PURPOSE:Immunotherapy for frontline mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) is effective; however, nearly half of the patients treated with single-agent PD-1 therapy will progress within 12 months. Preclinical studies in CRC and clinical data from other cancers suggest that vascular endothelial growth factor inhibition and chemotherapy can synergize with PD-L1 inhibition. METHODS:The NRG-GI004/SWOG-S1610 (COMMIT) three-arm prospective phase III open-label trial randomly assigned first-line dMMR/MSI-H mCRC patients (1:1:1) to either: mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU bolus 400 mg/m², and 46-hour infusional 5-FU 2,400 mg/m²)/bevacizumab (FFX/bev), or atezolizumab (atezo) monotherapy (840 mg IV once every 2 weeks), or the combination of FFX/bev/atezo. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Because of KEYNOTE 177 results, the FFX/bev arm was closed after 20 patients were enrolled. The study continued with atezo alone versus FFX/bev/atezo, with a revised sample size of 100 patients in the two remaining arms (120 patients across all three arms). RESULTS:From November 2017 to March 2025, a total of 102 patients were enrolled in the three arms: FFX/bev: n = 20, atezo: n = 41, and FFX/bev/atezo: n = 41. At a median follow-up of 46 months for the two arms (median age: 63.3 years; 47.6% female; 23.2% BRAF V600E mutated), PFS of FFX/bev/atezo was superior to that of atezo (hazard ratio [HR], 0.439 [95% CI, 0.23 to 0.84]; P = .0103) and below the critical value of 0.0152. The objective response rate was 86.1% versus 46%, and the disease control rate at 12 months was 64.7% versus 32.4% in the FFX/bev/atezo arm compared with the atezo-only arm, respectively. Grade 3 or higher adverse events of any attribution occurred in 52 patients (atezo: 18; combination arm: 34). CONCLUSION:The combination of FFX/bev plus atezo led to significantly longer PFS compared with atezo monotherapy in the first-line treatment of dMMR/MSI-H mCRC.

Background: Anti-programmed death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 antibodies are efficacious in various malignancies. The potential role of dual checkpoint inhibitors in many rare solid tumors is not established. Objectives: This study presents the results of ipilimumab–nivolumab in salivary gland neoplasm cohorts of the SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) trial. Design: DART is a prospective, open-label, multicenter (1016 US sites), multi-cohort phase II trial of ipilimumab (1 mg/kg intravenously (IV) every 6 weeks) plus nivolumab (240 mg IV every 2 weeks). Methods: We performed a prospective, multicenter phase II clinical trial of ipilimumab (1 mg/kg IV every 6 weeks) plus nivolumab (240 mg IV every 2 weeks) in three salivary gland neoplasm cohorts: major and minor salivary gland and adenoid cystic cancers. Patients with adenoid cystic salivary gland tumors ( N = 26) and other salivary gland neoplasms ( N = 34) were evaluable. The most common site of origin was the parotid (31%, N = 8 adenoid cystic group; 68%, N = 23 remaining histologies). Results: In the adenoid cystic group, objective response rate (ORR), 4% (complete response (CR) 0%, N = 0; partial response (PR) 4%, N = 1); 6-month progression-free survival (PFS) and overall survival (OS), 32% (95% confidence interval (CI) 18%–57%) and 84% (95% CI 71%–100%), respectively. In the remaining histologic subtypes, the confirmed ORR was 9% (CR, 0%, N = 0; PR, 9%, N = 3); stable disease (SD) >6 months/PR/unconfirmed PR = 35%; 6-month PFS and OS, 34% (95% CI 21%–55%) and 88% (95% CI 78%–100%), respectively. The most common toxicities were fatigue (39%) and diarrhea (26%); diarrhea (8%) was the most common grade 3–4 immune-related adverse event. Conclusion: In salivary gland tumors, combined ipilimumab plus nivolumab resulted in only a 4% ORR in adenoid cystic carcinoma and 9% in all other histologies combined, though the latter showed clinical benefit (included SD >6 months) in 35% of patients. Trial registration: ClinicalTrials.gov registry: NCT02834013.

End-of-life decision making in oncology is a complex landscape, encompassing clinical, ethical, cultural, and human dimensions. It occurs at the intersection of medical possibility, ethical complexity, cultural context, and human experience. Regardless of where they reside, patients at the end of life face profound choices regarding comfort, dignity, and the meaning of hope, regardless of whether cure is no longer attainable or treatment is no longer desired. Across Africa, palliative care, in general, has expanded through community-based and integrated models, yet access, including at life's end, remains limited by resource constraints, workforce shortages, and inadequate availability of essential medicines, particularly opioids. These inequities shape what choice means in practice, often constraining patient preferences and reinforcing the need for system-level integration and culturally responsive care. By contrast, medical aid in dying in the United States reflects a growing emphasis on autonomy and control at the patient level, and it generates evolving clinical practices and ongoing ethical debate. Within the end-of-life spectrum, hope persists as a dynamic and measurable construct associated with improved quality of life and potentially survival, while remaining adaptable to changing goals in advanced illness. Nonetheless, the human dimensions of care—including psychological distress, communication, and relational continuity—are frequently underemphasized in advanced cancer and at the end of life. Addressing these gaps is essential for ensuring that patients obtain support that emphasizes meaning, agency, and dignity at the end of life.

Abstract Background: Few effective treatment options for advanced NSCLC are available following frontline immune checkpoint inhibitor (ICI)-based therapy. The randomized, phase II Lung-MAP S1800A study of RP versus SOC for pts with NSCLC previously treated with ICI demonstrated benefit in overall survival (OS) with an improved toxicity profile over SOC. SWOG S2302 Pragmatica-Lung was pragmatically designed to evaluate OS while increasing representation in trial participation. The interim analysis was previously reported. Methods: S2302 is a registration-intent randomized phase III trial for pts with advanced NSCLC who previously received ICI for at least 84 days and platinum-based therapy, randomized to SOC or RP, stratified by immediate prior therapy including ICI (yes/no) and PS (0/1 v. 2). The pragmatic design led to eligibility focused on stage, prior therapy and safety. Laboratory assessment and imaging were not required. The primary objective was OS. The secondary objectives were to compare OS between the arms within key subgroups, including squamous cell carcinoma (SCC) and to summarize reports of serious and unexpected high-grade treatment-related AEs. The accrual goal was 800 based on 90% power for an HR of 0.77 using a 1-sided 2.5% level log-rank test. Full information was 616 OS events. Results: S2302 enrolled 838 pts with 419 in each arm from March 2023 to December 2024. Study data were released at an interim analysis for futility. Median age (range) was 68 (34-88), 22% non-white /13% Black, 15% rural, 29% SCC, 63% adenocarcinoma, 81% had ICI as the most recent treatment, 13% had PS2. With 582 deaths reported, OS was not different between the arms (HR 1.04 [0.88-1.22] p= 0.66; median OS (mOS) was 10.1 months (mos) for RP and 10.0 mos for SOC). In SCC, the HR (95% CI) was 0.90 [0.66-1.22] p= 0.25 with mOS of 10.7 mos for RP and 9.6 mos with SOC. In nonSCC, the HR (95% CI) was 1.10 [0.91-1.34] p= 0.84 with mOS of 9.8 mos for RP and 10.6 mos with SOC. Conclusions: The pragmatic trial design led to rapid accrual with increased participant representativeness. RP did not improve OS overall but was not worse than SOC. Of note, for SCC, the estimated HR is < 1 and the confidence interval is consistent with non-inferiority bounds. We interpret that RP for SCC may provide an option equivalent to SOC with better tolerability. Support: NIH/NCI/NCTN grants U10CA180888 and U10CA180819; and in part by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eli Lilly and Company Citation Format: Karen L. Reckamp, Mary W. Redman, Konstantin H. Dragnev, Maya Khalil, Brian S. Henick, James Moon, Pasarlai Ahmadzai, Michael LeBlanc, Daniel R. Carrizosa, Paul J. Hesketh, Ellen V. Sigal, Jeff Allen, Andreas N. Saltos, Bryan A. Faller, Roy S. Herbst, Charles D. Blanke, Jhanelle E. Gray. Final Results from S2302—PRAGMATICA-LUNG: A prospective randomized study of ramucirumab plus pembrolizumab (RP) versus standard of care (SOC) for participants (pts) previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT140.

LBA5003 Background: Circulating miR371 has been reported in retrospective studies as a biomarker with high accuracy for predicting aGCM. However, large prospective data of miR371 in identifying early stage disease are missing. S1823/GCC.1 (NCT04435756) is an international prospective cohort study designed to define the operating characteristics of plasma miR371 in detecting tumor relapse in pts with early stage aGCM managed with active surveillance (AS). Methods: Serial plasma samples for miR371 assessment were obtained within 56 days from new diagnosis of GCM (baseline) and every 6-12 months (according to risk of relapse) during AS, for maximum 3 years or until relapse. Samples most proximate to relapse were analyzed. Control pts were histology-matched 2:1 to cases. miR371 was measured by RT-PCR and expression was analyzed both qualitatively and quantitatively. Sensitivity, specificity, positive and negative predictive value (PPV and NPV) were evaluated to define miR371 operating characteristics. Results: 948 eligible pts were enrolled from June 2020 to May 2024 (median f/u= 32.7 months). The CSI and IIA pts managed with AS (n=630) formed the cohort of interest. At the time of data cutoff, 103 pts (16.3% overall; 14.7% of seminoma; 19.3% of nonseminoma) had relapsed. Results are from the 224 pts selected for the pre-specified interim analysis. PPV/NPV for the whole cohort was 0.66 (95% CI: 0.51, 0.80)/0.90 (95% CI: 0.88, 0.92), for seminoma 0.58 (95% CI: 0.36, 0.80)/ 0.92 (95% CI: 0.90, 0.94), for nonseminoma 0.75 (95%CI: 0.58, 0.92)/0.86 (95% CI: 0.83, 0.89). Sensitivity increased with stage at relapse (IIA,IIB, IIC/III) (p = 0.07) (Table). Conclusions: S1823 achieved the primary objective of defining the operating characteristics of plasma miR371 during AS. In aggregate, S1823 results showed high specificity and NPV suggesting potential clinical utilities of miR371 in managing pts with germ cell tumors. Future miR371-informed interventional trials to integrate miR371 in clinical practice are either underway or planned. Clinical trial information: NCT04435756 . Operating characteristics of miR371. Group N (Cases; Controls) Sensitivity (95% CI) Specificity (95% CI) Median time to relapse (mo) 1 Median miR371 at relapse (log RQ) 2 Overall 224 (69; 155) 0.54 (0.42, 0.65) 0.94 (0.90, 0.97) 5.8 17.17 Seminoma 108 (33; 75) 0.52 (0.35, 0.69) 0.93 (0.88, 0.99) 7.4 16.89 Nonseminoma 116 (36; 80) 0.56 (0.39, 0.72) 0.94 (0.88, 0.99) 5.3 17.50 Low-risk 184 (48; 136) 0.52 (0.38, 0.66) 0.93 (0.89, 0.98) 6.6 17.15 Moderate-risk 40 (21, 19) 0.57 (0.36, 0.78) 0.95 (0.85, 1.00) 4.1 17.27 Stage at Relapse 3 IIA 23 0.39 (0.19, 0.59) — 6.8 16.89 IIB 28 0.57 (0.39, 0.76) — 5.7 17.32 IIC/III 16 0.69 (0.46, 0.92) — 5.3 17.37 1 From orchiectomy; 2 Amongst miR371+ cases; RQ: relative expression; 3 Stage at relapse unavailable for 2 pts whose relapse was identified by STM only.

OBJECTIVE:The SWOG S1609 Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors (DART) trial is the first basket study to include a sub-cohort assessing ipilimumab and nivolumab in patients with primary vaginal cancers with differing histology. METHODS:DART is a prospective, open-label, multicenter, multi-cohort phase II clinical trial of ipilimumab (1 mg/kg intravenously) 6 weekly plus nivolumab (240 mg intravenously) 2 weekly across multiple rare tumor cohorts, with the vagina cohort (any vaginal histology) reported here. The primary endpoint was objective response rate (ORR) per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease [SD] ≥6 months), and toxicity are secondary endpoints. RESULTS:Seven evaluable patients (median age, 60 years; performance status 0-1; no prior exposure to immunotherapy) were analyzed, of whom 3 had adenocarcinoma, 2 had squamous cell carcinoma (SCC), one had small-cell carcinoma and one had undifferentiated histology. The ORR was 29%, with 1 patient (14%) with undifferentiated histology achieving complete response (lasting 14.8 months) and 1 patient with SCC histology (14%) attaining a partial response (lasting 45.2 months). The CBR was 43%. The 6-month PFS rate was 43% and the median OS was 11.7 months. Five patients (71.4%) experienced an adverse event (AE) with 4 (57.1%) having grade 3-4 AE's. CONCLUSION:Ipilimumab plus nivolumab showed efficacy (ORR was 29% and CBR of 43%) and durability (one patient with prolonged SD >6 months) in a sub cohort of patients with vaginal cancer of differing histology without new safety signals. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02834013.

INTRODUCTION:Clinical trial designs marked by extensive data collection, restrictive eligibility, and lengthy protocols create inefficiencies, increase costs, and hinder accrual. These are further compounded by staffing shortages and operational burdens. By incorporating pragmatic features, including simplified eligibility criteria, streamlined protocol, and data collection, the PROSPECT-Lung trial, CTIU2317-A082304-S2402 Perioperative versus Adjuvant Systemic Therapy in Patients with Resectable NSCLC, paves the way forward as a model for enhancing clinical trial efficiency and feasibility, while maintaining scientific rigor. METHODS:PROSPECT-Lung (CTIU2317-A082304-S2402) is a pragmatic, phase III, open-label, randomized trial comparing 3-year real-world event-free survival and overall survival using approved perioperative and adjuvant immunotherapy-based treatment strategies in patients with resectable NSCLC. Protocol length and data collection elements were compared with Alliance A081801, Integration of Immunotherapy into Adjuvant Therapy for Resected NSCLC: ALCHEMIST CHEMO-IO (ClinicalTrials.gov Identifier: NCT04267848), a phase III trial in the same disease setting, to quantify streamlining efforts. RESULTS:Relative to A081801, PROSPECT-Lung achieved major reductions in trial complexity. Protocol length decreased from 88 to 30 pages (65%), and data fields per patient were reduced from 2523 to 438 (82.6%), driven by streamlined summary versus cycle-by-cycle data collection. These efficiencies translate to estimated site workload reductions from 210 hours per patient in A081801 to 36.5 hours in PROSPECT-Lung. At full accrual, this equates to more than 190,000 hours saved in chart review, data entry, documentation, and quality control. CONCLUSION:By broadening eligibility and streamlining logistics, PROSPECT-Lung reduces burden for patients, investigators, and sites while preserving scientific integrity. This pragmatic approach, when appropriate and possible, provides a replicable model for future cancer trials, promoting efficiency, accessibility, and real-world relevance. CLINICALTRIALS: GOV IDENTIFIER:NCT06632327 (CTIU2317-A082304-S2402).

14 Background: Immunotherapy for frontline dMMR/MSI-H mCRC is highly effective, however, nearly half of pts treated with pembrolizumab monotherapy in the KEYNOTE 177 trial progressed within 12 months. Preclinical and other disease data suggest VEGF inhibition can synergize with PD-L1 inhibition. We hypothesized that combining PD-L1 pathway blockade (atezo) with FFX/bev would be more effective than atezo monotherapy. Methods: This three-arm prospective phase III open-label trial randomized first-line dMMR/MSI-H mCRC pts (1:1:1) to either: FFX/bev, or atezo monotherapy (840mg IV q2wks), or the combination of FFX/bev+atezo. Primary endpoint was progression-free survival (PFS) by intent-to-treat. Because of the KEYNOTE 177 results, COMMIT’s FFX/bev arm was closed (trial amended 6/4/20), leaving two arms: atezo monotherapy v FFX/bev+atezo with 80% power to detect a hazard ratio of 0.6 for PFS, one-sided alpha=0.025. The study was also modified to enroll 120 total pts. Secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR), duration of response, and overall survival. Results: Pt accrual was suspended on 3/31/25 because of the results from the Checkmate 8HW trial, while a pre-planned interim analysis occurred near the same time. From 11/2017 to 3/2025, a total of 102 pts were enrolled (median age 62 yrs; 48% female gender; 23% BRAF V600E mutation positive): FFX/bev: n=20, atezo: n=41, and FFX/bev+atezo: n=41. The interim analysis had a median follow-up of 3.5 yrs, 45 PFS events, and 65% information for the primary endpoint of PFS, demonstrating the superiority of the FFX/bev+atezo over atezo monotherapy, with a hazard ratio of 0.439 (95% CI 0.23-0.84, p=0.0103), which was below the critical value of 0.0152 based on the O’Brien Flemming monitoring boundary. Median PFS was 30.0 and 4.3 months, ORR was 80.6% v 46%, and DCR at 12 months was 62.9% v 32.4% in the FFX/bev+atezo arm compared to the atezo-only arm, respectively. Grade 3 or higher adverse events (AEs) occurred in 52 pts (atezo: 18; combination arm: 34). There were six total Grade 5 AEs (two unrelated, two unlikely, and two possible), of which one was in the atezo arm (death NOS/progression) and five were in the combination arm (two NOS deaths, one disease progression, one hepatic hemorrhage, and one cardiac arrest). Additional endpoint analyses are ongoing and will be presented. Conclusions: The combination of FFX/bev+atezo led to significantly longer PFS than atezo monotherapy in the first-line setting for dMMR mCRC. *Drs. Rocha Lima and Overman contributed equally. Clinical trial information: NCT02997228 .

Background Dual anti-CTLA-4/PD-1 inhibitors show efficacy in numerous malignancies. We are the first to report on the efficacy of ipilimumab-nivolumab immunotherapy in a dedicated cohort of patients with gynecologic clear cell carcinomas (CCCs), which are rare, aggressive cancers.Methods DART is a multicenter, multicohort phase II trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks), with primary objective as Response Evaluation Criteria in Solid Tumors (RECIST)-based overall response rate (ORR). Secondary objectives were ORR by immune RECIST (iRECIST), progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease (SD) ≥6 months), and toxicity.Results Overall, in this cohort of 32 patients with gynecologic CCC (N=19 ovarian, N=8 endometrial, N=5 cervical; 1–8 prior therapies; 3 had prior PD-1 inhibitor exposure), an ORR of 9.38% was seen. This included two complete responses (CRs) (both ovarian origin) that are ongoing at >3 years and one partial response (PR). Overall ORR increased to 12.5% when including one PR by iRECIST criteria for a patient with cervical CCC lasting 26 months, with an OS of 32.0 months. The CBR was 21.88% overall for all 32 (7/32) evaluable patients with gynecologic CCC. This included two CR, one PR, and two patients with SD >6 months with ovarian CCC and one PR by iRECIST and one SD >6 months in two patients with cervical CCC. PFS for the seven patients with CBR was 63.6+, 47.8+, 40.5+, 50.8+, 7.4, 26, and 58.1+ months. Median OS was 21.7 months for all 32 evaluable patients. Seven of 32 patients (21.9%) discontinued therapy because of toxicity; there were no treatment-related deaths.Conclusions Ipilimumab plus nivolumab demonstrated durable antitumor activity in certain patients with CCC of gynecological origin, particularly in those with CCC of ovarian origin. Safety is consistent with the known profile of ipilimumab and nivolumab. Correlative studies to better identify which patients will respond to combined ipilimumab and nivolumab are ongoing.Trial registration number NCT02834013.

BACKGROUND:A plant-based diet is associated with better survival among patients with nonmetastatic colorectal cancer (CRC), but its association in metastatic CRC is unknown. METHODS:Using an National Cancer Institute-sponsored trial (CALGB/SWOG 80405), we included 1284 patients who completed validated food frequency questionnaires at the initiation of metastatic CRC treatment. We calculated 3 indices: overall plant-based diet index (PDI), which emphasized consumption of all plant foods while reducing animal food intake; healthful plant-based diet index (hPDI), which emphasized consumption of healthful plant foods such as whole grains, fruits, and vegetables; and unhealthful plant-based diet index (uPDI), which emphasized consumption of less healthful plant foods such as fruit juices, refined grains, and sugar-sweetened beverages. We estimated the associations of 3 indices (quintiles) with overall survival (OS) and progression-free survival (PFS) using multivariable Cox proportional hazards regression. RESULTS:We observed 1100 deaths and 1204 progression events (median follow-up = 6.1 years). Compared with the lowest quintile, patients in the highest quintile of PDI had significantly better survival (hazard ratio [HR] for OS = 0.76 [0.62-0.94], Ptrend = .004; PFS = 0.81 [0.66-0.99], Ptrend = .09). Similar findings were observed for hPDI (HR for OS = 0.81 [0.65-1.01], Ptrend = .053; PFS = 0.80 [0.65-0.98], Ptrend = .04), whereas uPDI was not associated with worse survival (HR for OS = 1.16 [0.94-1.43], Ptrend = .21; PFS = 1.12 [0.92-1.36], Ptrend = .42). CONCLUSIONS:Our study suggests that a plant-based diet, especially when rich in healthful plant foods, is associated with better survival among patients with metastatic CRC. The cause of survival benefits warrants further investigation.

BACKGROUND:The combined use of anti-programmed cell death protein 1 (PD-1)/anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint inhibitors has been effective in various cancer types. The Southwest Oncology Group (SWOG) Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The purpose of the study was to evaluate the potential clinical benefit of ipilimumab and nivolumab in patients with SCCOHT. METHODS:DART was a prospective, open-labeled, multicenter (>1,000 US sites), multi-cohort phase II clinical trial of intravenous administration of ipilimumab (1 mg/kg, every 6 weeks) plus nivolumab (240 mg, every 2 weeks). The primary endpoint was overall response rate [ORR, confirmed complete response (CR) and partial response (PR)] per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease ≥6 months), and toxicity. Immune responses were also evaluated. RESULTS:Six patients (median age, 30.5 years; median, 2 prior therapies; no prior immunotherapy exposure) with advanced/metastatic SCCOHT were evaluable. ORR and CBR were both 16.7% (1/6) with one patient having a confirmed CR lasting 46.2+ months. However, another patient had a confirmed immune CR (iCR) with immune PFS (iPFS) of 53+ months [ORR/iORR, 33.3% (2/6)]. Notably, the latter patient had a progressing lesion at 24 weeks after initial response, but with renewed regression with ongoing therapy, suggesting delayed pseudo-progression. At 12-months, 3 patients remained alive. Median PFS was 1.4 months (range, 0.9 months-not reached); median OS was 14.2 months (2 months-not reached). No adverse events caused treatment discontinuation. CONCLUSION:Two of 6 patients (33.3%) with SCCOHT achieved durable CR/iCR and long-term survival with ipilimumab plus nivolumab. Correlative studies to determine response and resistance markers are ongoing.

Table S3. Sensitivity analysis of the association between plasma 25-hydroxyvitamin level and disease-free survival, overall survival, and time to recurrence, excluding patients who recurred or died within three months of blood collection

Figure S2. Dose-response relationship and test of linearity for the hazard ratio (HR) of disease-free survival (A), overall survival (B), and time to recurrence (C) by continuous predicted vitamin D scores, with reference of plasma 25-hydroxyvitamin D set at 12 ng/ml

11016 Background: Effective therapy following frontline immune checkpoint inhibitor (ICI)-based treatment for advanced non-small cell lung cancer (NSCLC) is needed as limited options are available. Lung-MAP S1800A was a Phase II randomized study of ramucirumab plus pembrolizumab versus standard of care (SOC) for patients with NSCLC previously treated with immunotherapy that demonstrated benefit in overall survival (OS) with an improved toxicity profile over SOC. S2302 Pragmatica-Lung trial was pragmatically designed to evaluate the impact on OS while reducing barriers to participation and decreasing clinical trial staff burden. We assessed reduction in barriers to participation and clinical staff burden in S2302 in relationship to S1800A. Methods: S2302 (NCT05633602) is a registration-intent randomized phase III trial for patients with advanced NSCLC who previously received PD-(L)1 inhibitor therapy for at least 84 days and platinum-based therapy, stratified by immediate prior line of therapy including PD-(L)1 inhibition (yes/no) and PS (0/1 v. 2). The pragmatic design has limited eligibility criteria, which are focused on stage, prior therapy and safety to enroll patients as would occur in real world practice. Laboratory assessment and imaging with RECIST reads are not required due to the OS endpoint. Data collection was developed to minimize the burden with fewer time points for data submitted, number of forms and number of data elements. Concomitant medications are not collected. Given the known safety profile of both study drugs, only related and unexpected grade 3/4 and all grade 5 adverse events are collected. Results: Accrual to S2302 was robust with 838 patients enrolled from March 2023 to December 2024 (21 months), averaging > 50 patients/month in the final 6 months. The trial enrolled 77% White and 13% Black patients. versus 87% and 8%, respectively on S1800A. Over 65% were ≥ 65 years of age. Reduced data collection on S2302 relative to S1800A results in an estimated decrease in the number of forms and data elements submitted within the first year on study by 45% and 66%, respectively. Conclusions: Incorporating pragmatic elements into S2302 resulted in robust accrual, increased participant representativeness and access for patients. The reduced burden on staff due to decreased data forms and elements is substantial. Pragmatic design elements should be considered as we develop trials to generalize to a broad and representative population. Clinical trial information: NCT05633602 .

Table S4. Hazard ratio of disease-free survival, overall survival, time to recurrence by quartiles of predicted vitamin D score

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

Patient level data of 16 evaluable patients with vulvar cancers treated on the DART immunotherapy protocol

Abstract Purpose: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART) trial presents initial results of ipilimumab/nivolumab in vulvar cancers. Patients and Methods: DART is a prospective/open-label/multicenter (1,016 US sites)/multicohort phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR; confirmed complete response and partial response (PR)] per RECISTv1.1, whereas progression-free survival (PFS), overall survival, clinical benefit rate (CBR; ORR plus stable disease ≥6 months), and toxicity were secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years; 0–6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. The ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); the PFS was 34.1, 16.7. 15.5, 7.2, and 7.0 months for these five patients, respectively. The median PFS and overall survival were 2.2 and 7.6 months, respectively. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3 to 4 adverse events occurred in 25% of patients (n = 4). There was one grade 1 to 2 adverse event (6.7%) that led to discontinuation and one (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in 3 of 16 patients, all of whom had durable responses lasting over 1 year. Notably, two additional patients experienced durable stable disease and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.

Figure S1. Diagram for study cohort derivation