Niraparib and dostarlimab in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with (chemo)radiotherapy (CRT): Results from the phase IB-II TTCC-2022-01 RADIAN trial.

Abstract

6096 Background: Treatment intensification with antiPD-(L)1 agents given concurrently to definitive CRT in LA-HNSCC have failed to improve survival. Beyond radiation sensitization, PARP inhibition is predicted to trigger immune responses via STING pathway activation and synergize with anti-PD-(L)1 agents. TTCC-2022-01 RADIAN Trial evaluates niraparib and dostarlimab in LA-HNSCC patients (pts) treated with CRT (cohort A) or RT alone (Cohort B-cisplatin ineligible) (Oliva M et al ASCO 2024). Results of cohort A are presented. Methods: Investigator-initiated, non-randomized phase 1b/II study of niraparib and dostarlimab in LA-HNSCC pts candidates for definitive CRT or RT alone conducted in 7 Spanish sites. In cohort A, pts received 500 mg dostarlimab intravenously on week (w)-3 prior to RT and 200-300 mg/day niraparib from w-2 until 48h before start of CRT (70Gy/35 fractions plus cisplatin 100mg/m 2 w1,4 and 7). Maintenance dostarlimab (500 mg/3w) plus daily niraparib started 4w post-CRT for up to 14 cycles. Eligibility criteria: newly-diagnosed stage III-IVA-IVB HPV-negative oro-hipopharyngeal or laryngeal SCC and stage III HPV-related oropharyngeal, ECOG 0-1, centrally-confirmed PD-L1 CPS≥1, and with no cisplatin/dostarlimab/niraparib contraindications. Primary endpoint was 1-year disease-free survival (1y-DFS). Secondary objectives include safety; overall response rate (ORR) and ctDNA dynamics. 17 pts per cohort were planned. Experimental treatment was expected to increase 1y-DFS up to 75.9 % vs 65% historical control. Results: From Dec 23 to Jun 25, 17 pts were enrolled: median age 65 y (41-68); 71% male; 88% smokers; larynx/hypopharynx/oropharynx (HPV-related)= 53/6/41% (43%); stage III/IVA/IVB=29/53/18%. All pts completed dostarlimab and niraparib pre-CRT with no serious or Grade(G) 3-4 treatment-related adverse events (TRAEs); 15/17 completed CRT: 2 pts died during this phase (1 G5 febrile neutropenia cisplatin-niraparib-related; 1 unknown cause); 14/17 pts started maintenance: 2 completed, 7 ongoing and 5 (36%) discontinued due to TRAEs. The most common grade ≥3 TRAEs were neutropenia (71%), lymphopenia and dysphagia (29% each). Niraparib dose reductions/interruptions occurred in 12 (71%) pts. Most common TRAEs leading to dostarlimab+niraparib maintenance discontinuation were immune-mediated pneumonitis (18%) and respiratory tract edema (12%). ORR was 100% (14 complete+1 partial response) in 15 evaluable pts. With a median follow-up of 8.5 months (95% CI: 8.3-11.1), 15/17 were alive with no disease recurrence or progression. Intention-to-treat 1y-DFS was 88% (95% CI:74.1-100). Conclusions: Dostarlimab and niraparib with CRT showed promising efficacy results in this preliminary analysis. Maintenance post-CRT was poorly tolerated leading to high rate of discontinuation. Clinical trial information: NCT05784012 .