ADP-ribose) polymerase (PARP) inhibition has demonstrated efficacy as a single agent in cancers with a DNA repair defect. We tested the combination of PARP inhibitor (niraparib) with the PD-1 inhibitor (dostarlimab) in R/M HNSCC patients (NCT04313504) with funding support from Tesaro/GSK. Methods: Patients with R/M HNSCC who failed at least one line of prior treatment including a PD-1 inhibitor and for whom no surgical or radiation curative options existed were eligible for the study. Patients received niraparib (200 mg daily) beginning one week prior to initiation of dostarlimab (500 mg q3wks x4 followed by 1000 mg q6wks). The primary endpoint was overall response rate (ORR) including complete response (CR), partial response (PR) and stable disease (SD) using RECIST v1.1. Fourteen patients were planned for the first stage and 10 additional patients for the second stage if ≥8 patients had a confirmed response. Safety was evaluated by CTCAE v5.0. Tumor PD-L1 immunohistochemistry was performed with 22c3 antibody and reported as combined positive score (CPS). TMB was considered high if ≥10Mut/Mb. Results: Ten of 24 planned patients were enrolled. Of the first 10 patients, 8 patients were evaluable by imaging and 1 patient clinically progressed on exam. Of the 9 evaluable patients, there were 0 CR, 1 PR, 1 SD, and 7 with progressive disease (PD). The trial was ended early for futility as it was not possible for at least 8 out of 14 patients to develop response. The patient with a PR remains on treatment past 24 months, was PD-L1 positive, had low TMB and no DDR deficiency. All patients had previously failed a PD-1 inhibitor. One patient had high TMB, 2 patients had a DDR, and 6 patients were PDL1 positive but 2 patients had insufficient tissue or indeterminate results for sequencing. Grade ≥ 3 adverse events occurred in 70% of patients with most common being hypertension (20%), hyponatremia (20%), and lung infection (20%). Conclusions: PARP-1 inhibition and PD-1 inhibition combined does not appear to enhance response over PD-1 inhibitor alone in R/M HNSCC who had previously failed PD-1 inhibitor treatment. However, a more focused population including those with DNA damage response (DDR) mutations and PD-1 treatment naïve may benefit. Clinical trial information: NCT04313504. Molecular breakdown of biomarkers using NGS. Biomarker n (%) TMB Total n=8 Low (0-9 mut/Mb) 7 (87.5) High (≥10 mut/Mb) 1 (12.5) PD-L1 CPS Total n=8 0 2 (25) ≥1 to 20 5 (62.5) ≥20 1 (12.5) DDR Total n=8 Yes 2 (25) No 6 (75)

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