Abstract This is a systematic analysis of CNS reporting in clinical trials for patients with NSCLC and actionable genomic alterations (AGA). We evaluated clinical trials with enrollment beginning in 2001-2021 to encompass all FDA-approved therapies for NSCLC with AGA. Of 79 trials, 57 study protocols were publicly available. The preplanned analysis included: CNS disease eligibility, brain imaging schedule, allowance of post-progression therapy, and CNS efficacy reporting. Studies with enrollment starting between (11/01/01-10/31/11) and (01/01/21-11/30/21) were compared to analyze trends in CNS-specific trial design elements. There were 79 published trials and 57 available protocols initiating enrollment from November 2001 to November 2021. Brain metastases were allowed in 97.5% of trials (77/79), and LMD in 11.4% of trials (9/79). Symptomatic CNS disease was not formally defined in any trial. Baseline corticosteroids were allowed in 27.3% of trials (21/77). Washout time for stereotactic radiation therapy ranged from 1 week (10.8%; 8/74), 2 weeks (52.7%; 39/74), 3 weeks (1.4%; 1/74), 4 weeks (20.3%; 15/74), 8 weeks (1.4%; 1/74), and not specified (13.5%; 10/74). On study brain imaging was mandated for all patients in 18.9% of trials (15), only for those with known brain metastases in 55.7% of trials (44), and not specified in 25.3% of trials (20). Allowance of local therapy for CNS oligoprogression was permitted in 29.1% of trials (23), not permitted in 16.5% of trials (13), and not specified in 54.4% of trials (43). RANO-BM was used in 6.3% of trials (5) while RECIST in 93.7% of trials (74). In the most recent 10 years, there is an increase in baseline brain imaging, allowance of asymptomatic untreated brain metastases, and an increase in reporting of systemic and intracranial efficacy. Our study highlights that uniform inclusion criteria, brain imaging requirements, stereotactic radiation therapy washout period, and CNS efficacy reporting are pertinent for future studies.

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 .

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only). Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline.

Abstract Background Despite improved outcomes with programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICI) in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), most patients develop resistance. Preclinical data demonstrate that Janus kinase inhibition (JAKi) restores T cell cytokine production and proliferation, potentiating ICI activity, with ruxolitinib plus ICI demonstrating superior tumor control across multiple murine models. Ruxolitinib may also reprogram immunosuppressive myeloid populations within the tumor microenvironment. In an investigator-initiated trial (NCT03681561), 53% of patients with relapsed/refractory Hodgkin’s Lymphoma previously failing anti-PD-1 therapy responded to ruxolitinib plus nivolumab, including 6 complete responses. High response rates were also observed with JAKi plus anti-PD-1 in NSCLC (NCT03425006). We aim to investigate whether combining ruxolitinib with anti-PD-1 therapy can overcome resistance in solid tumors. Methods This prospective, open-label, single-arm phase 1b study evaluates ruxolitinib plus retifanlimab in patients with advanced clear cell RCC or NSCLC progressing on prior PD-1/PD-L1 therapy. Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Key exclusions: prior JAKi, >1 prior line of PD-1/PD-L1 therapy, primary progression on prior ICI, or unresolved immune-related adverse event (>grade 1). A 3 + 3 dose escalation design evaluates ruxolitinib 15 mg and 20 mg twice daily with fixed retifanlimab 500mg intravenously (IV) every 4 weeks, followed by dose expansion. Treatment continues until progression, toxicity, or withdrawal. The primary objective is determining the recommended phase 2 dose (RP2D). Secondary objectives include objective response rate, duration of response, radiographic progression-free survival, overall survival, and safety. To further interrogate mechanisms of response and resistance, correlative studies evaluating tumor microenvironment, immune cell composition, and molecular profiling are ongoing. A Simon’s two-stage design is utilized for testing the null hypothesis (true response rate 10%) against an alternative of 30%, rejecting null if ≥ 6 responses occur in 25 participants (α = 0.05, power 80%). Assuming a dropout rate of 5%, we will target a minimum enrollment of 36 and maximum enrollment of 42 participants to ensure a maximum of 40 evaluable participants on the trial. The standard survival analysis will be conducted for the time-to-event endpoints. The study is activated at the University of California San Diego and is currently open to accrual. Clinical Trial Information: NCT07219576. Results Resistance to PD-1/PD-L1 blockade is a major unmet need in RCC and NSCLC, with few effective options after progression on frontline immunotherapy. PRISM tests a mechanistically rational combination, ruxolitinib to reverse chronic interferon-driven T cell dysfunction and immunosuppressive myeloid skewing, paired with retifanlimab to sustain antitumor T cell activity. Integrated correlative studies aim to identify biomarkers of response to guide patient selection. Our vision is to establish JAK inhibition as a tractable strategy for restoring checkpoint sensitivity across solid tumors, providing the foundation for a biomarker-driven randomized phase 2 trial in checkpoint-refractory disease. Conclusions NA

8629 Background: Taletrectinib is a next-generation, CNS-active, selective ROS1 tyrosine kinase inhibitor (TKI) approved by the US FDA for the treatment of patients with locally advanced or metastatic ROS1+ NSCLC based on results from two Phase 2 studies, TRUST-I (NCT04395677) and TRUST-II (NCT04919811). Here we report PROs with taletrectinib from TRUST-II. Methods: Patients with locally advanced or metastatic ROS1+ NSCLC were treated with taletrectinib 600 mg once daily in 21-day cycles. HRQoL and PROs for cancer-specific symptoms were evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30-item core module (QLQ-C30) and 13-item lung cancer module (QLQ-LC13). Questionnaires were only distributed to patients from North America and Europe. Data were collected at screening, then subsequently on Day (D)1 of every cycle (C) until C9D1, on D1 of every three cycles until C27D1, and every four cycles thereafter until the end of treatment (within 7 days of last dose). Changes from baseline over time were summarized using descriptive statistics. A change in score of ≥10 points from baseline was considered clinically meaningful. Time to first improvement (TFI) was assessed using Kaplan–Meier methods. Results: At data cutoff (August 31, 2025), the analysis set included 69 patients (23 TKI-naïve and 46 TKI-pretreated). Mean changes from baseline improved or remained stable for most domains across both questionnaires. For global health status/quality of life, the majority of patients showed clinically meaningful improvement or remained stable at multiple timepoints assessed (e.g. 74% of patients at C7). Mean cognitive function score improved or remained stable throughout treatment, with the majority (63–77%) of patients showing improvement or stability and only 9–23% of patients showing worsening at various assessment times. Common disease-related symptoms, including pain and fatigue (QLQ-C30), and dyspnea and coughing (QLQ-LC13), showed consistent clinically meaningful improvement throughout treatment, with a median TFI of 1–3 months across all patients. Coughing was particularly improved in TKI-naïve patients, with a median TFI of < 1 month. Conclusions: Taletrectinib was associated with improved or stable HRQoL in the majority of patients and with rapid relief of disease-related symptoms. In contrast to other ROS1 TKIs, taletrectinib demonstrated preservation of cognitive function over time. Together with the efficacy and safety results, these data further support the use of taletrectinib for patients with ROS1+ NSCLC. Clinical trial information: NCT04919811 .

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) therapy, but only 25% of patients have durable responses. TG4010, a mucin 1 (MUC1) vaccine, has demonstrated activity in NSCLC. We conducted a multi-institutional study to determine the safety and activity of nivolumab plus TG4010 in ICI naïve NSCLC patients (NCT02823990). The target accrual was 29 evaluable patients. The primary endpoint was the response rate requiring at least 10/29 responders. The study was terminated early due to slow accrual after enrolling 13 patients. The treatment was well tolerated. The most common adverse effects were fatigue (grades 1-3) and injection site reactions (grades 1-2). TG4010+ICI had limited benefit in NSCLC with 1 of 12 (8.3%) evaluable patients responding, 2 with disease control, and 9 progressing on therapy. The median overall survival was 7.23 months. One patient with a HER2 driver mutation (which prognosticates poor ICI response) achieved an ongoing durable complete response. This exceptional responder had significant baseline upregulation of GSEA pathways linked to interferon signaling, which may be critical for generating vaccine directed immune responses. In general, therapy decreased MUC1 expression in tumors and PD-1 on T cells and upregulated pathways of adaptive and innate immune responses within tumors and circulating immune cells. However, TCR sequencing demonstrated no T cell clonal expansion or epitope spreading, which may explain the lack of clinical benefit. TG4010+ICI appears to have limited benefit. Further study is needed to optimize the clinical efficacy, which may include a role in NSCLC with driver mutations or in combination with cytotoxic therapy.

Abstract Background: Taletrectinib is a next-generation, CNS-active, selective ROS1 TKI approved by the US FDA for the treatment of patients (pts) with locally advanced/metastatic ROS1+ NSCLC. Taletrectinib has shown robust efficacy, including intracranial (IC) activity, and a tolerable safety profile in both TKI-naïve and TKI-pretreated pts with ROS1+ NSCLC in the Phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) studies (Pérol M, et al. J Clin Oncol 2025). Here we report updated data for taletrectinib in TKI-naïve pts with ∼3 years of follow-up. Methods: The TRUST-I and TRUST-II study designs have been previously reported (Pérol M, et al. J Clin Oncol 2025). The efficacy population included pts from TRUST-I and TRUST-II with ≥1 measurable baseline lesion per RECIST v1.1 by independent review committee. Safety was evaluated in pts with ROS1+ NSCLC from Phase 1 and 2 trials who received ≥1 dose of taletrectinib 600 mg once daily. Results: As of Aug 31, 2025, the pooled efficacy analysis included 157 TKI-naïve pts (103 from TRUST-I; 54 from TRUST-II). With a median (m) follow-up of 35.5 months (mo), confirmed ORR was 89.8% (95% CI 84.0-94.1), mDOR was 49.7 mo (95% CI 38.6-NR), mPFS was 46.1 mo (95% CI 31.8-NR), and IC-ORR was 76.5% (95% CI 50.1-93.2). Data by trial are shown in the Table. Overall, there were no new safety signals, and safety was consistent between TKI-naïve pts and the safety population (n=363). Conclusions: With ∼3 years of follow-up in the pooled analysis and >4 years of follow-up in TRUST-I, taletrectinib demonstrated high and durable response rates in TKI-naïve pts with ROS1+ NSCLC, with a mDOR of >4 years. To the best of our knowledge, these results represent the highest ORR and longest DOR and PFS reported to date for an FDA-approved ROS1 TKI in this patient population. These data support taletrectinib as an effective and tolerable treatment option particularly in pts with advanced ROS1+ NSCLC who have not received a prior ROS1 TKI. Citation Format: Lyudmila Bazhenova, Jorge Nieva, Misako Nagasaka, Hidetoshi Hayashi, Qitao Yu, Scott Owen, Maurice Pérol, Feiwu Ran, Wei Wang, Xianyu Zhang, Michael Chen, Wei Li, Geoffrey Liu, Caicun Zhou. Taletrectinib in tyrosine kinase inhibitor (TKI)-naïve patients with ROS1+ non-small cell lung cancer (NSCLC): Updated data from TRUST-I and TRUST-II [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 CT300.

PURPOSE:To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer with driver alterations. METHODS:This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized controlled trials (RCTs), with the latest time frame spanning March-October 2025. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts was convened. The literature search included systematic reviews, meta-analyses, and RCTs. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS:This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Thirteen studies were identified in the latest search of literature to date. RECOMMENDATIONS:Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients with driver alterations.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

BACKGROUND:Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS:HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION:Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING:Summit Therapeutics.

Abstract Background: Taletrectinib is a next-generation, CNS-active, selective ROS1 TKI approved by the US FDA for the treatment of patients (pts) with locally advanced/metastatic ROS1+ NSCLC. In two Phase 2 studies, TRUST-I (NCT04395677) and TRUST-II (NCT04919811), taletrectinib showed robust efficacy, including intracranial (IC) activity and efficacy against G2032R mutations, and a tolerable safety profile in TKI-naïve and TKI-pretreated pts with ROS1+ NSCLC (Pérol M, et al. J Clin Oncol 2025). Here we report updated data in TKI-pretreated pts with ∼3 years of follow-up. Methods: The study designs of TRUST-I and TRUST-II have been previously reported (Pérol M, et al. J Clin Oncol 2025). The efficacy population included pts from TRUST-I and TRUST-II with ≥1 measurable baseline lesion per RECIST v1.1 by independent review committee. The safety population included pts with ROS1+ NSCLC from Phase 1 and 2 studies who received ≥1 dose of taletrectinib 600 mg once daily. Results: As of Aug 31, 2025, the pooled efficacy analysis included 113 TKI-pretreated pts (66 from TRUST-I [prior crizotinib]; 47 from TRUST-II [37 prior crizotinib, 10 prior entrectinib]). With a median (m) follow-up of 35.8 months (mo), confirmed ORR was 55.8% (95% CI 46.1-65.1), mDOR was 16.6 mo (95% CI 10.7-24.9), mPFS was 9.7 mo (95% CI 7.6-12.0), and mOS was 29.8 mo (95% CI 23.2-46.0). Responses were observed in pts with G2032R mutations (8/13; ORR 61.5% [95% CI 31.6-86.1]) and with CNS metastases (IC-ORR 65.6% [95% CI 46.8-81.4]). Data by trial are shown in the Table. Safety was similar between TKI-pretreated pts and the safety population (n=363). Conclusion: With longer follow-up, taletrectinib maintained durable responses in TKI-pretreated pts, including activity against CNS metastases and G2032R mutations, with a tolerable safety profile. These data support taletrectinib as an effective and tolerable treatment option for pts with ROS1+ NSCLC after prior TKI therapy. Citation Format: Geoffrey Liu, Jorge Nieva, Lyudmila Bazhenova, Chang-Min Choi, Qitao Yu, Shunichi Sugawara, Noriko Yanagitani, Filippo de Braud, Huijie Fan, Enriqueta Felip, Emilio Bria, Maurice Pérol, Feiwu Ran, Wei Wang, Xianyu Zhang, Michael Chen, Caicun Zhou. Taletrectinib in tyrosine kinase inhibitor (TKI)-pretreated patients with ROS1+ non-small cell lung cancer (NSCLC): Updated data from TRUST-I and TRUST-II [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 CT244.

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

Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion-positive (NTRK+) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including NTRK+ disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort (n = 51; 95% confidence interval (CI)), the response rate was 59% (44-72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0-NE). In the TKI-pretreated cohort (n = 69; 95% CI), the response rate was 48% (36-60); the median DOR was 9.8 months (7.4-13.0); and the median PFS was 7.4 months (3.9-9.7). Of 30 TKI-pretreated patients with NTRK solvent front mutations, 16 had a response (53%; 95% CI: 34-72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (n = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Here repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with NTRK+ solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use of repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116 .

[Box: see text]Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website.

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.