Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis—massive, localized chromosome shattering—recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers. Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features. This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities. See related commentary by Nadeem and Drapkin, p. 8

PURPOSE: With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C-mutant non–small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice. MATERIALS AND METHODS: We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity. RESULTS: Among 105 patients with advanced KRAS G12C-mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate. KEAP1 comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR], 3.19; P = .004; OS HR, 4.10; P = .003); no significant differences in rwPFS or OS were observed across TP53 (rwPFS HR, 1.10; P = .731; OS HR, 1.19; P = .631) or STK11 (rwPFS HR, 1.66; P = .098; OS HR, 1.73; P = .168) comutation status. Notably, almost all patients who developed grade 3 or higher treatment-related adverse events (G3+ TRAEs) had previously been treated with anti–PD-(L)1 therapy. Among these patients, anti–PD-(L)1 therapy exposure within 12 weeks of sotorasib was strongly associated with G3+ TRAEs ( P < .001) and TRAE-related sotorasib discontinuation ( P = .014). Twenty-eight percent of patients with recent anti–PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity. CONCLUSION: Among patients treated with sotorasib in routine practice, KEAP1 comutations were associated with resistance and recent anti–PD-(L)1 therapy exposure was associated with toxicity. These observations may help guide use of sotorasib in the clinic and may help inform the next generation of KRAS G12C-targeted clinical trials.

KRAS G12C mutations are critical in the pathogenesis of multiple cancer types, including non-small cell lung (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal (CRC) cancers. As such, they have increasingly become a target of novel therapies in the management of these malignancies. However, the therapeutic success of KRAS G12C inhibitors to date has been far more limited in CRC and PDAC than NSCLC. In this review, we briefly summarize the biochemistry of KRAS targeting and treatment resistance, highlight differences in the epidemiology of various G12C-mutated cancers, and provide an overview of the published data on KRAS G12C inhibitors for various indications. We conclude with a summary of ongoing clinical trials in G12C-mutant CRC and a discussion of future directions in the management of this disease. KRAS G12C mutation, targeted therapies, colorectal cancer, non-small cell lung cancer, pancreatic cancer, drug development.

In early December, the US Food and Drug Administration granted accelerated approval to adagrasib, a mutant-selective inhibitor of the Kirsten rat sarcoma viral homolog (KRAS), for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation after one prior therapy.¹ Adagrasib now joins sotorasib,² which received accelerated approval in May, 2021 for the same indication. In some ways, the arrival of adagrasib simply represents a continuation of what we learned a year prior: that KRAS was, at long last, an oncogene that we could shift from the “undruggable” column to the “druggable” one.³ But this approval underlies something else: a confluence of new biology, new chemistry, new clinical questions, and new avenues of drug discovery. From this vantage point, the approval of adagrasib looks not so much like the beginning of the end for KRAS-mutated cancers, but something much closer to the end of the beginning.

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a newly defined disease entity characterized by aggressive clinical behavior, diagnostic complexity, and poor prognosis. Given its rarity and heterogeneous histological presentation, establishing a definitive diagnosis can be challenging and relies heavily on comprehensive molecular and immunohistochemical evaluation. Here, illustrating the challenges highlighted by a real-world case, we describe the diagnostic pathway leading to SMARCA4-UT identification and discuss the differential diagnosis of thoracic tumors, relevant molecular evaluations, the molecular basis of SMARCA4-UT, and treatment implications. Recognition of this recently described entity is crucial, as an accurate diagnosis—as demonstrated by our case—can guide effective therapy and facilitate enrollment in targeted clinical trials.

Purpose: The development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation; however, to date, PARP inhibitors (PARPi) remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi therapy era are the context dependency of DDR alterations and the presence of preexisting resistance in this heavily pretreated population. Blood samples from patients with tumors harboring defects in DDR genes were used to evaluate the feasibility of a liquid biopsy platform to detect complex genomic events such as BRCA1/2 reversions, homologous recombination deficiency (HRD) signatures, pathogenic variant allele status, and differentially methylated regions for accurate quantitation of tumor fraction. Experimental Design: Pretreatment ctDNA samples from 173 patients enrolled in two phase 1/2 clinical trials (TRESR; NCT04497116 and ATTACC; NCT04972110) were selected for analysis. Results: In a phase I heavily pretreated patient population with DDR defects, complex genomic alterations (HRD, biallelic loss, and complex reversions) that historically require tumor tissue biopsies could be detected in ctDNA. Within the cohort of BRCA-associated tumor types previously treated with PARPi or platinum therapy, HRD reversions were detected in 44% of evaluable patients and included large genomic rearrangements leading to deletion of whole or partial exons which have been underrepresented in the literature because of technological limitations. Conclusions: This study showcases the genomic complexity of DDR-altered tumors as revealed through baseline ctDNA profiling, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.