4782 - A window of opportunity trial of preoperative nivolumab with or without tadalafil in squamous cell carcinoma of the head and neck (SCCHN): safety, clinical, and correlative outcomes

Background

Tadalafil is a phosphodiesterase-5 inhibitor was found to decrease MDSC, Treg, arginase and iNOS expression with an increase in cytotoxic effector T cells. In order to improve on the clinical efficacy of PD-1 blockade platform, we designed a window of opportunity trial to test the immunological and therapeutic effects of nivolumab and tadalafil combination.

Methods

We conducted an investigator-initiated, two-arm multi-institutional window of opportunity randomized trial in patients with SCCHN of any stage, who were candidates for complete surgical resection (NCT03238365). Subjects in the two cohorts received nivolumab 240 mg intravenously on day 1 and 15 followed by surgery on day 28. Subjects in the combination cohort received tadalafil 10 mg p.o. once daily for 4 weeks. Patients were stratified to HPV status. Imaging, blood and tumor were obtained pretreatment and post treatment and used for immunological correlatives. The primary endpoint was correlative analysis of immune cell polarization. We present results with complete study accrual.

Results

Of 47 randomized patients, 21 had HPV + tumors. 45/47 patients completed the treatment regimen. Grade 3 serious adverse event (SAEs) occurred in 18% of pts. No related AE’s resulted in delay of surgery. Preliminary evaluation of pathologic treatment effect (TE) was assessed on post treatment specimens showing that 25% of pts demonstrated no treatment effect (TE), 25% had 1-20% TE, 41% had 21-99%TE and 9% had CR. Patients receiving tadalafil amplified intratumoral transcript levels consistent with enhanced myeloid infiltration and T cell activation. This was associated with changes in cytokine levels in patients sera consistent with altered myeloid phenotypes.

Conclusions

Nivolumab +/- tadalafil demonstrated a range of treatment responses with 50% of pts having a pathologic TE > 21% in 4 weeks. In the context of PD-1 blockade, tadalafil enhanced T lymphocyte and myeloid cell infiltration. The mechanisms underlying this shift warrant further investigation.

Clinical trial identification

NCT03238365.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bristol-Myers Squibb.

Disclosure

All authors have declared no conflicts of interest.