8519 Background: Non-classical mutations (NCM) of epidermal growth factor receptor (EGFR) represent a broad group of oncogenic mutations in non-small cell lung cancer (NSCLC), often associated with resistance to osimertinib (e.g., P-loop and αC-helix compressing [PACC] mutations). Patients (pts) with NCM have inferior clinical outcomes with a high incidence of CNS metastases (CNSm). Silevertinib (BDTX-1535) is a fourth-generation, covalent EGFR TKI with high CNS penetrance targeting both EGFR classical mutations and NCM. The antitumor activity and safety of silevertinib in pts with advanced NSCLC were evaluated in a Phase 2 trial (NCT05256290). Methods: Pts with advanced EGFR NCM NSCLC who received no prior systemic therapy were enrolled (Cohort 3) based on a local molecular test. Silevertinib 200 mg was administered orally once daily. The primary endpoint of objective response rate (ORR) was assessed using RECIST v1.1. CNS ORR was assessed using Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) in pts with no prior CNS therapy. Secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and safety. Results: From February 2024 to July 2025, 43 pts with 35 unique NCMs (including 25 pts with PACC mutations) were enrolled in Cohort 3: median age 70.0 years, 72% female, 74% white, and 42% never smoked cigarettes. As of November 3, 2025, median follow-up was 7.2 months. ORR by RECIST v1.1 is shown in the table. Sixteen pts (37%) had CNSm, including 7 pts (16%) with measurable CNS disease. RANO-BM CNS response was 86% (n=6/7). Complete clearance of EGFR VAF ctDNA was observed in 21/26 (81%) evaluable pts. Serious treatment-related adverse events (TRAEs) were reported in 5 pts (12%), and 4 pts (9%) discontinued treatment due to TRAEs. The most common TRAEs included rash (19%, grade 3), diarrhea (19%, grade 3), stomatitis (9%, grade 3), and paronychia (5%, grade 3). While 77% of pts had a dose reduction, 19/22 (86%) patients with a radiographic response maintained or deepened their response after dose reduction, including all patients with CNS response. Conclusions: Silevertinib demonstrated robust antitumor activity in treatment-naïve pts with a broad spectrum of NCM EGFR driver mutations with high intracranial activity in pts with brain metastases. The safety profile was consistent with the known AEs of the EGFR TKI class. Clinical trial information: NCT05256290 . Data as of November 3, 2025 N ORR n (%) 95% CI DCR n (%) 95% CI ITT Population * 43 26 (60) (44.4, 75.0) 39 (91) (77.9, 97.4) PACC mutations 25 14 (56) (34.9, 75.6) 22 (88) (68.8, 97.5) Compound mutations † 16 11 (69) (41.3, 89.0) 15 (94) (69.8, 99.8) *No pts with classical (E746_A750del or L858R) mutations were enrolled. † Presence of ≥ 2 NCMs. As of December 27, 2025, the 6-month PFS rate was 86% overall and 80% in pts with CNSm; available PFS and DOR data will be presented.

Advances in immunotherapy (IT) and targeted therapy have transformed treatment for stage IV non-squamous non-small cell lung cancer (NS-NSCLC). However, real-world data comparing modern regimens to previous standards remains limited. Herein, we aim to determine whether survival outcomes have improved with contemporary therapies, We conducted a retrospective analysis of de novo stage IV NS-NSCLC at diagnosis treated at the Cleveland Clinic, OH, from 1/2010 to 12/2022. Baseline variables, including age, sex, race, performance status, smoking history, PD-L1 testing, and molecular profiling, were collected along with treatment regimens. Treatment responses were assessed. Overall survival (OS) and progression-free survival (PFS) were estimated. Multivariable Cox regression (CPH) was used to adjust for confounding. We identified 1,518 patients with NS-NSCLC, of which 97

Introduction: Data from two global protocols under the expanded access program, Study-436 and Study-442, evaluating the safety and efficacy of sotorasib in patients with advanced KRAS G12C-mutated NSCLC beyond the traditional registrational trial setting are presented. Methods: Patients were enrolled in 90 centers globally. Baseline characteristics and safety data for Study-436 and Study-442 and efficacy data for Study-436 were estimated. All data were summarized descriptively. Results: A total of 268 patients (n = 150 [Study-436] and n = 118 [Study-442]) received oral sotorasib (960 mg daily). At baseline, 21.3% and 31.0% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and a history of central nervous system (CNS) metastases, respectively.Treatment-related adverse events occurred in 64.9% of patients; diarrhea (31.3%) was the most common. The incidence of treatment-related adverse events was similar between patients with ECOG PS 0 to 1 (67.8%) and PS 2 (54.4%) and those with (69.9%) and without (62.7%) a history of CNS metastases. The median real-world progression-free survival and overall survival was 6.3 and 9.5 months, respectively. The median real-world progression-free survival was numerically similar in patients with ECOG PS 0 to 1 versus PS 2 (6.5 versus 5.6 mo) and in patients with versus without a history of CNS metastases (5.7 versus 6.5 mo); median overall survival followed similar trends. Improvement from ECOG PS 2 to ECOG PS 0 to 1 was observed by the end of first cycle of treatment (57.9%). Conclusions: Safety and efficacy outcomes of sotorasib in this study were not affected with ECOG PS 2 and the history of CNS metastases and were consistent with those reported in key clinical trials.

Background:Immune checkpoint inhibitors (ICIs) improve cancer survival but can cause neurologic immune-related adverse events. Ma2-IgG-associated paraneoplastic neurologic syndrome typically presents with central nervous system involvement in patients with testicular or lung cancers. We present a case of paraneoplastic brachial amyotrophic diplegia (BAD) associated with Ma2-IgG which developed after ICI. Case Report:This is a case report of an 86-year-old man with pleural mesothelioma treated with nivolumab and ipilimumab, who presented with progressive, asymmetric weakness of his upper extremities after 5 cycles of ICI. Examination did not reveal associated sensory deficits. Blood creatine kinase level was normal and acetylcholine receptor antibody testing result was negative. Magnetic resonance imaging revealed findings consistent with bilateral frontal temporal lobe encephalitis, but without concurrent cervical cord lesions. Cerebrospinal fluid analysis revealed mild pleocytosis and oligoclonal bands. Ma2-IgG was present in the cerebrospinal fluid (>1:32) and serum (>1:3200). Electrodiagnostic testing revealed diffuse chronic innervation and active denervation changes involving the upper extremities raising concern for a motor neuron disorder. He was diagnosed with having paraneoplastic BAD and encephalitis. A progressive course ensued, despite initial transient improvement with escalation of immunosuppression. Conclusion:Paraneoplastic BAD is an uncommon paraneoplastic phenomenon that can occur with Ma2-IgG in the setting of ICI use and atypical tumors.

8515 Background: Pts with STK11 , KEAP1 and/or KRAS -mutated mNSCLC may benefit from the addition of anti-CTLA-4 to anti-PD-(L)1-based chemo-immunotherapy. In the phase 3 POSEIDON study, 1L T+D+CT significantly improved OS vs CT in pts with mNSCLC. Exploratory analyses showed sustained OS improvement with T+D+CT vs CT in subgroups with STK11 , KEAP1 and/or KRAS mut; in each mut subgroup, magnitude of OS benefit with T+D+CT vs CT was numerically greater than with D+CT vs CT. The phase 2b, open-label, multicenter, US-based TRITON study is comparing 1L T+D+CT vs P+CT in pts with NSQ mNSCLC and STK11, KEAP1 and/or KRAS mut. Here we report results of a planned IA (data cutoff [DCO] 15 mo after 1st pt randomized) of objective response rate (ORR), duration of response (DoR) and safety. Methods: Pts with treatment [tx]-naïve, EGFR / ALK wild-type, NSQ mNSCLC and STK11 , KEAP1 and/or KRAS mut (ECOG PS 0/1) were randomized 1:1 to T+D+CT or P+CT. T+D+CT arm: T 75 mg + D 1500 mg + pemetrexed-platinum Q3W for 4 cycles, then maintenance D + pemetrexed Q4W until disease progression (PD); additional doses of T given at week 16 and, optionally, at mo 24. P+CT arm: P 200 mg + pemetrexed-platinum Q3W for 4 cycles, then maintenance P + pemetrexed Q3W until PD, for up to 24 mo. Randomization was stratified by mut type and tumor PD-L1 expression (≥1% vs <1%). The primary endpoint is PFS (RECIST v1.1; investigator-assessed) with planned sample size ~100 pts. Key secondary endpoints include OS, ORR, DoR and safety. Results: At DCO (12 Nov 2025), 41 pts were randomized to T+D+CT and 43 to P+CT. Overall, 27.4%, 21.4% and 78.6% of pts had STK11 , KEAP1 and KRAS mut (not mutually exclusive); 39.3% had PD-L1 <1%. In the T+D+CT vs P+CT arms, median (range) age was 69 (47–82) vs 69 (51–86) y, 48.8% vs 62.8% pts were male, 70.7% vs 72.1% were White and 14.6% vs 20.9% Black or African American, 78.0% vs 62.8% had ECOG PS 1. Median (range) safety follow-up for D/P was 5.6 (0.0–14.0)/5.1 (0.0–17.5) mo; median no. of D/P doses was 8/7. ORR (95% CI) was 39.0% (24.1–54.0) in the T+D+CT arm vs 34.9% (20.6–49.1) in the P+CT arm [unconfirmed ORR 48.8% (33.5–64.1) vs 41.9% (27.1–56.6)]. Median DoR (95% CI) was not reached (6.3–NR) vs 6.4 (4.2–NR) mo; 100% vs 58.3% pts remained in response at 6 mo. In KRAS mut-only pts (n=52; exploratory), ORR was 48.0% (12/25) with T+D+CT vs 33.3% (9/27) with P+CT. The sponsor remains blinded to PFS at this IA. With T+D+CT vs P+CT, 41.5% vs 41.9% of pts had Grade 3/4 AEs possibly related to tx (TRAEs); 2.4% vs 4.7% had TRAEs leading to tx discontinuation and 0% vs 2.3% had TRAEs leading to death. Conclusions: At IA, ORR and DoR results from the prospective TRITON study support a role for the addition of anti-CTLA-4 (T) to 1L anti-PD-L1 (D) + CT in pts with STK11 , KEAP1 and/or KRAS -mutated mNSCLC. Safety was similar in the two arms and consistent with known safety profiles. Clinical trial information: NCT06008093 .

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

8620 Background: Despite significant benefit from FDA-approved EGFR tyrosine kinase inhibitors (TKIs), patients with classical EGFR mutation positive non-small cell lung cancer (NSCLC) ultimately develop progressive disease due to mechanisms of resistance, including alterations of the EGFR pathway. A broad group of non-classical EGFR mutations (NCM), including P-loop and αC-helix compressing (PACC) mutations, and acquired C797S are major mechanisms of EGFR resistance. Silevertinib (BDTX-1535) is a fourth-generation covalent EGFR TKI with high CNS penetrance that targets classical mutations, NCM, and C797S mutations. Antitumor activity and safety of silevertinib in advanced NSCLC were evaluated in an open-label Phase 2 trial (NCT05256290). Methods: Patients (pts) with recurrent NSCLC following ≤ 2 lines of therapy with only 1 prior EGFR TKI (osimertinib preferred) and tumors positive for NCM (NCM Cohort) or C797S mutation (C797S Cohort) were enrolled based on a local molecular test. Based on dose optimization of silevertinib at 100 mg and 200 mg orally once daily, all patients after May 2024 received 200 mg once daily. The primary endpoint was ORR by RECIST v1.1, and secondary endpoints included progression-free survival (PFS), duration of response (DOR), dose optimization, and safety. Results: From August 2023 to January 2025, 41 pts were treated in the NCM Cohort (100 mg, n=11; 200 mg, n=30; 80% female; 56% white; 49% with CNS metastases) and 42 pts were treated in the C797S Cohort (100mg, n=9; 200mg, n=33; 62% female; 48% white; 31% with CNS metastases). In both cohorts, 29% of pts had received 2 prior therapies. As of November 3, 2025, median follow-up was 9.5 months for pts treated with the 200 mg dose. ORR and median duration of treatment (DoT) are shown in the table. Alterations of other oncogenic pathways (e.g. MET, RET, RAS, and RAF) were observed at baseline in approximately 20% of pts in post hoc analyses. For the 200 mg dose, serious treatment-related adverse events (TRAEs) were reported in 7 (11%) pts, and 5 (8%) of pts discontinued treatment due to TRAEs. The most common TRAEs at 200 mg included rash (13%, grade 3), diarrhea (8%, grade 3), stomatitis (2%, grade 3), and paronychia (2%, grade 3). Available PFS, DOR, and dose optimization results will be presented. Conclusions: Silevertinib demonstrated antitumor activity at 200 mg orally once daily in patients with recurrent NSCLC, EGFR NCMs, and acquired resistance C797S mutation with a safety profile consistent with the EGFR TKI class. Clinical trial information: NCT05256290 . Cohort Dose n ORR (%, 95% CI) Median duration of treatment, mo (range) NCM Cohort 200 mg 30 16.7% (5.6–34.7) 4.99 (0.99-11.47) PACC mutations 200 mg 23 21.7% (7.5–43.7) 4.86 (1.28-11.47) C797S Cohort 200 mg 33 36.4% (20.4–54.9) 4.76 (0.46-12.55)

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of certain sites within the body. Pleural mesothelioma is the most common type and represents approximately 85% of mesotheliomas. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for evaluation and treatment in patients with pleural mesothelioma. The NCCN Guidelines will continue to be updated annually based on available clinical evidence and panel consensus.

INTRODUCTION:Immune checkpoint inhibitors have limited efficacy in patients with EGFR-mutant (EGFR+) and ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy of pembrolizumab with carboplatin and pemetrexed in these patients. PATIENTS AND METHODS:EGFR+ or ALK+ NSCLC patients, previously treated with targeted therapy, were eligible. Carboplatin, pemetrexed and pembrolizumab were administered every 3 weeks for 4 cycles followed by maintenance pemetrexed and pembrolizumab. The primary endpoint was response rate (RR). Blood for circulating tumor cells (CTCs) was collected prior to the 1st and 3rd cycles. The plan was to enroll 28 evaluable patients in both EGFR+ and ALK+ cohorts. RESULTS:Of the 33 patients enrolled, 26 had EGFR+ and 7 had ALK+ NSCLC. RR (95% CI,) was 46% (27%, 67%) in EGFR+ and 29% (4%, 71%), in ALK+ patients, respectively. Median progression free survival (PFS) and overall survival (OS) in the EGFR+ cohort were 8.3 months (7.2-16.5) and 22.2 months (20.6-NE), respectively. In the ALK+ cohort, median PFS and OS were both 2.9 months. The median CTC count at baseline in 15 evaluable EGFR+ patients was 4 cells/mL (0-23). OS among EGFR+ patients with decreasing vs. increasing CTC count during treatment was not reached vs. 18.5 months, respectively (P = .52). The most common adverse events were fatigue, nausea, anemia and AST/ALT elevation. CONCLUSION:Pembrolizumab in combination with chemotherapy demonstrated encouraging RR of 42% and OS of 22 months among patients with recurrent EGFR+ NSCLC. The efficacy in ALK+ patients was not encouraging.

8077 Background: Neoadjuvant chemoimmunotherapy (chemo-IO) has emerged as a promising approach to improve disease-free survival (DFS) in patients with surgically resectable non-small cell lung cancer (NSCLC). While recent clinical trials have demonstrated the efficacy of combining chemotherapy with immune checkpoint inhibitors in this setting, DFS remains variable among patients. Currently, there is no reliable biomarker to predict the risk of recurrence in this population. Predictors such as PD-L1 expression have shown limited utility, underscoring an unmet clinical need to identify robust biomarkers for DFS. This study investigates whether radiomic texture features derived from pre-treatment CT scans are associated with DFS in patients with NSCLC undergoing neoadjuvant chemo-IO prior to surgery. Methods: The study included 101 patients with NSCLC (median age: 66 years, range: 34–85) treated at the Cleveland Clinic. All patients received neoadjuvant platinum-doublet chemotherapy combined with an anti-PD-1 inhibitor prior to surgery. Radiomic features characterizing tumor heterogeneity were extracted from pre-treatment CT images. Patients were divided into a training set (St=50) and a validation set (Sv=51). A least absolute shrinkage and selection operator (LASSO) Cox regression model was used to identify prognostic features for DFS in St. A radiomic risk score (RRS) was computed as a linear combination of the selected features and their corresponding coefficients. High- and low-risk groups were determined based on the median RRS in St. A Cox regression analysis was performed to assess the impact of each factor on DFS. Kaplan–Meier survival analysis, accompanied by log-rank tests, was conducted to evaluate the prognostic performance of the biomarkers. Results: In a univariable analysis, the RRS was significantly associated with DFS in both St (HR = 2.77, 95% CI: 1.84 – 4.1, P < 0.0001) and Sv (HR= 2.28, 95% CI: 1.48 – 3.5, P = 0.0002). Kaplan-Meier analyses revealed significantly shorter DFS in the high-risk group compared to the low-risk group in both St (P < 0.0001) and Sv (P < 0.011). In a multivariable analysis that included clinicopathologic factors (age, race, tumor stage, and PD-L1 expression) along with RRS, both RRS and PD-L1 expression were significantly associated with DFS in St (RRS: HR = 2.99, 95% CI: 1.89 – 4.7, P < 0.0001; PD-L1: HR = 1.57, 95% CI: 1.14 – 2.15, P = 0.005). However, in Sv, RRS was the only factor significantly associated with DFS (RRS: HR= 2.31, 95% CI: 1.49 – 3.6, P = 0.0001), while PD-L1 expression was not (HR = 1.27, 95% CI: 0.35 – 4.6, P = 0.71). Conclusions: Identifying patients with locoregional NSCLC at risk of recurrence after neoadjuvant chemo-IO is crucial for effective treatment planning. Preliminary findings suggest that radiomic features hold promise as a reliable, non-invasive biomarker for risk stratification and guiding treatment decisions.

e20084 Background: In the randomized phase III PACIFIC trial, combining durvalumab with chemoradiation (CRT) resulted in an improvement in overall-survival (OS) and progression free survival (PFS) when compared to CRT alone, regardless of PD-L1 status in locally advanced, unresectable stage III non-small cell lung cancer (NSCLC). There are limited real-world studies examining long term outcomes of locally advanced, unresectable stage III NSCLC. Methods: We conducted a retrospective analysis including adult patients with stage IIIB/C NSCLC at Cleveland Clinic Foundation from 1/2010-12/2022. Baseline variables included age, sex, race, performance status, and smoking history. RECIST 1.1 response criteria was used to assess treatment response. Multivariable cox regression was used to find associations with overall survival (OS) and progression free survival (PFS). Results: We identified 290 patients with Stage IIIB/C NSCLC, 140 patients were non-squamous cell carcinoma (non-SCC) and 150 patients with squamous cell carcinoma (SCC). Median age was 66 years, among which 61% were male, 83% white, and around 52% were current smokers. 72% received only CRT and 28% received CRT followed by Durvalumab. In the CRT alone group, the most common regimens used were Carboplatin and Paclitaxel (n=128, 44%) and Cisplatin and Etoposide (n=32, 11%). In the CRT + Durvalumab group, the most common regimen was Carboplatin and Paclitaxel (n=78, 27%). The most common radiation dose was 60 Gy delivered in 30 fractions (71%, 74%). The 2-year and 5-year OS for Non-SCC was 47% and 35% respectively. The 2-year and 5-year overall OS for SCC was 47% and 25% respectively. The median OS with CRT + Durvalumab was 37 months (95%CI: 26-NR) vs. 18 months (95%CI: 15-21) for CRT alone. In multivariable cox regression, CRT + Durvalumab was associated with improved OS (HR 0.5, 95%CI 0.40-0.79, p<0.001) compared to CRT alone. Increasing age (HR 1.02, 95%CI 1.01-1.04, p= 0.006) and male gender (HR 1.41, 95%CI 1.05-1.89, p= 0.020) were associated with worse PFS. Similarly, CRT + Durvalumab were associated with improved PFS (0.64, 95%CI 0.47-0.89, p= 0.005). Though CRT + Durvalumab was associated with a significant improvement in OS for Non-SCC (HR 0.50, 95%CI 0.31-0.81, p= 0.003), it was not statistically significant for SCC (HR 0.74, 95%CI 0.48-1.15, p = 0.2). Conclusions: We found that addition of Durvalumab to CRT was associated with increased OS and PFS in locally advanced, unresectable stage III NSCLC, like the results to the PACIFIC trial. This retrospective analysis did not show significant benefit in OS for SCC patients, which is different compared to the trial, and this could be due to study power, and overall fitness and health of the patients. Our study showed that SCC are associated with lower long-term survival compared to non-SCC subtypes.

Thymomas and thymic carcinomas are rare mediastinal tumors that originate in the thymus. Patients with thymoma may experience symptoms associated with autoimmune paraneoplastic diseases (such as myasthenia gravis), which typically do not occur in patients with thymic carcinoma. The NCCN Guidelines for Thymomas and Thymic Carcinomas provide guidance for the diagnosis, treatment, and surveillance of patients with thymoma and thymic carcinoma. Involvement of a multidisciplinary team with experience treating thymomas and thymic carcinomas is highly recommended.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

BACKGROUND:Combining atezolizumab with carboplatin plus etoposide (Carbo-E) improved overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC). However, there is a paucity of real-world outcomes. We present the largest and longest follow-up retrospective study evaluating treatment outcomes in ES-SCLC. METHODS:We conducted a retrospective cohort study to compare response rate, OS, and progression-free survival (PFS) in patients with ES-SCLC who received Carbo-E, Carbo-E and atezolizumab (Carbo-E-Atezo), and cisplatin and etoposide (Cis-E). We included all adult patients (≥ 18 years) treated at Cleveland Clinic between 1/2010-12/2022. Propensity score (PS) weighting and multivariable Cox proportional hazards regression adjusted for confounders. RESULTS:Among 602 ES-SCLC patients, 375 (62 %) received Carbo-E, 160 (27 %) received Carbo-E-Atezo, and 67 (11 %) received Cis-E. The median age was 67, 65, and 59 years, respectively. The median follow-up among survivors was 23.9 months (IQR: 13.3---57.3). Five-year unadjusted OS was 4.5 % (Carbo-E), 7 % (Carbo-E-Atezo), and 5.2 % (Cis-E). Carbo-E-Atezo was associated with a longer PS-adjusted median OS than Carbo-E (9.1 vs. 8.2 months, P = 0.039), but no difference was seen in PFS (5.5 vs. 5.5, P = 0.09) or response rate (P > 0.9). Compared to Carbo-E, Cis-E showed higher response rates (OR: 1.67, P = 0.03) but no improvement in OS (11 vs 8.3 months, P = 0.067) or PFS (7.7 vs. 5.5 months, P = 0.058). Cis-E did not differ significantly from Carbo-E-Atezo in response rate, OS, or PFS. CONCLUSION:Long-term outcomes in ES-SCLC remain poor. Atezolizumab added to Carbo-E modestly improved OS but not PFS. Cisplatin-based regimens increased response rates but did not improve survival.

8080 Background: Historically, pathological complete response (pCR), a potential early predictor of survival, was achieved by a small fraction of patients with non-small cell lung cancer (NSCLC) receiving neoadjuvant chemotherapy. Now with chemoimmunotherapy (chemo-IO) becoming the cornerstone of perioperative treatment, the rate of pCR has significantly increased to over 15%. Existing factors like PD-L1 expression and circulating tumor DNA clearance have shown limited efficacy in reliably predicting response to neoadjuvant chemo-IO, thus underscoring the need for novel biomarkers. In this study, we aim to investigate the potential of radiomic texture features derived from pre-treatment CT scans to predict pCR in patients with NSCLC undergoing neoadjuvant chemo-IO prior to surgery. Methods: The study included 101 patients with surgically resected NSCLC treated at Cleveland Clinic. All patients received neoadjuvant platinum-doublet chemotherapy combined with an anti-PD-1 inhibitor prior to surgery. Tumor stage, histology, PD-L1 expression levels, and treatment details (e.g., chemotherapy regimen, immunotherapy agent, number of treatment cycles) were collected for analysis. Pathological responses were assessed based on the percentage of residual viable tumor in the surgical specimen, with pathological complete response (pCR) defined as 0% viable tumor. Radiomic features were extracted from both intratumoral and peritumoral regions on pre-treatment CT images. Patients were randomly divided into training and validation cohorts, ensuring an equal distribution of pCR and non-pCR cases in the training set. The training cohort (St) comprised 50 patients, while the validation cohort (Sv) included 51 patients. A linear discriminant classifier (LDA) was trained using St and subsequently evaluated on Sv. The predictive performance was assessed using the area under the curve (AUC). Results: 37 of 101 patients (37%) achieved a pCR. Utilizing a combination of 5 peritumoral and intratumoral radiomic features extracted from pretreatment CT scans, the AUC for predicting pCR was 0.82 (95% CI: 0.79 − 0.86) in St and 0.78 (95% CI: 0.76 − 0.81) in Sv. In contrast, the predictive capability of PD-L1 expression alone yielded an AUC of 0.57 for pCR prediction. Moreover, no significant difference was observed in pCR rates between patients with low and high PD-L1 expression levels (P = 0.1). The integration of radiomic features with clinicopathologic factors, including age, race, tumor stage, and PD-L1 expression, resulted in a modest improvement in predictive performance (AUC = 0.8) but was not statistically significant (P > 0.5). Conclusions: This analysis suggests that radiomic features extracted from both intra- and peri-tumoral regions on pre-treatment CT images may be indicative of the probability of achieving a pCR in patients with NSCLC receiving neoadjuvant chemo-IO.

e20569 Background: Several seminal trials have reshaped the standard treatment of stage IV lung squamous cell carcinoma (SCC) over the last decade and introduced immunotherapy as an integral component to novel regimens. In our retrospective analysis, we aim to study the impact of front-line new regimens compared to conventional chemotherapeutic regimens on overall survival (OS) and progression free survival (PFS) in the largest and longest follow-up real world experience. Methods: Our study included adult patients (≥18 years) with de novo stage IV lung SCC at diagnosis at Cleveland Clinic Foundation (CCF) from 1/2010-12/2022. We excluded patients who did not receive therapy. Baseline variable such as sex, age, smoking history, performance status, PDL-1 testing, and molecular testing were collected. Response to treatment was assessed using RECIST 1.1 response criteria. OS and PFS were calculated from time of initiation of first-line therapy. We used multivariable cox hazard regression (CPH) to adjust for confounding. We compared two groups: 1. immunotherapy (IT), chemotherapy–immunotherapy (chemo-IT) and targeted therapies, which were grouped together as “modern therapies” and 2. conventional chemotherapy group (CTX). Results: We included 335 patients with stage IV SCC at diagnosis at CCF. Median age was 68 years (IQR: 62-75), 67% male, 84% white and 6.6% never smokers. Treatments administered included CTX (203, 61%), IT (60, 18%), Chemo-IT (68, 20%), and targeted therapy (4, 1.2%). The most common CTX were carboplatin + gemcitabine (93, 46%) and carboplatin + paclitaxel (N= 65, 32%), IT was pembrolizumab (N= 50, 83%), chemo-IT was carboplatin + paclitaxel + pembrolizumab (N = 51, 75%). For the whole cohort, the response rate was ~50%. With a median follow-up of 27.5 months, the 1-year and 2-year OS were 29% (95% CI 24-36) and 12% (95% CI 8.4-18) for CTX and 43% (95% CI 35-52) and 26% (95% CI 19-34) for modern therapies. On multivariable CPH, modern therapies were associated with increased OS compared to CTX regimens (HR 0.76, 95% CI 0.60-0.97, p = 0.025). PFS was also improved in modern regimens (p<0.05). Increasing age (as a continuous variable) was significantly associated with decreased OS (HR 1.02, 95% CI 1.01-1.03, P=0.003). Moreover, increasing neutrophils predicted higher mortality (HR 1.03, 95% CI 1.00-1.07, P= 0.041). Using multivariable CPH model, there was no difference in OS between carboplatin + paclitaxel and carboplatin + gemcitabine (HR 0.79, 95% CI 0.56-1.11, p=0.2). Conclusions: In the largest retrospective analysis of stage IV lung SCC that compares the front-line modern therapeutic modalities with the CTX, we confirmed the benefit of IT/targeted therapy on OS and PFS, using real world evidence. Long-term survival outcomes of stage IV SCC remain poor and further research is warranted to improve outcomes.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight signi ficant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classi fication and systemic therapy options.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.