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With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance. Significance: Clinical resistance to KRASG12C–EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis. ispartof: J Clin Oncol vol:41 issue:18 pages:3311-3317 ispartof: location:United States status: published

Background Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively. Methods We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed. Results A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. Conclusions Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).

Purpose: Gallbladder carcinoma (GBC) is an uncommon and aggressive disease, which remains poorly defined at a molecular level. Here, we aimed to characterize the molecular landscape of GBC and identify markers with potential prognostic and therapeutic implications. Experimental Design: GBC samples were analyzed using the MSK-IMPACT (Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets) platform (targeted NGS assay that analyzes 505 cancer-associated genes). Variants with therapeutic implications were identified using OncoKB database. The associations between recurrent genetic alterations and clinicopathologic characteristics (Fisher exact tests) or overall survival (univariate Cox regression) were evaluated. P values were adjusted for multiple testing. Results: Overall, 244 samples (57% primary tumors and 43% metastases) from 233 patients were studied (85% adenocarcinomas, 10% carcinomas with squamous differentiation, and 5% neuroendocrine carcinomas). The most common oncogenic molecular alterations appeared in the cell cycle (TP53 63% and CDKN2A 21%) and RTK_RAS pathways (ERBB2 15% and KRAS 11%). No recurrent structural variants were identified. There were no differences in the molecular landscape of primary and metastasis samples. Variants in SMAD4 and STK11 independently associated with reduced survival in patients with metastatic disease. Alterations considered clinically actionable in GBC or other solid tumor types (e.g., NTRK1 fusions or oncogenic variants in ERBB2, PIK3CA, or BRCA1/2) were identified in 35% of patients; 18% of patients with metastatic disease were treated off-label or enrolled in a clinical trial based on molecular findings. Conclusions: GBC is a genetically diverse malignancy. This large-scale genomic analysis revealed alterations with potential prognostic and therapeutic implications and provides guidance for the development of targeted therapies.

Anticancer therapy changes tumor physiology and genomics, making it a key variable in cancer studies. Although antineoplastics given at a single institution may be available in research-ready format, treatment at external institutions prior to receiving care at academic medical centers, common among patients at these centers, is often only described in free-text clinical notes, necessitating manual curation for downstream analysis. To overcome this bottleneck, we trained and validated natural language processing (NLP) models using initial consult notes to identify whether patients had received treatment at external institutions and studied the impact of these putative treatments on tumor genomics. Training data were derived from the AACR Project GENIE Biopharma Collaborative (BPC) for 2,663 patients at Memorial Sloan Kettering (MSK) across four cancer types. For each patient, we selected initial visits with medical and radiation oncologists based on an a priori note prioritization scheme and determined “ground-truth” prior external medications based on manually curated BPC administration records, whitelisting MSK-given medications. We trained logistic regression and clinical longformer models to identify external treatment receipt and evaluated model performance with 5-fold cross-validation. The clinical longformer model performed best across evaluation metrics, with an average area under the receiver operating characteristic curve of 0.972, macro-averaged precision/recall of 0.854/0.902 and macro-averaged F1 score of 0.876. Re-review of discrepant cases suggested that 75% of “false positives” may be due to curation error. We used our model to infer treatment status in a pan-cancer cohort with tumor genomic profiling using our institutional sequencing platform. Out of 48,447 patients, 11,900 were predicted to have received external treatment. Patients with putative external treatment had higher alteration frequencies in resistance-related genes than untreated patients and comparable to known pre-treated patients, including ESR1 in patients with breast cancer, AR in patients with prostate cancer, and EGFR T790M in patients with EGFR-mutated non-small cell lung cancer. Patients with putative external treatments, similar to known pre-treated patients, had shorter survival compared to treatment-naïve patients of the same cancer type. NLP can abstract external treatment status from clinical notes. When applied at scale, our model could help mitigate confounding variables and identify relationships between clinicogenomic variables and anticancer therapy. Citation Format: Thinh N. Tran, Karl B. Pichotta, Si-Yang Liu, Christopher Fong, Anisha Luthra, Brooke Mastrogiacomo, Steven Maron, Deborah Schrag, Sohrab P. Shah, Pedram Razavi, Bob T. Li, Gregory J. Riely, Nikolaus Schultz, Justin Jee. Identification of anti-neoplastic therapy given before initial visit at a referral center using natural language processing applied to medical oncology initial consultation notes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4259.

Intro: Half of all patients with NSCLC develop BM during their clinical course. While modern NSCLC-directed agents yield excellent systemic response, most patients require focal BM treatment. Prior reports of BM genomics have been limited by low numbers and a lack of matched specimens. Here, we report the largest cohort to date of molecularly-profiled NSCLC BM samples with comprehensive clinical follow-up. Methods: Clinical data and outcomes for 244 patients with NSCLC and resected BM were identified. Samples were assessed using MSK-IMPACT, a custom tumor-normal next generation sequencing assay. 51 (20.9%) patients had matched primary site tissue, and 44 (18%) patients had matched tissue from another metastatic site or CSF. Genomic alterations were filtered for driver variants using OncoKB. Publicly available genomic data for NSCLC primary samples was used for comparison against the primary samples from our BM cohort. Results: The most frequently altered genes in BM tumors were TP53 (72%), CDKN2A (34%), KRAS (31%), KEAP1 (26%), and EGFR (21%). CDKN2A was more frequently altered in BM samples compared to NSCLC primary lesions (34% vs 14%, p = 0.003). Additionally, cell cycle pathway alterations were enriched in BM (56% vs 31%, p = 0.002). BM samples also had a significantly higher fraction of genome altered (FGA) relative to primary samples (p < 0.0001). We then compared primary samples from BM patients against primary samples from metastatic NSCLC patients without BM and primary samples from non-metastatic NSCLC patients. We found an enrichment of alterations in TP53 (68.6% vs 27.7%, p < 0.0001), NKX2-1 (11.4% vs 1.7%, p = 0.006), SMARCA4 (11.4% vs 2.1%, p = 0.01), RB1 (11.4% vs 1.7%, p = 0.006), and FOXA1 (11.4% vs 0.9%, p = 0.001) in the primary samples from BM patients compared to non-metastatic patients. Next, we grouped patients based on CNS progression patterns and found that EGFR alterations were enriched in patients with leptomeningeal progression when compared to patients without progression (42% vs 18%, p = 0.03). Conclusions: In our cohort of molecularly-profiled NSCLC BM, we found an enrichment of cell cycle pathway alterations and a higher FGA in BMs compared to their primary tumor controls. Additionally, several genes were enriched in the primary tissue of patients that developed BM compared to primary tissue from non-metastatic patients. EGFR alterations were enriched in patients who develop leptomeningeal disease (LMD). Our work herein characterizes the genomic profiles of NSCLC patients with BM and identifies specific genes enriched in the primary tissue of BM patients compared to primary tissue from both non-BM metastatic patients and non-metastatic patients. Finally, our finding that EGFR alterations were enriched in patients with LMD suggests specific biologic underpinnings driving patterns of CNS progression. Citation Format: Henry Walch, Anna Skakodub, Kathryn R. Tringale, Harish N. Vasudevan, Jordan Eichholz, Daniel W. Kelly, Emily Lebow, Nelson S. Moss, Kenny Kwok Hei Yu, Bob T. Li, Boris Mueller, Atif Khan, Yao Yu, Simon Powell, Jorge S. Reis-Filho, Brandon S. Imber, Pedram Razavi, Daniel R. Gomez, Nikolaus Schultz, Luke R. Pike. Genomic characterization of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients identifies novel alterations associated with tropisms and disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6063.

Purpose: KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRASG12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRASG12C-mutant lung adenocarcinoma. Experimental Design: Patients who underwent resection of stage I–III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRASwt), G12C (KRASG12C), or non-G12C (KRASother). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed. Results: In total, 604 patients were included: 374 KRASwt (62%), 95 KRASG12C (16%), and 135 KRASother (22%). Three-year DFS was not different between KRAS-mutant and KRASwt tumors. However, 3-year DFS was worse in patients with KRASG12C than KRASother tumors (log-rank P = 0.029). KRASG12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3–10.8) vs. 6.1 (3.5–9.7); P = 0.021], compared with KRASother tumors. KRASG12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort. Conclusions: KRAS G12C mutations are associated with worse DFS after complete resection of stage I–III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRASG12C inhibitors may be investigated to improve survival.

PET scans using (18)F-FDG and somatostatin receptor imaging agents are both used in imaging of neuroendocrine neoplasms (NENs). We have suggested the “NETPET score,” using uptake of both PET tracers, as a prognostic biomarker in NENs. The name NETPET score was suggested previously to capture the score's intent to summarize information from dual PET imaging in neuroendocrine tumors. We previously demonstrated the effectiveness of the NETPET score in gastroenteropancreatic NENs (GEPNENs). Its prognostic relevance in bronchial NENs remains undetermined. Methods: This is a retrospective multicenter study (2011–2018) assessing patients who had advanced bronchial NEN and who underwent both (18)F-FDG and (68)Ga-DOTATATE PET within 60 d of each other. The NETPET score was assigned by experienced nuclear medicine physicians and compared with other clinical data such as World Health Organization grade. The primary outcome was overall survival; NETPET score and other prognostic variables were analyzed using univariate and multivariate analyses by the Cox proportional-hazards model. Results: Thirty-eight patients were included for review. The NETPET score and histology were significantly correlated with overall survival in univariate analyses (P = 0.003, P = 0.01). On multivariate analysis, only the NETPET score remained significant (P = 0.03). The NETPET score was significantly associated with histologic grade (P = 0.006, χ(2) test). Conclusion: The NETPET score is a prognostic biomarker in bronchial NENs as well as GEPNENs. Although it needs to be validated in prospective studies, it holds significant promise as a biomarker for a wide range of NENs.

Purpose: MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in MET exon 14–altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed. Experimental Design: We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of MET exon 14–altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated. Results: Seventy-five of 168 MET exon 14–altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (P > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (N = 15) or immunochemistry (N = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; P = 0.02). Conclusions: In MET exon 14–altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.

Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

OBJECTIVES: Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. MATERIALS AND METHODS: KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. RESULTS: Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing. CONCLUSION: Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib. ispartof: Lung Cancer vol:166 pages:270-278 ispartof: location:Ireland status: published

PURPOSE Although MET exon 14 ( METex14)–altered lung cancers were first identified more than a decade and a half ago, the frequency of CNS metastatic disease remains poorly defined. Furthermore, the seminal trial of crizotinib in these patients (PROFILE 1001) did not report patterns of CNS response or progression. PATIENTS AND METHODS Patients with pathologically confirmed, advanced non–small-cell lung cancers (NSCLC) harboring a METex14 alteration by targeted DNA/RNA sequencing were studied. The incidence of brain metastases and the outcomes of MET inhibition with crizotinib were analyzed. RESULTS Eighty-three patients with METex14-altered metastatic NSCLC were identified. The incidence of CNS metastases at diagnosis was 17% (95% CI, 10% to 27%). The lifetime incidence was 36% (95% CI, 26% to 47%); 83% of patients had parenchymal disease, and 17% had leptomeningeal disease. The probability of having brain metastasis at 1, 2, and 3 years was 24%, 35%, and 38%, respectively. Fifty-four patients received crizotinib. The median time to radiologic CNS progression was 5.8 months (range, 3.7-20.0 months). Patterns of crizotinib progression were as follows: intracranial only in 10% of patients, intracranial and extracranial in 12%, and extracranial only in 78%. In patients with brain metastases before treatment, the median time on crizotinib was 7.5 months (range, 7.2-11.7 months). CONCLUSION CNS metastases, including leptomeningeal disease, occurred in more than a third of patients with METex14-altered lung cancers. In crizotinib-treated patients with or without CNS metastases, CNS failure was seen in less than a quarter of patients on progression.

Structured Abstract Background Patients with lung cancers may have disproportionately severe COVID-19 outcomes. Understanding the patient-specific and cancer-specific features that impact severity of COVID-19 may inform optimal cancer care during this pandemic. Patients and methods We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n=102) at a single center from March 12-May 6, 2020. Thresholds of severity were defined a priori as hospitalization, ICU/intubation/DNI (a composite metric of severe disease including ICU stay, intubation and invasive mechanical ventilation, and/or transition to do not intubate [DNI]), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. HLA alleles were inferred from MSK-IMPACT (n=46) and compared to controls with lung cancer and no known non-COVID-19 (n=5166). Results COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer-deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease (Odds ratios for severe COVID-19 2.9, 95% CI 1.07-9.44 comparing the median [23.5 pack-years] to never and 3.87, 95% CI 1.35-9.68, respectively). Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. HLA supertypes were generally similar in mild or severe cases of COVID-19 compared to non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. Conclusion COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity., Highlights • COVID-19 is associated with high burden of severity in patients with lung cancer. • Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. Key Points This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.

Introduction: Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare with those of nonsarcomatoid SMARCA4-deficient non–small cell lung carcinomas (SD-NSCC). Methods: We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical, and genomic characteristics using 341–468 gene next-generation sequencing and other molecular platforms. Results: The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size (p < 0.0001), worse survival (p = 0.004), and more frequent presentation at younger age (30–50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers. Conclusions: SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.

BACKGROUND: While 2–4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P 2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

OBJECTIVES: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. MATERIALS AND METHODS: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. RESULTS: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p

Simple Summary Next-generation sequencing (NGS) has revolutionized care for patients with advanced and metastatic non-small cell lung cancer through the identification of specific oncogenic driver mutations and pairing with matched targeted therapies. The application of NGS technologies also has the potential to improve outcomes in patients with earlier-stage disease who undergo surgery as their first line of treatment. We review clinically relevant topics in this patient cohort, for whom NGS technologies have spearheaded our understanding of tumor heterogeneity, the underlying genomic features associated with lung adenocarcinoma histologic subtypes, the prediction of recurrence after surgery, the identification of minimal residual disease by circulating tumor DNA, the discernment of intrapulmonary metastases versus synchronous or metachronous disease, and the identification of patients with early-stage non-small cell lung cancer who are likely to benefit from induction or adjuvant therapies. Abstract During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of “targeted therapy” in advanced and metastatic disease. The use of specific tyrosine kinase inhibitors in patients with oncogenic driver alterations, such as EGFR, ALK, ROS1, BRAF V600E, MET, and NTRK mutations, among others, has changed treatment approaches and improved outcomes in patients with late-stage disease. Although NGS technology has mostly been used in the setting of systemic therapy to identify targets, response to therapy, and mechanisms of resistance, it has multiple potential applications for patients with earlier-stage disease, as well. In this review, we discuss the emerging role of NGS technologies to better understand tumor biology in patients with non-small cell lung cancer who are undergoing surgery with curative intent. In this patient cohort, we examine tumor heterogeneity, the underlying tumor genomics associated with lung adenocarcinoma subtypes, the prediction of recurrence after complete surgical resection, the use of plasma circulating tumor DNA for detection of early cancers and monitoring for minimal residual disease, the differentiation of separate primaries from intrapulmonary metastases, and the use of NGS to guide induction and adjuvant therapies.

PURPOSE Biliary tract cancers (BTCs), which include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC), and gallbladder cancer (GBC), have limited treatment options. We sought to comprehensively examine the clinical and molecular characteristics of BTCs with amplification or mutation of ERBB2. METHODS Demographic, outcome, and treatment response data were collected for patients with ERBB2-altered BTC identified by next-generation sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets from 2014 to 2018. RESULTS A total of 517 patients with BTC underwent next-generation sequencing (ICC, n = 313; EHC, n = 93; GBC, n = 111). Twenty-eight patients (5.4%) had ERBB2 alterations, including 2.7% with ERBB2 gene amplification, 2.3% with ERBB2 mutation, and 0.4% with concurrent amplification and mutation. The prevalence of ERBB2 gene alterations was significantly higher in GBC (12.6%) than in ICC (2.2%) and EHC (7.5%; P < .001). In ERBB2-amplified tumors, the median fold change was 6.4 (range, 2.1 to 19.7), while in ERBB2-mutant tumors, the most frequent mutated domain was the extracellular domain (32%), with all mutations in this region involving the S310 codon. Frequent co-altered genes in this cohort were TP53 (54%), PIK3CA (21%), and CDKN2A (18%); KRAS amplification/mutation was found in 7% of patients. One patient with ERBB2-amplified EHC who enrolled in a basket trial (ClinicalTrials.gov identifier: NCT02675829 ) had a partial response to the human epidermal growth factor receptor 2–targeted antibody-drug conjugate ado-trastuzumab emtansine. CONCLUSION ERBB2 alterations are present in 5.4% of BTCs. When present, the degree of ERBB2 gene amplification is often high, and S310 codon mutations are the most common hotspot. These features, along with the presented case, support further development of human epidermal growth factor receptor 2–targeted therapy in ERBB2-mutant and/or -amplified BTC.

Background Noninvasive genotyping using plasma cell-free DNA (cfDNA) has the potential to obviate the need for some invasive biopsies in cancer patients while also elucidating disease heterogeneity. We sought to develop an ultra-deep plasma next-generation sequencing (NGS) assay for patients with non-small-cell lung cancers (NSCLC) that could detect targetable oncogenic drivers and resistance mutations in patients where tissue biopsy failed to identify an actionable alteration. Patients and methods Plasma was prospectively collected from patients with advanced, progressive NSCLC. We carried out ultra-deep NGS using cfDNA extracted from plasma and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50 000× raw target coverage filtering somatic mutations attributable to clonal hematopoiesis. Clinical sensitivity and specificity for plasma detection of known oncogenic drivers were calculated and compared with tissue genotyping results. Orthogonal ddPCR validation was carried out in a subset of cases. Results In 127 assessable patients, plasma NGS detected driver mutations with variant allele fractions ranging from 0.14% to 52%. Plasma ddPCR for EGFR or KRAS mutations revealed findings nearly identical to those of plasma NGS in 21 of 22 patients, with high concordance of variant allele fraction (r = 0.98). Blinded to tissue genotype, plasma NGS sensitivity for de novo plasma detection of known oncogenic drivers was 75% (68/91). Specificity of plasma NGS in those who were driver-negative by tissue NGS was 100% (19/19). In 17 patients with tumor tissue deemed insufficient for genotyping, plasma NGS identified four KRAS mutations. In 23 EGFR mutant cases with acquired resistance to targeted therapy, plasma NGS detected potential resistance mechanisms, including EGFR T790M and C797S mutations and ERBB2 amplification. Conclusions Ultra-deep plasma NGS with clonal hematopoiesis filtering resulted in de novo detection of targetable oncogenic drivers and resistance mechanisms in patients with NSCLC, including when tissue biopsy was inadequate for genotyping.

Purpose: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. Experimental Design: We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. Results: Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82–17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). Conclusions: TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy. See related commentary by Cheng and Oxnard, p. 899

Introduction Patients with stage II to III lung adenocarcinomas are treated with adjuvant chemotherapy (ACT) to target the premetastatic niche that persists after curative-intent resection. We hypothesized that the premetastatic niche is a scion of resected lung tumor microenvironment and that analysis of tumor microenvironment can stratify survival benefit from ACT. Methods Using tumor and tumoral stroma from 475 treatment-naive patients with stage II to III lung adenocarcinomas, we constructed a tissue microarray and performed multiplex immunofluorescent staining for immune markers (programmed death-ligand 1 [PD-L1], tumor-associated macrophages [TAMs], and myeloid-derived suppressor cells) and derived myeloid-lymphoid ratio. The association between immune markers and survival was evaluated using Cox models adjusted for pathologic stage. Results Patients with high PD-L1 expression on TAMs or tumor cells in resected tumors had improved survival with ACT (TAMs: hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.12–2.85; tumor cells: HR = 3.02, 95% CI: 1.69–5.40). Among patients with high PD-L1 expression on TAMs alone or TAMs and tumor cells, ACT survival benefit is pronounced with high myeloid-lymphoid ratio (TAMs: HR = 3.87, 95% CI: 1.79–8.37; TAMs and tumor cells: HR = 2.19, 95% CI: 1.02–4.71) or with high stromal myeloid-derived suppressor cell ratio (TAMs: HR = 2.53, 95% CI: 1.29–4.96; TAMs and tumor cells: HR = 3.21, 95% CI: 1.23–8.35). Patients with low or no PD-L1 expression on TAMs or tumor cells had no survival benefit from ACT. Conclusions Our observation that PD-L1 expression on TAMs or tumor cells is associated with improved survival with ACT provides rationale for prospective investigation and developing chemoimmunotherapy strategies for patients with lung adenocarcinoma.

Purpose:Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.Experimental Design:A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS).Results:Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R–NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P < 0.0001).Conclusions:This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.

Background Ulixertinib is the first-in-class ERK1/2 kinase inhibitor with encouraging clinical activity in BRAF- and NRAS-mutant cancers. Dermatologic adverse events (dAEs) are common with ulixertinib, so management guidelines like those established for epidermal growth factor receptor inhibitor (EGFRi)-associated dAEs are needed. Patients and Methods This was an open-label, multicenter, phase I dose escalation and expansion trial of ulixertinib evaluating data from 135 patients with advanced malignancies enrolled between March 2013 and July 2017. Histopathological features, management, and dAEs in 34 patients are also reported. Twice daily oral ulixertinib was administered at 10 to 900 mg in the dose escalation cohort (n = 27) and at 600 mg in 21-day cycles in the expansion cohort (n = 108). Results The incidence of ulixertinib-induced dAEs and combined rash were 79% (107/135) and 76% (102/135). The most common dAEs included acneiform rash (45/135, 33%), maculopapular rash (36/135, 27%), and pruritus (34/135, 25%). Grade 3 dAEs were observed in 19% (25/135) of patients; no grade 4 or 5 dAEs were seen. The presence of at least 1 dAE was associated with stable disease (SD) or partial response (PR) (OR = 3.64, 95% CI 1.52–8.72; P = .003). Acneiform rash was associated with a PR (OR = 10.19, 95% CI 2.67–38.91; P

Introduction: Sotorasib, a first-in-class KRASG12C inhibitor, has been FDA-approved for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapies based on the Phase 1/2 global, single-arm CodeBreaK100 trial. We will report the longest follow-up for a KRASG12C inhibitor, including 2-year survival, safety, and genomic profiles associated with durable clinical benefit. Methods: Sotorasib was administered orally at 960 mg once daily to patients who progressed on prior therapies and had KRAS p.G12C-mutated locally advanced, metastatic NSCLC. Primary endpoint was objective response rate (ORR) assessed by central review. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. In an exploratory analysis, baseline tumor tissue and/or plasma samples were collected and analyzed for genomic alterations. Tumor samples were analyzed for PD-L1 levels to evaluate correlates with prolonged tumor response, defined as patients with PFS ≥ 12 months, in comparison with those with PFS ≤ 3 months. Results: In the first analysis of the combined Phase 1 and Phase 2 study (N=174), the median number of prior lines of therapy was 2.0 (range 1-4+). 90.2% received prior anti-PD1 or anti PD-L1 treatment; 82.8% received both prior platinum-based chemotherapy and anti-PD1/PD-L1. Updated ORR by central review was 40.7% (95% CI: 33.2, 48.4) and median DOR was 12.3 months (7.1, 14.6). Median PFS and OS was 6.3 months (95% CI: 5.3, 8.2) and 12.5 months (10.0, 17.8). One and two-year OS was 50.8% and 30.3%. Sotorasib was well-tolerated in the long-term with mild and manageable toxicities, and no new safety signals emerged. Prolonged tumor response was observed across PD-L1 expression, including in tumors with low PDL-1 expression and STK11 co-mutation that may derive less benefit from immunotherapy. Conclusions: In the longest follow-up of any KRASG12C inhibitor, sotorasib continued to demonstrate a favorable safety profile and durable efficacy, including a 2-year OS observed in 30% of patients. Current analyses continue to support long-term clinical benefit across subgroups in patients with KRAS p.G12C-mutated NSCLC, and additional biomarker data will be presented. Citation Format: Grace K. Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S. Falchook, Antoine Italiano, Juergen Wolf, Adrian G. Sacher, Toshiaki Takahashi, Suresh S. Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, Qui Tran, Simon Jones, Agnes Ang, Abraham Anderson, Antreas A. Hindoyan, David S. Hong, Bob T. Li. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT008.

8540 Background: The standard of care for patients with inoperable early stage or locally advanced NSCLC is definitive stereotactic body radiotherapy (SBRT) or conventional radiation therapy (RT) with systemic therapy. Circulating tumor DNA (ctDNA) testing can be used for the assessment of MRD and predict risk of recurrence. Few studies have prospectively evaluated MRD detection and ctDNA dynamics specifically among patients with early or locally advanced NSCLC receiving definitive RT. Methods: In a prospective clinical cohort of patients with stage I-III NSCLC (n = 17), serial plasma samples (n = 70) were collected before and after SBRT as well as before, during, and after conventional RT with or without concurrent systemic therapy and adjuvant durvalumab. Patients were followed-up for a median of 29 months (range: 4 to 54 months) with the last serial plasma collected at a median of 5 months from completion of RT (range: 1 – 26 months). A personalized, tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA and tracked 16 tumor variants among 16 patients and 15 tumor variants in one patient. This study evaluated the prognostic value of ctDNA, correlating MRD status with clinical outcomes, in addition to ctDNA clearance kinetics during RT. Results: Among 17 patients with early-stage and locally advanced NSCLC, baseline ctDNA was detected in 82% of patients (14/17). Clinical progression was confirmed radiographically for 53% (9/17). All events of clinical progression were detectable by ctDNA (sensitivity 100%, 0.63 – 1.0), with a median lead-time of 5.5 months for MRD detection compared to radiographic disease progression. Durable ctDNA clearance was observed in 29% (5/17) of patients, all of whom then remained recurrence-free until the end of follow-up (median 12 months; specificity 100%, 95% CI 0.6 – 1.0). Transient ctDNA clearance was observed in 3 patients, and recurrent ctDNA was detected before or at the time of disease progression in all 3. ctDNA status after treatment at a single time point and longitudinally were highly predictive of disease recurrence (p < 0.0001). Conclusions: ctDNA detection is feasible for patients with stage I-III NSCLC undergoing definitive chemoradiation. and can serve as a powerful predictive biomarker for disease recurrence. High baseline detection rate is essential for feasibility of a ctDNA-based MRD assay. Residual detectable ctDNA represents a powerful predictive tool to identify patients who might benefit from intensification of adjuvant therapy following definitive RT.

2008 Background: Approximately 30% of patients with NSCLC present with BM, and up to 50% of patients ultimately develop BM. While modern NSCLC-directed agents yield excellent systemic response, most patients require focal treatment. Prior reports of BM genomics have been limited by low numbers, missing clinical data, and lack of matched specimens. Here, we report the largest cohort to date of molecularly profiled NSCLC BM samples with clinical correlates. Methods: Clinical data and outcomes for 244 patients with NSCLC and resected BM were identified, and BM samples were assessed with one of four versions (341, 410, 468, 505) of MSK-IMPACT, a custom FDA-approved next generation sequencing-based tumor sequencing assay. 51 (20.9%) patients had matched primary site tissue, and 44 (18%) patients had matched tissue from another metastatic site or CSF. Genomic alterations were filtered for driver variants using OncoKB. Results: Median age was 66 years (range 31-91), and median follow-up was 2.3 years (IQR 1.3-4.3). Adenocarcinoma was the most common histology (183, 78%). Half presented with a single BM, and 121 (51%) patients were treatment naive. Most (197, 83%) received adjuvant stereotactic radiosurgery (SRS) to the resection site and 28% received SRS to additional BM. After resection, 130 (55.1%) had CNS progression, often regional (54, 42%). SRS to new BMs (32%) was the most common salvage treatment. Median overall survival from BM diagnosis was 2.5 years (95%CI 2.1-3.2). Median CNS-progression-free survival was 1.2 years (95%CI 0.9-1.4). The most frequently altered genes in BM samples were TP53 (72%), CDKN2A (34%), KRAS (31%), KEAP1 (26%), and EGFR (21%). CDKN2A was more frequently altered in BM samples when compared to NSCLC primary samples (34% vs 14%, p = 0.003, q = 0.034). With regard to overrepresented gene sets, cell cycle pathway alterations were enriched in BM (56% vs 31%, p = 0.002, q = 0.022). BM samples had a significantly higher fraction of genome altered relative to the primary samples (p < 0.0001, q < 0.0001). After grouping patients based on type of CNS progression, we found that EGFR alterations were enriched in patients with leptomeningeal failures when compared to both patients without progression (42% vs 18%, p = 0.03, q = 0.93) and to patients with either local or regional progression (42% vs 19%, p = 0.03, q = 0.9). Conclusions: In the largest-ever assembled cohort of genomically-profiled NSCLC BM, we found significant enrichment for CDKN2A and cell cycle pathway alterations in BM compared to extracranial disease, as well as a higher fraction of genome altered, in BMs compared to matched primary tumor controls. We also observed EGFR alteration enrichment in patients who develop LMD, suggesting specific biologic underpinnings driving patterns of CNS failure. Further investigation into the role of systemic therapy and time course will elucidate potential mechanisms for CNS failure in patients with NSCLC.

102 Background: Sotorasib, a specific, irreversible KRASG12C inhibitor, has been approved in multiple countries for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapy based on the global phase 1/2 CodeBreaK100 trial. Here we describe putative mechanisms of acquired resistance to sotorasib from the largest single dataset evaluated to-date. Methods: Patients with advanced KRAS p.G12C-mutated NSCLC or CRC from the CodeBreaK100 Ph1/2 trial who received sotorasib monotherapy at 960 mg once daily were analyzed for efficacy. Primary endpoint was objective response rate (ORR) assessed by central review. To investigate biomarkers of resistance to sotorasib, an exploratory endpoint was defined to examine acquired genomic alterations at disease progression. Plasma samples collected at baseline and progression were analyzed for genomic alterations with the 23-gene Resolution Bioscience ctDx Lung test for NSCLC and the 74-gene Guardant 360 ctDNA test for CRC. Acquired genomic alterations were defined by their absence at baseline and presence at progression. Results: In 174 pts with NSCLC and 91 pts with CRC-treated with sotorasib, the ORR were 41% and 12% respectively. Median progression-free survival and median overall survival were 6.3 months (mos) and 12.5 mos for NSCLC pts and 4.2 mos and 13.4 mos for CRC pts (median follow-up: 22.5 mos NSCLC; 12.5 mos CRC). A total of 67 NSCLC pts and 45 CRC pts had a plasma sample sequenced both at baseline and at progression. At least one new acquired genomic alteration at progression was detected in 19 (28%) NSCLC pts and in 33 (73%) CRC pts (Table). The acquired genomic alterations were heterogeneous in both NSCLC and CRC, with variants detected across multiple genes and pathways. The most prevalent putative pathway of resistance in both NSCLC and CRC was the receptor tyrosine kinase (RTK) pathway. Secondary RAS alterations occurred more frequently in CRC versus NSCLC pts (16% vs. 3%). Conclusions: Based on the largest descriptive dataset to-date, diverse mechanisms of acquired resistance occur in KRAS p.G12C-mutated NSCLC and CRC pts treated with sotorasib. New RTK pathway alterations frequently emerged at progression, highlighting the potential role for combining sotorasib with upstream inhibitors of RTK, such as SHP2 or EGFR inhibitors. Serial plasma DNA analysis revealed acquired resistance patterns that support the development of KRASG12C inhibitor combination therapies. Clinical trial information: NCT03600883. [Table: see text]

3135 Background: MAPK1 encodes ERK2, a kinase component of the mitogen activated signaling (MAPK) pathway. ERK2 E322K is a known activating mutation that leads to increased phosphorylation and ERK signaling. In vitro studies found this mutation to be associated with resistance to dabrafenib, trametinib, but potential sensitivity to ERK inhibitors. Despite its potential as a drug target, little is known about the clinicopathologic characteristics of this hotspot mutation across solid tumors. Methods: Patients with solid tumors underwent tumor next-generation sequencing at Memorial Sloan Kettering Cancer Center between Jan 2015 and Sep 2020 using the MSK-IMPACT assay. Using the cBioPortal database and clinical charts, we analyzed tumors harboring MAPK1/ERK2 E322K mutations, assessed their clinicopathologic characteristics, co-mutational status and overall survival (OS). OS was measured from time of tumor sequencing to date of death or last follow-up. Results: A total of 37 tumor samples from 35 patients were identified in 59,822 tumors sequenced (0.06%) to harbor an ERK2 E322K mutation. The distribution across tumor types was as follows: head and neck squamous cell carcinoma (29%), bladder cancer (20%), lymphomas (9%), colorectal cancers (9%), gastric cancers (9%), cholangiocarcinoma (6%), cervical cancers (6%), lung cancers (6%), germ cell tumor (3%), Merkel cell carcinoma (3%), and breast cancers (3%). The OS in patients with metastatic disease and ERK2 E322K was 22.29 months (95%CI: 7.56-NA) months. Other mutations in RAS pathway frequently co-occurred with ERK2 E322K mutation (17/37, 46%). Concurrent mutations are also involved in pathways of cell cycle (71%), PI3K (71%), TP53 (66%), NOTCH (57%), RTK (51%), HIPPO (29%), TGF-beta (29%), WNT (26%), NRF2 (20%), MYC (14%). The median TMB score of samples from solid malignancies was 12.3 (range:0-101, quartiles: 6.9-33.0) mutation/Mb. Two patients (2/35, 6%) had microsatellite-instability high (MSI-H) tumors. The most frequent concurrent activating mutations include ARID1A (29%), FBXW7 (26%), PI3KCA (22%), PI3KR1/2/3 (20%), CDKN2A (11%), PTEN (8%), BRCA1/2(8%), FGFR3 (8%), BRAF (6%), Only one of these 35 patients received treatment targeting BRAF/MEK/ERK pathway and achieved partial response. One patient with NSCLC harboring a concurrent EGFR L858R mutation did not respond to erlotinib. One patient with PI3KCA mutated head and neck cancer did not respond to PI3K inhibitor. Two patients had TMB score of 100.9 and 12.9 mutation/Mb had partial response to pembrolizumab. Conclusions: ERK2 E322K mutation is a rare oncogenic mutation across diverse solid tumor types, associated with a high co-occurrence of other activating mutations and a high TMB. The lack of response to other targeted therapies suggests ERK2 E322K is a potential driver mutation. These findings may inform treatment and further development of ERK inhibitors.

TPS9137 Background: The standard of care (SOC) for patients with oncogene driver subsets of metastatic NSCLC is guided by specific molecular characterization and includes immunotherapy, chemoimmunotherapy, and matched targeted therapies. Although targeting HER2 has transformed the care of patients with breast and gastric cancers, there is currently no approved HER2-targeted therapy for NSCLC. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients (median, 2 prior lines) with unresectable or metastatic HER2-mutant NSCLC, T-DXd demonstrated durable and robust anticancer activity, with a confirmed objective response rate (ORR) of 55% and median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of 9.3, 8.2, and 17.8 months, respectively (Li et al. N Engl J Med. 2022). Given the efficacy observed in later-line settings and the unmet need for targeted therapies in patients with HER2-mutant NSCLC, evaluating the efficacy of T-DXd in the first-line setting vs SOC is important to determine the optimal treatment. Here we describe the phase 3 DESTINY-Lung04 trial (NCT05048797) evaluating T-DXd as a first-line treatment in patients with NSCLC harboring HER2 mutations. Methods: DESTINY-Lung04 is an open-label, randomized, multicenter, phase 3 study evaluating the efficacy and safety of first-line T-DXd vs SOC in patients with unresectable, locally advanced (not amenable to curative therapy), or metastatic nonsquamous NSCLC with HER2 exon 19 or 20 mutations (detected in tissue or circulating tumor DNA). Patients must be naive to systemic therapy with palliative intent in the locally advanced or metastatic disease setting and must not have tumors with EGFR or other targetable oncogenic alterations. Patients with brain metastases must have previously completed local therapy. Patients will be randomized to receive T-DXd or SOC (platinum [investigator’s choice of cisplatin or carboplatin], pemetrexed, and pembrolizumab). The primary endpoint is PFS defined by RECIST version 1.1 per blinded independent central review (BICR). Secondary endpoints include OS, ORR, and DOR (by RECIST 1.1 per BICR and investigator), investigator-assessed PFS (by RECIST 1.1) and time to second progression or death (per local standard clinical practice), central nervous system PFS (by RECIST 1.1 per BICR), landmark PFS at 12 months (by RECIST 1.1 per BICR and investigator), and landmark OS at 24 months. Safety and tolerability, pharmacokinetics, immunogenicity, and patient-reported outcomes, including pulmonary symptoms and tolerability, will be assessed. Clinical trial information: NCT05048797.

4114 Background: Gallbladder cancer (GBC) is a molecularly distinct entity among biliary tract tumors. ERBB2 amplification and mutation have been described in GBC, however, clinical and genomic characterization of the ERBB2-altered subgroup has been limited. Methods: Patients with GBC treated at Memorial Sloan Kettering and Pontificia Universidad Católica de Chile with genomic tumor profiling between 2014 and 2021 were included. Clinical information was retrieved from electronic medical records. Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: During the study period 260 GBC patients underwent genomic profiling. The prevalence of ERBB2 alterations was 14% including 8% with ERBB2 gene amplification, 4.2% with ERBB2 mutation, 1.5% with concurrent amplification and mutation and 0.4% with ERBB2 fusion. There was no age difference between GBC patients with and without ERBB2 alterations (63.6 vs. 65.4; p = 0.36) and in both subgroups there was a majority of female patients (75% vs. 84%; p = 0.44). Patients with ERBB2-altered tumors had a different genomic profile with lower concurrent KRAS alterations (2% vs. 12%; p = 0.14) and higher prevalence of TP53 alterations (81% vs. 59%; p = 0.01). There was no difference in the prevalence of PIK3CA mutations (13% vs. 9%; p = 0.38). GBC patients with ERBB2 alterations had a longer overall survival (22.3 vs. 12.1 months; HR 0.54 95% CI 0.3 to 0.98). Conclusions: ERBB2 amplification and mutation are the most frequent potentially targetable alterations in GBC (14%). ERBB2-driven GBC has higher concurrent alterations of TP53, while KRAS alterations appear to be less frequent. While no particular clinical feature was associated with this subgroup, overall survival was longer.

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd-related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd-related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms. SEARCH STRATEGY AND SELECTION CRITERIA: References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors' own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.

IMPORTANCE: Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence. OBJECTIVE: To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018. MAIN OUTCOMES AND MEASURES: The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model. RESULTS: Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P

Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance.

PURPOSECell-free DNA (cfDNA) analysis offers a noninvasive means to access the tumor genome. Despite limited sensitivity of broad-panel sequencing for detecting low-frequency mutations in cfDNA, it may enable more comprehensive genomic characterization in patients with sufficiently high disease burden. We investigated the utility of large-panel cfDNA sequencing in patients enrolled to a Phase I AKT1-mutant solid tumor basket study.METHODSPatients had AKT1 E17K-mutant solid tumors and were treated on the multicenter basket study (ClinicalTrials.gov identifier: NCT01226316 ) of capivasertib, an AKT inhibitor. Serial plasma samples were prospectively collected and sequenced using exon-capture next-generation sequencing (NGS) analysis of 410 genes (Memorial Sloan Kettering [MSK]-Integrated Molecular Profiling of Actionable Cancer Target [IMPACT]) and allele-specific droplet digital polymerase chain reaction (ddPCR) for AKT1 E17K. Tumor DNA (tDNA) NGS (MSK-IMPACT) was also performed on available pretreatment tissue biopsy specimens.RESULTSAmong 25 patients, pretreatment plasma samples were sequenced to an average coverage of 504×. Somatic mutations were called in 20/25 (80%), with mutant allele fractions highly concordant with ddPCR of AKT1 E17K ( r2= 0.976). Among 17 of 20 cfDNA-positive patients with available tDNA for comparison, mutational concordance was acceptable, with 82% of recurrent mutations shared between tissue and plasma. cfDNA NGS captured additional tumor heterogeneity, identifying mutations not observed in tDNA in 38% of patients, and revealed oncogenic mutations in patients without available baseline tDNA. Longitudinal cfDNA NGS (n = 98 samples) revealed distinct patterns of clonal dynamics in response to therapy.CONCLUSIONLarge gene panel cfDNA NGS is feasible for patients with high disease burden and is concordant with single-analyte approaches, providing a robust alternative to ddPCR with greater breadth. cfDNA NGS can identify heterogeneity and potentially biologically informative and clinically relevant alterations.

Background Data on drug-induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and the safety of drug rechallenge. Methods This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge. Results Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune-based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty-six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0-1.09; P = .035). Conclusions In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives.

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. Significance: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs. See related commentary by Rolfo and Russo, p. 643. This article is highlighted in the In This Issue feature, p. 627

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Background The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. Patients and methods Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. Results Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%–62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%–51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%–46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. Conclusions TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

Purpose: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non–small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. Experimental Design: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6). Results: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51–1; negative predictive value = 0.93 (95% CI, 0.80–0.99)]. Conclusions: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.

Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer. Significance: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors. See related commentary by Koleilat and Kwong, p. 1094. This article is highlighted in the In This Issue feature, p. 1079

BACKGROUND: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use. METHODS: Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided. RESULTS: Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P

Introduction In ret proto-oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%–32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%–58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)–rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3–2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0–4.9 months). Conclusions Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.