Sankar, K. Nathan

8519 Background: Non-classical mutations (NCM) of epidermal growth factor receptor (EGFR) represent a broad group of oncogenic mutations in non-small cell lung cancer (NSCLC), often associated with resistance to osimertinib (e.g., P-loop and αC-helix compressing [PACC] mutations). Patients (pts) with NCM have inferior clinical outcomes with a high incidence of CNS metastases (CNSm). Silevertinib (BDTX-1535) is a fourth-generation, covalent EGFR TKI with high CNS penetrance targeting both EGFR classical mutations and NCM. The antitumor activity and safety of silevertinib in pts with advanced NSCLC were evaluated in a Phase 2 trial (NCT05256290). Methods: Pts with advanced EGFR NCM NSCLC who received no prior systemic therapy were enrolled (Cohort 3) based on a local molecular test. Silevertinib 200 mg was administered orally once daily. The primary endpoint of objective response rate (ORR) was assessed using RECIST v1.1. CNS ORR was assessed using Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) in pts with no prior CNS therapy. Secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and safety. Results: From February 2024 to July 2025, 43 pts with 35 unique NCMs (including 25 pts with PACC mutations) were enrolled in Cohort 3: median age 70.0 years, 72% female, 74% white, and 42% never smoked cigarettes. As of November 3, 2025, median follow-up was 7.2 months. ORR by RECIST v1.1 is shown in the table. Sixteen pts (37%) had CNSm, including 7 pts (16%) with measurable CNS disease. RANO-BM CNS response was 86% (n=6/7). Complete clearance of EGFR VAF ctDNA was observed in 21/26 (81%) evaluable pts. Serious treatment-related adverse events (TRAEs) were reported in 5 pts (12%), and 4 pts (9%) discontinued treatment due to TRAEs. The most common TRAEs included rash (19%, grade 3), diarrhea (19%, grade 3), stomatitis (9%, grade 3), and paronychia (5%, grade 3). While 77% of pts had a dose reduction, 19/22 (86%) patients with a radiographic response maintained or deepened their response after dose reduction, including all patients with CNS response. Conclusions: Silevertinib demonstrated robust antitumor activity in treatment-naïve pts with a broad spectrum of NCM EGFR driver mutations with high intracranial activity in pts with brain metastases. The safety profile was consistent with the known AEs of the EGFR TKI class. Clinical trial information: NCT05256290 . Data as of November 3, 2025 N ORR n (%) 95% CI DCR n (%) 95% CI ITT Population * 43 26 (60) (44.4, 75.0) 39 (91) (77.9, 97.4) PACC mutations 25 14 (56) (34.9, 75.6) 22 (88) (68.8, 97.5) Compound mutations † 16 11 (69) (41.3, 89.0) 15 (94) (69.8, 99.8) *No pts with classical (E746_A750del or L858R) mutations were enrolled. † Presence of ≥ 2 NCMs. As of December 27, 2025, the 6-month PFS rate was 86% overall and 80% in pts with CNSm; available PFS and DOR data will be presented.

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

8106 Background: Due to lack of prospective data, the optimal first line treatment approach for patients (pts) with pure LCNEC histology remains uncertain. Methods: Across 17 centers, we conducted a retrospective analysis of metastatic pure LCNEC (diagnosed at local institutions) who received 1st-line systemic therapy between 2015-2023. Pts were either treated with chemotherapy (chemo), immunotherapy (IO), or a combination (chemoIO). Clinical outcomes were progression-free survival (PFS), overall survival (OS), objective response rates (ORR), and treatment-related adverse events (trAE) as defined using CTCAE 5.0. Survival analysis by genomic alteration status ( TP53, RB1, STK11, KEAP1, KRAS) and PD-L1 status were performed. Results: We identified 161 pts with median age of 67 years (IQR: 58-83) at 1st line systemic therapy; 54% (n = 87) were males. Median follow-up was 55 months (mo), 62 mo, and 29 mo for the chemo, IO, and chemoIO groups, respectively. 79% (n = 127) were former or current smokers. 1st-line treatments were chemo (n = 94), IO (n = 11), or chemoIO (n = 56). Of 85 pts with PD-L1 status, 58 (68%) were 0% and 27 (32%) were ≥1%. The most common chemo regimen was platinum-etoposide (n = 72, 78%). ChemoIO regimens included carboplatin/etoposide/atezolizumab (n = 23, 43%) and carboplatin/pemetrexed/pembrolizumab (n = 17, 31%). In the IO group, 1 patient received dual IO. Lung (n = 74, 46%) and liver (n = 71, 41%) were the most common sites of metastasisThere was no significant difference in PFS across the groups (median PFS [mPFS] chemoIO: 5.7 mo, 95% CI: 5.0-6.3, chemo: 5.1 mo, 95% CI: 3.1-5.9; IO: 3.6 mo, 95% CI: 1.7-6.5) on multivariable analysis adjusting for ECOG and “M” stage (p = 0.2 and 0.24 for chemoIO-chemo and chemoIO-IO comparisons, respectively). There was no difference in OS (mOS chemo: 11 mo, 95% CI: 7.6-17.4; IO: 13.6 mo, 95% CI: 5.9-not reached; chemoIO: 12.2 mo, 95% CI: 7.4-20.6, p = 0.5 and 0.8 for chemoIO-chemo and chemoIO-IO comparisons, respectively). ORR was 35.2% (31/88) in chemo, 25% (2/8) in IO, and 35.7% (20/56) in chemoIO ( p= 0.46). There were no significant differences in PFS and OS outcomes by treatment group when divided by genetic profile (n = 79, methods), or by PD-L1 status (0% vs ≥1%). Any grade trAE occurred in 48 (51%), 5 (45%), and 28 (50%) pts treated with chemo, IO, and chemoIO, respectively. Grade ≥3 toxicity profiles are shown (table). Conclusions: For 1st-line treatment of LCNEC, similar PFS, OS, and ORR were seen for chemo, IO, and chemoIO. This questions the added benefit of chemoIO compared to chemo alone, and warrants future clinical trials to discern the optimal 1st line treatment. [Table: see text]

8013 Background: For patients (pts) with unresectable locally-advanced NSCLC, standard of care involves durva consolidation after concurrent CRT, although its benefit in ALK+ tumors is unclear. The ALINA trial demonstrated adjuvant efficacy of alectinib in resected ALK+ NSCLC, but the optimal consolidation strategy for unresectable locally-advanced ALK+ NSCLC remains elusive. Methods: This multi-institutional international retrospective analysis included pts with stage III unresectable ALK+ NSCLC who received an ALK TKI, durva, or obs alone after concurrent CRT between 2015-2022. Baseline characteristics of age, sex, smoking history, and PD-L1 status were collected. Clinical outcomes including real-world progression-free survival (rw-PFS), overall survival (OS), and treatment-related adverse events (trAE) as defined using CTCAE 5.0 were assessed, and multivariate cox regression models were performed. Results: Sixty-four pts across 16 institutions were included. The median age was 57 (IQR 49-66) and 61% were females. The majority had adenocarcinoma (97%) and had never smoked (58%). 15 received ALK TKI (10 alectinib, 3 crizotinib, 1 brigatinib, 1 lorlatinib), 30 received durva, and 19 received obs alone. There was no significant difference in stage of cancer (IIIA, B, or C) or PD-L1 status among groups. After adjusting for stage and age at CRT initiation, median rw-PFS was significantly longer for ALK TKI (rw-PFS not reached [NR], 95% CI 22.7-NR) vs durva (11.3 months (mo), 95% CI 9.2-18.5, p= 0.005, HR = 0.12) or obs (7.4 mo, 95% CI 3.4-12.5, p < 0.0001). Two (13%) pts progressed on ALK TKI. 25 pts (83%) progressed on durva leading to treatment with ALK TKI in 23, and 18 (95%) progressed while under obs leading to treatment with ALK TKI in 15. 3-year OS was 100% for ALK TKI vs 90.5% for durva vs 63.5% for obs. Median OS was NR (95% CI NR-NR) for both ALK TKI and durva vs 70.6 mo (24.9-NR) in the obs group ( p= 0.03 for both ALK TKI and durva compared to obs). Median duration of therapy was 24.7 mo with ALK TKI and 6.5 mo with durva. Grade ≥3 trAE occurred in 27%, 7%, 6% of pts treated with ALK TKI (1 fatigue, 1 diarrhea, 1 hyperbilirubinemia, 1 pneumonitis), durva (1 fatigue, 1 neutropenia), and obs (1 neutropenia) respectively. Treatment discontinuation due to toxicity occurred in 4 (27%) with ALK TKI and in 3 (10%) with durva. Conclusions: In this retrospective study of stage III ALK+ NSCLC, consolidation ALK TKI demonstrated clinically meaningful improvement in PFS and OS over durva and obs, while showing a slightly higher rate of trAE over dura and obs. Furthermore, we show a high rate of progression following CRT alone in ALK+ NSCLC. These findings underscore the need for prospective molecularly driven trials to determine the optimal consolidation therapy for unresectable ALK+ NSCLC.

8567 Background: Adjuvant osimertinib (osi) improves disease-free survival (DFS) in patients (pts) with resected, early-stage, EGFR-mutant (EGFRmut) NSCLC, yet the benefit of osi after CRT in pts with unresectable locally advanced NSCLC is unknown. Post-hoc analysis of the PACIFIC trial showed a lack of survival benefit with consolidation durva versus placebo in pts with EGFRmut NSCLC. Comparisons between consolidation durva and EGFR TKIs in unresectable EGFRmut NSCLC following CRT are lacking. Methods: We conducted a multi-institutional retrospective analysis of pts with stage III unresectable EGFRmut NSCLC (exon19 deletion, exon21 L858R), who received EGFR TKI or durva after ≥ 2 cycles of platinum-based chemotherapy plus definitive radiation therapy between 2015-2022. Baseline characteristics including age, sex, smoking history, PD-L1 status, and outcomes on DFS, overall survival (OS), and safety were collected. Multivariable (MVA) cox regression analysis was used for statistical analysis. Treatment-related adverse events (trAE) were defined using CTCAE 5.0. Results: Seventeen pts from 12 institutions received an EGFR TKI (osi, n=15; erlotinib, n=2), and 13 pts received consolidation durva. Median follow-up was 23 months. Median age of all pts was 61 years (IQR:52-72) and 76.7% were female. Most pts in both groups had never-smoked and had adenocarcinoma. All pts received ≥ 60 Gy of radiation with concurrent chemotherapy. PD-L1 expression was ≥ 50% in 1/10 (10%) pts treated with durva vs 6/13 (46.2%) treated with TKI, p=0.09. Median duration on treatment for EGFR TKI and durva was 12.2 months and 4.8 months, respectively. Pts treated with EGFR TKI had significantly longer 24-month DFS versus pts treated with durva after adjusting for stage (3A vs 3B vs 3C) (Table). Any grade tRAE occurred in 58.8% (10/17) of pts treated with EGFR TKI vs 38.5% (5/13) with durva. Grade > 3 tRAE occurred in 15.4% (1 pneumonitis and 1 AST/ALT elevation) of pts treated with durva but in none of pts treated with EGFR TKI. Three pts within each arm came off treatment due to toxicity (EGFR TKI: 1 pneumonitis and 2 dermatitis; durva: 1 of each pneumonitis, Type 1 diabetes, AST/ALT elevation). Conclusions: EGFR TKI therapy after definitive CRT was associated with significantly longer DFS compared to durva in this retrospective study of pts with stage III unresectable EGFRmut NSCLC, without unanticipated safety signals. Follow-up is ongoing and OS outcomes will be evaluated subsequently. Further investigation is warranted to define the optimal therapy for locally advanced EGFRmut NSCLC. [Table: see text]