Citations

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.

Abstract Background: Effective treatments (Tx) are needed for MTAP-del cancers (10-15% of all cancers). BMS-986504 (formerly MRTX1719) is a potential first-in-class MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor that selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP-del but not MTAP-wild-type cells. In the first-in-human phase 1/2 CA240-0007 study, BMS-986504 was well tolerated and showed clinical activity in heavily pretreated pts across multiple advanced solid tumors with homozygous MTAP-del. Here, we report results of exploratory PD analyses of PRMT5 inhibition with BMS-986504 in CA240-0007. Methods: Pts with advanced, unresectable or metastatic solid tumors with homozygous MTAP-del received BMS-986504 (50 to 800 mg) in 3-wk cycles. Symmetric dimethylarginine (SDMA) and intron retention are known PD BMs of PRMT5 inhibition. Therefore, PD effects of BMS-986504 were assessed via changes in plasma and tumor SDMA levels (mass spec and IHC), intron retention, and gene expression (RNASeq) based on samples collected at baseline (BL) and cycle 2 day 1 (C2D1). Additional analyses correlating efficacy outcomes with PD results and select mutations at BL were performed in clinically evaluable pts as of 19-SEP-24. Results: Robust PD modulation of the PRMT5 pathway was observed with BMS-986504. Among pts with matched samples (n = 63), median plasma SDMA levels were reduced by 56% from BL (122.6 ng/mL) to C2D1 (53.8 ng/mL). There were dose-dependent reductions in median plasma SDMA with the greatest reductions at 400 mg QD (59.7% [n = 20]), 400 mg BID (61.9% [n = 9]) and 600 mg QD (59.1% [n = 14]). These PD effects were corroborated in the tumor. Median tumor SDMA levels decreased from an HScore of 285 at BL to 0 at C2D1. Consistent with the SDMA decreases, increased intron retention was observed in 9/11 pts with matched samples. BMS-986504 led to downregulation of several gene pathways including DNA repair and mitotic spindle formation, and MYC and E2F targets, as assessed by RNASeq. There was no significant change in expression of MAT2A, PRMT5, or other PRMT genes, suggesting a lack of compensation for PRMT5 inhibition through these genes. Responses were observed with BMS-986504 across EGFR, KRAS, and TP53 mutation subgroups. Additional correlative analyses among BMs and efficacy outcomes will be presented. Conclusions: BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del. Citation Format: Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papadopoulos, Melissa L. Johnson, Alexander I. Spira, Cesar A. Perez, Hani M. Babiker, Richard Zuniga, Candace L. Haddox, Tapsi Kumar, Yidi Qin, Wen-Chi Chou, Peter Olson, Kenna Anderes, Alice Wozniak, Curtis Chin, Ming Lei, Jason T. Henry. Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del) [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 CT079.

Abstract Recent studies have described the tumor microenvironment and the key transcription factors in untreated small cell lung cancer (SCLC), but less is known about the salient features in recurrent SCLC (rSCLC). This information could provide valuable insight about the effectiveness of second and later line therapies. In this study, we compared transcriptome profiles (by RNA-seq) of rSCLC against untreated primaries (pSCLC). rSCLC samples (n=23) were obtained from frozen biopsies in patients enrolled in our MC1923 (NCT04607954) phase 2 clinical trial whose disease progressed after chemoimmunotherapy. The pSCLC group (n=73) included publicly available data from fresh frozen primary tumors after surgical resections. Normalized expression data were used in immune deconvolution and gene set enrichment analysis (GSEA) in molecular signature database. Additional GSEA included gene sets describing ASCL1 (A), NEUROD1 (N), ASCL1 and NEUROD1 (AN), and POU2F3 (P) transcription factor activities which are used for subtyping of SCLC. Immune deconvolutions by multiple software algorithms suggested depletion of immune infiltrates in rSCLC compared with pSCLC including dendritic cells, B cells, CD8+ T cells, and M1 macrophages. Furthermore, we found decreased chemotaxis and increased apoptosis of dendritic cells, reduced TNF signaling, and reduced lymphocyte co-stimulation in rSCLC by GSEA. Additionally, in comparisons with pSCLC, rSCLC tumors had significantly lower enrichment scores for POU2F3 activity, representing the SCLC-P subtype (p < 0.007). Importantly, the SCLC-P was recently reported to be more immune inflamed than the other A, N, and AN subtypes. Altogether, our analyses provide strong evidence that the tumor microenvironment of rSCLC is significantly more immunosuppressed and with reduced immune cell infiltrates compared to pSCLC. Developing therapeutic strategies aimed at “warming” the tumor microenvironment and enhancing anti-tumor immune activity in ongoing multimodal therapies of recurrent SCLC will likely provide significant benefits to patients. Citation Format: Farhad Kosari, Mohamed Ali, Sarah H. Johnson, Alex Adjei, Julian R. Molina, Aaron S. Mansfield, Anastasios Dimou, Kaushal Parikh, Mohamed Shanshal, Katherine E. Smith, Ailsa G. Luce, Anna J. Schwecke, Janet Lensing, Ying-Chun Lo, John C. Cheville, George Vasmatzis, Konstantinos Leventakos. Small cell lung cancer (SCLC) at recurrence has a “colder” tumor microenvironment than primary SCLC according to gene expression profiling [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 6614.

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer that displays rapid proliferation and early metastatic potential. It accounts for approximately 15% of lung cancers and is strongly associated with tobacco carcinogens. Despite patients' initial response to systemic therapy, the majority develop early resistance and relapse. The outcomes of patients with metastatic SCLC are poor, prompting the need for new therapies. Over the past decade, the treatment landscape for NSCLC (non-small cell lung cancer) has significantly changed with the immergence of novel targeted therapies and immunotherapies. However, inroads of these therapies into SCLC have posed significant challenges due to its molecular and genomic heterogeneity. Despite the challenges of this disease, promising new first-in-class immunomodulatory agents have emerged and are currently undergoing extensive research. Herein, we review the current treatment paradigm of immunotherapy in SCLC and discuss future directions of this evolving field.

Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer. Newer advances in common and novel oncogenic drivers continue to occur at vigorous speed, making it challenging to stay up to date with the rapidly evolving field. In this article, we review the emerging perspectives in the treatment of actionable targets in lung cancer. We focus on the development of newer KRAS-directed therapies, particularly on non-G12C mutations, pan-RAS inhibitors, and RAS-GTP inhibitors. We also describe the current standard of care for EGFR- and ALK-altered NSCLC and dive into the novel treatments expected to be in the clinic soon. A similar approach is taken toward MET, HER2, RET, ROS1, and FGFR alterations as emerging targets in non-small-cell lung cancer. Finally, we conclude this review with the current body of evidence for targeting TROP-2 as a novel target, potentially of importance in post-targeted therapy scenarios.

Abstract Objective Data extraction from the published literature is the most laborious step in conducting living systematic reviews (LSRs). We aim to build a generalizable, automated data extraction workflow leveraging large language models (LLMs) that mimics the real-world 2-reviewer process. Materials and Methods A dataset of 10 trials (22 publications) from a published LSR was used, focusing on 23 variables related to trial, population, and outcomes data. The dataset was split into prompt development (n = 5) and held-out test sets (n = 17). GPT-4-turbo and Claude-3-Opus were used for data extraction. Responses from the 2 LLMs were considered concordant if they were the same for a given variable. The discordant responses from each LLM were provided to the other LLM for cross-critique. Accuracy, ie, the total number of correct responses divided by the total number of responses, was computed to assess performance. Results In the prompt development set, 110 (96%) responses were concordant, achieving an accuracy of 0.99 against the gold standard. In the test set, 342 (87%) responses were concordant. The accuracy of the concordant responses was 0.94. The accuracy of the discordant responses was 0.41 for GPT-4-turbo and 0.50 for Claude-3-Opus. Of the 49 discordant responses, 25 (51%) became concordant after cross-critique, increasing accuracy to 0.76. Discussion Concordant responses by the LLMs are likely to be accurate. In instances of discordant responses, cross-critique can further increase the accuracy. Conclusion Large language models, when simulated in a collaborative, 2-reviewer workflow, can extract data with reasonable performance, enabling truly “living” systematic reviews.

Importance Numerous studies show that early palliative care improves quality of life and other key outcomes in patients with advanced cancer and their caregivers, although most lack access to this evidence-based model of care. Objective To evaluate whether delivering early palliative care via secure video vs in-person visits has an equivalent effect on quality of life in patients with advanced non–small cell lung cancer (NSCLC). Design, Setting, and Participants Randomized, multisite, comparative effectiveness trial from June 14, 2018, to May 4, 2023, at 22 US cancer centers among 1250 patients within 12 weeks of diagnosis of advanced NSCLC and 548 caregivers. Intervention Participants were randomized to meet with a specialty-trained palliative care clinician every 4 weeks either via video visit or in person in the outpatient clinic from the time of enrollment and throughout the course of disease. The video visit group had an initial in-person visit to establish rapport, followed by subsequent virtual visits. Main Outcomes and Measures Equivalence of the effect of video visit vs in-person early palliative care on quality of life at week 24 per the Functional Assessment of Cancer Therapy-Lung questionnaire (equivalence margin of ±4 points; score range: 0-136, with higher scores indicating better quality of life). Participants completed study questionnaires at enrollment and at weeks 12, 24, 36, and 48. Results By 24 weeks, participants (mean age, 65.5 years; 54.0% women; 82.7% White) had a mean of 4.7 (video) and 4.9 (in-person) early palliative care encounters. Patient-reported quality-of-life scores were equivalent between groups (video mean, 99.7 vs in-person mean, 97.7; difference, 2.0 [90% CI, 0.1-3.9]; P = .04 for equivalence). Rate of caregiver participation in visits was lower for video vs in-person early palliative care (36.6% vs 49.7%; P < .001). Study groups did not differ in caregiver quality of life, patient coping, or patient and caregiver satisfaction with care, mood symptoms, or prognostic perceptions. Conclusions and Relevance The delivery of early palliative care virtually vs in person demonstrated equivalent effects on quality of life in patients with advanced NSCLC, underscoring the considerable potential for improving access to this evidence-based care model through telehealth delivery. Trial Registration ClinicalTrials.gov Identifier: NCT03375489

e20588 Background: MET exon 14 skipping mutations are seen in about 3% of patients (pts) with NSCLC, with 2 FDA approved METi for pts with stage IV NSCLC harboring it. Besides the original clinical trials, there is a paucity of real-world data about their outcomes, and adverse events (AE). Our aim was to compare and analyze the utilization of capmatinib (cap) and tepotinib (tep) in this population. Methods: We performed a retrospective chart review of the electronic medical records of all pts with stage IV NSCLC treated with METi between the date of FDA-accelerated approval of these drugs, 5/6/20 for cap and 2/3/21 for tep, and 12/1/23. All pts were treated at the Mayo Clinic Health System. We collected data about baseline characteristics, diagnosis, AE, and outcomes. Chi-squared test was used to compare the frequency of AE, while Kaplan-Meier method was used to calculate median progression free survival (mPFS). Results: A total of 49 pts were treated with METi. Cap was used in 45 pts, 14 received tep, and 10 pts received both, with tep following cap. In the cap group, median age of diagnosis was 74 years (y), 42.22% were male, and the median number of previous lines of therapy (mPLT) was 0. In the tep group, median age of diagnosis was 72 y, 21.43% were male, and the mPLT was 2. Median ECOG at the time of diagnosis was 1 in both groups. There was no statistically significant difference between AE in both groups. Peripheral edema occurred in 75.56% pts who received cap, and in 64.29% with tep (p = 0.41). Pneumonitis happened in 4.44% with cap, and 7.14% with tep (p = 0.69). Creatinine elevation was seen in 37.78% with cap, while 42.86% with tep (p = 0.73), grade 3 elevation was seen in 5.88% and 16.67% respectively. Abnormality in liver function tests occurred in 35.56% of pts in the cap group, and 28.57% in the tep group (p = 0.63), grade 3/4 abnormality occurred in 31.25% and 0% respectively. Finally, pancreatic enzymes elevation was seen in 33.33% of patients in each group (p = 0.67), with none being grade 3/4. Cap was discontinued in 20% of pts due to AE, while it happened in 28.57% of pts with tep. Dose reduction happened in 64.44% of pts who received cap, and 42.86% who received tep. The mPFS was 12.03 months (m) in the cap group, and 8.94 m in the tep group, which was not statistically significant (p = 0.18). Similarly, the mPFS in those treated with tep following cap was 8.94 m. Conclusions: We performed the first real-word comparison between cap and tep. The results demonstrated similar outcomes with both drugs, and no significant differences in AE, suggesting these agents can be employed equivalently. Importantly, rates of therapy discontinuation and dose reduction were high with both, indicating the importance of closely monitoring these pts. The retrospective nature and small sample size are initial limitations that can be overcome with future multi-centric prospective studies.

e13806 Background: Immune checkpoint inhibitor therapy-related (ICI) pneumonitis poses a significant challenge for patients with cancer. It is associated with increased clinical morbidity and mortality, often resulting in prolonged hospital stays and delays and/or discontinuation of cancer-directed treatment. Early detection and prompt treatment of ICI pneumonitis is critical to improve patient outcomes. Therefore, our institution implemented a remote patient monitoring (RPM) program leveraging in-home, electronic health record-integrated technology and virtual centralized nursing to monitor vital signs and patient symptoms in “high-risk” patients treated with immunotherapy. Methods: Patients receiving immunotherapy deemed to be “high-risk” for ICI pneumonitis seen at Mayo Clinic Rochester, Minnesota were offered enrollment in the RPM program beginning in June 2023. High-risk patients included those with pre-existing lung disease (chronic obstructive pulmonary disease, interstitial lung disease); those with a history of resolved ICI pneumonitis being rechallenged with immunotherapy; and those with grade 1 ICI pneumonitis continuing immunotherapy. Eligible patients who agreed to participate in the program were provided a kit consisting of RPM technology and electronic symptom questionnaires. The kit included an armband for continuous vital sign monitoring, a blood pressure monitor, a scale to measure weight, and a pre-connected cellular-enabled tablet for questionnaire answering. RPM data utilized real-time electronic health system integration and predetermined parameters to alert RPM nurses. Pre-specified escalation care pathways were then used to respond and escalate care, as necessary. The primary outcome of this pilot study was to assess the feasibility of implementing an RPM program in this patient population with a secondary outcome to determine the ability to detect ICI pneumonitis before significant clinical symptoms. Results: Sixteen patients were enrolled of whom 5 declined participation (2 due to inconvenience and 3 for unclear reasons) resulting in 11 patients who underwent monitoring. Five patients graduated monitoring without detection of ICI pneumonitis within a 4-month timeframe. Six patients are currently undergoing RPM. 372 alerts occurred of which 8 (2%) were escalated to physician review. These alerts included elevated heart rate in 4, shortness of breath in 3, and elevated blood pressure in 1. One patient was triaged to an emergency department and diagnosed with grade 2 ICI pneumonitis. Conclusions: We show that RPM in patients who are at high-risk for developing ICI pneumonitis can be effectively integrated into a care model and monitor pneumonitis related symptoms. Further studies are needed to prove whether RPM is beneficial in this population including other ICI toxicities.