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PURPOSE Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb–mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. PATIENTS AND METHODS This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. RESULTS By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. CONCLUSION In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.

PURPOSE We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer. [Media: see text]

Extensive-stage small-cell lung cancer is a therapeutically challenging disease. After more than two decades without clinical progress, the addition of programmed cell death protein 1 axis blockade to platinum-based chemotherapy has demonstrated sustained overall survival benefit and represents the current standard of care in the first-line setting. Despite this benefit, resistance emerges relatively rapidly in virtually all patients. Although newer treatments are being incorporated in the relapse setting, marked therapeutic resistance is typically observed in patients with relapsed small-cell lung cancer (SCLC), underscoring the need of developing more effective therapies in this setting. Notably, recent progress in the understanding of the molecular biology of SCLC might bring possibilities toward molecularly informed therapeutic strategies for patients with SCLC, which could have a significant impact for improving outcomes in this disease. Here, we review current treatment options and recent progress made in the first-line and relapsed SCLC, including the role of biomarkers and new evolving therapeutic strategies.

641 Background: Immune checkpoint inhibitors have become a cornerstone in the management of mRCC. However, to identify the most suitable patients for this treatment is an unmet medical need. We aimed to explore the utility of DL integrating clinical and molecular data to predict response to immunotherapy. Methods: We conducted a retrospective analysis using publicly available data from patients treated with nivolumab in the clinical trials Checkmate 009, 010 and 025. The primary objective was to assess the performance of different DL models (autoencoder and convolutional neural network (CNN)) predicting the PFS of these patients. With that scope, we followed several research lines including the creation of combined datasets with clinic and RNA sequencing and comparing the results of the DL models against the performance of traditional machine learning (ML) models. Finally, we came up with an interpretability analysis of those black-box models using LIME and SHAP values. Results: Clinical and transcriptomic data were available from 181 nivolumab-treated patients. Outcomes achieved confirmed that we can model the response for NIVOLUMAB using RNA sequencing data. (Table) However, DL models have not demonstrated to be significantly better than traditional ML methods when predicting response (p= 0.068). Deep autoencoder provided 68.9% accuracy, but the most accurate model was logistic regression classifier which achieved 86.4% of hit rate. Interpretability results revealed that most relevant genes for the decision making were related with the immune response and the regulation of kinases. Regarding interpretability, best results were achieved integrating both transcriptomic and clinical data (7 out of 10 DL and ML tested models achieved higher hit rates with combined data set. Logistic regression classifier improved its accuracy in 11%). Conclusions: The integration of clinical and molecular data could lead to more accurate predictions of outcome than any dataset by its own. However, further research is intended in the field of the DL analysis, as data codification and data structure could bias the results. The ongoing study ART (Artificial Intelligence in Renal Tumors) will address this issue prospectively. [Table: see text]

TPS282 Background: Enhancer of zeste homolog 2 (EZH2) encodes the histone methyltransferase component of the polycomb repressive complex-2, inducing transcriptional silencing of target genes, and is altered in cancers such as follicular lymphoma (FL), small cell lung cancer (SCLC), and metastatic castration-resistant prostate cancer (mCRPC). We evaluated the pharmacokinetics (PK), safety, and antitumor activity of PF-06821497, a potent and selective inhibitor of EZH2, in an ongoing phase I trial (NCT03460977 ) in patients (pts) with SCLC, CRPC, and FL as monotherapy and in combination with standard of care therapies. For pts with CRPC, the PF-06821497 recommended dose for expansion (RDE) is 1250 mg BID, in combination with enzalutamide plus androgen deprivation therapy (E). Part 2B of this trial further explores outcomes for pts dosed with PF-06821497 and E compared with E monotherapy. Methods: Part 2B compares the safety and efficacy of twice-daily PF-06821497 in combination with E (160 mg daily) (treatment arm) versus E monotherapy (control arm) administered continuously in patients with mCRPC previously treated with abiraterone. At trial entry, all pts will have evidence of prostate cancer progression per the modified Prostate Cancer Working Group 3 Criteria. Prior treatment with E is not allowed. Approximately 80 participants will be randomized in a 1:1 fashion into two arms, in US, Spain, and other countries. Approximately 40 participants are required in each arm to have 80% power in the study in order to detect a hazard ratio of 0.5 (E plus PF-06821497: E alone). Patients randomized to E alone have the option to add PF-06821497 to their regimen upon confirmed radiographic disease progression. The primary objectives are to confirm the safety and tolerability of PF-06821497 in combination with E in pts with mCRPC, and to assess the effect of PF-06821497 in combination with E versus E monotherapy on radiographic progression free survival. Secondary objectives include further evaluation of anti-tumor activity of PF-06821497, and assessment of single and multiple dose PK when given in combination with E. The impact of PF-06821497 in combination with E and of E alone in men with mCRPC on patient reported outcomes will also be assessed. Clinical trial information: NCT03460977 .

PURPOSE Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents. METHODS We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non–NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children’s Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures. RESULTS In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors ( P = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; P = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children’s Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; P = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; P = .9). CONCLUSION Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

305 Background: Measuring and tracking quality of care is highly relevant in today’s healthcare. The Quality Oncology Practice Initiative (QOPI) program is a referral for evaluating oncology practices worldwide. The ECO Foundation (Excellence and Quality in Oncology), a collaboration of oncology experts from the major Spanish hospitals involved in cancer treatment, reached an agreement with ASCO (American Society of Clinical Oncology) to include Spanish hospitals in its QOPI program. Methods: We analyzed the scores of the QOPI rounds from 14 Spanish hospitals, which submitted their charts from 2016 to 2021, and the measures obtained from 2018 to 2021, regarding the core/symptom, breast, colorectal (CRC) and NSCLC modules, in comparison with the QOPI aggregate measures. Results: Since 2016, 14 Spanish hospitals have participated in the QOPI program, achieving the certification 12 of them, and 3 are in process. Along the years, they have obtained a score over 85%, being 87,41% the worse in 2021, and 92,80% the best in 2020. We also analyzed the outstanding measures from 2018 onwards. The highest scores in Spanish hospitals were for information of infertility risks and chemotherapy intent prior to prescription, and documented plan for oral chemotherapy. However, measures regarding pain addressed, appropriate antiemetic therapy for high- and moderate-emetic-risk antineoplastic agents and action taken to address problems with emotional well-being by the second office visit, were among the lowest scored measures. When we focused in breast and NSCLC modules, Spanish hospitals didn´t show negative values, highlighting in the administration of Tamoxifen or AI within 1 year of diagnosis by patients with AJCC Stage IA (T1c) and IB - III ER or PR positive and in the status documentation for patients with initial AJCC Stage IV or distant metastatic NSCLC. In CRC module, Spanish hospitals showed lower scores in colonoscopy before or within 6 months of curative colorectal resection or completion of primary adjuvant chemotherapy. Conclusions: This study evaluates QOPI scores in Spain, showing that repeated participation enhances quality of care, although there is room for improvement. ECO Foundation will continue supporting Spanish practices to increase their participation aiming of improve oncology care in Spain.