Abstract Background: STK-012 is a first-in-class α/β-IL-2R biased partial agonist that drives antitumor activity by selectively stimulating CD25+ antigen-activated T-cells and avoids hallmark IL-2 toxicities by sparing pleiotropic activation of lymphocytes including NK cells. In this phase 1a/b study, STK-012 is combined with standard of care pembrolizumab + chemotherapy (PCT) in 1L PD-L1 negative NSQ NSCLC where PCT alone has poor outcomes (ORR 32% and median PFS 6.2 months). Methods: 1L NSQ NSCLC subjects received STK-012 SC Q3W + PCT. Serial blood samples were analyzed for changes in cytokines in chemoluminescence assays, T cell proliferation and activation markers were analyzed in spectral flow cytometry, and T cell clonality was analyzed by TCR sequencing. Data are shown for a cohort of 22 efficacy-evaluable 1L NSCLC subjects (N=18 PD-L1<1%, N=4 PD-L1=1%) which was enriched for loss-of-function tumor suppressor gene (LoF TSG) mutations (n=11; STK11, KEAP1, SMARCA4) or mucinous histology (n=5) associated with a “cold” TME and primary immune resistance. Results: STK-012 + PCT demonstrated an ORR of 55% in all efficacy evaluable patients; 50% in patients with PD-L1<1% tumors; 55% in LoF TSG mutations; and 80% in mucinous histology. STK-012 + PCT induced sustained proliferation of CD8+ and CD4+ T cells (13X and 5x increase from baseline, respectively), proliferation of antigen activated T cells including PD-1+ CD8+ (14X) and 4-1BB+ CD8+ (14X) and re-invigoration and proliferation of previously exhausted CD39+ (11x) and TIM3+ (18x) CD8+ T cells. After the first cycle, 3.35% of the total T cell repertoire were T cell clones which were newly detected or expanded >10x (n=12). STK-012 + PCT induced key cytokines IFNγ and IL-18 characterizing an activated CD8+ T cell response and increased IP-10 which is associated with enhanced T cell trafficking into tumor tissues (13x,14x and 23x mean increase from baseline, respectively). Sustained elevation of cytokines across treatment cycles (IFNγ median peak of 71, 95, 96 pg/mL in C1, C2 and C6) was observed, supportive of the emerging durability of the combination. Induction of cytokines TNFα and IL-6 was limited (median peak 4, 6 pg/mL), consistent with limited activation of naïve T cells and NK cells and the lack of capillary leak syndrome with STK-012. Conclusions: STK-012 + PCT led to robust cytokine induction, proliferation and expansion of antigen activated T cells, proliferation of previously exhausted T cells, and remodeling of the T cell repertoire. The addition of STK-012 to PCT has the potential to overcome resistance in immune excluded populations including PD-L1<1% tumors, LoF TSG mutations and mucinous histology. A global, randomized Phase 2 study, SYNERGY-101, of STK-012 + PCT vs. PCT in 1L PD-L1<1% NSQ NSCLC is ongoing (NCT05098132). Citation Format: Salman Punekar, Adam Jacob Schoenfeld, Edward B. Garon, So Yeon Kim, Kai He, Jennifer Marks, Brian S. Henick, Stephen V. Liu, Nagashree Seetharamu, Alexander Spira, Justin Gainor, Tim Larson, Ticiana A. Leal, Cameron Oswalt, Benjamin Izar, Alize Marangoz-Stager, Vic Danh, Grace Lunardi, Krystle Bach, Naiyer A. Rizvi, Alex Azrilevich, Anita Mehta-Damani, Martin Oft. Selective immune activation of antigen activated T cells with STK-012, an a/b IL-2 receptor biased partial agonist, with pembrolizumab and chemotherapy in 1L PD-L1 negative non-squamous NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6740.

e20699 Background: SOT recipients are at increased risk of malignancy due to immunosuppression. Lung cancer is among the most common post-transplant cancers, yet molecular characteristics and treatment patterns remain poorly defined. As targeted therapies shape non-small cell lung cancer (NSCLC) care, understanding tumor genomics is essential. Methods: We conducted a single-institution retrospective study of SOT recipients diagnosed with lung cancer 2007-2025. Demographic, transplant, histologic, molecular, treatment, and survival data were abstracted. Molecular analyses focused on NSCLC, including PD-L1 tumor proportion score (TPS) and next-generation sequencing (NGS). Overall survival (OS) was assessed by molecular and treatment subgroups. Results: 85 SOT recipients developed lung cancer (73 NSCLC - 43 adenocarcinoma [adenoCa], 30 squamous). Median age at diagnosis was 66 years, median time from transplant to diagnosis was 5.4 years, and median follow-up was 9 months. Lung was the most common transplanted organ (33%), followed by kidney (28%) and heart (22%). 53 NSCLC patients had TPS assessed, and 49 had NGS. TPS did not differ significantly by histology; most tumors had low TPS ( < 1%) (44% adenoCa vs 60% squamous), while intermediate TPS (10–50%) was more frequent in adenoCa (25% vs 15%). Actionable mutations were identified more often in adenoCa patients (42% vs 3%, p = 0.0001), most commonly KRAS G12C (15%) and classical EGFR mutations (14%). There was no significant difference in OS between patients with actionable versus non-actionable mutations (1-year OS 68% vs 52%). In contrast, OS differed significantly by treatment strategy (p < 0.0001), with 1-year OS of 50% for chemoimmunotherapy, 43% for targeted therapy and 14% for chemotherapy. Conclusions: NSCLC after SOT has a molecular landscape comparable to the general population, supporting comprehensive molecular profiling. However, TPS was lower and co-mutation patterns differed, suggesting immunosuppression may affect tumor biology. Despite frequent actionable mutations, survival was driven more by treatment strategy than molecular status, highlighting potential underuse of targeted approaches, low uptake of immunotherapy despite strategies to improve post-transplant safety, and the need for further study on transplant-specific tumor biology. Actionable mutations and systemic therapy patterns by stage of NSCLC. Characteristics Stage I (n=34) Stage II (n=7) Stage III (n=7) Stage IV (n=29) Total (n=77) p value N (%) N (%) N (%) N (%) N (%) Actionable Mutation 0.2 No 22 (64.7%) 6 (85.7%) 7 (100%) 23 (79.3%) 58 (75.3%) Yes 12 (35.3%) 1 (14.3%) 0 (0%) 6 (20.7%) 19 (24.7%) Systemic Therapy 0.0005 Chemotherapy 2 (5.9%) 3 (42.9%) 2 (28.6%) 16 (55.2%) 23 (29.9%) Chemoimmunotherapy 0 (0%) 0 (0%) 0 (0%) 2 (6.9%) 2 (2.6%) Targeted Therapy/Chemo 4 (11.8%) 1 (14.3%) 1 (14.3%) 7 (24.1%) 13 (16.9%) None 28 (82.4%) 3 (42.9%) 4 (57.1%) 4 (13.8%) 39 (50.6%)

BACKGROUND:20% of patients with cancer are estimated to be ineligible for phase III trials because of restrictive eligibility criteria. Ineligibility rates for earlier phase trials are even greater. In response, several groups, including the US Food and Drug Administration, have advocated for more inclusive study designs. We examined Kirsten rat sarcoma virus (KRAS) G12C inhibitor trials to determine if inclusivity has shifted in the development of molecularly targeted therapies. METHODS:We evaluated phase I-III studies of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC) by applying criteria from 15 US trials to a multi-institutional real-world cohort of patients with metastatic NSCLC and universal KRAS testing (n = 2383). Eligibility analysis, multivariate logistic regression for ineligibility, and a Cox proportional hazards model were used on patients with KRAS G12C-mutated NSCLC (n = 185) to compare trial enrollment and overall survival under various eligibility modifications. RESULTS:Of patients with metastatic KRAS G12C-mutated NSCLC, 60%-70% were ineligible for any KRAS inhibitor clinical trial, including studies aiming to establish first-line standard of care. Eligibility criteria remained unchanged from phase I to phase III. Performance status, renal function, and active brain metastases were the main causes of trial ineligibility. Liberalizing criteria for renal function and brain metastases increased enrollment by 25% without affecting overall survival (P = .49), whereas allowing worse performance status reduced study effect sizes (P = .001 in second-line and P = .04 in first-line). CONCLUSIONS:Most patients with metastatic KRAS G12C-mutated NSCLC are excluded from trials. There is substantial potential to refine trial entry criteria to better balance generalizability, safety, speed, and success.

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.

Background Despite treatment, approximately one-third of patients with head and neck squamous cell carcinoma (HNSCC) die within 5 years of diagnosis. Here, we assessed molecular and clinical features that correlate with biological sex and overall survival in HNSCC.Methods We analyzed HNSCC cases in The Cancer Genome Atlas, which includes tumors from 382 males and 141 females. When possible, findings were validated with the National Cancer Institute's Surveillance, Epidemiology, and End Results dataset (November 2023 Submission, 1975-2021).Results Tumors from females had a significantly lower fraction of genome altered, along with fewer aneuploidy events. HNSCCs in females had increased expression of immune genes and higher overall immune infiltrate. Females showed worse overall survival in HNSCC compared to males (hazard ratio [HR]: 1.39). This disparity was statistically attributable to age at diagnosis as well as HPV status, as HNSCCs in females were less likely to be HPV-positive than in males. For laryngeal squamous cell carcinoma (L-HNSCC), females also had significantly worse outcomes (HR: 3.42), but here the disparity could not be attributed to available clinicogenomic features such as HPV or smoking status. The association of biological sex with outcome in L-HNSCC was also observed in the SEER database and was not present among patients diagnosed before the age of 50.Conclusion Biological sex is associated with differences in survival and tumor genomic features in HNSCC. HPV infection status, diagnosis age, and tumor location contribute to a worse prognosis for females with HNSCC, particularly strong in L-HNSCC.

BACKGROUND:This first-in-human clinical study explored lomvastomig, an immunoglobulin G1-based Fc-silenced bispecific antibody that simultaneously blocks the immune checkpoint receptors programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain-3. METHODS:Lomvastomig was characterized in cell cultures and preclinically in cancer mouse models. The phase 1, open-label, multicenter clinical study of lomvastomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with four tumor-specific cohorts, which enrolled checkpoint inhibitor (CPI)-experienced patients with melanoma and non-small-cell lung cancer (NSCLC) and CPI-naïve patients with SCLC and esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, maximum tolerated dose (MTD)/recommended dose for expansion (RDE), pharmacokinetics, drug receptor occupancy, and antitumor activity. RESULTS:39 and 95 patients were enrolled in the dose-escalation and expansion parts, respectively. Lomvastomig was well tolerated up to the highest tested dose of 2,100 mg every 2 weeks (Q2W). One dose-limiting toxicity was reported at 1,200 mg (grade 3 troponin T increase). No MTD was reached, and 2,100 mg Q2W was established as the RDE. Linear pharmacokinetics across the studied dose range suggested target saturation. Peripheral blood drug receptor occupancy on CD3+ and CD8+ was saturated at >90% throughout treatment for doses ≥70 mg. Objective responses were observed at 2,100 mg lomvastomig during dose-escalation (21%; n=19), and in the CPI-experienced melanoma (8%, n=38) and CPI-naïve ESCC (20%, n=15) expansion cohorts. CONCLUSIONS:Lomvastomig had a tolerable and manageable safety profile at 2,100 mg Q2W. Clinical activity was limited in CPI-experienced patients with melanoma and NSCLC, while an encouraging signal was observed in CPI-naïve patients with ESCC. TRIAL REGISTRATION NUMBER:NCT03708328 (registration date: 2018-10-09).

Metastasis accounts for 90% of cancer-related deaths. Extravasation is a necessary step for cancer metastasis. Currently, there are no drugs that specially target extravasation. Most cancer therapies target either proliferation or angiogenesis. We previously identified "angiopellosis" as the dominant mechanism by which vascular endothelial cells undergo conformational changes and actively "push" circulating cancer cells out of blood vessels. In this study, we developed an image-based high-throughput drug screening assay by coculturing cancer membrane-coated spheres with endothelial monolayers. Through this platform, we identified Bay 61-3606 as a lead angiopellosis inhibitor. Bay 61-3606 substantially reduced cancer cluster extravasation, an activity solely supported by angiopellosis and associated with higher metastatic potential, in both zebrafish and mouse models. Furthermore, Bay 61-3606 decreased distant metastases in murine models of lung carcinoma and triple-negative breast cancer. Mechanistically, Bay 61-3606 targeted the c-Jun amino-terminal kinase signaling pathway, down-regulating COL8A1 expression in endothelial cells and impairing the angiopellosis process.

The rapid integration of immune checkpoint inhibitors (ICIs) into standard oncology protocols has birthed a new frontier in clinical rheumatology: immune‐related adverse events (irAEs). By disrupting the programmed cell death‐1 (PD‐1)/PD‐L1 and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) axes to restore antitumor T cell activity, these therapies inadvertently breach peripheral tolerance. This results in a spectrum of de novo autoimmune and inflammatory syndromes that frequently mimic established rheumatic diseases, including inflammatory arthritis and myositis. Although ICIs have revolutionized survival outcomes, the resultant irAEs pose a significant clinical challenge, affecting nearly 50% of patients and often necessitating the expertise of rheumatologists for management. This manuscript explores the unique rheumatologic phenotype of ICI‐induced toxicities, emphasizing the urgent need for a shift from broad‐spectrum glucocorticoid use toward targeted, mechanism‐driven therapies that do not compromise the abscopal antitumor effect. We review the current landscape of clinical trials investigating the repurposing of traditional disease‐modifying antirheumatic drugs and advanced biologics. Specifically, we discuss the efficacy and safety of tumor necrosis factor–alpha inhibitors, interleukin‐6 receptor antagonists, and JAK inhibitors in the context of steroid‐refractory irAEs. We further analyze the molecular commonalities between idiopathic autoimmune diseases and ICI‐induced inflammation. As the patient population receiving ICIs grows, the rheumatologist's role as a co‐manager is increasingly essential. This review highlights the need for standardized grading and treatment algorithms for rheumatologic irAEs and advocates collaborative research to separate immunotherapy toxicities from its oncological benefits.

e23519 Background: Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm often driven by kinase fusions, most commonly involving anaplastic lymphoma kinase (ALK). Although tyrosine kinase inhibitors (TKIs) have demonstrated activity in unresectable IMT, the role of targeted therapy perioperatively is not well established. We evaluated the molecular profiles and clinical outcomes of IMTs at a single institution, describing the prevalence of actionable gene fusions and use of neoadjuvant targeted therapy. Methods: We performed a retrospective review of all patients with IMT at Columbia University Irving Medical Center from 2005 to 2025. Clinical and treatment data were analyzed. RNA-based fusion testing was performed on archival tumor specimens when available, and prior DNA/RNA sequencing results were reviewed when available. Results: Twenty-seven IMT patients were included. 59% were male and the average age at diagnosis was 41 years (range 1.5-81). Tumors arose in multiple sites, including the lung (22%), kidney (15%), head and neck (15%), and gastrointestinal tract (15%). 14 tumors underwent successful RNA-based sequencing, of which 12 (86%) harbored kinase fusions. ALK fusions were present in 9 (64%), ROS1 in 2 (14%), and a VCAN-IL23R fusion in one case. FN1-ALK was the most common fusion subtype (n=3), all occurring in bladder IMTs. Surgical resection was the primary treatment for 26/27 patients. Four patients received neoadjuvant therapy. Two patients with ALK-rearranged IMTs were treated with neoadjuvant ALK inhibition, resulting in one complete metabolic response (alectinib) and one partial response (crizotinib) prior to resection. The VCAN-IL23R case demonstrated recurrence and progression despite multimodal therapy. Two additional patients developed recurrence managed surgically. Conclusions: Kinase fusions were common (86% of sequenced tumors) and molecularly diverse in this IMT cohort, supporting routine use of RNA-based fusion profiling. Despite the high prevalence of actionable alterations, TKI use remained limited. The favorable responses to neoadjuvant ALK inhibition demonstrate the potential role for perioperative targeted therapy. The aggressive clinical phenotype seen in the VCAN-IL23R fusion case suggests that rare non-ALK fusions may represent biologically distinct IMT subsets with limited treatment options. Together, these findings support earlier incorporation of molecular testing with expanded investigation of rare gene fusions and highlight the need for prospective evaluation of perioperative TKI strategies. IMT molecular fusion profiles. Fusion Type N (%) Fusion partner(s) Tumor location Age range ALK 9 (64) FN1 (3), CLTC, MCC, TMP4, CLIP2, CSTF3, KIF5B Bladder (3), lung (3), head/neck (2), breast 2-77 ROS1 2 (14) FN1, TFG Lung, small intestine 13-18 IL23R 1 (7) VCAN Liver 12 No fusion detected 2 (14) N/A Epididymis, head/neck 70-78

Targeted CCR5 inhibition replicates CCL5 loss with reduced tumor cell proliferation in vitro and in vivo.

LBA8505 Background: Savo, a highly selective MET -TKI, combined with osi, may overcome acquired MET -driven resistance in EGFRm advanced NSCLC after PD on EGFR-TKIs. Here we report primary results of the prespecified interim analysis (IA) in SACHI study, comparing efficacy and safety of savo + osi with chemo in this disease setting. Methods: In this randomized, open-label, phase 3 study, 250 EGFRm and MET amp advanced NSCLC patients (pts) post PD on first-line EGFR-TKI were planned ( MET copy number ≥5 or MET /CEP7 ratio of ≥2.0 by FISH for pts with prior 1 st /2 nd generation [G] EGFR-TKI; MET copy number ≥10 for pts with prior 3 rd G EGFR-TKI); T790M negative after PD on 1 st /2 nd G EGFR-TKI was required. Eligible pts were randomly assigned (1:1) to receive savo 400 or 600 mg QD (for body weight of < 50, or ≥ 50 kg respectively) + osi 80 mg QD, or chemo (pemetrexed + carboplatin/cisplatin), stratified by brain metastases, prior use of 3G EGFR-TKI, and type of EGFR mutations. Crossover to savo + osi after IRC-PD was permitted for chemo group. The primary endpoint, PFS by investigator (INV) per RECIST 1.1, was hierarchically tested via a stratified log-rank test in 3G EGFR-TKI treatment-naïve set firstly, then in ITT set. This is a prespecified IA conducted via an independent data monitoring committee to assess efficacy superiority or sample size re-estimation. Results: From 15 Oct 2021 to 30 Aug 2024 (DCO for IA), 211 pts were randomized to receive savo + osi or chemo (n=106 vs 105). Baseline characteristics were well balanced. mPFS by INV was significantly longer with savo + osi vs chemo in both 3G EGFR-TKI treatment-naïve set and ITT set ( p < 0.0001 in both sets), which met prespecified IA efficacy boundary ( p <0.0099 and 0.0228 in 2 sets, respectively); in 3G EGFR-TKI treated pts, mPFS was also significantly prolonged with savo + osi (6.9m vs 3.0m, HR=0.32, p < 0.0001). IRC-assessed PFS benefits were consistent (table). OS was immature at this DCO. Grade ≥3 TEAE occurred in 56.6% vs 57.3% of pts with savo + osi vs chemo; savo + osi had lower rates of hematologic events than chemo. Conclusion: Savo + osi significantly improved PFS versus chemo in MET amp NSCLC post EGFR-TKI, and the combination was safe and well tolerated. Savo + osi is a potential new treatment option for this genomically defined population. Clinical trial information: NCT05015608 . ITT set Savo + osiN=106 ChemoN=105 Hazard ratio/Odds ratio Two sided -p value mPFS (95% CI) (INV), m 8.2 (6.9, 11.2) 4.5 (3.0, 5.4) 0.34 <0.0001 mPFS (95% CI) (IRC), m 7.2 (5.7, 11.1) 4.2 (4.0, 5.7) 0.40 < 0.0001 ORR (95% CI) (IRC), % 63.2 (53.3, 72.4) 36.2 (27.0, 46.1) 3.05 < 0.0001 mDoR (95% CI) (IRC), m 9.7 (5.8, 12.4) 4.3 (2.8, 5.1) NA NA mOS (95%CI), m* 22.9 (16.8, NE) 17.7 (14.9, 26.3) 0.84 0.4191 *52.4% of pts in chemo group were crossover to receive savo + osi or other MET Inhibitors.

Supplementary Figures S1-S6 and figure legends.

Confirmation of CCL5 knockout clones.

11171 Background: Eligibility criteria (EC) are the primary method to assess patient appropriateness for clinical trials. There is a tradeoff between narrowing EC for patient safety and matching trial populations to the real-world population likely to receive the study agents. There is little evidence to guide optimal EC design. In 2017, ASCO proposed modifications to EC to increase the generalizability of trial findings. We previously reported a single-center experience and now report a multi-center cohort of non-small cell lung cancer (NSCLC) patients (pts) with KRAS G12C mutations to determine whether EC for trials of KRAS G12C inhibitors allowed enrollment of pts seen as part of routine care at three academic medical centers. Methods: We extracted EC for Phase I-III trials of six KRAS G12C inhibitors (sotorasib, adagrasib, olomorasib, divarasib, JDQ443 and RMC-6291) that were published or made available by sponsors. We defined a consensus set of eligibility criteria. We retrospectively reviewed pts with NSCLC and KRAS G12C mutations detected on universal testing of NSCLCs at Columbia University Irving Medical Center, Memorial Sloan Kettering and Weill Cornell Medicine from 2018 to 2023. Pts were re-evaluated at times of progression and last follow up. Pts were deemed trial-eligible if they met all EC, borderline if they had one laboratory value <20% from cutoff, or otherwise ineligible. Associations between demographic factors with odds of meeting eligibility criteria were determined using a multivariate logistic regression. Results: We identified 185 pts with KRAS G12C mutant advanced NSCLC who received treatment. Only 64 (35%) of these pts would have qualified for a second-line (2L) study of a KRAS G12C inhibitor. 15 (8%) had borderline eligibility and 106 (57%) were ineligible. 33/56 (60%) pts who received 2L KRAS G12C inhibitors would not have met consensus EC. Common reasons for 2L ineligibility included poor performance status (59, 49%), renal dysfunction (45, 37%), active brain metastases (33, 18%) and cytopenias (18, 15%). Age was associated with ineligibility (OR 1.07 per year, p = 0.006). Medicaid insurance was associated with a four-fold higher rate of ineligibility compared to Medicare but was not statistically significant (OR 4.86, p = 0.079). Liberalizing criteria for renal dysfunction and brain metastases would increase enrollment potential by 25% without decreasing the median overall survival of the broadened eligible cohort, whereas allowing worse performance status would decrease survival and effect sizes (1L HR 0.86 versus 0.74, p = 0.04; 2L HR 0.530 versus 0.423, p < 0.001). Conclusions: Our data indicate substantial differences between the real-world population of patients treated with KRAS G12C inhibitors and those who were trial eligible. Efforts should focus on improving clinical trial generalizability without compromising safety.

Loss of tumor-derived CCL5 reduces tumor cell proliferation in TE-1 cells.

Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CINhigh cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.