Bazhenova, Lyudmila

9007 Background: Since transition to virtual interviews, application and interview inflation have increased the work burden of GME recruitment. In 2021, AAMC ERAS implemented a process that allows applicants to assign signals to top programs of interest. There is a paucity of guidance on optimal use of ERAS signals (ES), resulting in apprehension and uncertainty amongst applicants and program directors (PD). For the 2026 ERAS cycle, Hematology/Oncology programs (HOP) had the option to participate in ES, in which applicants are provided 5 gold (G) signals and 15 silver (S) signals. First-hand knowledge on how ES was utilized by HOP, as well as PD perceptions about ES, may guide best practices on ES. Methods: During the ASCO Oncology Training Program Leadership Retreat in November 2025, an anonymous survey, assessing HOP utilization and perception of ES, and the impact of ES on recruitment practices, was launched. One PD from each HOP was invited to complete the survey while onsite. Results: 88 HOP (46% of ACGME HOP) are represented. 97% (n=85) utilized ES. Of HOP who used ES, 74% are academic. 32% are small (1-9 fellows), 43% medium (10-19 fellows), and 25% large (20+ fellows). 79% received 400+ applications. 69% reviewed applications without signals but gave higher consideration to signaled applicants. 25% only reviewed applications with signals. 28% used ES when creating rank list; 45% think ES utilization is appropriate during ranking. 85% reported ES did not alter their approach to applicants requiring visa sponsorship. 78% felt ES made the interview selection process easier. 66% were more satisfied with this year’s recruitment process compared to years without ES. The most requested change to ES was reduction of allowed signals, especially silver. 98% will use ES next year. Conclusions: Despite limited knowledge on ES impact on recruitment, nearly all surveyed HOP participated in ES this past year and will continue. Most HOP view ES positively though many desire changes, particularly with the number of signals. Most HOP consider all applications regardless of ES. However, some HOP with larger applicant pool are using ES as inclusion criteria for interview consideration. Signals are a strong predictor for interview invitation when internal selection criteria are met. The “borderline” applicant may be the greatest benefactor from ES, viewed similarly to the non-signaled applicant who meets internal selection criteria. Sharing PD perspectives and real-life data from this year’s ES process breeds opportunities for further improvement and increased confidence with ES. Likelihood HOP offer interview invitation based on quality of application and signals (%, n=85). Internal Selection Criteria Signal Extremely Likely Likely Neutral Unlikely Extremely Unlikely Met G 73 22 5 0 0 S 42 47 8 2 1 None 8 27 24 22 19 Nearly met G 4 35 39 19 3 S 0 9 52 28 11 Not met G 0 2 12 41 45 S 1 1 6 30 62

8001 Background: The ALCHEMIST clinical trial platform, launched by the National Clinical Trials Network (NCTN) in 2014, screened patients with resected non-small cell lung cancer (NSCLC) for molecular markers and tailored post-operative adjuvant therapy trials. A081105 evaluated whether adjuvant erlotinib improved overall survival (OS) following complete resection in patients with early stage EGFR mutated lung adenocarcinoma. Methods: A081105 was a randomized phase III trial enrolling patients with completely resected stage IB (≥4 cm), II, or IIIA non-squamous NSCLC (per the 7 th TNM staging classification) harboring EGFR exon 19 deletion or L858R mutations. Patients were randomized 1:1 to erlotinib 150 mg daily for up to 2 years or placebo/observation, stratified by stage, prior chemotherapy, EGFR mutation subtype, and ECOG performance status. The primary endpoint was OS in the per-protocol (PP) population with centrally confirmed EGFR mutations, designed to detect a hazard ratio (HR) of 0.67 in favor of erlotinib with a power of 86% and one sided type I error rate of 5%. Secondary endpoints included OS and disease free survival (DFS) in a modified intent-to-treat (mITT) population with local or centrally confirmed EGFR mutations, and safety. A prespecified backstop analysis was conducted after a minimum of 5 years of follow-up on all patients. Results: Trial enrollment was discontinued when 390 of the intended 450 patients had been enrolled due to the proven benefit of adjuvant osimertinib. Among 390 enrolled patients, the arms were balanced for age (median: 67.0 years), sex (70% female), race (70% white), stage (II: 51%, IIIA: 37%), prior chemotherapy (82%), ECOG PS 0 (60%), and exon 19 deletion (57%). Adjuvant erlotinib did not significantly improve OS compared with placebo/observation in the overall PP population (364 patients, 108 events, HR 0.89; 95% CI, 0.59–1.34; 1-sided P = 0.29) or within exon 19 deletion (HR: 0.94) or L858R mutation (HR: 0.82) subgroups. Five-year OS rates were 78.6% versus 77.9%, respectively. Results were consistent in the mITT analysis (379 patients, 113 events, HR 0.86; 95% CI, 0.58–1.28). Erlotinib improved DFS (mITT: 181 events, median: 68 vs 50 months, HR 0.74; 95% CI, 0.55–1.01). Across both arms, 11% of patients started non-protocol treatment (Osimertinib: 9%) prior to disease progression, and 9% withdrew consent for all follow-up prior to recurrence. In the erlotinib arm, 3 deaths on study were reported; grade 3 or higher adverse events were reported on 39% of patients. Median duration of treatment on Erlotinib arm was 16 months; only 37% of patients completed the planned treatment. Conclusions: In resected EGFR -mutant NSCLC, adjuvant erlotinib did not improve overall survival but improved DFS. Additional studies are exploring efficacy in selected subsets of patients using genomics and proteomic analyses. Clinical trial information: NCT02193282 .

3014 Background: Macrocyclic next-generation tyrosine kinase inhibitors (TKIs) have transformed outcomes in ALK- and ROS1-positive NSCLC; such creatively designed medicines are similarly needed to improve outcomes in EGFR-mutant NSCLC. Using a novel, mutant-selective macrocyclic structure, BH-30643 was designed for super-potency against driver EGFRm, largely sparing wildtype (WT) EGFR, and with unique invulnerability to resistance from C797S with or without T790M. Here we report emerging first-in-human dose-escalation data from the SOLARA trial (NCT06706076). Methods: Phase 1 dose escalation used a BOIN design with backfill at potentially efficacious doses. Expansion cohorts targeted populations of interest. Patients (pts) had advanced NSCLC with EGFR and/or HER2 mutations detected on local testing (tissue or plasma). Measurable disease was required; asymptomatic untreated brain metastases (BM) were permitted. Objectives included safety, PK, and RECIST response rate (ORR). Plasma NGS was performed at baseline and on treatment. Results: As of 01/05/2026, 72 pts enrolled into dose escalation and backfill across 7 dose levels at a total daily dose of 20mg -160mg, median age 62, 44% Asian, 65% with history of BM, median of 3 prior lines of treatment (range 1-12). EGFR mutations included classical (38 pts), exon20ins (14 pts) and other/atypical (18 pts) or HER2 mutations (2 pts). Plasma exposures at doses of 40mg BID and above achieved > 10x coverage over target EC90 and exceeded exposure levels of most contemporary EGFR TKIs. Common TRAE ( > 10%) were WT EGFR-associated, including diarrhea (38%), rash (28%), fatigue (15%), stomatitis (13%), and were predominantly grade 1. Bilirubin elevation was seen in 26 pts (36%) related to off-target UGT1A1 inhibition (Gilbert’s-like). Grade 3 TRAE were seen in 15 pts (18%), most commonly bilirubin (8/15); DLTs included bilirubin increase and mucositis, occurring at doses ≥ 60mg BID. No pneumonitis was observed. Responses were observed across diverse EGFRm subsets, including in CNS. Including expansion pts, 28 pts enrolled with C797S on their most recent informative molecular testing (6 with concurrent MET+ or KRAS+), with 23 still on therapy. Of 17 with on-treatment scans, partial responses (confirmed or ongoing) were seen in 10 (59%); ORR was comparable with (50%) or without (66%) T790M. Of 9 pts with baseline C797S detected in ctDNA (3 with T790M), 7 had > 99% reduction of C797S VAF on treatment. Conclusions: Leveraging a novel macrocyclic scaffold, BH-30643 is the first TKI monotherapy to demonstrate clinical responses against C797S both with or without T790M. High plasma exposures combined with super-potency, CNS activity, and favorable safety offers potential for deep and durable EGFR inhibition. Enrollment into backfill and expansion cohorts is ongoing to better characterize activity in both TKI-naïve and resistant pts. Clinical trial information: NCT06706076 .

Background: Mu opioid receptors (MORs) in peripheral tissues mediate adverse effects of opioids that impair health-related quality of life (HRQoL) and may stimulate cancer progression via mitogenic signaling. Naloxegol, a peripherally acting MOR antagonist (PAMORA), is approved for opioid-induced constipation. Safety and efficacy of naloxegol have not been evaluated concurrently with systemic cancer therapy. Methods: We conducted a randomized, double-blind, placebo-controlled trial of naloxegol in patients with advanced lung adenocarcinoma starting first-line systemic therapy. Results: Only 50 patients were enrolled; the trial was terminated early due to slow accrual. Two of the three components of the feasibility primary endpoint were not met (accrual and PRO completion). At 6 months, FACT-L emotional well-being was better with naloxegol (p = 0.0113). There were trends towards better Trial Outcome Index (p = 0.0505) and physical well-being (p = 0.0628) with naloxegol. Bowel function favored naloxegol for constipation (p = 0.0223), rectal pain during defecation (p = 0.0075), and abdominal pain from constipation (p = 0.0113). Adverse event frequency and severity, PRO-CTCAE, urinary hesitancy, pain scores, and progression-free and overall survival were comparable between naloxegol and placebo. Conclusions: Naloxegol appears to be safe and tolerable, with a signal of improved HRQoL and previously unappreciated benefit for emotional well-being, without adverse clinical outcomes. Our findings should be confirmed in larger studies. ClinicalTrials.gov ID: NCT03087708.

8513 Background: The MET pathway is a known mediator of EGFR-TKI resistance and represents a therapeutic vulnerability to select MET-TKIs. Savo is an oral, highly selective MET-TKI that, when combined with osi, has the potential to overcome MET-driven resistance after progressive disease (PD) on osi. The Phase 2 SAVANNAH study has demonstrated clinically meaningful activity with the combination of savo + osi in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC and MET overexpression/amplification (NCT03778229). Isolating the efficacy of savo in the use of savo + osi is a key question for this combination. Methods: A subset of SAVANNAH included eligible pts who had EGFRm advanced NSCLC with MET overexpression (IHC 3+ intensity in ≥90% of tumor cells [IHC3+/≥90%]) and/or amplification (≥10 MET gene copies by FISH [FISH10+]) after PD on first-line (1L) osi; asymptomatic stable brain metastases (treated/untreated) were allowed. Pts were randomized 2:1 (double-blind) to savo 300 mg BID + osi 80 mg QD, or savo 300 mg BID + PBO (stratified by investigator [INV] assessed baseline [BL] brain metastases [yes/no]), until INV-assessed PD per RECIST 1.1. Brain imaging occurred at BL and PD; pts with brain metastases were re-imaged at each tumor assessment to PD. Endpoints included objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) by BICR and INV; CNS PFS, and presence/absence of CNS lesions at PD by BICR. Results: Overall, 73 pts were randomized (savo + osi n=48; savo + PBO n=25). At BL, median age: 67 vs 65 years, female: 73% vs 64%, White: 73% vs 52% in the savo + osi and savo + PBO arms, respectively. Efficacy outcomes (ORR, DoR, and PFS) were higher with savo + osi than savo + PBO (Table). CNS PFS events by CNS BICR occurred in 5/14 (36% savo + osi) and 2/4 pts (50% savo + PBO). In pts without BL brain metastases, none of the 13 pts (savo + osi) with RECIST PD by BICR had a new CNS lesion; 6/11 pts in the savo + PBO arm developed a new CNS lesion. Conclusions: In EGFRm advanced NSCLC with MET IHC3+/≥90% and/or FISH10+ status after PD on 1L osi, efficacy of savo 300 mg BID + osi was numerically greater than savo + PBO and showed promising CNS activity. To date, this is one of the largest randomized data sets presented evaluating an oral MET-TKI in EGFRm NSCLC. Efficacy findings from SAVANNAH suggest that targeting both EGFR and MET is key and support further investigation of savo + osi and CNS activity in the Phase 3 SAFFRON study. Clinical trial information: NCT03778229 . Assessment Savo + osi (n=48) Savo + placebo (n=25) ORR, % (95% CI) BICR 58 (43, 72) 16 (5, 36) INV 54 (39, 69) 24 (9, 45) DoR, mo, median (95% CI) BICR 11.8 (6.0, NC) 4.5 (2.6, NC) INV 8.0 (4.9, 11.7) 4.2 (2.6, NC) PFS, mo, median (95% CI) BICR 8.3 (5.8, 15.1) 3.6 (1.4, 5.7) INV 7.6 (5.6, 11.0) 2.7 (1.4, 4.1) BICR, blinded independent central review; CI, confidence interval; mo, months; NC, not calculable.

Abstract Background: Savo is an oral, potent and highly selective MET-TKI. In the Phase 2 SAVANNAH study (NCT03778229), savo + osi had a high rate of durable responses in pts with EGFRm advanced NSCLC and high MET OverExp and/or Amp levels. Early clearance of plasma EGFRm may predict outcomes. We report an exploratory analysis of plasma EGFRm clearance and its association with MET tissue biomarker status, ORR and PFS. Methods: Pts with EGFRm advanced NSCLC and MET OverExp and/or Amp with PD on 1L+ osi received savo 300 mg QD, 300 mg BID or 600 mg QD + osi 80 mg QD. MET OverExp/Amp was centrally confirmed (by IHC [Roche], 3+ intensity in ≥50% of tumor cells [MET IHC3+/≥50%]; by FISH [Abbott Molecular], MET gene copy number ≥5 or MET:CEP7 ratio ≥2 [FISH5+], or at higher thresholds of MET IHC3+/≥90% or FISH10+). Baseline (BL) and Wk 3 plasma EGFRm (Ex19del/L858R) were analyzed by ddPCR (Biodesix) as an estimate of tumor burden. MET Amp was not monitored in ctDNA due to low detection sensitivity. Clearance was defined as undetected EGFRm ctDNA at Wk 3, when detected at BL. PFS was investigator-assessed (RECIST 1.1). DCO: Aug 23, 2024. Results: Of 344 pts with evaluable BL ctDNA, 259 (75%) had detected EGFRm ctDNA. Of these, 225 had evaluable ctDNA at Wk 3 (82 [36%] had EGFRm clearance at Wk 3). Confirmed ORR was higher in pts with EGFRm Wk 3 clearance (56/82; 68%) vs non-clearance (38/143; 27%). PFS was longer in pts with vs without EGFRm clearance at Wk 3 (Table). Across all pts evaluable for ctDNA at Wk 3, clearance rates were higher in pts with vs without high MET (69/162 [43%] vs 13/63 [21%]; odds ratio [95% CI] 0.35 [0.16, 0.72]). Similar results were seen in the savo 300 mg QD + osi subgroup. Conclusions: In SAVANNAH, among pts with detected EGFRm ctDNA at BL, clearance at Wk 3 was associated with improved ORR and PFS. Plasma EGFRm clearance at Wk 3 is enriched in pts with MET IHC3+/≥90% or FISH10+ status, consistent with improved efficacy in this biomarker subgroup. Citation Format: Jonathan W. Riess, Filippo de Marinis, Benjamin Levy, Tae Min Kim, Laura Bonanno, Quincy Chu, Marcello Tiseo, Adrian Sacher, Silvia Novello, Christina Baik, Lyudmila Bazhenova, Jacques Cadranel, Giulio Metro, Cheng-Ta Yang, Tsung-Ying Yang, Gee-Chen Chang, Konstantinos Leventakos, Lorenzo Livi, James Chih-Hsin Yang, Lecia V. Sequist, John Argue, Wanning Xu, Aleksandra Markovets, Ryan Hartmaier, Myung-Ju Ahn. SAVANNAH: Clearance of plasma EGFRm in patients with EGFRm MET-overexpressed (OverExp) and/or -amplified (Amp) NSCLC post-osimertinib (osi) treated with savolitinib (savo) + osi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB416.

9002 Background: KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutation occurs in ̃14% of NSCLC. Adagrasib, an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib is optimized for favorable pharmacokinetic (PK) properties, including long half-life (̃24 h), dose-dependent PK, and central nervous system penetration; it has demonstrated objective response and favorable tolerability in the Phase 1/1b setting. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combination regimens in patients with advanced solid tumors harboring a KRASG12C mutation. Here we report the first disclosure from all patients enrolled in Cohort A, a Phase 2 cohort with registrational intent, evaluating adagrasib given 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy and anti-PD-1/L1 therapy. Study objectives include evaluating efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]), safety, PK, and exploratory correlative analyses. Objective tumor response was assessed per RECIST v1.1 by blinded independent central review (BICR). Results: As of the 15 October 2021 data cutoff, 116 patients with NSCLC harboring a KRASG12C mutation were enrolled and treated, with a median follow-up of 12.5 months. Baseline characteristics include median age 64 years, 65% female, and 15.5%/83.6% with ECOG PS 0/1; 98.3% of patients received adagrasib following prior treatment with immunotherapy and chemotherapy, with a median of 2 prior systemic therapies. The ORR (by BICR) was 42.9% (48/112) and the disease control rate was 79.5% (89/112); 31 patients remain on treatment. Median DOR was 8.5 months (95% CI 6.2–13.8), median PFS was 6.5 months (95% CI 4.7–8.4), median OS was 12.6 months (95% CI 9.2–NE). Treatment-related AEs (TRAEs) of any grade occurred in 97.4% of patients, grade ≥3 TRAEs in 45.7%, 2 grade 5 TRAEs, and 8 (6.9%) TRAEs led to discontinuation. The most commonly reported (≥25%) TRAEs (any grade) were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), fatigue (40.5%), ALT/AST increased (27.6%/25%), blood creatinine increased (25.9%); the most commonly reported (≥5%) TRAEs (grade 3/4) were lipase increased (6%) and anemia (5.2%). Additional subgroup analyses will be presented, including selected demographics, molecular markers and sites of metastases. Conclusions: Adagrasib is well tolerated and demonstrates promising efficacy in pretreated patients with NSCLC harboring a KRASG12C mutation. A Phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRASG12C-mutant NSCLC is ongoing (NCT04685135). Clinical trial information: NCT03785249.

9065 Background: BRG is a potent and selective ALK inhibitor with preclinical and clinical activity against wild-type ALK and a broad range of mutants associated with clinical CRZ resistance, including G1202R. Herein we examine the association between BRG efficacy and ALK mutation status using plasma specimens from the initiation of BRG treatment (baseline [BL]) and the end of BRG treatment (EOT) in CRZ-resistant ALK+ NSCLC pts enrolled in the BRG Ph1/2 or pivotal Ph2 (ALTA) trials. Methods: Plasma samples were analyzed using the Resolution Bioscience ctDx Lung Panel v3.0. BRG activity was described using the confirmed objective response rate (cORR) (RECIST v1.1). Data are reported as of May 31, 2016 for the Ph1/2 (NCT01449461) and ALTA (NCT02094573) trials. Results: Of 291 CRZ-resistant ALK+ NSCLC pts enrolled in the Ph1/2 (N = 69) and ALTA (N = 222) trials, evaluable plasma samples were obtained from 67 pts at BL. cORR to BRG in these pts was 49% (33/67). An ALK fusion was detected in plasma in 45% (30/67) of these pts (cORR 57% [17/30]), of whom 33% (10/30) had secondary ALK mutations (cORR 50% [5/10]) and 67% (20/30) did not (cORR 60% [12/20]). Best responses in pts with secondary ALK mutations were: 2 CR (ALK amplification [Amp] copy number [CN] = 10; T1151M); 3 PR (L1196M; E1408V; Amp CN = 6); 4 SD (L1196M; E1419K; F1174C; C1156Y+S1206F+G1269A); 1 PD (T1151R+C1156Y+E1161D+F1174L). Of 67 pts with evaluable plasma at BL, 35 discontinued BRG therapy, of whom 20 had evaluable samples collected at EOT. No new mutations were detected at EOT in 75% (15/20) of pts. Complex mutation patterns were associated with resistance in the remaining 25% (5/20): High-level ALK-Amp (CN = 58); ALK-Amp (CN = 14)+MET-Amp (CN = 6); ALK-S1206F+S1206C+Amp (CN = 6); ALK-G1202R+L1196M+L1198Q; ALK-G1202R+BRAF-V600E+KRAS-G12D. Conclusions: ALK fusions were detected in plasma in < 50% of CRZ-resistant ALK+ NSCLC pts. BRG had substantial activity in ALK fusion–positive pts with a range of CRZ-resistance mutations. Neither primary nor secondary resistance to BRG was associated with any single plasma ALK mutation. The therapeutic implications of complex secondary resistance patterns associated with BRG require further exploration. Clinical trial information: NCT01449461, NCT02094573.