Bar, Jair

8524 Background: Teliso-V is a c-Met–directed antibody-drug conjugate comprising telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E (MMAE) payload. In the Ph2 LUMINOSITY study (NCT03539536), Teliso-V showed durable responses and manageable safety (Camidge et al, JCO 2024;42:3000-11) resulting in its accelerated approval in locally advanced/metastatic NSQ NSCLC with high c-Met protein OE (3+, ≥50%), as determined by an FDA-approved test. MET amp is a negative prognostic risk factor in advanced NSCLC, frequently associated with recurrent disease. High levels of MET amp and c-Met OE are hallmarks of MET -addicted tumors. Here, we analyzed the effects of MET amp on clinical responses to Teliso-V in LUMINOSITY. Methods: MET amp was evaluated by FISH and ctDNA in baseline samples from 108 NSQ EGFR WT NSCLC pts with c-Met OE (3+, ≥25%). MET amp by FISH was defined as having focal MET amp (MET/CEP7 ≥2.0) with MET gene copy number (GCN) ≥4. MET amp (focal) by ctDNA was defined as having plasma MET GCN ≥4 with no co-amplification in CDK6 and EGFR. c-Met OE by Immunohistochemistry (IHC; SP44) was defined as 3+ tissue staining intensity in ≥25% tumor cells (high c-Met OE: 3+, ≥50%; intermediate [int] c-Met OE: 3+, 25% to 49%). Exploratory analysis of tumor response was assessed in 76 efficacy evaluable pts with c-Met OE and MET amp assay results. Results: MET amp was detected in 34% (37/108) of pts with c-Met OE (3+, ≥25%) and was enriched by c-Met levels: 22% (11/50) in pts with Int c-Met OE (3+, 25% to 49%) and 45% (26/58) in pts with high c-Met OE (3+, ≥50%). The effects of MET amp on tumor response in LUMINOSITY are shown in Table 1. The majority of c-Met OE pts (79%) with PFS ≥10 mo (n=14) had GCN ≥10 and/or c-Met IHC 3+ ≥50%. No new safety signals were reported in pts with c-Met OE and MET amp. Conclusions: MET amp is more common in pts with high c-Met OE in this retrospective subgroup analysis. Tumor activity with Teliso-V was observed regardless of MET amp status. The impact of MET amp in pts with c-Met OE will be further evaluated in ongoing Phase 3 study (NCT04928846). Teliso-V efficacy in NSQ EGFR -WT NSCLC pts with c-Met OE with or without MET amp in LUMINOSITY. Total c-Met OE(3+, ≥25%) Total c-Met OE(3+, ≥25%) Intermediate c-Met OE(3+, ≥25%-49%) Intermediate c-Met OE(3+, ≥25%-49%) High c-Met OE(3+, ≥50%) High c-Met OE(3+, ≥50%) MET amp(N) No (N=53) Yes (N=23) No (N=30) Yes (N=7) No (N=23) Yes (N=16) ORR %(95% CI) 28 (18.0, 41.6) 39 (22.2, 59.2) 23 (11.8, 40.9) 57 (25, 84.2) 35 (18.8, 55.1) 31 (14.2, 55.6) PFS,median, mo(95% CI) 5.26 (3.71, 8.11) 8.02 (4.47, 14.65) 5.32 (2.69, 8.11) 7.52 (4.47, NA) 4.17 (3.25, 8.87) 8.02 (3.06, 25.92) OS,median, mo(95% CI) 14.5 (8.18, 17.38) 13.86 (6.54, 22.24) 14.03 (3.65, 17.02) 9.79 (6.54, NA) 16.26 (5.59, 36.44) 13.86 (3.06, 30.29)

AbstractThe discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene has revolutionized the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). These therapies offer improved survival and reduced side effects compared with conventional treatments. Recent advancements have significantly reshaped the treatment paradigm for EGFR‐mutant non‐small cell lung cancer. TKIs are now incorporated into the management of early stage and locally advanced disease, and phase 3 trials have explored combination strategies in metastatic settings. Although these intensified approaches improve progression‐free survival, they come with increased toxicity and higher costs, underscoring the need for precise patient selection to maximize benefit. Emerging data on biomarkers, such as co‐mutations and circulating tumor DNA, show promise for refining treatment decisions. In addition, significant progress in understanding resistance mechanisms to EGFR TKIs has broadened therapeutic options. This review provides a comprehensive overview of the current landscape of EGFR‐mutant nonsmall cell lung cancer, highlighting recent breakthroughs and discussing strategies to optimize treatment based on the latest evidence.

8618 Background: Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate comprising the mAb telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E. In the phase 2 LUMINOSITY trial (NCT03539536), Teliso-V monotherapy 1.9 mg/kg showed durable responses and a generally manageable safety profile in patients (pts) with c-Met protein–overexpressing (OE) non-squamous (NSQ) EGFR -wildtype (WT) non-small cell lung cancer (NSCLC). Herein we present an analysis of efficacy outcomes according to prior platinum or prior platinum and immune checkpoint inhibitor (ICI)-based therapies. Methods: Pts (≥18 years) with locally advanced/metastatic c-Met protein–OE NSQ EGFR -WT NSCLC who had ≤2 prior lines of therapy, including ≤1 line of chemotherapy, were treated with 1.9 mg/kg Teliso-V Q2W. c-Met protein overexpression (by immunohistochemistry clinical trial assay for MET [SP44] [Roche]) was defined as ≥25% tumor cells with 3+ staining intensity (high: ≥50% 3+; intermediate [int]: 25 to <50% 3+). The primary endpoint was overall response rate (ORR) by independent central review per RECIST v1.1. Results: As of 21 Feb 2024, 172 pts received ≥1 dose of Teliso-V and 168 pts were included in efficacy analyses (c-Met high, n=84; c-Met int, n=84). In the c-Met OE total population, 97.6% of pts received prior platinum and 78.6% received prior platinum + ICI. Efficacy data for pts with prior platinum and platinum + ICI therapies are shown in the Table. Among the 172 dosed pts, the most common any-grade treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (31%), peripheral edema (16%), and fatigue (14%). The most common grade ≥3 TRAE was peripheral sensory neuropathy (7%). Conclusions: This analysis demonstrated that Teliso-V elicited durable responses in pts with c-Met protein–OE NSQ EGFR -WT NSCLC regardless of whether they had received prior platinum or platinum + ICI therapies; the efficacy outcomes in these subgroups were consistent with those in the overall pt population. Clinical trial information: NCT03539536 . Platinum Platinum + ICI Overall ORR, a n/N (%) [95% CI] c-Met OE total c-Met high c-Met int 48/164 (29.3) [22.4, 36.9]28/81 (34.6) [24.3, 46.0]20/83 (24.1) [15.4, 34.7] 38/132 (28.8) [21.2, 37.3]22/67 (32.8) [21.8, 45.4]16/65 (24.6) [14.8, 36.9] 49/168 (29.2) [22.4, 36.7]29/84 (34.5) [24.5, 45.7]20/84 (23.8) [15.2, 34.3] Median DOR, a mo [95% CI] c-Met OE total c-Met high c-Met int 7.2 [5.5, 11.3]9.0 [3.8, 12.0]7.2 [4.7, 11.5] 7.2 [5.5, 11.0]9.0 [3.8, 11.3]7.2 [5.3, 11.5] 7.2 [5.5, 11.0]7.2 [4.2, 12.0]7.2 [4.7, 11.5] a Per independent central review. DOR, duration of response.

8019 Background: Neoadjuvant and perioperative chemo-immunotherapy studies report 15%-20% of pts initiating NACT-I do not undergo surgical resection. Methods: Real-world data of pts who initiated NACT-I was collected retrospectively for January 1 st 2022 till September 30 th 2024. Pts and treatment details, reason for not undergoing resection (as assessed by the clinicians) and later treatments and outcomes were recorded. Total number of pts who initiated NACT-I in this period was identified from each center's records. Missing data was not imputed. Results: Data was collected from 10 centers in 4 countries (USA, Israel, Switzerland, France). Out of 330 pts that started NACT-I 43 pts (13%; range 4-33% in different centers) did not undergo surgical resection. Of these 43 pts, 34.9% became unresectable due to disease progression (PD). 20.9% in retrospect were non-resectable and did not regress as expected. 11.6% in retrospect were non-operable. 11.6% suffered toxicity and became unfit for surgery. 7% of pts refused surgery, 14% were not resected for other reasons (Table). Of the non-resected pts, 9.3% died prior to any second-line treatment. As a second line, 44.2% of the non-resected pts were treated with chemo-radiation, 14% with radiation alone, 7% chemotherapy and immunotherapy, 4.7% immunotherapy alone and 2.3% chemotherapy alone. 7% received palliative radiation followed by chemo or immunotherapy, 7% had follow-up alone. Conclusions: The rate of no surgical resection in this real-world multi-national cohort was 13%, in line with the rate in reported studies. Most un-resected pts underwent appropriate staging. Most were male, with high rate of T3/T4. Survival rate at 12 months was 73.7%. The most common causes for no surgery were PD or being upfront unresectable. The patients with the worst outcome were those who experienced PD during NACT-I. N (% out of 43 non-resected) Male (%) Age (median) PET Done prior to any therapy (%) Brain MRI staging (%) Documented MDT decision of NACT-I (%) Documented surgeon evaluation prior to NACT-I decision (%) T3-4 (%) N2a/b (9th V TNM; %) Survival rate at 12 month (95% CI) 43 (100.0) 69.8 71 95.3 95.0* 96.6* 86.2* 69.8 40.5 73.7% (50.5-87.2%) PD 15 (34.9) 80.0 67 93.3 100.0* 100.0* 92.3* 80.0 40.0 68.2% (14.2-89.7%) In retrospect not resectable 9 (20.9) 55.6 69 100.0 100.0 100.0* 50.0* 77.8 33.3 76.2% (33.2-93.5%) In retrospect not operable 5 (11.6) 80.0 71 100.0 60.0 100.0* 33.3* 40.0 20.0 100.0% (100.0-100.0%) Toxicity 5 (11.6) 80.0 72 100.0 100.0 100.0* 100.0* 80.0 80.0 80.0% (20.4-96.9%) Patient refusal 3 (7.0) 0.0 72 100.0 100.0 100.0 100.0 66.7 33.3 100% (100.0-100.0%) Other ** 6 (14.0) 83.3 75 83.3 100.0* 75.0* 100.0 50.0 40.0* 50.0% (11.1-80.4%) Percentages relate to the total of each row, besides 1st column relating to total of 43. *% of available data. **Death (n=3), intra-operative decision (n=2), additional malignancy (n=1).

8013 Background: For patients (pts) with unresectable locally-advanced NSCLC, standard of care involves durva consolidation after concurrent CRT, although its benefit in ALK+ tumors is unclear. The ALINA trial demonstrated adjuvant efficacy of alectinib in resected ALK+ NSCLC, but the optimal consolidation strategy for unresectable locally-advanced ALK+ NSCLC remains elusive. Methods: This multi-institutional international retrospective analysis included pts with stage III unresectable ALK+ NSCLC who received an ALK TKI, durva, or obs alone after concurrent CRT between 2015-2022. Baseline characteristics of age, sex, smoking history, and PD-L1 status were collected. Clinical outcomes including real-world progression-free survival (rw-PFS), overall survival (OS), and treatment-related adverse events (trAE) as defined using CTCAE 5.0 were assessed, and multivariate cox regression models were performed. Results: Sixty-four pts across 16 institutions were included. The median age was 57 (IQR 49-66) and 61% were females. The majority had adenocarcinoma (97%) and had never smoked (58%). 15 received ALK TKI (10 alectinib, 3 crizotinib, 1 brigatinib, 1 lorlatinib), 30 received durva, and 19 received obs alone. There was no significant difference in stage of cancer (IIIA, B, or C) or PD-L1 status among groups. After adjusting for stage and age at CRT initiation, median rw-PFS was significantly longer for ALK TKI (rw-PFS not reached [NR], 95% CI 22.7-NR) vs durva (11.3 months (mo), 95% CI 9.2-18.5, p= 0.005, HR = 0.12) or obs (7.4 mo, 95% CI 3.4-12.5, p < 0.0001). Two (13%) pts progressed on ALK TKI. 25 pts (83%) progressed on durva leading to treatment with ALK TKI in 23, and 18 (95%) progressed while under obs leading to treatment with ALK TKI in 15. 3-year OS was 100% for ALK TKI vs 90.5% for durva vs 63.5% for obs. Median OS was NR (95% CI NR-NR) for both ALK TKI and durva vs 70.6 mo (24.9-NR) in the obs group ( p= 0.03 for both ALK TKI and durva compared to obs). Median duration of therapy was 24.7 mo with ALK TKI and 6.5 mo with durva. Grade ≥3 trAE occurred in 27%, 7%, 6% of pts treated with ALK TKI (1 fatigue, 1 diarrhea, 1 hyperbilirubinemia, 1 pneumonitis), durva (1 fatigue, 1 neutropenia), and obs (1 neutropenia) respectively. Treatment discontinuation due to toxicity occurred in 4 (27%) with ALK TKI and in 3 (10%) with durva. Conclusions: In this retrospective study of stage III ALK+ NSCLC, consolidation ALK TKI demonstrated clinically meaningful improvement in PFS and OS over durva and obs, while showing a slightly higher rate of trAE over dura and obs. Furthermore, we show a high rate of progression following CRT alone in ALK+ NSCLC. These findings underscore the need for prospective molecularly driven trials to determine the optimal consolidation therapy for unresectable ALK+ NSCLC.

PURPOSE Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536 ) aimed to identify the optimal c-Met protein–overexpressing non–small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor ( EGFR )-wildtype NSCLC. METHODS Eligible patients had locally advanced/metastatic c-Met protein–overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR -wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%–<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS In total, 172 patients with nonsquamous EGFR -wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION Teliso-V was associated with durable responses in c-Met protein–overexpressing nonsquamous EGFR -wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Abstract Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with metastatic non-small cell lung cancer (NSCLC). However, clinical management is challenging. The PD-L1 biomarker does not optimally guide the choice between ICI monotherapy and combination ICI-chemotherapy, and there are currently no biomarkers to predict immune-related adverse events (irAEs). Here, we describe a versatile platform based on plasma proteomics and machine learning for generating predictive tools to support treatment decisions. Methods: Pre-treatment plasma samples were collected from 616 NSCLC patients receiving ICI-based therapy (NCT04056247). Clinical benefit (CB) data and irAEs were recorded. Proteomic profiling of plasma samples was performed using the SomaScan® assay, covering ~7000 proteins per sample. Proteins associated with Clinical Benefit (progression-free survival at 12 months) were classified as resistance-associated proteins (RAPs). Proteins associated with grade ≥3 irAEs occurring within the first 100 days of treatment were classified as toxicity-associated proteins (TAPs). RAPs and TAPs were integrated into two separate machine learning-based models, yielding CB and irAE probabilities, respectively. The CB model used a CB probability threshold to assign patients a PROphet-positive or PROphet-negative result. Bioinformatic analysis was performed on RAPs and TAPs. Results: CB and irAE models displayed strong predictive performance with a high correlation between predicted probability and observed CB or irAE rate (CB model: R2=0.98; p-value&lt;0.0001; irAE model: R2= 0.92; p-value &lt;0.0001). In the CB model, patients classified as PROphet-positive achieved significantly longer overall survival (OS) than PROphet-negative patients, with a median OS of 25.9 vs. 10.8 months (hazard ratio, HR = 0.51; p-value&lt;0.001). Furthermore, patients with PD-L1 ≥50% tumors and a PROphet-negative result had significantly longer OS with ICI-chemotherapy in comparison to ICI monotherapy (HR=0.23, p-value = 0.0003), suggesting that combination therapy is preferable for such patients despite high PD-L1 levels. Bioinformatic analysis showed that RAPs related to immune regulation, angiogenesis, chemo-resistance, and other potential resistance mechanisms displayed higher expression levels in patients who did not benefit from treatment. Neutrophil- and inflammation-related proteins were significantly enriched in patients who experienced irAEs. Conclusions: We describe two machine-learning based predictive tools that may be used separately or in combination to inform treatment decisions based on the patient’s likelihood to benefit from ICI therapy and to develop serious irAEs. Our findings also provide biological insights related to treatment resistance and immune-related toxicity. Citation Format: Michal Harel, Petros Christopoulos, Igor Puzanov, Jair Bar, Iris Kamer, Niels Reinmuth, Ina Koch, Mor Moskovitz, Adva Levy-Barda, Alona Zer, Michal Lotem, David Farrugia, Rivka Katzenelson, Gillian Price, Abed Agbarya, Helen Cheley, Adam Hassani, Mahmoud Abu-Amna, Tom Geldart, Anirban Chatterjee, Andreas Polychronis, Maya Gottfried, Yanyan Lou, Tatiana Harkovsky, Alison Brewster, Ido Wolf, Ella Tepper, Ben Yellin, Itamar Sela, Coren Lahav, Yehonatan Elon, Raya Leibowitz, Adam P. Dicker, Young Kwang Chae, Ryan J. Sullivan, David Carbone, David Gandara, Jarushka Naidoo. Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1208.

PURPOSE Current guidelines for the management of metastatic non–small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247 ) of patients undergoing PD-1/PD-L1 inhibitor–based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor–based treatments, evidenced by high concordance between predicted and observed CB ( R 2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). CONCLUSION Plasma proteome–based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor–based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

9122 Background: Initial treatment selection for advanced NSCLC patients without driver mutations is mainly based on evaluating PD-L1 expression levels in the tumor tissue. However, PD-L1 assays are only moderately predictive. In addition, the guidelines for the PD-L1≥50% subpopulation are not definitive, enabling the usage of immune checkpoint inhibitors (ICI) either as a monotherapy or combined with chemotherapy. Here we aim to provide a decision-making tool for the first-line treatment of advanced NSCLC patients based on plasma derived biomarkers obtained before treatment initiation. Methods: Pre-treatment plasma samples were collected from 545 NSCLC patients receiving ICI-based therapy. Clinical benefit was evaluated based on progression-free survival (PFS) at 12 months as a threshold. Deep plasma proteomic profiling was performed using aptamer technology. Based on the proteomic profiles, a computational model, termed PROphet, was developed and evaluated in a blinded manner on the validation subset (n = 272). The model output, clinical benefit probability, was used to stratify the patients into two groups, PROphet-positive or -negative. Results: The model displayed good performance with a high correlation between the predicted clinical benefit and the observed clinical benefit rate (R2= 0.97), outperforming a PD-L1-based prediction model (R2= 0.35). Patients classified as PROphet-positive achieved significantly longer overall survival (OS) than PROphet-negative patients, with a median OS of 25.9 versus 10.8 months (hazard ratio, HR = 0.51; 95% confidence interval, CI = 0.37-0.70; p-value < 0.001). Next, we examined the clinical utility of combining the PROphet output with PD-L1 levels by comparing different treatment modalities. Focusing on PD-L1≥50%, patients with PROphet-positive results displayed similar OS and PFS when receiving ICI monotherapy or ICI-chemotherapy (OS HR = 0.77; CI = 0.42-1.43; p-value = 0.4096), suggesting that these patients may consider monotherapy, thus avoiding chemotherapy-related toxicity. Conversely, PD-L1≥50% patients with a PROphet-negative result displayed a significantly longer OS and PFS when receiving ICI-chemotherapy in comparison to ICI monotherapy, with a median OS that was not reached versus 11.10 months in the combination therapy and monotherapy groups, respectively (HR = 0.29; CI = 0.14-0.59; p-value < 0.001). These patients should consider combination therapy, avoiding a treatment that is suboptimal for them. Results for PD-L1 1-49% and < 1% provide additional clinical information for each subgroup. Conclusions: Plasma proteomic profiling can provide biomarkers that accurately predict the benefit of ICI-based treatment. The model output complements tissue PD-L1 expression levels as a tool to assist therapeutic decisions.