Phan, Minh

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 .

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR &amp;lt;1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683