Riess, Jonathan W.

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 .

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

Thymomas and thymic carcinomas are rare mediastinal tumors that originate in the thymus. Patients with thymoma may experience symptoms associated with autoimmune paraneoplastic diseases (such as myasthenia gravis), which typically do not occur in patients with thymic carcinoma. The NCCN Guidelines for Thymomas and Thymic Carcinomas provide guidance for the diagnosis, treatment, and surveillance of patients with thymoma and thymic carcinoma. Involvement of a multidisciplinary team with experience treating thymomas and thymic carcinomas is highly recommended.

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.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.