Zandberg, Dan P.

Abstract Purpose: Relapse is a major cause of failure in human papillomavirus–independent head and neck squamous cell carcinoma. Clinicopathologic criteria for adjuvant treatment remain imprecise and have not changed for decades. We investigated whether ctDNA in lymphatic exudate collected via surgical drains (“lymph”) 24 hours after surgery identified molecular residual disease (MRD) and compared its performance with time-matched plasma. Experimental Design: Using an ultra-sensitive tumor-informed sequencing approach, tumor variants were called in lymph and plasma to classify patients as ctDNA positive or ctDNA negative, trained in an initial cohort of 36 patients, and replicated in an independent cohort of 37 patients. Progression-free survival was compared in ctDNA(+) versus ctDNA(–) patients. Results: Lymph identified MRD in two independent multi-site cohorts (initial cohort sensitivity = 76% and specificity = 63%; log-rank P = 0.01; replication cohort sensitivity = 65% and specificity = 70%; log-rank P = 0.04). Lymph performance was enhanced in locoregional relapse (sensitivity = 78% and specificity = 67%; log-rank P = 0.0004) and generalized to early-stage patients. Analysis of matched plasma collected at this early timepoint was not predictive of recurrence (sensitivity = 35% and specificity = 72%; log-rank P = 0.7). In patients with intermediate-risk pathology, lymph ctDNA was associated with recurrence (sensitivity = 88% and specificity = 67%; log-rank P = 0.0008), suggesting an opportunity for improved stratification of patients who may benefit from additional adjuvant treatment. Conclusions: Postoperative lymph is a novel, proximal, and early source of MRD with the potential to introduce more precision into adjuvant therapy decision-making and improve outcomes, especially for patients with intermediate-risk human papillomavirus–independent head and neck squamous cell carcinoma.

PURPOSE Continued improvement in outcomes is needed for advanced cutaneous squamous cell carcinoma (cSCC). Methods Alliance A091802 is a randomized phase II trial of avelumab (800 mg IV once every 2 weeks) plus cetuximab (500 mg/m 2 IV once every 2 weeks) versus avelumab alone once every 2 weeks for up to 2 years. Cetuximab was given for 1 year in the avelumab + cetuximab arm. Crossover at progression to avelumab + cetuximab was allowed. Randomization was 1:1, stratified by PD-L1 and HIV status. Patients had distant metastatic or unresectable locally advanced cSCC, were anti–PD-1/PD-L1 monoclonal antibody–naive, had no previous cetuximab in the advanced setting, had an Eastern Cooperative Oncology Group performance status of 0-2, and could be HIV+ (CD4 >200, viral load <200). Patients with chronic lymphocytic leukemia, immunosuppression, or active autoimmune diseases were excluded. The primary end point was progression-free survival (PFS; null hypothesis: median = 12 months v alternative hypothesis: 21 months or a 75% improvement, power of 80% with one-sided alpha .2, n = 57, 37 PFS events required). Secondary end points were overall survival, objective response rates (ORRs), clinical benefit rate, and toxicity. RESULTS Sixty patients were enrolled; 57 patients were evaluable. The median age was 72 years, all were HIV–; 75.4% was PD-L1+, 84.2% had head/neck origin, 47.4% had distant metastasis, and there were no differences in baseline characteristics by arm. Avelumab + cetuximab significantly improved PFS versus avelumab (median, 11.1 [7.6-not reached (NR)] v 3.0 months [2.7-13.6] hazard ratio, 0.48 [95% CI, 0.23 to 0.97], P = .018). Avelumab patients who crossed over (n = 9) to combination had a median PFS after crossover of 11.3 months (5.8-NR). The confirmed ORR was 27.6% with avelumab + cetuximab and 21.4% with avelumab. Grade 3 treatment-related adverse events occurred in 48.3% and 21.5% of patients with avelumab + cetuximab (most common: rash [20.7%], infusion reaction [20.7%]) and avelumab, respectively. CONCLUSION Avelumab + cetuximab significantly improved PFS versus avelumab alone in patients with advanced cSCC. Alliance A091802 supports a larger confirmatory study with the combination of cetuximab and PD-1:PD-(L)1 blockade.

6002 Background: There is a need for continued improvement in outcomes with systemic therapy for advanced cSCC. Pre-clinical data suggest immunologic synergy between IgG1 mAb therapy targeting EGFR and PD-1:PD-(L)1 blockade. Methods: Alliance A091802 is a randomized phase II trial of avelumab (AV) (800 mg) plus cetuximab (C) (500 mg/m2) vs. AV alone every 2 weeks for up to 2 years (yrs). C was given for 1 yr in the AV+C arm. Crossover at progression to AV+C was allowed in the AV arm. Randomization was 1:1 and stratified by PD-L1 [+(>1%) vs. -] and HIV status (+ vs. -). Eligible patients (pts) had distant metastatic or unresectable locally advanced cSCC, anti-PD-1/PD-L1 mAb naive, no prior cetuximab in the advanced setting, ECOG PS 0-2, HIV+ if CD4 >200 and VL <200. Pts with CLL, immunosuppression, or active autoimmune diseases were excluded. The primary endpoint was progression-free survival (PFS) (Ho: Median=12 mo vs Ha: 21 mo or a 75% improvement, power of 80% with one-sided alpha 0.2, n=57, 37 PFS events required). Secondary endpoints were overall survival (OS), confirmed response rate (ORR), clinical benefit rate, and toxicity. After 31/37 events, an early unplanned analysis (along with sensitivity analyses) was performed because it became apparent that 37 events would not be reached. These results were submitted to the Alliance Data and Safety Monitoring Board, which recommended releasing the data. Data cutoff was 1/16/25. Results: 60 pts were enrolled between 2019-2023; 57 pts were evaluable. Median age was 72 yrs (41‒93), 96.5% were white, 91.2% male, all HIV-; 75.4% PD-L1+. 84.2% were head/neck origin, 47.1% had distant metastasis, and there were no differences in baseline characteristics by arm. AV+C significantly improved PFS compared to AV [median 11.1 months (mo) (7.6‒not reached (NR)) vs. 4.8 mo (2.8‒NR) hazard ratio (HR) 0.53 95% CI (0.26‒1.09), one-sided p=0.041]. The median OS of AV+C vs. AV was NR (25.2‒NR) vs. 35.8 mo (18.6‒NR) HR 0.77 (0.33‒1.78) p=0.267. ORR was 31.0% in the AV+C arm and 21.4% in the AV arm. Treatment-related adverse events (TRAE) of any grade (G) occurred in 93% and 78.6%, respectively, and were G>3 in 48.3% and 21.5% of pts in the AV+C [most common G3 TRAEs were rash (20.7%) and infusion-related reaction (20.7%)] and AV arms, respectively. There were no G5 events. Outcomes after crossover and by PD-L1 status will be presented subsequently. Conclusions: Avelumab plus cetuximab significantly improved PFS vs. avelumab alone in advanced cSCC pts, without unexpected toxicity. Alliance A091802 supports a larger confirmatory study with combination cetuximab and PD-1:PD-(L)1 blockade. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180868 (NRG Oncology); U10CA180888 (SWOG); https://acknowledgments.alliancefound.org . EMD Serono CrossRef Funder ID: 10.13039/100004755. Clinical trial information: NCT03944941 .

Background Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. Methods In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. Results Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. Conclusions Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. Trial registration number NCT02475213.