Shorter Median Progression-free Survival Research Articles

Serum mass spectrometry for treatment monitoring in patients with multiple myeloma receiving ARI0002h CAR T-cells.

Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM.

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination

BackgroundKRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions.MethodsCell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model.ResultsOur research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression.ConclusionsWe posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

Analysis of clinical characteristics and prognosis of lung cancer patients with CPFE or COPD: a retrospective study

BackgroundLung cancer (LC) commonly occurs in patients with combined pulmonary fibrosis and emphysema (CPFE) and chronic obstructive pulmonary disease (COPD), but comparative research is limited. This study examines clinical characteristics, treatments, and prognosis in LC patients with CPFE or COPD.MethodsThe retrospective study involved 75 lung cancer patients with CPFE and 182 with COPD. It analyzed clinical features, tumor pathology, pulmonary function, laboratory parameters, and treatment responses.ResultsNotable differences were found between the CPFE + LC and COPD + LC groups. Both groups were mostly elderly, male smokers. The CPFE + LC group had higher BMI and more adenocarcinoma and squamous cell carcinoma, while COPD + LC had predominantly squamous cell carcinoma. CPFE + LC tumors were mostly in the lower lobes; COPD + LC’s were in the upper lobes. The CPFE + LC group showed higher tumor metastasis rates, more paraseptal emphysema, and elevated levels of TG, CEA, NSE, and Killer T Cells. In advanced stages (IIIB-IV), the CPFE + LC group receiving first-line treatment had shorter median progression-free survival (PFS) and a higher risk of progression or death than the COPD + LC group, regardless of whether it was non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). No significant PFS difference was found within CPFE + LC between chemotherapy and immunotherapy, nor in immune-related adverse events between groups, with interstitial pneumonia being common.ConclusionThis study emphasizes distinct lung cancer characteristics in CPFE or COPD patients, highlighting the need for tailored diagnostic and treatment approaches. It advocates for further research to improve care for this high-risk group.

Real-world treatment patterns and outcomes in US patients (pts) with advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy (PBC) and anti–PD-(L)1 treatment.

8627 Background: Effective treatment options for advanced or metastatic NSCLC are limited, especially for pts who progress after treatment with PBC and an anti–programmed cell death 1 protein (PD-1) or ligand 1 (PD-L1) regimen. Examining real-world treatment patterns and long-term outcomes, we report on progression-free survival (PFS) and overall survival (OS) in pts with NSCLC who previously received PBC and anti–PD-(L)1 regimens. Methods: This study used the nationwide Flatiron Health electronic health record–derived deidentified database. Pts included in the analysis were ≥18 years old with an initial diagnosis of advanced or metastatic NSCLC and an ECOG PS of 0 or 1 who had received prior PBC and anti–PD-(L)1 therapy in 1 (in combination) or 2 (in sequence) lines and had initiated ≥1 subsequent line of treatment between 2018 and 2023; the start date of subsequent treatment (defined as the index regimen) was the index date. Pts were followed up until death or last available data through Mar 31, 2023. Pt characteristics, treatment patterns, and outcomes were analyzed for the overall pt group and according to initial treatment cohort (cohort 1: first-line [1L] PBC plus anti–PD-(L)1; cohort 2a: 1L PBC and second-line [2L] anti–PD-(L)1; or cohort 2b: 1L anti-PD-(L)1 and 2L PBC). PFS and OS were estimated using Kaplan-Meier methods. Results: Of 1793 pts, most were in cohort 1 (73.5%), with fewer pts in cohorts 2a (22.5%) and 2b (4.1%). The majority of pts in cohort 2b had PD-L1 ≥50% (n = 57, 78.1%), while the percentage was lower in cohorts 1 (n = 262, 19.9%) and 2a (n = 72, 17.9%). Most pts (n = 1626, 90.7%) had stage IV disease. Median time from advanced diagnosis to index date was 10.5 months (range, 1.1-103.8); median follow-up from index date was 7.8 months (range, 0.0-65.0). A broad range of treatments were used after PBC and anti–PD-(L)1 regimens; among all pts, the most common were docetaxel + ramucirumab and docetaxel monotherapy. Among all pts, median PFS and OS from the time of starting these index regimens were 5.29 and 11.20 months, respectively; PFS and OS were similar across cohorts. Conclusions: A broad range of subsequent treatments were used following PBC and anti–PD-(L)1 regimens, most commonly docetaxel with or without ramucirumab. Short median PFS and OS underscore a significant unmet need among pts previously treated with PBC and anti–PD-(L)1. [Table: see text]

TTF-1 negativity as a biomarker of outcomes to immunotherapy, chemoimmunotherapy, and KRAS G12C inhibitors in lung adenocarcinoma.

8608 Background: Thyroid transcription factor 1 (TTF-1) expression is routinely assessed in lung adenocarcinomas (LUAD) and is negative (TTF-1Neg) in 15-20% of cases. Whether these tumors differ from LUAD expressing TTF-1 (TTF-1Pos) in terms of biologic features and outcomes is unclear. Methods: Patients (pts) with LUAD and available TTF-1 expression by IHC at five institutions were included. Clinicopathologic, genomic, and outcomes data were compared according to TTF-1 expression. Results: Among 3,315 pts with LUAD, TTF-1 was negative in 15% (N=499). Compared to TTF-1Pos (N=2,816), pts with TTF-1Neg LUAD were more likely male (44% vs 38%, P=0.01), smokers (82% vs 74%, P<0.001), with stage IV disease at diagnosis (76% vs 71%, P<0.001), and lower median PD-L1 tumor proportion score (TPS, 1% vs 10%, P<0.001). At stage IV diagnosis, TTF-1Neg cases less commonly had brain metastasis than TTF-1Pos cases (35% vs 44%, P=0.04), but more frequently had bone metastasis (53% vs 45%, P=0.03). TTF-1Neg LUAD was enriched for KRAS, STK11, KEAP1, SMARCA4, and CDKN2A mutations (q<0.05), while TTF-1Pos LUAD was enriched for EGFR and MET mutations (q<0.05). Compared to TTF-1Pos LUAD, TTF-1Neg LUAD had higher prevalence of KRAS G12D (12% vs 4%, P<0.001) and G12V mutations (11% vs 7%, P=0.001), but similar frequency of G12C mutations (14% vs 15%, P=0.82). The association between TTF-1 and treatment outcomes was next investigated. Pts with stage III unresectable TTF-1Neg LUAD who received durvalumab after chemo-radiation (N=20), compared to TTF-1Pos cases (N=174), had shorter median progression-free survival (mPFS, 7.6 vs 24.7 months, P=0.01) and overall survival (mOS, 22.7 months vs not reached, P=0.01). Among pts with stage IV LUAD, TTF-1Neg cases treated with immune checkpoint inhibitors (N=237), compared to TTF-1Pos (N=1,161), had worse objective response rate (ORR, 17% vs 28%, P<0.001), mPFS (2.5 vs 4.7 months, P<0.001) and mOS (9.8 vs 20.9 months, P<0.001). Similarly, pts with TTF-1Neg LUAD (N=297) treated with chemoimmunotherapy, compared to TTF-1Pos cases (N=920), had worse ORR (27% vs 42%, P<0.001), mPFS (4.6 vs 8.1 months, P<0.001) and mOS (11.2 vs 23.4 months, P<0.001). TTF-1 negativity retained its association with worse outcomes after adjusting for treatment line, ECOG performance status, smoking status, PD-L1 TPS, STK11/ KEAP1 mutation status in multivariable cox regression models. Lastly, pts with KRAS G12C mutated TTF-1Neg LUAD treated with KRAS inhibitors (N=25), compared to TTF-1Pos (N=138), had worse ORR (12% vs 35%, P=0.03), mPFS (2.7 vs 5.9 months, P<0.001), and mOS (4.4 vs 12.1 months, P<0.001). After excluding mucinous LUAD cases, which are more commonly TTF-1Neg, similar results were observed. Conclusions: TTF-1 negativity identifies a unique clinicopathologic and genomic subset of LUAD with worse outcomes to diverse systemic therapies.

Prognostic Value of Prothrombin Time and Activated Partial Thromboplastin Time in Newly Diagnosed Patients with Multiple Myeloma

To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma (MM). The clinical data of 116 newly diagnosed MM patients in the Second Hospital and Third Hospital of Shanxi Medical University from October 2014 to March 2022 were analyzed retrospectively, and the patients were divided into two groups: normal PT and APTT group and prolonged PT or APTT group. The differences in sex, age, classification, staging, bleeding events, laboratory indicators [including hemoglobin (Hb), platelet count (PLT), serum calcium, serum albumin (ALB), lactate dehydrogenase (LDH), serum creatinine and β2-microglobulin], and cytogenetic characteristics between the two groups of patients were compared. The effect of prolonged PT or APTT on survival of patients with MM was analyzed. Compared with patients in normal PT and APTT group, patients in prolonged PT or APTT group were more likely to experience bleeding events (χ2=5.087, P =0.024), with lower ALB levels (χ2=4.962, P =0.026) and PLT levels (χ2=4.309, P =0.038), and higher serum calcium levels (χ2=5.056, P =0.025). The positive rates of del17p, del13q and 1q21+ in prolonged PT or APTT group were higher than those in normal PT and APTT group, but the difference was not statistically significant (P >0.05). K-M survival analysis showed that the prolonged PT or APTT group had a shorter median progression-free survival (PFS) (P =0.032) and overall survival (OS) (P =0.032). Multivariate Cox analysis showed that prolonged PT or APTT (HR=2.116, 95%CI :1.025-4.372, P =0.043) and age ≥65 years (HR=2.403, 95%CI : 1.195-4.836, P =0.014) were independent risk factor for OS in newly diagnosed MM patients. However, prolonged PT or APTT had no significant effect on PFS of newly diagnosed MM patients (HR=1.162, 95%CI : 0.666-2.026, P =0.597). Newly diagnosed MM patients with prolonged PT or APTT have worse clinical indicators, shorter PFS and OS. Prolonged PT or APTT is an independent risk factor for OS in MM patients.

Portal hypertension is associated with poorer outcome and clinical liver decompensation in patients with HCC treated with Atezolizumab-Bevacizumab

BackgroundPortal hypertension (PHT) often complicates hepatocellular carcinoma (HCC) treatment and prognosis. We aimed to assess PHT's impact on AtezoBev outcomes and identify predictors of acute variceal bleeding (AVB) and clinical ascites occurrence. MethodsA prospective cohort of 200 HCC patients treated with AtezoBev was studied alongside a retrospective cohort of 123 patients treated with Sorafenib. We assessed factors influencing progression-free survival (PFS), overall survival (OS), AVB and clinical ascites development, focusing on PHT parameters, and comparing outcomes within and between the two cohorts (time-dependent Cox model and adjusted survival curves). ResultsAmong the AtezoBev cohort, 10% experienced AVB, 24% had high-risk esophageal varices (EV) and 46% vascular invasion. Median PFS and OS in the AtezoBev cohort was 5.13 and 12.2 months. AVB (HR=1.81;[95%CI:1.03–3.17]) and clinical ascites occurrence (HR=2.29;[95%CI:1.52–3.45]) were independently associated with mortality. AVB incidence was 12% at 12 months in AtezoBev patients and EV, history of AVB<6months and vascular invasion were independently associated with AVB. The Sorafenib cohort had shorter median PFS and OS, with similar AVB incidence and only EV were associated with AVB. ConclusionsPHT-related events significantly affect not only liver decompensation but also OS in AtezoBev-treated patients. We suggest a more widespread use of NSBB to prevent liver decompensation, with intensified prophylaxis for high-risk patients.

Prognostic value of circulating tumor cells combined with neutrophil-lymphocyte ratio in patients with hepatocellular carcinoma.

Circulating tumor cell (CTC) count and neutrophil-to-lymphocyte ratio (NLR) are both closely associated with the prognosis of hepatocellular carcinoma (HCC). To investigate the prognostic value of combining these two indicators in HCC. Clinical data were collected from patients with advanced HCC who received immune therapy combined with targeted therapy at the Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan, China, from 2021 to 2023. The optimal cutoff values for CTC programmed death-ligand 1 (PD-L1) (+) > 1 or CTC PD-L1 (+) ≤ 1 and NLR > 3.89 or NLR ≤ 3.89 were evaluated using X-Tile software. Patients were categorized into three groups based on CTC PD-L1 (+) counts and NLR: CTC-NLR (0), CTC-NLR (1), and CTC-NLR (2). The relationship between CTC-NLR and clinical variables as well as survival rates was assessed. Patients with high CTC PD-L1 (+) expression or NLR at baseline had shorter median progression-free survival (mPFS) and median overall survival (mOS) than those with low levels of CTC PD-L1 (+) or NLR (P < 0.001). Meanwhile, patients in the CTC-NLR (2) group showed a significant decrease in mPFS and mOS. Cox regression analysis revealed that alpha-fetoprotein (AFP), CTC PD-L1 (+), and CTC-NLR were independent predictors of OS. The time-dependent receiver operating characteristic curve showed that the area under the curve of CTC-NLR at 12 months (0.821) and 18 months (0.821) was superior to that of AFP and CTC PD-L1 (+). HCC patients with high CTC PD-L1 (+) or NLR expression tend to exhibit poor prognosis, and a high baseline CTC-NLR score may indicate low survival. CTC-NLR may serve as an effective prognostic indicator for patients with advanced HCC receiving immunotherapy combined with targeted therapy.

Associations between BMI, morphomics and survival in 528 patients with metastatic pancreatic cancer.

637 Background: Literature describing associations between patient body mass index (BMI) and survival in pancreatic ductal adenocarcinoma (PDA) remains inconsistent. This heterogeneity may be due to studies using pre-diagnosis BMI and including few metastatic patients despite high prevalence at diagnosis. Furthermore, BMI may not adequately reflect other body compositions such as those reflected via morphomic variables (subcutaneous fat, visceral fat, muscle, and fascia) that may have unique associations with survival. In this study, we sought to explore the relationships between detailed body composition in patients with metastatic PDA on both overall survival (OS) and progression-free survival (PFS). Methods: We evaluated data and scans from a phase 3 clinical trial in which 528 patients with metastatic PDA with no prior chemotherapy were randomized to either FOLFIRINOX or modified FOLFIRINOX plus devimistat. No differences in response rate, median PFS or OS were observed. Of the 528 enrolled patients, 377 had baseline CT scans eligible for morphomic evaluation for which Analytic Morphomics was used to measure body composition. For analysis, morphomic variables were summed across the T10-T12 and L1-L4 vertebrae and then divided into tertiles. BMI at diagnosis was evaluated in tertiles and per WHO standards. Cox proportional hazards models and cubic splines were used to evaluate associations between BMI, morphomic variables and PFS, OS. Univariate and multivariate models were evaluated. Kaplan-Meier plots were created to evaluate median survival times between those in the highest and lowest tertiles (R v4.3.1). Results: We did not observe an association between BMI and PDA patient survival: HR (95% CI) comparing BMI ≥30 (obese) to 18.5-24.9 (healthy weight), PFS 0.96 (0.66, 1.39), p-trend=0.80; OS 0.87 (0.64, 1.18), p-trend=0.30. However, multiple morphomic variables were significantly associated with PFS and/or OS in univariate and multivariate models when comparing the highest to lowest tertile. More subcutaneous fat was associated with longer median OS (12.4 vs 10.5 mos, p=0.006; HR (95% CI) 0.41 (0.25-0.68), p-trend=0.001). More dense visceral fat was associated with shorter median PFS (6.0 vs 9.1 mos, p=0.05, HR (95% CI) 1.52 (1.00-2.33), p-trend=0.047). A higher muscle to fascia ratio was associated with longer PFS (9.3 vs 6.5 mos, p=0.03; HR (95% CI) 0.58 (0.38-0.88), p-trend=0.01) and median OS (13.9 vs 10 mos, p=0.005; HR (95% CI) 0.53 (0.38-0.76), p-trend=0.0004). Conclusions: BMI was not associated with PFS or OS in this large prospective study of patients with metastatic PDA receiving chemotherapy. However, morphomic variables including subcutaneous fat area, visceral fat density, and the muscle to fascia ratio were statistically significantly associated with metastatic PDA patient survival.

Clinical characteristics and prognosis of newly diagnosed multiple myeloma patients with FGFR3 gene mutations

Objective: This study aimed to investigate the influence of FGFR3 gene mutations on the clinical characteristics and prognosis of patients with newly diagnosed multiple myeloma (NDMM) . Methods: A total of 198 patients with NDMM admitted to the Department of Hematology in Jiangsu Province Hospital between January 2016 and February 2023 were retrospectively analyzed. Next-generation sequencing and cytoplasmic light chain immunofluorescence with fluorescence in situ hybridization were performed for all patients. The prognostic significance of FGFR3 mutation and clinical features were analyzed using the Log-rank test and Cox proportional hazards model. Results: Among 198 patients, 28 carried the FGFR3 gene mutation. These patients had significantly lower serum albumin levels, higher β(2)-microglobulin levels, advanced Revised International Staging System stages, more frequent occurrence of t (4;14) , and shorter median progression-free survival (PFS) time (28 months vs 33 months, P=0.024) and overall survival (OS) time (54 months vs undefined, P=0.028) than patients without FGFR3 mutation. Additionally, patients carrying either FGFR3 mutation or t (4;14) had lower PFS (30 months vs 38 months, P=0.012) and OS (54 months vs undefined, P=0.017) than those without. The Cox proportional hazards model identified FGFR3 mutation as an independent risk factor for PFS and OS. Conclusion: FGFR3 gene mutation was an unfavorable independent prognostic predictor for NDMM.

Abstract B126: Co-clinical trial of novel bispecific anti-HER2 antibody Zanidatamab in Patient-Derived Xenografts

Abstract Background: Zanidatamab is a bispecific HER2-targeted antibody in clinical development which has demonstrated antitumor activity in a broad range of HER2 amplified/expressing solid tumors. We report the antitumor activity of zanidatamab in vivo by utilizing patient-derived xenograft (PDX) models developed from pre-treatment or post-progression biopsies from the first-in-human zanidatamab phase I study (NCT02892123). Methods: PDXs were established by implanting 1-2 core biopsies from HER2 expressing tumors into immunodeficient mice. The PDXs that developed were expanded and treated with zanidatamab monotherapy or novel combinations targeting co-alterations and the relevant treatment controls. PDXs models were also characterized by DNA and RNA sequencing, HER2 IHC, and reverse phase protein arrays (RPPA). Antitumor activity in patients was assessed by RECIST1.1. Antitumor activity in PDXs was assessed by change in tumor volume from baseline, objective response, and event-free survival defined as time to tumor volume doubling (EFS-2). Results: From the thirty-six patient tumors implanted, 19 PDX models were established (52.7% take rate) from 17 individual patients. Established PDXs represented a broad range of HER2-expressing cancers; however, a higher take-rate was observed in gastrointestinal (GI) tumors (64.0%) compared to non-GI tumors (27.3%). Patients whose biopsies grew as PDXs had shorter median progression-free survival (PFS) and overall survival (OS) than patients whose biopsies did not grow as PDXs (PFS: 58 days vs 112 days; OS: 92 days vs. 574 days). PDXs were developed from patients with a range of objective responses to zanidatamab. In vivo testing in PDXs demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab in 2 of 4 post-progression PDXs and demonstrated that MET inhibitors have single agent activity and enhance zanidatamab activity in vitro and in vivo in a post- zanidatamab progression model. Conclusions: Our findings provide evidence that PDXs can be developed from pre-treatment biopsies in clinical trials and may provide insight into mechanisms of resistance. Citation Format: Timothy P DiPeri, Kurt W Evans, Bailiang Wang, Ming Zhao, Argun Akcakanat, Maria Gabriela Raso, Yasmeen Q Rizvi, Xiaofeng Zheng, Anil Korkut, Kaushik Varadarajan, Burak Uzunparmak, Ecaterina E Dumbrava, Shubham Pant, Jaffer A Ajani, Paula Pohlmann, V Behrana Jensen, Milind Javle, Jordi Rodon, Funda Meric-Bernstam. Co-clinical trial of novel bispecific anti-HER2 antibody Zanidatamab in Patient-Derived Xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B126.

Anti-PD-1 Antibody Sintilimab in Combination with Anlotinib and Pegaspargase As a Highly Effective Salvage Regimen for the Treatment of Relapsed or Refractory Natural Killer /T-Cell Lymphoma

Natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive neoplasm associated with Epstein-Barr virus (EBV) infection. When patients experience relapse or disease progression after initial treatment, options for salvage therapy are limited. Targeting the PD-1/PD-L1 pathway has emerged as a highly potent treatment approach for NKTCL. However, the overall response rate (ORR) and complete response (CR) rate were limited with a short median progression-free survival (PFS) of 2.7 months. Therefore, improving the efficacy of immune checkpoint inhibitors is a critical clinical concern. In this study, we reported the efficacy and safety of a novel triplet regimen called LEAP, which combines PD-1 blockade (sintilimab 200mg on day 1), pegaspargase (2500U/m2 capped at 3750U on day 1), and angiogenesis inhibitor anlotinib (8mg on day 1-14), as a salvage treatment for relapsed/refractory (R/R) NKTCL. From March 2019 to May 2020, a total of 33 patients with R/R NKTCL were included in this study. The median age of patients was 48 years (range: 18-76), with 75.8% being male. At study entry, 88% of patients had stage IV disease, while 4 patients had stage II disease, with a history of primary refractory response to radiotherapy and L-asparaginase-based combination therapy. Moreover, 69.7% of patients had refractory disease, including those who were progressive or non-responsive to L-asparaginase-based regimens. Additionally, 10 patients experienced relapse or disease progression within 6 months after prior L-asparaginase-based therapy, and 10 patients had a history of PD-1/PD-L1 blockade monotherapy. A total of 221 cycles of the LEAP regimen were administered to these patients. The median number of cycles was 8 (range: 2-8). All patients reported at least one or more adverse events (AE). Hematological toxicities were mild, with no grade 3/4 neutropenia, anemia, or thrombocytopenia observed. Non-hematological AEs were common, and the most frequent (&amp;gt;20%) included hypofibrinogenemia (66.7%), hyperbilirubinemia (57.5%), APTT prolongation (54.5%), ALT elevation (54.5%), AST elevation (51.5%), hypoalbuminemia (48.5%), appetite loss (60.6%), nausea (57.5%), fatigue (57.5%), weight loss (42.4%), and edema (27.3%). These adverse events were typically attributed to pegaspargase. Other adverse events such as hyponatremia (24.2%), hypertriglyceridemia (21.2%), hyperglycemia (21.2%), hypothyroidism (30.3%), hypertension (24.2%), fever (39.4%), and dysphonia (21.2%) were most likely due to sintilimab or anlotinib. Most adverse events were manageable with supportive care. Among the 33 patients, the ORR was 81.8%, and CR was 45.5. The progression-free survival (PFS) rate at 1-year was 54.6% (95% CI, 36.3% to 70.0%), and at 2 years, it was 44.2% (95% CI, 26.6% to 60.4%). The median PFS time was 21.7 months. The overall survival (OS) rate at 1-year was 66.7% (95% CI, 47.9% to 80.0%), and at 2 years, it was 51.5% (95% CI, 33.5% to 66.9%). The median OS time was not reached during the study period. In conclusion, our study demonstrates that the LEAP regimen has a favorable safety profile, and is highly effective as a salvage treatment for patients with relapsed and refractory NKTCL.

Efficacy and Safety of Axicabtagene Ciloleucel (Axi-cel) for the Treatment of Relapse/Refractory Non-Hodgkin Lymphoma: Real-World Data in Chinese Population

Background: Autologous CD-19 directed chimeric antigen receptor (CAR) T-cell therapy has become the standard of care of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who have received two or more prior lines of therapy. In June 2021, Axi-cel was approved by the China National Medical Products Administration (NMPA) for the treatment of these patients as the first commercial CAR-T product in China. To better understand the efficacy and safety of commercial Axi-cel in Chinese R/R NHL patients in a real-world setting, we conducted this multi-center, non-interventional study (ChiCTR2100047990). The accrual goal is 200 patients, and the primary endpoint is mOS. Here we made the pre-specific interim analysis and the reported the clinical outcomes. Methods: We included R/R NHL patients treated with commercial Axi-cel at 17 authorized treatment centers from November 2021 to February 2023. All the patients signed written informed consent. We reported best objective response rate (bORR), best complete response (bCR) rate and adverse events of special interest (AESI), including cytokine release syndrome (CRS) and neurological events (NE). Results: To the cut-off date of June 8, 2023, a total of 101 R/R NHL patients had undergone efficacy evaluation at month 3. The median age of patients was 56.5 (22, 80) years, with 23 patients (22.8%) aged 65 years or older. Fifty-nine patients were male. The baseline characteristics of these patients included 81 (80.2%) with diffuse large B-cell lymphoma, 4 (4.0%) with primary mediastinal B-cell lymphoma, and 7 (6.9%) with high-grade B-cell lymphoma. More than 50% of patients had an International Prognostic Index (IPI) score ≥3. The median number of prior treatment was 2. Thirty-eight patients (37.6%) had received 3 or more previous therapies and 10 patients (9.9%) had undergone autologous stem cell transplantation (ASCT). The primary refractory subgroup reached 46 (45.5%), and 41(40.6%) patients were refractory to second-line or subsequent therapy. Notably, compared to the baseline characteristics of Axi-cel real-world studies for R/R LBCL in other countries, a greater proportion of Chinese patients had an ECOG PS score ≥2 (32.7%), HBsAg (+) with normal HBV-DNA (23.1%), HBsAg (-) accompany with HBcAb (+) (37.1%). Bridging therapy was given in 73 patients (72.3%), while combination anti-lymphoma therapy was used after Axi-cel infusion and before disease progression in 52 patients (51.5%). The median follow-up was 12.7 months. The bORR and bCR rate was 83.2% (95%CI, 74.4 - 89.9) and 63.4% (95%CI, 53.2 - 72.7), respectively (Fig 1). The bORR was consistent across covariates including disease type, cell of origin and refractory subgroup, ECOG PS score ≥2, HBsAg (+) and normal HBV-DNA, and HBsAg (-) accompany with HBcAb (+), etc.. The median duration of response (DOR) was 13.7 months (95% CI, 11.1 - NA). mDOR was not reached in bCR patients (95% CI, 11.2 - NA), while patients with best response as PR have a median DOR as 4.7 months (95% CI, 1.8- 6.7). Median progression-free survival (PFS) was 14.6 months (95% CI, 7.6 - NA). Patients with ECOG PS score ≥2 had a shorter median PFS [7.6 months (95%CI 3.0 - NA)] compared to patients with PS 0-1 [14.6 months (95%CI 12.1 - NA)]. Median PFS also differed among patients based on their response at month 3. Patients with CR/PR/non-response at month3 had a median PFS of NR (95% CI, 12.1 - NA), NR (95%CI, 6.1 - NA) and 3.0 months (95%CI, 2.4 - 3.3), respectively (Fig 2). The median OS was not reached, and the estimated OS at 12 months was 80.4% (95%CI, 70.5 - 87.2). No new safety signals were observed in the Chinese population. The most common adverse events of grade ≥3 were decreased white blood cell count (82.2% of patients), neutropenia (81.3%) and lymphocytopenia (68.2%). CRS of any grade occurred in 90 patients (84.1%), with 15 patients (14.0%) experiencing grade ≥3. NE of any grade occurred in 27 patients (25.2%), with only 1 patient (0.9%) experiencing grade 4. No grade 5 CRS or NE appeared. Conclusions: This pre-specific interim analysis demonstrated the consistent efficacy of Axi-cel in Chinese R/R NHL patients, while NE of any grade and ≥grade 3 were lower. Similar to the result of the ZUMA-1 study, response at month 3 may predict PFS in Chinese R/R NHL patients treated with Axi-cel in real-world practice.

Outcomes of Patients with Extramedullary Disease in Triple-Class Exposed Relapsed/Refractory Multiple Myeloma from the LocoMMotion + MoMMent Studies

Introduction: Patients (pts) with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM) represent a particularly difficult-to-treat population. A pooled analysis of the prospective, non-interventional, multinational LocoMMotion (NCT04035226) and MoMMent (NCT05160584) studies previously demonstrated suboptimal outcomes in pts with TCE RRMM. Extramedullary disease (EMD) is an aggressive feature of multiple myeloma characterized by the presence of plasmacytomas that have spread beyond the bone marrow. A recent systematic literature review (Bladé et al, 2022) found that the prognosis of pts with EMD is poor, as most current treatment (tx) options are notably less efficacious in pts with EMD than in those without EMD. The review also found that there are few prospective studies evaluating tx approaches in pts with EMD. Additional prospective data are needed to better understand current txs and outcomes for pts with EMD. In this analysis, we describe current txs and outcomes in pts with TCE RRMM with EMD over the past 3 years in LocoMMotion and MoMMent. Methods: Data were pooled from LocoMMotion (median follow-up [mFU], 26.4 months [mo; range, 0.1-35.0]; enrolled Aug 2019-Oct 2020; N=248) and MoMMent (mFU, 9.3 mo [range, 0.4-15.3]; enrolled Nov 2021-Jul 2022; N=54). Both studies have similar designs; eligible pts received ≥3 prior lines of therapy (LOT; LocoMMotion allowed &amp;lt;3 prior LOT if pts were double refractory to a proteasome inhibitor and immunomodulatory drug), were TCE, had measurable disease and documented progressive disease since their last LOT, and had an ECOG performance status (PS) of 0 or 1 at screening. EMD was defined as extramedullary plasmacytoma reported by the investigator. The assessment of plasmacytoma was not mandated but, per protocol, it was anticipated that extramedullary plasmacytomas would be prospectively assessed by clinical examination or radiologic imaging at baseline (BL) for all pts with a history of plasmacytomas, or if clinically indicated prior to the first dose of standard-of-care (SOC) therapy. If an assessment was not performed, the pt was considered not to have BL plasmacytoma. Responses were evaluated per IMWG criteria by a response review committee. A Cox proportional hazards model and Kaplan-Meier methodology were used to estimate medians, 95% CIs, and survival curves (unadjusted and adjusted for potential confounders) for progression-free survival (PFS) and overall survival (OS). Results: The pooled analysis included 302 pts with mFU of 24.3 mo (95% CI, 21.0-25.6; data cut-off, Oct 27, 2022 [LocoMMotion], Mar 13, 2023 [MoMMent]). 30 pts had EMD at BL and 272 did not. Anatomical locations of plasmacytomas in these pts included vertebra, liver, pelvis, skin, and lymph nodes, suggesting a mix of purely extramedullary (harder to treat) and bone-related plasmacytomas. Duration of study follow-up was similar for pts with EMD (26.5 mo [95% CI 17.3-31.9]) and those without (24.3 mo [95% CI 20.3-25.6]). BL demographics and disease characteristics were generally comparable, with ≥10% difference in ISS stage III, LDH &amp;gt;245 U/L, and ECOG PS of 1 observed in pts with EMD. A greater proportion of pts with EMD than those without EMD were penta-drug exposed (56.7% vs 45.2%) and had received prior autologous stem cell transplant (76.7% vs 62.5%). Pts with EMD received 21 unique SOC tx regimens, primarily chemotherapy based (Table). The ORR was lower for pts who had EMD vs those who did not (7/30; 23.3% [95% CI 9.9-42.3] vs 89/272; 32.7% [27.2-38.6]). Pts with EMD also had a shorter median PFS (2.3 mo [95% CI 1.6-4.4] vs 5.1 mo [4.4-6.0]) and median OS (7.2 mo [95% CI 5.4-18.6] vs 15.1 mo [12.0-18.5]) compared with those without EMD (Figure). The adjusted survival curves have similar patterns to the unadjusted. Among the 30 pts with EMD, there were 23 and 21 PFS and OS events, respectively; conclusions based on time-to-event data should therefore be interpreted with caution due to a small sample size. Conclusions: These results indicate that there is a significant unmet medical need for better tx options in this population of pts with TCE RRMM, specifically in pts with EMD. This need is illustrated by the poor outcomes observed with existing txs and the absence of an effective established SOC for this condition. Conducting clinical trials with innovative therapies, using clearly defined criteria for EMD, is essential to address the unmet medical needs of these pts.

The prognostic power of [11C]methionine PET in IDH-wildtype diffuse gliomas with lower-grade histological features: venturing beyond WHO classification.

IDH-wildtype (IDH-wt) diffuse gliomas with histological features of lower-grade gliomas (LGGs) are rare and heterogeneous primary brain tumours. [11C]Methionine (MET) positron emission tomography (PET) is commonly used to evaluate glial neoplasms at diagnosis. The present study aimed to assess the prognostic value of MET PET in newly diagnosed, treatment naïve IDH-wt gliomas with histological features of LGGs. Patients with a histological diagnosis of IDH-wt LGG who underwent preoperative (< 100days) MET PET/CT and surgery were retrospectively included. Qualitative and semi-quantitative analyses of MET PET images were performed. Progression-free survival (PFS) and overall survival (OS) were analysed by Kaplan-Meier curves. Cox proportional-hazards regression was used to test the association of imaging and clinical data to PFS and OS. We included 48 patients (M:F = 25:23; median age 55). 39 lesions were positive and 9 negative at MET PET. Positive MET PET was significantly associated with shorter median PFS (15.7months vs. not reached, p = 0.0146) and OS time (32.6months vs. not reached, p = 0.0253). Incomplete surgical resection and higher TBRmean values were independent predictors of shorter PFS on multivariate analysis (p < 0.001 for both). Higher tumour grade and incomplete surgical resection were independent predictors of OS at multivariate analysis (p = 0.027 and p = 0.01, respectively). MET PET is useful for the prognostic stratification of patients with IDH-wt glial neoplasms with histological LGGs features. Considering their huge biological heterogeneity, the combination of MET PET and molecular analyses may help to improve the prognostic accuracy in these diffuse gliomas subset and influence therapeutic choices accordingly.

Impact of Concurrent Genomic Alterations on Clinical Outcomes in Patients With ALK-Rearranged NSCLC

IntroductionALK tyrosine kinase inhibitors have exhibited promising activity against advanced ALK-rearranged NSCLC. However, co-occurring genetic alterations, such as CDKN2A/B or TP53, may negatively affect the efficacy of targeted therapies. MethodsFrom December 2017 to December 2022, this study cohort analyzed next-generation sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin American cancer centers. Clinicopathologic and molecular features were associated with clinical outcomes and risk of brain metastasis (BrM) in patients with and without concurrent somatic alterations. ResultsAll patients (N = 116) received a second-generation ALK tyrosine kinase inhibitor, and alectinib was selected in 87.2% of cases. Coalterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). The loss of CDKN2A/B was associated with an increased risk of BrM, with a cumulative incidence of 33.3% versus 7.4% in the non-coaltered subgroup. Compared with patients without coalterations, patients with concurrent CDKN2A/B loss (n = 21) had a shorter median progression-free survival (10.2 versus 34.2 mo, p < 0.001) and overall survival (26.2 versus 80.7 mo, p < 0.001). In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer progression-free survival and OS despite the presence of other somatic coalterations, TP53 mutations, BrM, and Eastern Cooperative Oncology Group Performance Status. ConclusionsThis study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was substantially associated with worse outcomes and a higher risk of brain metastases. The evidence presented in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.

Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma.

Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.

Impact of 1q gains on treatment outcomes of patients with newly diagnosed multiple myeloma in a real-world Swedish population receiving modern treatment.

Amplification of 1q (amp(1q); ≥4 1q copies) has repeatedly been reported to predict a worse outcome in multiple myeloma (MM), whereas the impact of gain of 1q (gain(1q); three 1q copies) is less clear. We investigated survival of MM in relation to amp(1q) and gain(1q) by retrospectively analysing 346 consecutively newly diagnosed MM (NDMM) patients. Of these, 62 (18%) had amp(1q), 97 (28%) gain(1q) and 187 (54%) a normal number of 1q copies (no1q). The patients with amp(1q) had a shorter median progression-free survival than those with gain(1q) or no(1q) (13.1 months, 95% confidence interval [CI] 8.2-18.1 months vs. 36.1 months, 95% CI 23.1-49.1 months vs. 25.4 months, 95% CI 19.8-31.1 months, p = .005). The 3-year overall survival (OS) was 56% for amp(1q), 76% for gain(1q) and 80% for no1q (p = .003). In the multivariate analysis, the presence of amp(1q) was independently associated with a shorter OS (hazard ratio 1.99, 95% CI 1.03-3.82, p = .039), whereas gain(1q) had no negative effect on survival. Our results thus suggest that amp(1q) should be considered a high-risk abnormality in NDMM and that new treatment strategies should be explored to mitigate its negative effect on survival.

Tumor-intrinsic features associated with progression-free survival (PFS) in patients (pts) with relapsed and refractory multiple myeloma (RRMM) treated with idecabtagene vicleucel (ide-cel).

8035 Background: Ide-cel, a B-cell maturation antigen chimeric antigen receptor T cell therapy, has demonstrated frequent, deep, and durable responses in pts with RRMM in the KarMMa (NCT03361748), KarMMa-2 (NCT03601078), and KarMMa-3 (NCT03651128) trials. A previous analysis of KarMMa showed comparable efficacy of ide-cel across molecular high-risk/resistance (HR/R) features such as biallelic p53 inactivation, 1q amplification, t(4;14), and CRBN dysregulation, and identified a baseline gene expression pattern (PC4) associated with PFS (Martin N, et al. Hemasphere 2022;6:(S6):1452). We aim to identify additional genomic features associated with ide-cel efficacy in KarMMa and KarMMa-2, and evaluate samples from KarMMa-3 pts as an independent validation cohort. Methods: Transcriptional and genomic profiles were assessed at baseline in CD138+ cells from bone marrow from pts in KarMMa, KarMMa-2 cohort 1, and KarMMa-3. Gene copy number aberrations were evaluated for associations with response. Analyses were post hoc and exploratory, and a P-value, or false discovery rate (FDR), of &lt; 0.05 was used to identify associations of interest. Results: In evaluable pts in KarMMa (n = 70), single copy number loss was observed at 2 loci that associated with PFS, a broad region across 14q (n = 16) and deletion at 1p31.2 (n = 6). These were generally independent and collectively represented 30% (21/70) of pts. Both were associated with shorter median PFS (mPFS) in KarMMa (cohort mPFS, 8.8 mo, n = 128; Munshi et al. N Engl J Med 2021;384:705-16) after FDR correction (del 14q, mPFS, 4.0 mo; del 1p31.2, mPFS, 2.3 mo). No pt with 1p loss achieved a best overall response (BOR) better than partial response. Pts with loss vs non-loss of 14q had similar BOR distribution, but poorer mPFS within each BOR (10.4 vs 29.7 mo for loss vs non-loss in pts with complete response/stringent complete response). Due to small sample size in KarMMa-2 cohort 1 (n = 18), these data were aggregated with those from KarMMa. When combined, previously described associations with HR/R features were maintained except for biallelic p53 inactivation, which showed a stronger association with shorter PFS in the aggregate dataset (n = 83, P = 0.04) than in KarMMa (n = 65, P = 0.09). KarMMa-3 (n = 210) analysis is ongoing and will be used as a validation cohort for these findings. Consistent trends for the association of the PC4 gene signature with PFS were observed in KarMMa-2 but were not statistically significant and limited by sample size. Conclusions: Two novel genomic HR/R features associated with PFS were identified using samples from KarMMa; validation is ongoing using samples from KarMMa-3. The PC4 gene signature was consistent in 2 RRMM cohorts. A modest association between biallelic p53 disruption and PFS emerged with increased sample size and will be studied in KarMMa-3.

Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (pts) with pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC).

9008 Background: Sotorasib is a first-in-class oral, irreversible KRASG12C inhibitor approved for adults with pretreated KRAS G12C-mutated advanced NSCLC. In CodeBreaK 200, the first KRASG12C inhibitor randomized phase 3 trial, sotorasib demonstrated superior progression-free survival (PFS) and overall response rate (ORR) vs docetaxel and a more favorable safety profile. We report prespecified exploratory biomarker analyses comparing sotorasib vs docetaxel efficacy in molecularly-defined KRAS G12C-mutated advanced NSCLC subsets. Methods: In CodeBreaK 200, 345 pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib 960 mg daily or IV docetaxel 75 mg/m2 Q3W. Primary endpoint was PFS by blinded independent central review (RECIST 1.1; key secondary endpoint: ORR). In prespecified exploratory analyses, baseline tissue and plasma samples were analyzed for key genomic alterations (eg, STK11, KEAP1, EGFR, MET, TP53), by central targeted next-generation sequencing (Skoulidis N Engl J Med 2021), and PD-L1 protein level by local standard of care testing in biomarker-evaluable cases; biomarker status was correlated with PFS and ORR. Inferred tumor mutation burden by plasma circulating tumor DNA (sum of mutant molecular variant reads) was assessed. Association of baseline genomic alterations with long-term benefit (PFS ≥ 6 m) vs early progression (PFS &lt; 3 m; no complete/partial response) was evaluated. Results: Most prevalent KRAS G12C co-alterations in biomarker-evaluable cases with available tumor and/or plasma samples (n=317) were TP53 (181 [57.1%]), STK11 (119 [37.5%]), and KEAP1 (82 [25.9%]) in CodeBreaK 200, consistent with CodeBreaK 100; 55 (17.4%) pts had STK11 and KEAP1 co-alterations. Sotorasib showed superior clinical benefit vs docetaxel independently of PD-L1 expression and across all prespecified subgroups (eg, STK11, KEAP1, TP53) . No clinical response occurred with either treatment in 26 (8.2%) pts with additional KRAS alterations, including amplifications. High baseline plasma tumor burden was associated with greater odds of early progression vs long-term benefit in both arms (odds ratio, 3.54 [95%CI 1.83-6.85] per tertile increase; p&lt;0.0001). Correlation of KRAS G12C co-alterations with response detected a signal toward shorter median PFS (sotorasib, 2.8 m [95%CI 1.6-3.4]; docetaxel, 7.5 m [95%CI 3.0-NE]) with sotorasib vs docetaxel in pts with KRAS G12C and NOTCH1 co -altered tumors. Conclusions: Sotorasib demonstrated consistent clinical benefit vs docetaxel in all prespecified molecularly-defined subgroups (eg, STK11, KEAP1, TP53) in this exploratory analysis of CodeBreaK 200. No predictive biomarkers were confirmed, but novel hypothesis-generating signals were observed. Clinical trial information: NCT04303780 .