Abstract Backgrounds: BRAF genomic alterations (GAs) have been identified in various tumors and are categorized into three distinct classes. Based on their impact on RAS-independent kinase activity, class 1 (monomer) and class 2 (dimer) are significant treatment targets and class specific regimens are being developed. However, the distribution of these classes across different primary sites has not yet been clarified. In patients with pancreatic cancer (PC), class 2 BRAF GAs have occasionally been encountered in clinical practice. Because precision oncology is limited in PC, BRAF GAs are precious target. To elucidate the patterns of BRAF GAs in PC, we investigated two extensive databases. Methods: We analyzed the Japanese nationwide C-CAT data and the AACR Project GENIE data. BRAF GAs were annotated using OncoKB and AlphaMissense and classified into three classes based on the published literature. Results: In the C-CAT data (N=107,714), as summarized in the table, BRAF GAs (n=3559, 3.3%) were frequently observed in thyroid, skin, and colorectal cancers, but these were mainly class 1(mostly V600E). In contrast, PC showed a distinct profile: among 11,959 patients with PC, BRAF GAs were detected in 230 (1.92%), Class1 was relatively rare (15.6%) and 60.4% (139/230) were class 2. These were mainly composed of in-frame deletions (n=97), with N486_P490del (n=79) and fusions (n=28). In GENIE data (N=250,018), 1.6% (169/10,730) of patients with PC harbored BRAF GAs. Although proportion of V600E was higher than that in C-CAT (19.5%), class 2 was dominant (63%, 108/169), such as fusions(n=48) and N486_P490del (n=28). Among BRAF N486_P490del positive solid tumors, pancreas was dominant primary site in both C-CAT (82%, 79/96) and GENIE (52%, 28/53). Conclusions: Class 2 BRAF GAs, especially N486_P490del and fusions, are distinctive alterations in patients with PC, and the development of class 2 specific targeted therapies is urgently needed. Citation Format: Kiyoaki Ochi, Chigusa Morizane, Kouya Shiraishi, Takafumi Koyama, Kuniko Sunami, Rui Kitadai, Yusuke Okuma, Tetsuro Shiraishi, Eiichiro So, Yuno Goto, Shiho Hakui, Keita Fujisaki, Kazunori Onuma, Yasuhiro Komori, Daiki Yamashige, Mao Okada, Shota Harai, Yuta Maruki, Yasuyuki Kawamoto, Yoshikuni Nagashio, Susumu Hijioka, Hideki Ueno, Takushi Okusaka. BRAF N486_P490del and fusions as distinctive gene alterations in pancreatic ductal adenocarcinomas: Analysis of C-CAT and AACR Project GENIE data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3991.

BACKGROUND/AIM:The mesenchymal-epithelial transition (MET) receptor plays a key role in cell growth and survival. The MET exon 14 (METex14) skipping mutation occurs in 3% to 4% of patients with non-small cell lung cancer (NSCLC) and leads to prolonged MET signaling and oncogenesis. MET tyrosine kinase inhibitors (TKIs), such as tepotinib and capmatinib, are effective for METex14-altered NSCLC; however, their impact on patients with a poor performance status (PS) is unclear. We retrospectively analyzed clinical outcomes of MET-TKI treatment for NSCLC with the METex14 skipping mutation. PATIENTS AND METHODS:We reviewed 59 cases of NSCLC with the METex14 skipping mutation diagnosed at the National Cancer Center Hospital between June 2020 and April 2024. Clinical data included demographics, PS, histology, PD-L1 expression, treatment response, progression-free survival (PFS), and overall survival (OS). RESULTS:Forty-nine patients (median age, 72 years; range=50-87 years; 53.1% male) received MET-TKIs (tepotinib or capmatinib). Thirty-seven patients and 12 patients had PS scores of 0 or 1 and ≥2, respectively. The median PFS and median OS of patients who received MET-TKI treatment were 5.6 months and 18.7 months, respectively. Thirty-seven patients who received first-line MET-TKI treatment had median PFS, median OS, and a median overall response rate (ORR) of 5.6 months, 21.3 months, and 48.6%, respectively. For patients with a PS score ≥2 (n=9), the median PFS, median OS, and median ORR were 0.95 months, 1.3 months, and 11.1%, respectively. A PS score ≥2 was strongly associated with shorter OS. Two of nine (22.2%) patients with a poor PS experienced improvement. CONCLUSION:MET-TKIs are effective for NSCLC with the METex14 skipping mutation; however, their efficacy for patients with a poor PS is limited.

The EXTRA trial was the first to identify predictive biomarkers for afatinib efficacy in epidermal growth factor receptor (EGFR)-mutant NSCLC. We analyzed the clinical data of older adult patients before translational analysis. This prospective study involved untreated patients with EGFR-mutant NSCLC who received afatinib at an initial dose of 40 mg/day, followed by stepwise dose reductions, ultimately reaching 20 mg administered every other day. Treatment efficacy and adverse events (AEs) were compared between non-older and older adult patients. Among the 103 patients, 71 were aged < 75 years, and 32 were aged ≥ 75 years. Despite increased dose reductions in the older adults, progression-free survival was comparable: 21.5 vs. 18.6 months for non-older and older adults, respectively. The median overall survival (OS) was not reached in either group; the 2-year OS rates were 82% and 75% in non-older and older adults, respectively. Median post-progression survival in patients administered second-line drug therapy was 14.3 and 11.2 months in non-older (n = 42) and older adults (n = 20), respectively. Among older adults, 31 (97%) patients experienced AEs of all grades, and only six patients had grade ≥ 3 AEs with no grade 5 AEs. Afatinib demonstrated comparable therapeutic efficacy and safety in older and non-older adult patients with advanced EGFR-mutant NSCLC.Trial registration: UMIN-CTR identifier (UMIN000024935).

BACKGROUND/AIM:Bone metastases (BMs) of non-small cell lung cancer (NSCLC) are associated with skeletal-related events that impair quality of life. Tartrate-resistant acid phosphatase 5b (TRACP-5b) is considered a marker of osteoclastic activity; however, its prognostic utility for NSCLC patients with BMs remains unclear. This study aimed to evaluate the association between longitudinal changes in TRACP-5b and BM progression in a relatively homogeneous population of patients with epidermal growth factor receptor (EGFR)-mutated NSCLC treated with osimertinib. PATIENTS AND METHODS:Patients with EGFR-mutated NSCLC receiving osimertinib between January 2019 and May 2024 were retrospectively identified. Serum TRACP-5b levels were measured at five predefined time points: osimertinib initiation (Point 1), the first computed tomography scan for response evaluation (Point 2), the two assessments immediately preceding disease progression (Points 3 and 4), and the time of progression (Point 5). Patients were classified by BM progression status and matched 1:1 on prior denosumab administration and EGFR mutation type to reduce baseline imbalance. Mixed-effects models for repeated measures were used to assess longitudinal differences in TRACP-5b levels, adjusting for relevant covariates. RESULTS:Thirty-six patients (18 per group) were included. Least-squares mean TRACP-5b levels were generally comparable between groups from Points 2 to 4, whereas higher levels were observed at Point 5 in the BM progression group (difference, 49.4 mU/dl; 95%CI=3.0-95.7). TRACP-5b levels increased from Points 3 to 5 only in the BM progression group. CONCLUSION:Serial monitoring of TRACP-5b may provide supplementary information for detecting BM progression in patients with NSCLC treated with osimertinib.

BACKGROUND:Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may improve outcomes in metastatic EGFR-mutant NSCLC, but VEGF inhibitors are not universally effective. We evaluated the impact of VEGFA and VEGFR2 expressions on EGFR-TKI outcomes. METHODS:EGFR-mutant NSCLC patients from the National Cancer Center Hospital, were retrospectively analysed. The early-stage cohort comprised stage I-IIIA patients (1997-2019). The advanced-stage cohort included metastatic patients (2018-2022). VEGFA/VEGFR2 expressions were dichotomised by median transcripts per million. RESULTS:Among 447 early-stage patients (median age 66), high VEGFA was associated with smoking, TP53 co-mutation, higher Brinkman Index, and higher tumour mutation burden (all p < 0.01). High VEGFA predicted shorter relapse-free survival (HR 2.10, 95% CI 1.63-2.71, p < 0.01) and overall survival (HR 2.07, 95% CI 1.46-2.95, p < 0.01). VEGFR2 expression showed no prognostic impact. In 146 relapsed patients receiving first-line EGFR-TKIs, high VEGFA was linked to shorter progression-free survival (PFS) overall (HR 1.70,95%CI 1.13-2.56, p = 0.009), particularly for first/second-generation EGFR-TKIs (HR 1.66,95%CI 1.08-2.54 p = 0.023), but not for osimertinib (p = 0.491). In 60 advanced-stage patients on osimertinib, PFS was unaffected by VEGFA (p = 0.102). CONCLUSIONS:High VEGFA is associated with aggressive biology and inferior outcomes, correlating with shorter PFS for first/second-generation EGFR-TKIs but not for osimertinib.

BACKGROUND:Epidermal growth factor receptor (EGFR) exon 19 deletion subtypes may be associated with differential survival outcomes following EGFR-tyrosine kinase inhibitor treatment. However, evidence remains scarce, particularly regarding osimertinib, and the underlying biological mechanisms are poorly understood. We aimed to compare survival outcomes among EGFR exon 19 deletion subtypes in patients with non-small cell lung cancer (NSCLC) treated with osimertinib. METHODS:In this multicenter retrospective study, patients with NSCLC were stratified according to exon 19 deletion subtypes. Whole-exome sequencing data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange registry and Memorial Sloan Kettering Clinicogenomic Harmonized Oncologic Real-World Dataset were analyzed to investigate co-occurring genomic alterations. RESULTS:Overall, 111 patients with advanced EGFR exon 19 deletion-positive NSCLC were analyzed and 86.5% received osimertinib as first-line therapy. Patients with non-E746_A750del (n = 25) had shorter progression-free survival (PFS) than those with E746_A750del (n = 86) (median: 14.3 vs. 20.6 months; p < 0.05). Among non-E746_A750del subtypes, L747_A750delinsP (n = 4) had a particularly poor prognosis, with significantly worse survival than those with E746_A750del (median PFS: 3.5 vs. 20.6 months; p < 0.001, and median overall survival: 11.8 vs. 48.5 months; p < 0.001). In public database analyses, non-E746_A750del had a higher rate of RBM10 co-mutations, whereas L747_A750delinsP was characterized by frequent CDKN2A/B homozygous deletions and MYC amplifications. CONCLUSIONS:Non-E746_A750del was associated with poorer outcomes, with L747_A750delinsP potentially being a high-risk subtype. Differences in co-occurring genomic alterations may contribute to the prognostic heterogeneity among exon 19 deletion subtypes.

Nuclear protein in testis (NUT) carcinoma is an extremely rare and aggressive malignancy characterized by NUTM1 gene rearrangement. It frequently develops in the lungs or the head and neck region as a poorly differentiated squamous cell carcinoma. The prognosis is generally poor and particularly dismal in cases with a pulmonary origin. Given the lack of an established standard treatment and the rapid disease progression, recently, immune checkpoint inhibitors (ICIs) have attracted attention, particularly in combination with platinum-based chemotherapy. We report a case series of four patients with pulmonary NUT carcinoma who received ICI-containing regimens as first-line therapy. Three patients received ICIs in combination with platinum-based chemotherapy and showed transient tumor shrinkage, although all ultimately experienced disease progression and died. One patient received ICI monotherapy owing to poor performance status and showed no clinical response. The median progression-free and overall survival were 53 and 108 days, respectively. Given the limited treatment options for NUT carcinoma, a combination of ICIs with platinum-based chemotherapy may represent a potential first-line treatment option. However, their efficacy remains limited.

BACKGROUND:Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have been approved for HER2-mutant NSCLC, real-world outcome data especially in the second-line setting remains limited. METHODS:This non-interventional study utilized the Center for Cancer Genomics and Advanced Therapeutics national database to identify patients with HER2-mutant NSCLC who received second-line treatment in Japan. The primary objective was to characterize this population. Secondary objectives included describing second-line treatments and clinical outcomes (overall response rate [ORR], disease control rate [DCR], time on treatment [ToT] and reasons for second-line treatment termination). RESULTS:Among 3012 NSCLC patients identified, 168 (5.6%) had a HER2 mutation. In all NSCLC and HER2-mutant patients, median age was 66.0 years; 38.1% and 53.6% were female; 68.2% and 42.3% had a history of smoking; and 25.8% and 31.0% had brain metastases. In HER2-mutant patients, use of molecular targeted therapy (MTT, 44.6%) and chemotherapy (36.9%) as second-line treatment were comparable, followed by immunotherapy (15.5%), and immunochemotherapy (3.0%). Overall, median ToT with second-line treatment was 4.8 months (95% CI: 4.1-6.2). The longest median ToT was observed with MTT (8.1 months, 95% CI: 4.8-9.7), followed by chemotherapy (3.9 months, 95% CI: 2.5-5.2), immunochemotherapy (3.2 months, 95% CI: 0.4-not reached) and immunotherapy (5.5 months, 95% CI: 3.8-8.5). The ORR was 33.1% (95% CI: 25.4-41.6) and DCR was 78.4% (95% CI: 70.6-84.9). CONCLUSIONS:MTT was the most common second-line treatment, however, outcomes were generally poor, emphasizing the unmet need for effective second-line treatments for HER2-mutant NSCLC.

Radiation oesophagitis, a common adverse event of radiation therapy for limited-disease small cell lung cancer (LD-SCLC), results in significant weight loss. This study retrospectively evaluated the association between weight loss and treatment outcomes in patients with LD-SCLC undergoing chemoradiotherapy and explored the associated factors. Patients with LD-SCLC treated with concurrent chemoradiotherapy between 2010 and 2023 were included. We compared the characteristics of patients with and without radiation oesophagitis or ≥ 5

Abstract Background: Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in non-small cell lung cancer (NSCLC), yet durable benefit is achieved in only a minority of patients. The biological mechanisms underlying tumor response to ICIs—including primary resistance (PriR), acquired resistance (AcqR), and long-term response (LTR)—remain poorly understood. Methods: We reviewed patients with advanced or recurrent NSCLC who initiated first-line ICI monotherapy at the National Cancer Center Hospital (Japan) between 2015-2020. Patients were classified as LTR (defined as progression-free survival ≥48 months), AcqR (initial disease control followed by progression <48 months), or PriR (best response PD). Clinical characteristics were characterized across these groups. Pretreatment tumor RNA-seq data were subjected to transcriptomic analyses. Differential pathway activity was evaluated using Hallmark and Reactome GSEA, and immune-cell composition was inferred using CIBERSORT. Results: A total of 216 patients were included in the clinical cohort. Pretreatment tumor RNA-seq data were available for 46 patients (LTR, n=10; AcqR, n=23; PriR, n=13). Compared with responders (LTR + AcqR), PriR tumors showed marked enrichment of inflammatory and immunosuppressive programs, including IL6-JAK-STAT3, TNFα/NF-κB, complement, glycolysis, and hypoxia pathways, suggesting a metabolically stressed and suppressive microenvironment that hinders initial immune activation. In contrast, responders exhibited higher interferon-γ (IFN-γ) signaling and T-cell activation signatures. In a direct comparison between LTR and AcqR, LTR tumors uniquely preserved strong IFN-γ-driven inflammation, intact MHC class I antigen-presentation machinery, and robust cytotoxic and memory T-cell programs. AcqR tumors showed attenuation of antigen-presentation and effector-immune pathways, suggesting that reduced immunogenicity contributes to progression after an initial response. Among PD-L1-high tumors, LTR cases again maintained intact antigen-presentation machinery and sustained IFN-γ-driven cytotoxic T-cell activity, whereas AcqR tumors demonstrated attenuation of these programs. Conclusion: Compared with PriR and AcqR tumors, LTR tumors showed higher IFN-γ activity, preserved antigen-presentation activity, and sustained effector T-cell signaling. PriR tumors were characterized by inflammatory and metabolically stressed immunosuppressive programs, whereas AcqR tumors showed loss of antigen-presentation and effector-immune activity after the initial response. These features may help identify patients likely to achieve durable ICI benefit and suggest potential targets to overcome resistance. Citation Format: Yoshihiro Masui, Tatsuya Yoshida, Jun Miyakoshi, Ryoko Higashiyama, Akiko Tateishi, Yuki Shinno, Tomonori Mizutani, Yusuke Okuma, Hidehito Horinouchi, Kouya Shiraishi, Takashi Kohno, Yasushi Goto. Immunologic and transcriptional features associated with long-term response and resistance to immune checkpoint inhibitors in non-small cell lung cancer checkpoint inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6460.

Abstract Background: In the ClarIDHy trial, ivosidenib significantly improved progression-free survival (PFS) compared with placebo in patients with previously treated IDH1-mutant cholangiocarcinoma (CCA) and is currently awaiting insurance approval in Japan. However, approximately 40% of patients in both arms experience disease progression within 2 months, suggesting underlying biological heterogeneity within IDH1-mutant CCA. We hypothesized that genomic co-alterations may serve as potential determinants of this heterogeneity. Methods: We analyzed patients with intrahepatic cholangiocarcinoma (iCCA) in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and June 2025. Point mutations were annotated using OncoKB, and copy number variants and rearrangements were evaluated using C-CAT (approval number CDU2021-001N). Additionally, we reviewed institutional patients with IDH1-mutant iCCA diagnosed between October 2001 and October 2025, with detailed pathological and radiological assessments (approval number 2018-149). Results: Among 2484 patients with iCCA, 353 had IDH1 mutations (14.2%). IDH1-mutant iCCA tended to show longer overall survival (OS) and time to treatment failure (TTF) for first-line therapy than IDH1-wild type (median OS, 22.4 vs. 20.1 months; HR, 0.83; P=0.054; median TTF, 7.8 vs. 6.4 months; HR, 0.87; P=0.068). In IDH1-mutant iCCA, KRAS mutations and CDKN2A loss were less frequent than IDH1-wild type (KRAS mutations, 11.6% vs. 27.6%, P<0.001; CDKN2A loss, 17.8% vs. 27.5%, P<0.001). Among IDH1-mutant iCCA, KRAS mutations showed a trend toward shorter OS (median, 17.0 vs. 23.2; HR, 1.60; P=0.069) and were associated with shorter TTF (median, 5.7 vs. 8.5 months; HR, 1.86; P=0.0039). CDKN2A loss was correlated with shorter OS (median, 17.6 vs. 23.7 months; HR, 1.58; P=0.037). IDH1-mutant iCCA without KRAS mutations or CDKN2A loss demonstrated significantly longer OS (median, 24.9 vs. 17.6 months; HR, 0.61, P=0.010) and TTF (median, 8.4 vs. 6.1 months; HR, 0.70, P=0.020) than the other subsets. In multivariate analysis, KRAS mutations predicted shorter OS (HR, 1.75; P=0.046) and TTF (HR, 1.77; P=0.012). In an institutional cohort of 37 patients, only one case was pathologically classified as large-duct type and harbored KRAS mutation, with all other cases classified as small-duct type. Radiologically, IDH1-mutant iCCA without KRAS mutations and CDKN2A loss tended to present in a peripheral location (60.0% vs. 33.3%) and intratumoral transversing vessels (84.0% vs. 55.6%). Conclusions: IDH1 mutations less frequently co-occur with KRAS mutations and CDKN2A loss. IDH1-mutant iCCA without these co-alterations exhibited favorable clinical outcomes and distinct radiopathological characteristics, highlighting the biological heterogeneity associated with genomic co-alterations in IDH1-mutant iCCA. Citation Format: Eiichiro So, Chigusa Morizane, Kouya Shiraishi, Nobuyoshi Hiraoka, Miyuki Sone, Takafumi Koyama, Rui Kitadai, Yusuke Okuma, Takashi Kohno, Tetsuro Shiraishi, Yuno Goto, Shiho Hakui, Kiyoaki Ochi, Keita Fujisaki, Kazunori Onuma, Yasuhiro Komori, Daiki Yamashige, Mao Okada, Shota Harai, Yuta Maruki, Yasuyuki Kawamoto, Yoshikuni Nagashio, Susumu Hijioka, Hideki Ueno, Kenro Hirata, Takanori Kanai, Takuji Okusaka. Prognostic impact and clinical characteristics of KRAS mutations and CDKN2A loss in IDH1-mutant intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5346.

BACKGROUND:Pembrolizumab 400 mg every 6 weeks (Q6W) was approved based on population pharmacokinetic (pop-PK) modeling rather than pharmacokinetic measurements, leaving real-world concentrations insufficiently characterized. The impact of concentration changes when switching from 200 mg every 3 weeks (Q3W) to Q6W on immune-related adverse events (irAEs) remains unclear. This study aimed to evaluate the association between the change in pembrolizumab dosage and irAE occurrence. METHODS:We retrospectively identified patients with advanced non-small cell lung cancer who switched pembrolizumab from Q3W to Q6W between March 2017 and September 2023. Serum concentrations were quantified; pop-PK analysis estimated maximum concentration (eCmax) and estimated trough exposure (eCtrough). Intercycle variability was expressed as percentage coefficient of variation (%CV) using all available 200 mg Q3W cycles. Early irAEs were defined as events within 126 days.Associations between pop-PK metrics and irAEs (including pneumonitis) after switching were explored. Clinical correlates of %CV-eCmax were also assessed. RESULTS:79 patients switched, and pop-PK analysis was feasible in 66 patients. The median age was 70 years, 50 were male, and 62 had a smoking history. The median Q3W cycles were 6, and the median follow-up period after switching was 463 days. After switching, 45 events occurred new or worsened irAEs, with 19 pneumonitis, and 22 had early irAEs, with 13 early pneumonitis.Among the 64 patients who received ≥2 cycles of Q3W, those who developed irAEs after switching showed higher %CV-eCmax during Q3W. Similar associations were observed for early irAEs, pneumonitis, and early pneumonitis.%CV-eCtrough during Q3W was not associated with irAEs after switching, with an association observed only for early pneumonitis.High %CV-eCmax during Q3W was associated with increased odds of irAEs, pneumonitis, early irAEs, and early pneumonitis. No significant associations were observed between %CV-eCtrough and irAEs or early irAEs.Higher platelet count and renal dysfunction were independently associated with increased %CV-eCmax. CONCLUSIONS:High intercycle eCmax variability during 200 mg Q3W is associated with an increased risk of new or worsened irAEs, particularly pneumonitis, after switching to 400 mg Q6W, suggesting that intercycle variation in Cmax may be an important safety consideration when switching to 400 mg Q6W.

e20534 Background: De novo oncogenic amplification, including EGFR and MET represents a biologically relevant layer of genomic heterogeneity in EGFR -mutated non–small cell lung cancer (NSCLC) and may influence the clinical efficacy of first line (1L) osimertinib. However, the clinical significance of baseline de novo oncogenic amplification at treatment initiation remains incompletely understood. Methods: We retrospectively identified patients with advanced EGFR -mutated NSCLC who underwent The Oncomine Dx Target Test (DxTT) at National Cancer Center Hospital, Japan (Jan 2020–Aug 2025) and received 1L osimertinib. We reanalyzed the DxTT-generated BAM files using Ion Reporter Software v5.18 (NCCH Oncomine Focus v1.2 workflow). Copy number variants (CNV) amplification such as EGFR and MET was defined as a 5th-percentile estimated copy number ≥4 (≥2 copies above diploid) . PFS was assessed using the Kaplan–Meier method and the Cox proportional hazards model. Data cutoff: January 11, 2026. Results: A total of 109 patients were included in the study. The median age (range) was 66 years (30-86); 76 patients (69.7%) were female and 64 (58.7%) were never smokers. The primary EGFR mutation was ex19 del in 51 (46.8%) and L858R in 50 (45.9%). EGFR amplification was the most frequent (26/109, 23.9%), whereas other potentially actionable amplifications were uncommon, including FGFR1 (3/109, 2.8%), MET (2/109, 1.8%), and ERBB2 (2/109, 1.8%). Overall, PFS did not differ significantly by EGFR amplification status (median PFS [ EGFR amp+ vs. amp-]: 18.4 vs. 15.6 months; p=0.63). In subtype stratified analyses, EGFR amplification was associated with longer PFS in the ex19del subgroup but shorter PFS in the L858R subgroup. An adjusted Cox model showed a significant EGFR amplification-by-subtype interaction (p=0.031). The effect of EGFR amplification (amp+ vs. amp−) differed by subtype: ex19del HR 0.41 (95% CI, 0.16-1.04; p=0.061) versus L858R HR 1.72 (95% CI, 0.66-4.45; p=0.266). Among EGFR amplification positive patients, EGFR copy numbers (CN) were widely distributed (median 11.1; IQR 7.8-22.8; max 106.9), with CN 4-<10 in 42.3%, CN 10-<20 in 26.9%, and CN ≥20 in 30.8%. No clear difference in PFS was observed according to EGFR CN high vs. low as the cutoff 11.1 (HR, 0.75; 95% CI, 0.26–2.19; p = 0.60). In this EGFR amplification subgroup, 8 (30.8%) harbored co-occurring gene amplifications ( MYC [n=3]), and PFS did not differ significantly between EGFR amplification only and EGFR amplification plus other amplifications (median PFS, 13.1 months [95% CI, 8.8-NR] vs. 32.2 months [95% CI, 4.4-NR]; p=0.48). Conclusions: The prognostic association of de novo EGFR amplification with 1L osimertinib benefit appears to be dependent on EGFR subtype, which supports an interpretation and molecular stratification that integrates EGFR subtype and amplification status, beyond EGFR mutation status alone.

INTRODUCTION:Antibody-drug conjugates (ADCs) and bispecific antibodies (BiAbs) are emerging treatments for small cell lung cancer (SCLC). However, optimal patient selection remains unclear. Delta-like ligand 3 (DLL3) is a promising therapeutic target, but its clinical utility is not fully established, and data on other targetable proteins such as trophoblast cell-surface antigen 2 (TROP2) and B7-H3 remain limited. To our knowledge, no prior study has assessed multiple therapeutic targets within the same patient before and after treatment. This study examined changes in DLL3 and other targets in de novo and transformed SCLC. MATERIALS AND METHODS:We retrospectively analyzed 15 patients with SCLC (9 de novo and 6 transformed SCLC) with tumor biopsies at diagnosis and progression. Immunohistochemistry assessed DLL3, TROP2, B7-H3, MET, and HER2. H-score changes, with a ≥ 100-point difference considered significant. RESULTS:In de novo SCLC, DLL3 fluctuated in 3/9 cases, B7-H3 and MET increased in 2/9 and 1/9 cases, respectively, while HER2 became negative in 1/9 case. Protein co-expression was seen in 5 of 9 cases. In transformed SCLC, DLL3 expression increased in 6/6 cases, while TROP2 and HER2 were downregulated. B7-H3 and MET showed a decreasing trend in 4/5 cases. Co-expression was observed in 3/5 cases, all showing DLL3 and B7-H3 positivity, with additional co-expression of MDM2 or MET. CONCLUSION:Therapeutic target proteins in SCLC exhibit dynamic changes, emphasizing the need for biomarker-driven strategies. Rebiopsy may guide therapeutic decisions, and further research is needed to optimize patient selection for ADCs and BiAbs.

BACKGROUND:Sarcopenia is associated with poor outcomes of various cancers treated with immune checkpoint inhibitors. Durvalumab is the standard of care for patients with locally advanced (LA) non-small cell lung cancer (NSCLC) after chemoradiation therapy (CRT). However, the effect of sarcopenia on the efficacy and safety of durvalumab in patients with LA-NSCLC remains unclear. METHODS:This single-center retrospective study was conducted between 2018 and 2021. Body composition indices were measured using computed tomography scans taken at the third lumbar vertebra before and after CRT. The cutoff values were set based on the change ratios for each index before and after CRT. Tumor response, survival, and the efficacy and safety of durvalumab were compared between patients who showed skeletal muscle loss and those who did not. RESULTS:Among 153 eligible patients (median age: 65 years; 74.5% men), skeletal muscle index (SMI) significantly decreased during CRT. With the threshold set at a -10% change in SMI, no significant difference in objective response rate (ΔSMI ≤ -10% vs. ΔSMI > -10%: 76.6% vs. 75.7%, p = 1.000), progression-free survival (hazard ratio [HR], 0.99, p = 0.983), overall survival (HR 1.04, p = 0.909), or the frequency of immune-related adverse events (44.9% vs. 44.2%, p = 1.000) was observed between the two groups. CONCLUSIONS:Although muscle loss during CRT is common, it does not compromise the efficacy or safety of subsequent durvalumab therapy in patients with LA-NSCLC. Future studies are needed to delineate sarcopenia criteria specific to LA-NSCLC and assess interventions, including rehabilitation and pharmacotherapy.

Comprehensive genomic profiling (CGP) has progressed rapidly and plays an important role in advancing precision medicine in oncology. However, CGP provides opportunities for molecular-targeted therapy, but it also unveils incidental germline findings, posing challenges and opportunities in patient care. We present the case of a 32-year-old female patient, diagnosed with stage IVB lung adenocarcinoma harboring an EGFR p.L746_A750del, who was also subsequently diagnosed with Li-Fraumeni syndrome (LFS) through CGP testing. Remarkably, despite the presence of EGFR mutation, the response to EGFR-tyrosine kinase inhibitor was poor, whereas the response to cytotoxic anticancer drugs and immunotherapy was favorable. After the diagnosis of LFS, she underwent genetic counseling and has been screened for the development of a second cancer based on the Toronto protocol. This case highlights the importance of family history interviews and considering the practice of germline genomic testing for optimal management of lung cancer patients with a hereditary cancer syndrome such as LFS. Further research is warranted to delineate the impact of germline variants on treatment outcomes and secondary cancer prevention in lung cancer. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

TPS8664 Background: The additionof antiangiogenic agents to standard first-line treatment with a programmed cell death protein 1 (PD-1) inhibitor and platinum doublet chemotherapy has shown efficacy in patients with metastatic non–small cell lung cancer (NSCLC). Ivonescimab is a novel tetravalent bispecific antibody that targets PD-1 and vascular endothelial growth factor. In a phase 2 trial, ivonescimab plus chemotherapy showed objective response rates (ORRs) of 71.4% and 54.2% and median progression-free survival (PFS) of 11.1 and 13.3 months in patients with metastatic squamous (SQ) and nonsquamous (NSQ) NSCLC, respectively (1). Methods: The multiregional, randomized, double-blind, phase 3 HARMONi-3 trial (NCT05899608) will compare the efficacy and tolerability of ivonescimab plus chemotherapy with pembrolizumab plus chemotherapy as first-line treatment in patients with metastatic SQ or NSQ NSCLC who have not previously received systemic treatment for metastatic disease and whose tumors have no known actionable mutations for which approved first-line therapies are available. Patients will be randomly assigned (1:1) to receive ivonescimab 20 mg/kg every 3 weeks (Q3W) or pembrolizumab 200 mg Q3W combined with chemotherapy (paclitaxel or nab-paclitaxel plus carboplatin for SQ or pemetrexed plus carboplatin for NSQ) for up to 4 cycles, followed by maintenance with ivonescimab or pembrolizumab alone for SQ or in combination with pemetrexed for NSQ for up to 24 months. Randomization will be done in blocks by histology (SQ and NSQ) and stratified by sex (female vs male), age (<65 vs ≥65 y), geographic region (East Asia vs rest of world), presence or absence of liver or brain metastases at baseline, previous PD-1 or programmed death ligand 1 (PD-L1) inhibitor treatment >6 months before the development of metastatic disease (yes vs no), and PD-L1 tumor proportion score (≥1% or <1%). The dual primary end points are overall survival and PFS (assessed by investigators per RECIST v1.1). The secondary end points are ORR, disease control rate, duration of response, safety, pharmacokinetics, and immunogenicity. Patients are being recruited in Asia, Europe, and North America, with a target enrollment of 1080 patients (45-50% SQ and 50-55% NSQ). 1. Zhang L et al, ELCC 2024, FPN: 68P. Clinical trial information: NCT05899608 .

Previous studies have demonstrated that 10%-25% of patients receive gene-matched therapy (GMT) after comprehensive genomic profiling (CGP). However, its real-world clinical effects remain unclear. This study assessed the feasibility of integrating the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository that documented genomic and clinical data and the quality indicator (QI) dataset that included cancer-specific data and administered treatment as a model case of real-world data study of cancer genomic medicine in Japan. We successfully integrated these two datasets and included 1162 patients diagnosed with solid tumors at the National Cancer Center Hospital between 2019 and 2021 who underwent CGP testing. Of these, 432 (37.2%) had druggable mutations, 96 (8.3%) received GMT, and 218 (18.8%) received non-GMT. Among 314 patients who initiated either GMT or non-GMT after CGP, the median 2-year overall survival (OS) was 19.0 and 19.7 months for GMT and non-GMT, respectively (hazard ratio: 0.87, 95% confidence interval: 0.56-1.35, p = 0.53). Stratified analysis by prior treatment lines (0-1 vs. ≥ 2) demonstrated no significant differences in survival. Sensitivity analyses yielded consistent results. This study demonstrated that integrating the C-CAT repository and QI datasets enables real-world comparisons of GMT and non-GMT outcomes. Unlike previous clinical trials reporting enhanced survival with GMT, our findings indicated no significant OS difference. Potential explanations include differences in cancer type, CGP timing, study population selection, and immortal time bias. Future multicenter studies would clarify the real-world utility of the CGP and GMT.

INTRODUCTION:Thymic epithelial tumors are rare cancers originating from the thymus, with an annual incidence of 0.13 per 100,000 persons. Therefore, the standard of care was approved primarily based on the results of single-arm phase II trials. If the disease is resectable and localized, a multidisciplinary treatment combining surgical resection, radiotherapy, and pharmacotherapy should be considered. Pharmacotherapy is the mainstay of treatment for metastatic and recurrent diseases. AREAS COVERED:This review delineates the distinct difference in treatment strategies of chemotherapy in patients with thymomas and thymic carcinomas. Thymomas typically respond to a cisplatin and anthracyclines, often supplemented with steroids, whereas thymic carcinomas, which do not typically involve anthracyclines as key drugs, are treated with platinum-based doublet chemotherapy. Lenvatinib has emerged as a pivotal key drug for refractory thymic carcinoma. In addition, single-agent cytotoxic chemotherapy, molecular targeted therapies, and immune checkpoint inhibitors is considered as key drugs for thymic carcinomas. EXPERT OPINION:Current research is focused on developing novel therapeutics such as antibody-drug conjugates (ADCs), angiogenesis inhibitors, multi-kinase inhibitors, and further immune checkpoint inhibitors, expanding the prospects for pharmacotherapy in thymic malignancies.