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e20120 Background: In May 2024, the FDA approved tarlatamab, a Delta-like ligand (DLL3)/CD3-targeted bispecific T-cell engager, for patients with extensive-stage small cell lung cancer (SCLC) with disease progression following platinum-based chemotherapy and at least one other prior line of therapy. We aim to evaluate the real-world outcomes of agent. Methods: We conducted a retrospective multi-site single center analysis of adult patients who received tarlatamab at Mayo clinic sites including Arizona, Florida, Iowa, Minnesota, and Wisconsin. Data analysis was performed with Blue Sky statistics version 10.4. Results: Twenty patients with a median age 67 years (range 43-76) were included. Patients were predominantly women (55%) and all had a history of tobacco use. Metastatic disease commonly involved liver (55%) and CNS (60%). Majority (90%) had received prior PDL-1 therapy. 25% (5/20) of patients received prior gamma knife and in addition 10% (2/20) received whole brain radiation treatment in our cohort. Median time from CNS radiation and tarlatamab initiation was 4 months (range 3-28). Other characteristics, outcomes, and toxicity are presented in Table 1. Cytokine release syndrome (CRS) Grade (G) 1 was observed in 45% patients. G 2, 3 and 4 CRS were observed in 5% patients respectively. G 1 CRS was managed with acetaminophen initially followed dexamethasone 10mg or methylprednisone 1g if no improvement in 24 hours. Tocilizumab was used 20% patients for G 1,2,3 and 4 CRS depending on clinical course. Immune effector cell-associated neurotoxicity (ICANS) G 1 occurred in 10% patients, followed by G 2 in 15% and G 3 in 5% patients. ICANS was managed in a multidisciplinary fashion. All patients had resolution of CRS and ICANS. Conclusions: In this study investigating the real-world outcomes and toxicity of tarlatamab, a higher incidence of ICANS was observed than that reported in the DeLLphi-301 trial. The association between presence of CNS metastatic disease, prior CNS radiation and incidence of ICANS needs to be explored further. Mayo Clinic report of tarlatamab real world outcomes and toxicity. Patient Characteristics, Tarlatamab Outcomes and Toxicity Mayo Clinic Report DeLLphi-301 trial- Part 1 & 2 DeLLphi-301 trial- Part 3 ECOG no. (%) 2-4 4 (20) 0 (0) 0 (0) Metastatic Disease no.(%) 19 (95) 98 (98) 32 (94) Median no. of previous lines of therapy (range) 3 (2-4) 2 (1-6) 2 (2-6) Objective Response (%) 30% 40% CRS no (%) 12 (60) 49 (49) 19 (56) ICANS no (%) 6 (30) 7 (7) 4 (12) Neutropenia Grade 3 no (%) 2 (10) 6 (6) 2 (6) Fatal CRS, ICANS or Neutropenia 0 (0) 0 (0) 0 (0)

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).

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

Perioperative therapy has become a critical component in the management of resectable non–small cell lung cancer (NSCLC), particularly in the era of precision medicine. Although molecular testing is standard in metastatic NSCLC, its incorporation into early-stage disease remains essential for guiding treatment decisions. Reflex molecular testing pathways are necessary to optimize tissue utilization and ensure timely results. However, liquid biopsies, although valuable in advanced disease, have limited sensitivity in early-stage NSCLC, reinforcing the need for tissue-based next-generation sequencing. Targeted therapies have revolutionized treatment for oncogene-driven NSCLC, with adjuvant osimertinib now standard for EGFR-mutant disease and ongoing investigations into ALK tyrosine kinase inhibitors (TKIs). However, unanswered questions remain regarding the inclusion of perioperative TKI therapy, the role of molecular residual disease assessment, and whether specific TKIs offer greater benefit for high-risk subgroups. The role of immunotherapy (IO) in oncogene-driven NSCLC remains controversial. Although perioperative chemo-IO has demonstrated survival benefits in unselected NSCLC, its efficacy in EGFR, ALK, and other actionable alterations is unclear. Tumors harboring KRAS and BRAF mutations may respond better because of a more immune-inflamed microenvironment, and remains an active area of investigation. As the landscape of perioperative therapy continues to evolve, ongoing trials will help define the optimal integration of targeted therapies and IO in oncogene-driven NSCLC. Addressing these unanswered questions will be crucial in refining treatment strategies and improving patient outcomes.

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.

Background Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited. Methods This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were included. Treatment-related adverse events (trAEs) were graded per Common Terminology Criteria for Adverse Event V.5.0. Objective response rates (ORR) were evaluated by Response Evaluation Criteria in Solid Tumors V.1.1 when available. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Results Among 110 pts, median age at ICI initiation was 65 (IQR: 59–75). Median follow-up time since ICI initiation was 36 (95% CI: 26 to 51) months. Melanoma (38%, n=42) and non-small cell lung cancer (24%, n=26) were the most common. 68 (62%) patients received ICIs as first-line, and 29 (26%) patients were treated with combination anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen 4. The most common location of cardiac metastasis was in the atria (37%, n=41) and ventricles (35%, n=39). 15 patients (13.6%) had bilateral cardiac/pericardial metastasis, 44 (40%) had left-sided, and 43 (39.8%) had right-sided. At ICI initiation, 21% (n=23) had a cardiac thrombus. Cardiology referrals and cardiac MRIs at the time of cancer diagnosis were completed on 58 (53%) and 52 (47%) patients, respectively. Cardiac events occurred in 40 (36%) patients, including arrhythmias (n=14, 13%), arterial/venous emboli (n=4, 3.6%), and cardiac tamponade (n=3, 2.7%). 53 (47%) patients developed trAEs; most common were colitis/diarrhea (n=16, 15%), dermatitis (n=13, 12%), and hepatitis (n=9, 8.2%). ICI-related major cardiac trAEs occurred in 2 (1.8%) patients. 22 patients (20%) developed grade ≥3 trAE. Patients with multiple cardiac metastases had significantly lower responses to ICI-based regimens compared with patients with single cardiac metastasis (11% vs 63%, p=0.02). For melanoma, ORR, median PFS, and median OS were 38%, 9.0 months, and 28.9 months, respectively. 83% of patients with melanoma had concordant responses in overall disease burden and cardiac disease. 91 patients discontinued ICIs, and the main reason was progression or death in 55 (49%) patients. Conclusions Among patients with pre-existing cardiac metastasis, ICIs demonstrated meaningful clinical efficacy with no increase in safety signals. Most patients had concordant responses in the overall disease burden and cardiac mass. Multidisciplinary teams are crucial for the appropriate management of patients with cardiac metastasis.

ABSTRACT Background There has been a lack of updated epidemiological data on the incidence and survival outcomes for patients with small cell lung cancer (SCLC) in the United States over the last two decades. Methods A retrospective, population‐based study was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) program to identify patients with SCLC from 2000 to 2020. Trends in cancer incidence, incidence‐based mortality rates, 1‐year relative survival rates and 1‐year observed survival were evaluated utilizing the SEER database. Results The database identified a total of 188,426 SCLC patients during the study period from 2000 through 2020. The age‐adjusted incidence rate slowly declined, on average, by 3% (95% CI: −3.2% to −2.8%) each year from 9 per 100,000 in 2000 to 4.6 per 100,000 in 2020. The decline is evident for all age groups, sexes, and races. Incidence‐based mortality also declined slowly from 6.6 in 2005 to 3.5 in 2020. However, survival outcomes, including 1‐year relative survival and 1‐year observed survivals, have not improved significantly over the last two decades. Conclusion This study found that the incidence of SCLC has decreased from 2000 to 2020, likely due to a reduction in smoking rates, underscoring the importance of smoking abstinence. An improvement in incidence‐based mortality is likely related to an enhanced medical care and a decrease in the incidence of SCLC, but the lack of improvement in survival outcomes reflects the need for more effective systemic therapy.

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.

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.

8071 Background: Data from the PACIFIC study demonstrated a 5-yr median progression free survival (PFS) and overall survival (OS) of 16.9 and 47.5 months respectively for patients with stage 3A and stage 3B NSCLC demonstrating a high risk of relapse. The 8th ed. of the IASLC staging project reports that the 60-month OS for stage 3A, B and C disease is 41%, 24% and 12% respectively, indicating that improved treatment options are needed for this patient population. Induction chemo-IO (ID chemo-IO) followed by concurrent chemo-radiation (CRT) has not been fully investigated due to concerns regarding the toxicity profile, but this may representant an important unexplored avenue for research. We aim to describe the outcomes of patients who received ID chemo-IO followed by CRT with or without maintenance IO. Methods: We conducted a retrospective study across all Mayo Clinic sites. Patients were included if they were diagnosed with Stage 3 NSCLC deemed ineligible for resection and/or requiring raditation over a large-field ] by a multidisciplinary team with plans for ID chemo-IO prior to CRT and maintenance IO. A total of 927 cases of stage 3 NSCLC patients were screened and those receiving ID chemo-IO followed by CRT were extracted (n = 36). Clinical endpoints are PFS, OS, overall response rate (ORR) and treatment related adverse events (TrAE) defined using CTCAE 5.0. Results: The median age was 67 years, 52.8% were female, all patients were past smokers and 97.2% identified as white. The tumor histologies were adenocarcinoma (66.67%), squamous (27.8%), mucinous adenocarcinoma (2.8%) and sarcomatoid (2.8%). Majority were Stage 3B (47.2%) followed by 3C (38.9%) and 3A (13.9%). N2 and N3 disease was noted in 36.1% and 55.6% of patients respectively. PD-L1 by IHC was > 1-49% (47.2%), > 50% (22.2%) and < 1% (19.4%). Patients received ID chemo-IO with pembrolizumab (83.3%), nivolumab (11.1%) and atezolizumab (2.78%). Average number of ID chemo-IO cycles were 3.67 cycles. The ORR to ID chemo-IO was 86.11%. The median PFS was 23.67 mths and the median OS was 32.07 months. About 94% of patients received CRT afterwards and 66.67% received maintenance IO with pembrolizumab (53.17%) or durvalumab (45.83%). Any grade TrAE occured in 58.33% of patients. Pneumonitis was the most common event (38.9%). Grade 3 -4 pneumonitis was noted in 28.5% (4/11) patients. Other toxicities included hepatitis (8.3%), colitis (11.1%) and myasthenia gravis (2.8%) and 22% of these TrAE’s were grade 3 or 4. Conclusions: Our results indicate that ID chemo-IO shows promise as a therapeutic approach for patients with unresectable stage III NSCLC, especially for patients deemed ineligible or high risk for upfront radiation. Further investigation is needed through a randomized clinical trial to systematically explore and validate the safety and efficacy of ID chemo-IO.