Abstract Background: EP0031 (lunbotinib, A400), a first-in-class, next-generation selective RET inhibitor (SRI), has broad potency against common RET alterations, including resistance mutations, and has greater potency, antitumor activity, and CNS penetration/activity compared with first-generation SRIs (1,2). Clinical data indicates that EP0031 is active in patients who are SRI-naïve or have received prior SRI treatment, including those with brain metastases and/or on-target RET resistance mutations, and has acceptable tolerability (2,3,4). Resistance to first-generation SRIs is heterogeneous, characterized by RET-dependent and -independent pathways (4). SRI + chemotherapy may represent a promising strategy to address underlying disease heterogeneity. There is growing evidence that RET fusion-positive NSCLC is sensitive to pemetrexed-based chemotherapy and preclinical evidence confirms strong synergy between EP0031 and chemotherapy. This is the first study to evaluate this combination approach. Study Design and Methods: This is an ongoing phase I/II trial. A monotherapy RP2D of 90 mg daily was selected based on dose optimization data (4). Phase II expansion cohorts are recruiting patients with advanced RET fusion-positive NSCLC (NCT05443126) across three cohorts: (1) SRI-naïve patients receiving first-line therapy with EP0031 (N=25); (2) SRI-naïve patients receiving first-line therapy with EP0031 in combination with platinum-pemetrexed (N=25); and (3) Patients previously treated with a first-generation SRI, receiving second-line treatment with EP0031 in combination with platinum-pemetrexed (N=25). Key inclusion criteria include age ≥ 18 years, an Eastern Cooperative Oncology Group performance status ≤ 1, and RET fusion-positive NSCLC measurable by RECIST v1.1, with or without asymptomatic, stable brain metastases. EP0031 is administered orally, continuously once daily. In combination cohorts, the chemotherapy doublet is administered every 21 days at standard doses for four cycles followed by pemetrexed maintenance. Each combination cohort has a 3+3 safety run-in before expansion in 25 patients at the combination RP2D. Endpoints include tumor response per RECIST v1.1, progression-free survival, and overall survival. Other key endpoints include safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetic parameters. Circulating tumor DNA is collected to evaluate the emergence of on- and off-target mutations. The study is currently recruiting across the US, Europe, and the UAE. References 1. Zhou Q, et al. J Clin Oncol 2023:41:16_suppl, abstract 3007 2. Garralda E, et al. J Clin Oncol 2024:42:16_suppl, abstract 8556 3. Garralda E, et al. Ann Oncol 2024; 35: S824, abstract 1295P 4. Alonso G, et al. J Clin Oncol 2025: 43:16_suppl, 8598 Citation Format: Jaime Rubio-Perez, Elena Garralda, Benjamin Besse, Mihaela Aldea, Yasir Elamin, Pilar Garrido, Saad Khan, Judy Wang, Luis Paz Ares, Daniel Morgensztern, Philippe Cassier, Salmon Punekar, Stephen V Liu, Matthew H Taylor, Liz Joseph, Andrew G Gianoukakis, Jacobi Hines, Javier Garcia-Corbacho, Pascale Tomasini, David Spigel, Matthew G Krebs, Antoine Italiano, Mohammad Al Masri, Geoff Fisher, Sonia Serrano, Hendrik-Tobias Arkenau, Alex Drilon. A phase I/II study to evaluate EP0031 (lunbotinib), a next-generation selective RET inhibitor, as monotherapy and in combination with chemotherapy, in patients with advanced RET-fusion-positive 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 CT213.

8598 Background: EP0031 (A400/KL590586), a first in class next gen selective RET inhibitor (SRI) with FDA Fast Track Designation, has broad potency against common RET alterations, including resistance mutations. It has greater potency, antitumor activity, and CNS penetration/activity compared with 1 st gen SRIs (Garralda et al. JCO 2024; 42:16; abstr 8556; Zhou et al. JCO 2023; 41:16, abstr 3007). We report final data from the dose finding and optimization Phase 1 trial in the US and Europe. Methods: The study recruited pts with RET-altered NSCLC, medullary thyroid cancer (MTC) and other solid tumors and included pts ≥ 18 years, PS 0 or 1, with/without asymptomatic, stable brain mets, who received EP0031 QD in 28 days’ cycles. Results: A total of 40 pts (23 F, 17 M, median age 59 y), 22 NSCLC (20 SRI pre-treated, 1-6 prior lines), 12 MTC (7 SRI pre-treated, 1-4 prior lines) and 6 pts with other tumors (4 SRI pre-treated) were enrolled across 4 cohorts: 20 (n=3), 60 (n=10), 90 (n=16) and 120 (n=11) mg QD. The 60, 90 and 120mg cohorts were expanded for dose optimization. 9 pts had stable brain mets at baseline. No DLTs were observed. Most frequent G1/2 TEAEs (≥20%) were headache, anemia, ALT/AST increase, constipation, dizziness, hyperphosphatemia, blurred vision, keratitis, blood creatinine increased, dry mouth, dyspnea and fatigue. G3 TEAEs were rare and included (≥5%): hyponatremia, hypertension, anemia, AST/ALT increase, headache, diarrhea and ulcerative keratitis. Interruptions, reductions and discontinuations related to study drug were seen in 16 (40%), 8 (20%) and 1 (2.5%) pt. 25 pts with prior SRI were response evaluable. 5 PRs and 6 SDs reported in 15 NSCLC pts, with complete resolution of brain mets in 3/5 pts. Median DoR was 7.3mo (range 5.4-16.3). In 7 MTC pts, 2 PRs (DoR 6.6 – 9.2mo) and 2 SDs seen. Of 3 pts with other tumors, a pancreatic cancer pt had SD for 3.5 mo, and a pt with papillary thyroid cancer was clinically stable for 9 mo. In pts who were SRI naïve, 1 CR and 1 PR were reported in 2 NSCLC pts; and 5 PRs (1 uPR) were reported in all MTC pts. Baseline on-target RET resistance mutations were detected in 6/31 prior SRI pts (19.4%) with evidence of activity in 3, and sustained reduction and clearance of ctDNA (including RET resistant mutations: G810R solvent front and L730V, L730I roof mutations). Plasma exposures increased proportionately with dose. 90mg QD was selected as RP2D, with plasma levels >IC 90 for all relevant RET fusions/mutations. Conclusions: There is a need for new treatments for pts that progress on 1 st gen SRIs. EP0031 was associated with durable responses in advanced RET altered solid tumors previously treated with SRI, including pts with brain mets, with a manageable safety profile. These data confirm that the first in class next gen SRI EP0031 has the potential to address a high unmet need. Phase 2 trials are evaluating EP0031/KL590586 in US, Europe, UAE and China. Clinical trial information: NCT05443126 .

INTRODUCTION:Treatment selection in patients with advanced NSCLC is based on programmed death-ligand 1 (PD-L1) expression, which is usually scored manually and is subject to intra- and inter-pathologist variability. A PD-L1 clone-agnostic artificial intelligence (AI) model for AI-based measurement of PD-L1 (AIM-PD-L1) was developed and assessed in advanced NSCLC using clinical samples from two phase 3 trials. METHODS:IMpower110 evaluated atezolizumab versus chemotherapy in PD-L1-positive metastatic, stage IV, squamous or nonsquamous NSCLC. IMpower150 evaluated atezolizumab, carboplatin, and paclitaxel, with or without bevacizumab, versus carboplatin, paclitaxel, and bevacizumab in patients with metastatic nonsquamous NSCLC. AIM-PD-L1 was developed and deployed on SP263-stained whole slide images (IMpower110, n = 509; IMpower150, n = 766) for digital scoring of tumor cell (TC) PD-L1 expression and identification of human-interpretable features (HIFs) associated with survival outcomes. RESULTS:Overall percentage agreements between scoring methods for TC more than or equal to 50% and more than or equal to 1% cutoffs were high. Survival analyses were similar for PD-L1 subgroups between scoring methods at both TC cutoffs. A nonsignificant improvement in survival outcomes was observed in patients treated with atezolizumab-containing regimens and classified as positive by digital scoring but missed by manual scoring. Two HIFs in the cancer epithelium-density of all PD-L1-positive TC and immune cells-were nominally associated with overall survival. Many HIFs were identified to be predictive of significantly improved progression-free survival with atezolizumab-containing regimens versus control. CONCLUSIONS:AIM-PD-L1 digital SP263 PD-L1 scoring is concordant with manual scoring, revealing similar predictivity for benefit, and could potentially be used as a predictive marker for patient stratification and selection for anti-PD-(L)1 therapy.

All early phase protocols activated at Sarah Cannon Research Institute between 2021-2023 were reviewed (n=286 protocols). Information such as class of therapy, study design, and dose optimization plan (if applicable) were extracted from review of each protocol. Fisher’s exact test was used to compare proportions across categories and a p-value <0.05 was considered statistically significant. 268 unique protocols including 215 first in human trials (80%) were initiated with 179 different sponsors between 2021 and 2023. Trial classification by mechanism of action included 114 targeted therapies (43%), 109 immunotherapies (41%), 29 antibody drug conjugates (11%), 12 Immune effector cellular therapies (4%), and 4 chemotherapies (1%). Most trials employed a Bayesian dose escalation design (53%) versus rule-based (3+3), and this did not vary significantly year-over-year. 32% of trials (N=86) had a dose optimization plan. 47 trials (18%) included a dose optimization plan with randomization while 39 trials (14%) discussed optimization without randomization. The percentage trials with a dose optimization plan increased annually from 2021-2023 (22%, 29%, and 47% respectively; p=0.002). There was an increase in the proportion of trials which included backfill cohorts from 2021 (60%) to 2022-2023 (76%) (p=0.007) in addition to the proportion of protocols which allowed intra-patient dose escalation (45% in 2021 versus 57% in 2022-2023, p<0.001). The number of additional patients required in the trials with a dose optimization plan ranged from 12 - 200 with a median of 40. The inclusion of patient reported outcomes in early phase protocols was low at 12% from 2021-2023 and only 3 protocols (1%) addressed enrollment of underrepresented groups in the protocol. Overall, there has been a trend towards increased implementation of a dose optimization plan within early phase protocols since the announcement of the FDA’s Project Optimus initiative in 2021. Moreover, Bayesian designs, backfill cohorts, and intra-patient dose escalation are common in contemporary dose escalation studies. However, patient-centered outcomes and underrepresented populations are not routinely addressed in these protocols. Updated analysis including early phase clinical trials activated in 2024 is planned. Deepak Bhamidipati, Suzanne Jones, David Spigel, Gerald Falchook, Manish Patel, Howard Burris, Vivek Subbiah. The impact of Project Optimus and FDA guidance on study design of early-phase clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4514.

INTRODUCTION:Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 5%. The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against first-line treatment with programmed cell death protein-1 inhibitors in this setting in patients with a PD-L1 combined positive score < 1 or TAP score < 1%, due to an unfavorable benefit-risk profile. Thus, we retrospectively analyzed data from RATIONALE-305 in patients with a PD-L1 TAP score ≥ 1%. METHODS:Adult patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC were randomized to tislelizumab 200 mg or placebo with ICC every 3 weeks. Efficacy and safety outcomes of tislelizumab plus ICC versus placebo plus ICC were retrospectively assessed in those with a PD-L1 TAP score ≥ 1%. RESULTS:At the final analysis cutoff (February 28, 2023), 432 patients received tislelizumab plus ICC and 453 received placebo plus ICC, and had a PD-L1 TAP score ≥ 1%. Clinically meaningful improvements to OS were observed with tislelizumab plus ICC compared with placebo plus ICC [15.0 months (95% confidence interval [CI] 13.3-16.7) vs. 12.8 months (95% CI 12.1-14.1), respectively; stratified hazard ratio 0.77 (95% CI 0.67-0.90)]. Progression-free survival, overall response rate, duration of response, and disease control rate, were also improved. OS improvements were maintained at a 3-year data cutoff (February 28, 2024). Tislelizumab plus ICC had an acceptable safety profile with no new safety signals. CONCLUSIONS:Tislelizumab plus ICC is an effective and tolerable first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC with a PD-L1 TAP score ≥ 1%. TRIAL REGISTRATION NUMBER:NCT03777657.

Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 5

Homozygous deletion of the MTAP gene occurs in 10-15% of all human cancers. To benefit this large patient population, MTA-cooperative PRMT5 inhibitors, including TNG908, TNG462, and TNG456 were developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Clinical trial eligibility for most MTA-cooperative PRMT5 inhibitors is restricted to patients with tumors with confirmed MTAP loss either detected by next-generation sequencing or immunohistochemistry. MTAP loss most commonly occurs as a co-deletion event with the proximal CDKN2A gene and the chromosomal 9p breakpoints are not uniform. Previously, we reported that homozygous loss of only the terminal exon (exon 8), an event reported to occur in only 0.5% of MTAP-deleted tumors, is insufficient for complete loss of MTAP activity in preclinical assays. Here, we report initial evidence for the clinical impact of MTAP truncations, as opposed to complete deletion, on the activity of MTA-cooperative PRMT5 inhibitors. Kimberly J. Briggs, Andre Mignault, Jordi Rodon, Victor Moreno, David Spigel, Capucine Baldini, Candace Haddox, Angela Hirbe, Ignacio Garrido-Laguna, Ibiayi Dagogo-Jack, Emiliano Calvo, Alexander Spira, Matthew R. Tonini, Douglas A. Whittington, Steven A. Lombardo, Binzhang Shen, Hannah Stowe, Shangtao Liu, Hongxiang Zhang, Satoshi Yoda, Brian Doyon, Wenhai Zhang, Minjie Zhang, Kevin M. Cottrell, Samuel Meier, Yi Yu, Teng Teng, Heidi Rego, Jennifer Morawiak, Heather DiBenedetto, Ellen Hooper, Adam Crystal. Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4608.

73 Background: While most prostate cancer (PCa) patients (pts) initially respond to androgen deprivation therapy, resistance commonly develops, resulting in castration-resistant PCa. In certain patients, androgen receptor ( AR ) mutations permit tumor cells to proliferate despite the absence of circulating androgens. This study leverages real-world clinicogenomic data to investigate the prevalence and clinical implications of AR mutations and co-mutations. Methods: We analyzed 3,753 pt records with PCa who underwent next-generation sequencing (NGS) from January 1, 2014 to October 1, 2024. NGS was ordered by >400 physicians from >180 community-based oncology clinics across the Sarah Cannon Research Institute network, and results were collated with pt medical records in the software platform, Genospace. Pts were stratified into AR -mutated ( AR m; 306 pts), AR -amplified ( AR amp; 231 pts), and AR wild-type ( AR WT; 3,216 pts) cohorts. Pts with multiple primary cancers were excluded. Results: AR mutations were detected in 306 pts (8%), with a higher detection rate in plasma- versus tissue-based NGS (15% vs 2%; p<0.01). AR mutations were more common in older pts, with 68% of AR m pts >70 years old compared to 53% of AR WT pts (p<0.01). The most common AR mutations included L702H (51%, 156 pts), T878A (38%, 115 pts), H875Y (23%, 70 pts) and W742C (8%, 25 pts), and over half of AR m pts reported multiple AR mutations (51%, 156 pts). Several genes were more frequently mutated in AR m versus AR WT pts, including TP53 (43% vs 32%), PTEN (10% vs 6%), BRCA2 (9% vs 4%), RB1 (5% vs 2%), and BRCA1 (4% vs 1%; p<0.01 for all). AR m pts reported a higher frequency of microsatellite instability (MSI) compared to AR WT pts (11% vs 2%; p<0.01). Within the AR m cohort, MSI was more frequently detected by tissue- versus plasma-based NGS (26% vs 7%; p<0.01). Specific AR mutations were enriched in MSI versus microsatellite stable (MSS) pts, including H875Y (50% vs 20%) and V716M (31% vs 2%; p<0.01 for both). Additionally, BRCA1/2 mutations were more common in AR m/MSI pts versus AR m/MSS pts ( BRCA1 : 15% vs 3%; BRCA2 : 35% vs 6%; p<0.01 for both). Pts in both the AR m (3.3 yrs) and AR amp (2.1 yrs) cohorts exhibited shorter overall survival from metastatic staging compared to the AR WT cohort (9.0 yrs; p<0.01 for both). Neither specific AR mutations nor MSI status correlated with survival outcomes. Conclusions: AR mutations are frequently detected by plasma-based NGS in the real-world setting, possibly due to test selection at disease progression and/or sampling of tumor heterogeneity. However, plasma-based NGS may miss other critical alterations, such as MSI status. The high co-occurrence of MSI in AR -mutated PCa suggests potential for combination therapies involving immunotherapy and novel AR degraders. These findings emphasize the need for tissue- and plasma-based genomic profiling to guide therapeutic decisions and optimize treatment strategies for advanced PCa.

To evaluate long-term outcomes, treatment costs, and quality of life associated with curative treatment of newly diagnosed stage I non-small cell lung cancer (NSCLC), by comparing surgery to stereotactic body radiation therapy (SBRT). Multicenter consecutive prospective study of newly diagnosed stage I NSCLC patients independently assigned surgery or SBRT by a multidisciplinary tumor board, recruited prior to therapy initiation (n = 59). Outcomes included total hospital charges, toxicities, complications, readmissions, and patient satisfaction/ quality of life (FACT-L). Multivariable logistic regression models analyzed the association of treatment type with dichotomous endpoints controlling for age, Charlson Comorbidity Index (CCI), and pre-treatment FACT-L; multiple linear regression was used for delta FACT-L. Of the 55 evaluable patients, 19 (35

OBJECTIVE:RATIONALE-305 (NCT03777657) demonstrated that tislelizumab plus chemotherapy statistically improved overall survival versus placebo plus chemotherapy as first-line treatment in patients with advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC). This analysis examined patient-reported outcomes (PROs) at final analysis. METHODS:Adults with previously untreated, unresectable, or metastatic GC/GEJC were randomized (1:1) to tislelizumab or placebo intravenously once every 3 weeks plus chemotherapy. PROs assessed health-related quality of life (HRQoL) using EORTC QLQ-C30 and EORTC QLQ-STO22. A mixed model for repeated measures was used for PRO endpoints at treatment cycles 4 and 6, and time to deterioration was analyzed. RESULTS:Tislelizumab arm had improved outcomes over placebo arm in least-squares (LS) mean change from baseline to cycle 6 for QLQ-C30 global health status/quality of life (GHS/QoL) (LS mean difference, 2.52 [95% CI: 0.29-4.74]), physical functioning (2.46 [0.49-4.43]), fatigue (-3.01 [-5.78 to -0.24]), and STO22 index score (-1.62 [-3.12 to -0.12]) as well as maintenance of upper gastrointestinal symptoms (-1.74 [-3.55-0.06]) and pain/discomfort (-1.88 [-4.03-0.27]). Patients receiving tislelizumab plus chemotherapy had a lower risk for deterioration of GHS/QoL (hazard ratio 0.77 [95% CI: 0.60-0.98]), physical functioning (0.72 [0.57-0.92]), STO22 index score (0.64 [0.45-0.92]), pain/discomfort (0.74 [0.58-0.96]), and upper gastrointestinal symptoms (0.73 [0.56-0.95]). CONCLUSIONS:Advanced GC/GEJC patients treated with tislelizumab plus chemotherapy versus placebo plus chemotherapy in first-line had sustained and improved HRQoL. These results, along with previous efficacy and safety data, support tislelizumab plus chemotherapy as a first-line treatment option for GC/GEJC. TRIAL REGISTRATION:The RATIONALE-305 trial is registered on ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT03777657).ClinicalTrials.gov identifier: NCT03777657.

Lymphocyte antigen 6 complex locus G6D (LY6G6D) is a promising target in metastatic colorectal cancer (mCRC) due to its differentiated expression in tumor vs. normal tissues, and higher prevalence in microsatellite-stable CRC. Linclatamig (or BLYG8824A) is a humanized, IgG1, LY6G6D × CD3 T cell-engaging bispecific antibody (TCB), that binds to LY6G6D and CD3+ T cells, forming an immunologic synapse to facilitate T cell-mediated killing of LY6G6D+ cells. This study evaluated the safety, pharmacokinetics (PK), biomarkers, and anti-tumor activity of linclatamig in patients (pts) with LY6G6D+ mCRC. Pts aged ≥18 years with locally advanced or metastatic LY6G6D+ CRC refractory to established therapies, measurable disease by RECIST v1.1 and ECOG 0/1 were enrolled. Escalating doses of intravenous linclatamig were administered in 21-day cycles, beginning with a step-up dose on Cycle 1, Day 1 (C1D1), followed by a (higher) target dose on C1D8 and on D1 of every cycle (C2D1 onward). Pts (n=46) (prior therapy: median 4 lines; range 2-11) received linclatamig (median 3 cycles; range 1-37) at step-up doses 0.2-180 mg and target doses 0.6-1500 mg across 13 dose-escalation cohorts. The maximum tolerated dose was not reached. Dose-limiting toxicities included immune effector cell-associated neurotoxicity syndrome in 2 pts at 180 mg step-up dose, and respiratory distress in the context of CRS and tumor flare in 1 pt at 100 mg step-up dose. Most frequently reported adverse events (AEs) of any grade (Gr) and irrespective of causality were CRS (94%), anemia (48%), diarrhea (50%), fatigue (50%), dry skin (37%), and rash maculopapular (30%). Most frequent treatment-related Gr ≥3 toxicities were reduced lymphocyte count (13%), diarrhea (11%), and anemia (9%). CRS, mainly Gr 1/2, occurred at step-up C1D1 doses ≥5.4 mg and was mostly limited to C1. Skin-related AEs (74%) including alopecia were reported, consistent with LY6G6D expression in hair follicle bulbs. PK data indicated dose proportionality and faster-than-typical IgG1 clearance. Anti-tumor activity was limited, with 1 confirmed and 2 unconfirmed partial responses. Increased blood levels of IFNg, IL6, and T cell activation supported the mechanism of action. Tumor RNA of responders showed CD8B and activated NK cell enrichment, whereas tumors of pts with disease progression had more fibroblasts, TGFb, myeloid inflammation signatures, and KRAS signaling. This first-in-human study (NCT04468607) targeting LY6G6D in mCRC pts demonstrated a tolerable safety profile for linclatamig up to 1500 mg. Step-up dosing mitigated CRS severity, although skin toxicities indicated possible on-target/off-tumor effects. Limited anti-tumor activity of linclatamig was observed in pts with heavily pre-treated mCRC. Marwan Fakih, Jayesh Desai, Iosune Baraibar, Ignacio Melero, David Spigel, Eric Chen, Ben Markman, Arshdeep Pooni, Amy A. Lo, Rosanna S. Kwok, Stephanie Hilz, Zao Li, Pranay Dogra, Neha N. Shah, Andrew G. Polson, Douglas Leipold, Wei Zou, Mengsong Li, Luciana Molinero, Simon Heidegger, Victor Moreno. Phase 1 dose-escalation study of linclatamig, a LY6G6D×CD3 T cell-engaging bispecific antibody, in patients with colorectal cancer [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 CT157.

PURPOSE:A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown. PATIENTS AND METHODS:Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA versus tissue ERBB2 concordance, genomic co-alterations, and ctDNA dynamics and association with response. RESULTS:Forty-one (98%) of 42 patients had genomic alterations detected in ctDNA at C1D1, and 29 (69%) had ERBB2 amplification in ctDNA. There was a strong correlation between the ERBB2 copy number on next-generation sequencing in tissue and C1D1 ERBB2 ctDNA copy number. Thirty-seven percent achieved a molecular response by C3D1 on P + T, which was associated with prolonged progression-free survival and overall survival. CDKN2A and KRAS mutations were associated with shorter overall survival, and a trend was seen with PIK3CA mutations. Several emerging co-alterations were identified in ctDNA at progression, including in the MAPK and PI3K pathways and other tyrosine receptor kinases. CONCLUSIONS:ctDNA can detect ERBB2 amplification in many, but not all, patients with ERBB2 amplification detected in tumor samples. ctDNA molecular response was associated with better survival, and ctDNA co-alterations may offer insights into mechanisms of intrinsic and acquired resistance.

TPS3173 Background: Mutations in exon 20 of the EGFR gene account for approximately 4% to 10% of all EGFR mutations in Non-Small Cell Lung Cancer (NSCLC). Most of these mutations are insertions (EGFR ex20ins) that reduce the binding of first, second, and third generation tyrosine kinase inhibitors (TKI) to the ATP-binding pocket of the EGFR. Amivantamab, a bispecific anti-EGFR/c-MET-receptor antibody, is approved for the treatment of NSCLC with EGFR ex20ins mutations. However, there is significant unmet need for new oral agents that lack the limitations of intravenous administration and associated infusion-related toxicities and possess improved target engagement, mutant selectivity, and tolerability. PFL-721/STX-721 is an orally bioavailable, irreversible small-molecule inhibitor targeting a broad range of EGFR- and HER2-activating ex20ins mutations. PFL-721/STX-721 is highly selective for EGFR ex20ins mutations compared to wild type EGFR and exhibits greater selectivity compared to other EGFR mutant inhibitors. In addition, PFL-721/STX-721 has demonstrated superior anti-proliferation and antitumor effects compared to other investigational anti-EGFR ex20ins agents in relevant tumor models in vitro and in vivo. These observations suggest a more robust clinical risk-to-benefit profile and support further clinical investigation of PFL-721/STX-721. Methods: PFL-721/STX-721-101 (NCT06043817) is an open-label, first-in-human (FIH), Phase 1/2 study evaluating the safety, tolerability, pharmacokinetic (PK) exposure, and preliminary antitumor activity of PFL-721/STX-721 in participants with locally advanced or metastatic NSCLC harboring EGFR/HER2 ex20ins mutations. It consists of 3 parts: Part 1 Dose Escalation, Part 2 Recommended Phase 2 Dose (RP2D) selection, and Part 3 Dose Expansion. In Part 1, participants with NSCLC harboring EGFR or HER2 ex20ins mutations will be enrolled into sequential cohorts to receive ascending oral doses of PFL-721/STX-721 administered daily in 28-day treatment cycles. The main goal is to identify the maximum tolerated dose (MTD) and optimal biological dose (OBD) of PFL-721/STX-721. In Part 2, participants with NSCLC harboring EGFR ex20ins mutations who have received 1 to 2 prior lines of treatment, including a platinum-containing chemotherapy regimen and excluding EGFR targeted therapies with the exception of amivantamab, will be randomized 1:1 to receive PFL-721/STX-721 at the MTD or OBD in order to determine the optimal RP2D. Finally, Part 3 will further test the anticancer efficacy of PFL-721/STX-721 is administered at the RP2D. PFL-721/STX-721-101 is actively enrolling at 18 sites in 7 countries globally. Clinical trial information: NCT06043817 .

Immune checkpoint inhibitors are important for treatment across tumor types but are not universally effective in controlling disease. Early understanding of tumor response, or lack thereof, can inform treatment decisions. This study evaluates changes in circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) for associations with response to programmed cell death 1 ligand 1 (PD‐L1) blockade. We sequenced cell‐free DNA collected at the start of therapy, on treatment, and at the end of therapy for 153 patients treated with atezolizumab as part of the pan‐tumor MyPathway study (NCT02091141). ctDNA tumor fraction (TF) and bTMB were assessed for correlation with progression‐free survival (PFS) and overall survival (OS). We found that molecular response (MR, ≥50% decrease in TF at cycle 3 day 1) was associated with improved PFS (9.7 vs 1.5 months from C3D1; HR = 0.27) and OS (21.1 vs 14.3 months from C3D1; HR = 0.44). These findings were consistent when limited to patients with stable disease (SD; PFS HR = 0.55; OS HR = 0.39). bTMB was correlated with tissue‐based TMB (tTMB) when TF was high (≥1%), but not with OS in this cohort. In total, 61% of baseline samples had predicted clonal hematopoiesis (CH) variants. No correlation between maximum variant allele frequency (maxVAF) of predicted CH and TF was seen. In summary, MR is associated with outcomes for patients treated with atezolizumab and could stratify patients with SD. While CH was common, maxVAF for CH variants was not associated with ctDNA TF. Quantification of ctDNA enables therapy response monitoring and is critical for interpretation of bTMB as a proxy for tTMB.

At the first planned interim analysis of the phase 3 ADRIATIC study (NCT03703297), consolidation D significantly improved the dual primary endpoints of overall survival (OS; HR 0.73; 95% CI 0.57-0.93; p=0.0104) and progression-free survival (PFS; HR 0.76; 95% CI 0.61-0.95; p=0.0161) vs P in patients (pts) with LS-SCLC with no progression after cCRT. Although PD-L1 is not currently a validated immunotherapy biomarker in SCLC (unlike NSCLC) and is generally expressed at low levels in this setting, PD-L1 was evaluated as a potential biomarker in ADRIATIC. Pts with stage I-III LS-SCLC (stage I/II inoperable), WHO performance status 0/1, and no progression after cCRT, were randomized 1-42 days post cCRT to D (n=264), D + tremelimumab (n=200; arm remains blinded), or P (n=266). The VENTANA PD-L1 (SP263) immunohistochemistry assay was used for central retrospective testing of pre-cCRT tissue samples. OS and PFS were assessed in the PD-L1-evaluable population and in subgroups with PD-L1 expression ≥1% on tumor cells (TC) and/or immune cells (IC) (secondary endpoint) and <1% on TC and IC (data cutoff: Jan 15, 2024). Among 162 (61.4%) and 171 (64.3%) pts in the D and P arms who were evaluable for PD-L1, improvements in OS (HR [D vs P] 0.73 [95% CI 0.53-0.99]) and PFS (HR 0.80 [0.60-1.06]) were of similar magnitude to those in the ITT population. Of the PD-L1-evaluable pts, 51.9% (84/162) in the D arm and 57.3% (98/171) in the P arm had PD-L1 TC or IC ≥1%. D appeared to improve OS and PFS vs P in subgroups with TC or IC ≥1% and with TC and IC <1% (Table), consistent with the ITT population. Among the PD-L1-evaluable population in ADRIATIC, 54.7% (182/333) of pts had PD-L1 TC or IC ≥1%. Consolidation D appeared to improve OS and PFS vs P irrespective of PD-L1 expression based on a cutoff of 1% on TC and/or IC, further supporting consolidation D as the new standard of care in pts with LS-SCLC with no progression after cCRT. Christine Hann, Ying Cheng, David Spigel, Byoung Chul Cho, Jian Fang, Yuanbin Chen, Yoshitaka Zenke, Qiming Wang, Reyes Bernabe, John Wen-Cheng Chang, Sema Sezgin Goksu, Lin Wu, Gyeong-Won Lee, Michael Thomas, Yuichiro Ohe, Frank Griesinger, Leah Szadkowski, Hema Gowda, Yashaswi Shrestha, Suresh Senan. Durvalumab (D) vs placebo (P) after concurrent chemoradiotherapy (cCRT) in limited-stage small-cell lung cancer (LS-SCLC): Outcomes by PD-L1 expression in ADRIATIC [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 CT094.

8014 Background: At the first planned interim analysis of ADRIATIC, consolidation D significantly improved the dual primary endpoints of overall and progression-free survival (PFS) vs P in patients (pts) with LS-SCLC and no progression after cCRT. We assess clinical characteristics, patterns of progression, and associated molecular biomarkers in EPs (pts with PFS <6 mos) and LTPs (PFS or censored after >12 mos) in the D and P arms. Methods: Pts with stage I–III LS-SCLC, WHO performance status (PS) 0/1, and no progression after cCRT were randomized to D (n=264), D + tremelimumab (n=200; arm still blinded), or P (n=266) for up to 24 months. Pre-cCRT tumor samples were collected at screening and immune-related biomarkers (CD8, MHC I, PD-L1, T-cell inflamed signature [TIS], CD8A , and STING pathway) were assessed by immunohistochemistry or RNA sequencing for their role in response to immunotherapy (IO). Results: At data cutoff (15 Jan 2024), 83 (31.4%) and 113 (42.8%) pts in the D arm and 97 (36.5%) and 100 (37.6%) in the P arm were EPs and LTPs, respectively. For EPs and LTPs, respectively: 67.5% and 61.1% in the D arm and 74.2% and 72.0% in the P arm were male; 44.6% and 54.9% in the D arm and 51.5% and 48.0% in the P arm had WHO PS 0; and 90.4% and 89.4% in the D arm and 91.8% and 89.0% in the P arm were current/former smokers. Among EPs, 47.0% vs 45.4% had extrathoracic (ET) only progression, 43.4% vs 43.3% had intrathoracic (IT) only progression, and 6.0% vs 1.0% died without progression in the D vs P arms, respectively. Among LTPs, 16.8% and 25.0% of pts in the D and P arms had progression events, which were mostly IT (D: 14.2%; P: 16.0%). Similar rates of PD-L1+ tumors were observed in EPs and LTPs in both arms (Table). Trends for higher TIS and STING pathway expression were seen in LTPs vs EPs in the D arm but not the P arm. CD8 density, and CD8A and MHC I expressions were lower in EPs vs LTPs in both arms, regardless of D vs P (Table). Conclusions: Exploratory analyses suggest similar rates of IT and ET progression with D and P in EPs, but mostly IT progression in LTPs. Compared with EPs, LTPs were generally characterized by a pre-cCRT tumor microenvironment more conducive to fostering an IO response, with higher antigen presentation and cytotoxic marker expression potentially enhancing D’s mechanism of action. Clinical trial information: NCT03703297 . D, EPs P, EPs D, LTPs P, LTPs PD-L1 TC or IC ≥1%, n (%) 25 (52.1) 32 (55.2) 40 (56.3) 42 (61.8) MHC I n, median TC score* (%) 42, 65.0 46, 75.0 66, 77.5 56, 80.0 CD8 density n, median cells/mm 2 39, 46.7 43, 50.7 57, 94.2 53, 78.7 RNASeq BEP, n 17 27 29 24 CD8A expression † 1.1 1.1 1.3 1.7 TIS value † 2.3 3.1 3.2 3.4 STING signature value † 0.28 1.4 0.90 1.4 *% MHC I-positive TCs in the total tumor area. † Median. BEP, biomarker-evaluable population; TC, tumor cell; IC, immune cell.

11098 Background: Inclusion criteria for participating in oncology clinical trials have grown more complex, often challenging the enrollment process. Our objective was to improve the process of identifying and enrolling patients by incorporating personalized medicine assistance into the initial patient intake and trial selection procedure at a major community-based phase 1 oncology unit. Methods: A virtual personalized medicine review board (vPMRB) comprised of two PhD scientists reviewed patients for suitable trial options based on molecular sequencing results and scientific rationale during the intake and screening processes at a phase I oncology clinic. vPMRB reviews leveraged a propriety clinical trial identification software, Genospace, to generate patient-trial matches based on general inclusion/exclusion criteria including disease, histology, staging, and biomarker criteria. Trial options were returned via email and added to patients’ charts in the electronic health record for reference by their clinical care team. Trial candidates were screened for trial options and consented for treatment on trial by the enrollment nursing (ERN) team. Data pertaining to vPMRB review, trial screening, trial consent, and trial enrollment were collected by the vPMRB and ERN teams and combined to determine consent and enrollment rates. Results: Between 1/1/2024 and 12/31/2024, 953 patient reviews for 815 unique patients were completed by the vPMRB with an average turnaround time of 4 ± 5 business hours. 900 (94%) of these reviews included potential trial options for the patient. Of 790 reviewed patients with sufficient information for comparison with enrollment team data, 473 (60%) were screened for trial options by the ERN team in 2024. Of these, 343 (73%) consented to a trial and 270 (57%) started trial treatment in 2024. Comparatively, of the 744 patients reviewed for trial options by the ERN team, but not the vPMRB, 431 (58%) were consented to a trial and 313 (42%) started trial treatment in 2024. 167 (35%) patients consented to a trial and 130 (28%) patients started a trial recommended by the vPMRB for that patient in 2024. Conclusions: vPMRB review was associated with increased trial enrollment compared to patients without vPMRB review. Upcoming research will explore the effects of further personalized medicine integration techniques, including the involvement of team members in therapeutic strategy meetings held by clinical care teams, along with the use and effectiveness of clinical trial matching software in a phase 1 unit. Trial consenting and screening rates in 2024 for patients with and without vPMRB review. vPMRB Review No vPMRB Review Patients screened for trial by enrollment team 473 744 Consented on Trial 343 (73%) 431 (58%) Started Trial 270 (57%) 313 (42%) Consented on trial surfaced in vPMB review 167 (35%) N/A Started on trial surfaced in vPMB review 130 (28%) N/A

BACKGROUND:Survival for non-small-cell lung cancer (NSCLC) remains unacceptably low, even in stage IA-IIA. Current guidelines recommend adjuvant treatment for patients considered to be at high risk in stages IB and IIA, but suggest criteria that have not been validated to predict benefit. A previously validated, CLIA-certified 14-gene expression profile has identified patients with high-risk non-squamous NSCLC tumours in stages IA-IIA who benefitted from adjuvant chemotherapy in a non-randomised prospective study. In this prespecified interim analysis, we aimed to assess the efficacy and safety of platinum-based adjuvant chemotherapy in patients with stage IA-IIA molecular high-risk non-squamous NSCLC in a randomised trial. METHODS:AIM-HIGH, a randomised, phase 3 trial, was done at 45 centres in France, Germany, and the USA. Patients aged 18 years or older with stage IA-IIA non-squamous NSCLC, an adequate tumour sample, and an Eastern Cooperative Oncology Group performance status of 0-1 underwent risk stratification with the 14-gene assay. Patients with a molecular high risk, defined as those receiving a high-risk or an intermediate-risk score, were randomly assigned (1:1) to four cycles of platinum-based adjuvant chemotherapy (using local institutional standard of care regimens) or observation. Randomisation was stratified according to age, sex, and tumour size of 4 cm or more. The primary outcomes for the study and for this prespecified interim analysis were 48-month and 24-month disease-free survival, respectively, in the modified intention-to-treat (mITT) population, which was defined as randomly assigned patients who continued to meet eligibility criteria either at chemotherapy initiation or at random assignment to observation; an early interim analysis was prespecified to detect a large difference between groups. This trial is registered at ClinicalTrials.gov, NCT01817192, and is closed to enrolment. FINDINGS:Between Sept 11, 2020, and Feb 7, 2025, 449 patients were enrolled and underwent risk stratification. 236 patients with molecular high risk were randomly assigned to chemotherapy (n=124) or observation (n=112). At the time of the prespecified interim analysis, 87 patients were evaluable in the mITT population (47 [54%] males and 40 [46%] females; median age 63 years [IQR 52-74]) in the chemotherapy group and 107 (58 [54%] males and 49 [46%] females; 66 years [56-76]) in the observation group. 48 (55%) patients in the chemotherapy group and 58 (54%) patients in the observation group had stage IA disease; 34 (39%) and 44 (41%), respectively, had stage IB disease, and five (6%) and five (5%), respectively, had stage IIA disease. Six (3%) of 200 patients in the mITT population had died at the time of the interim analysis. 24-month disease-free survival was 96% (95% CI 92-100) with adjuvant chemotherapy versus 79% (70-90) with observation (hazard ratio 0·22 [0·06-0·76]; p=0·0087). INTERPRETATION:The 14-gene assay identified patients with molecular high risk who benefitted from adjuvant chemotherapy. Use of the assay to determine eligibility for adjuvant therapy in stage IA-IIA non-squamous NSCLC has the potential to substantially improve otherwise persistently poor outcomes. FUNDING:Razor Genomics.

PURPOSE:We investigated the efficacy and toxicity of thoracic radiation therapy (RT) plus concurrent and consolidation carboplatin with either solvent-based paclitaxel (sb-paclitaxel) or solvent-free nanoparticle albumin-bound paclitaxel (nab-paclitaxel). METHODS AND MATERIALS:This multicenter phase 1/2 randomized trial included patients with inoperable stage IIIA/B nonsmall cell lung cancer (AJCC 7) and an Eastern Cooperative Oncology Group performance status of 0-1. In phase 1, 6 patients received weekly nab-paclitaxel (50 mg/m²) and carboplatin (AUC 2) with concurrent thoracic RT (60 Gy in 30 fractions), followed by nab-paclitaxel (100 mg/m²) on days 1, 8, and 15 and carboplatin (AUC 6) on day 1 for two 21-day cycles. In phase 2, 92 patients were randomly assigned to weekly sb-paclitaxel (50 mg/m²) or nab-paclitaxel (40 mg/m²) with concurrent RT, followed by consolidation therapy with sb-paclitaxel or nab-paclitaxel and carboplatin for 2 cycles. RESULTS:Two phase 1 patients had dose-limiting toxicities, setting the phase 2 nab-paclitaxel dose at 40 mg/m². For the phase 2 cohort, 2-year overall survival was 67% for sb-paclitaxel and 56% for nab-paclitaxel (P = .10), with progression-free survival of 44% and 27%, respectively (P = .14). Fewer patients completed consolidation with nab-paclitaxel (26%) versus sb-paclitaxel (58%) (P = .005). Grade 3 and higher adverse events were more frequent with nab-paclitaxel (56%) than with sb-paclitaxel (30%) (P = .029). CONCLUSIONS:Nab-paclitaxel was associated with higher toxicity and numerically lower efficacy than sb-paclitaxel when used with thoracic radiation in locally advanced nonsmall cell lung cancer.