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Response to Dabrafenib Plus Trametinib in a Patient With an Uncommon Activating BRAF Mutation: A First in Non–Small Cell Lung Cancer

John A. Sharp, Daniel Jones, Julia K. Rotow, Panos M. Fidias, Erin Bertino, and Dwight H. Owen

Mutations in BRAF are present in 4% of non–small cell lung cancer (NSCLC), of which half are well-characterized activating variants affecting codon 600 (classified as class I). These mutations, most commonly BRAF V600E, have been associated with response to BRAF/MEK-directed small molecule kinase inhibitors. NSCLC with kinase-activating BRAF mutations occurring at other codons (class II variants) represent a substantial portion of BRAF-mutated NSCLC, but use of targeted therapy in these tumors is still under investigation. Class II mutations have been described in other tumor types and have been associated with response to BRAF/MEK-targeted agents, although optimal treatment strategies for these patients are lacking. This report presents a case of a woman with metastatic NSCLC harboring a class II BRAF p.N486_P490del variant who had a sustained clinical response to combination therapy with dabrafenib and trametinib. This first report of the use of BRAF/MEK-targeted therapy for this variant in NSCLC supports consideration of such treatment for tumors with class II BRAF variants.

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KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer

Dwight H. Owen, Bhavana Konda, Jennifer Sipos, Tom Liu, Amy Webb, Matthew D. Ringel, Cynthia D. Timmers, and Manisha H. Shah

BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine–refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V–activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.

ClinicalTrials.gov identifier: NCT01723202

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CLO20-054: A Phase 2 Trial of Nivolumab and Temozolomide in Advanced Neuroendocrine Tumors (NETs): Interim Efficacy Analysis

Dwight H. Owen, Lai Wei, Ashima Goyal, Ye Zhou, Sheryl-Ann Suffren, Rajani Jacob, Carly Pilcher, Gregory A. Otterson, Claire F. Verschraegen, Manisha H. Shah, and Bhavana Konda

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Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon

Jarred Burkart, Dwight Owen, Manisha H. Shah, Sherif R. Z. Abdel-Misih, Sameek Roychowdhury, Robert Wesolowski, Sigurdis Haraldsdottir, Julie W. Reeser, Eric Samorodnitsky, Amy Smith, and Bhavana Konda

Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating BRAF V600E mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although BRAF-directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of BRAF mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the BRAF V600E mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role BRAF mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from BRAF-directed therapies but also strategies to avoid development of resistance.

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Harmonized Outcome Measures for Use in Non–Small Cell Lung Cancer Patient Registries and Clinical Practice

Martin J. Edelman, Daniel P. Raymond, Dwight H. Owen, Michelle B. Leavy, Kari Chansky, Sriram Yennu, Felix G. Fernandez, Carolyn J. Presley, Tithi Biswas, Gwendolyn P. Quinn, Matthew B. Schabath, Seth Sheffler-Collins, Laura Chu, and Richard E. Gliklich

Background: Lung cancer is the leading cause of cancer-related death in the United States and globally, and many questions exist about treatment options. Harmonizing data across registries and other data collection efforts would yield a robust data infrastructure to help address many research questions. The purpose of this project was to develop a minimum set of patient and clinician relevant harmonized outcome measures that can be collected in non–small cell lung cancer (NSCLC) patient registries and clinical practice. Methods: Seventeen lung cancer registries and related efforts were identified and invited to submit outcome measures. Representatives from medical specialty societies, government agencies, health systems, health information technology groups, patient advocacy organizations, and industry formed a stakeholder panel to categorize the measures and harmonize definitions using the Agency for Healthcare Research and Quality’s supported Outcome Measures Framework (OMF). Results: The panel reviewed 66 outcome measures and identified a minimum set of 8 broadly relevant measures in the OMF categories of patient survival, clinical response, events of interest, and resource utilization. The panel harmonized definitions for the 8 measures through in-person and virtual meetings. The panel did not reach consensus on 1 specific validated instrument for capturing patient-reported outcomes. The minimum set of harmonized outcome measures is broadly relevant to clinicians and patients and feasible to capture across NSCLC disease stages and treatment pathways. A pilot test of these measures would be useful to document the burden and value of the measures for research and in clinical practice. Conclusions: By collecting the harmonized measures consistently, registries and other data collection systems could contribute to the development research infrastructure and learning health systems to support new research and improve patient outcomes.

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Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non–Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

Angel Qin, Songzhu Zhao, Abdul Miah, Lai Wei, Sandipkumar Patel, Andrew Johns, Madison Grogan, Erin M. Bertino, Kai He, Peter G. Shields, Gregory P. Kalemkerian, Shirish M. Gadgeel, Nithya Ramnath, Bryan J. Schneider, Khaled A. Hassan, Nicholas Szerlip, Zoey Chopra, Sara Journey, Jessica Waninger, Daniel Spakowicz, David P. Carbone, Carolyn J. Presley, Gregory A. Otterson, Michael D. Green, and Dwight H. Owen

Background: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non–small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. Patients and Methods: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. Results: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4–12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19–2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. Conclusions: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.

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Association Between Pretreatment Chest Imaging and Immune Checkpoint Inhibitor Pneumonitis Among Patients With Lung Cancer

Alexander Wong, Maria Riley, Songzhu Zhao, Jessica Zimmer, Matthew Viveiros, Jing Gennie Wang, Vincent Esguerra, Mingjia Li, Gabrielle Lopez, Kari Kendra, David P. Carbone, Kai He, Asrar Alahmadi, Jacob Kaufman, Regan M. Memmott, Peter G. Shields, Jeremy Brownstein, Karl Haglund, Meng Welliver, Gregory A. Otterson, Carolyn J. Presley, Lai Wei, Dwight H. Owen, and Kevin Ho

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

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Non–Small Cell Lung Cancer, Version 4.2024

Gregory J. Riely, Douglas E. Wood, David S. Ettinger, Dara L. Aisner, Wallace Akerley, Jessica R. Bauman, Ankit Bharat, Debora S. Bruno, Joe Y. Chang, Lucian R. Chirieac, Malcolm DeCamp, Aakash P. Desai, Thomas J. Dilling, Jonathan Dowell, Gregory A. Durm, Scott Gettinger, Travis E. Grotz, Matthew A. Gubens, Aditya Juloori, Rudy P. Lackner, Michael Lanuti, Jules Lin, Billy W. Loo Jr, Christine M. Lovly, Fabien Maldonado, Erminia Massarelli, Daniel Morgensztern, Trey C. Mullikin, Thomas Ng, Dawn Owen, Dwight H. Owen, Sandip P. Patel, Tejas Patil, Patricio M. Polanco, Jonathan Riess, Theresa A. Shapiro, Aditi P. Singh, James Stevenson, Alda Tam, Tawee Tanvetyanon, Jane Yanagawa, Stephen C. Yang, Edwin Yau, Kristina M. Gregory, and Lisa Hang

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.