Adashek, Jacob J.

Importance Although cancer-related mortality continues to decline, lung cancer remains the No. 1 cause of cancer deaths in the US. Almost half of the patients with non–small cell lung cancer (NSCLC) are diagnosed with early-stage, local or regional disease and are at high risk of recurrence within 5 years of diagnosis. Observations Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with metastatic NSCLC and have recently been tested in multiple clinical trials to determine their efficacy in the neoadjuvant or adjuvant setting for patients with local or regional disease. The landscape for perioperative ICIs in lung cancer is evolving rapidly, with recently reported and soon to mature clinical trials; however, the recent data highlight the potential of ICIs to increase response rates and decrease rates of relapse in early stages of lung cancer. Concurrently, novel applications of cell-free DNA may guide perioperative management strategies. Conclusions and Relevance This article reviews the various approaches of incorporating perioperative use of immunotherapeutic agents for the treatment of early stages of NSCLC.

Abstract BRAF plus MEK inhibitor combinations are currently FDA-approved for melanoma, non–small cell lung cancer, and anaplastic thyroid cancer. The lack of clinical benefit with BRAF inhibition in BRAF V600–mutated colorectal cancer has prevented its tissue-agnostic drug development. We reviewed the AACR GENIE database for the prevalence of BRAF V600 mutations across tumor types. We reviewed the literature for case reports of clinical responses, outcomes in patients with BRAF V600 mutation—positive nonmelanoma malignancies who received BRAF inhibitor therapy, and data from published adult and pediatric trials. BRAF V600 mutations are prevalent across multiple nonmelanoma malignancies (>40 different tumor types), lead to oncogene addiction, and are clinically actionable in a broad range of adult and pediatric nonmelanoma rare malignancies. Continued tissue-agnostic drug development is warranted beyond the current BRAF plus MEK approved cancers.

AbstractActivating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.

Abstract Background: BRAF and MEK inhibitors are currently FDA approved for melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. The lack of clinical benefit with BRAF inhibition in BRAF V600+ colorectal cancer (CRC) has prevented its tissue-agnostic drug development. However, updated results from Vemurafenib-Basket study (Cancer Discov. 2020 May;10(5):657-663 ) and the NCI-match trial ( J Clin Oncol. 2020 Nov 20;38(33):3895-3904) reveal that BRAF pathway inhibition is active in > 20 unique cancer types. Objective: We aimed to describe the characteristics of BRAF V600 and study real-world outcomes using a clinico-genomic analysis using the AACR Genie database and the current medical literature. Methods: We reviewed the AACR GENIE database for the prevalence of BRAF V600 mutations across tumor types. We conducted a literature search (using PubMed from 2012-2019) for case reports of clinical response and outcomes in patients with BRAF V600 mutation-positive non-melanoma cancers who received BRAF inhibitor therapy. Results: Among 96,324 samples, BRAF V600 mutations were seen in 43 different tumor types across 2,963 samples (3.07 %) in the AACR GENIE database. BRAF V600 was most commonly present in thyroid cancer (40.9%), parathyroid cancer (31.8%), melanoma (26.1%), histiocytosis (25.7%), and head and neck NOS (14.3%). Literature review revealed total of 178 cases across 69 tumor types. The most common cases included Erdheim-Chester disease (n = 30, 16.9%), papillary thyroid carcinoma (n=16, 8.9%), anaplastic thyroid carcinoma (n = 13, 7.3%), and hairy cell leukemia (n = 13, 7.3%). Furthermore, dabrafenib (BRAF), dabrafenib/trametinib (BRAF+MEK), trametinib(MEK), vemurafenib (BRAF), vemurafenib/trametinib (BRAF+MEK), vemurafenib/cobimetinib (BRAF+MEK) were used in 34% (n =56), 16% (n = 27), 4% (n = 6), 44% (n = 72), 1% (n = 1), 2% (n =3), respectively. Overall, median PFS was 6.5 months, and median OS was 28.5 months with a median duration of response (DOR) of 8 months. Conclusion: BRAF V600 mutations are prevalent across multiple non-melanoma cancers, lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers. Continued drug development is warranted beyond the current BRAF+/- MEK approved cancers. Citation Format: Jacob J. Adashek, Aakash P. Desai, Arjun K. Menta, Jason Roszik, Vivek Subbiah. Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1479.

Abstract Background: Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions have been recognized as potent drivers of oncogenesis in multiple malignancies. Recently, highly potent and selective RET inhibitors, selpercatinib and pralsetinib have been FDA approved for RET fusion+ NSCLC and selpercatinib for RET+ thyroid cancers. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Patients and methods: 96,324 samples from 89,754 patients available from AACR Project Genie database version 8 were analyzed for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types accessed July 21, 2020. The races of the samples within the cohort were 69,962 (72.6%) white, 5,388 (5.6%) Black, 4,909 (5.1%) Asian, 163 (0.17%) Native American, 48 (0.05%) Pacific Islander, and 15,854 (16.5%) were unknown. Results: There were 56,382 (58.5%) samples from primary tumors, 24,204 (25.1%) samples from unspecified metastasis sites, 4,798 (5.0%) from distant organ metastasis, 1,379 (1.4%) from lymph node metastasis, 1,279 (1.3%) from local recurrence, and 8,282 (8.6%) unknown. In 96,324 tumor samples there were 2,706 (2.81%) RET alterations. This included 223 (0.23%) fusions, 1,689 RET mutations found (1.75%) in 21 tumor histologies, and 794 (0.82%) RET amplifications identified; where the most abundant tissues harboring RET fusions were NSCLC (n = 121), papillary thyroid cancer (n = 53), breast cancer (n = 8) and colorectal cancer (n = 7) and the most abundant tissues harboring RET missense mutations were NSCLC (n = 355), colorectal cancer (n = 292), melanoma (n = 236), and thyroid cancer (n = 127). NSCLC samples with RET fusions had significantly co-altered KRAS, SETD2, PVRL4, EZH1, and RRAGC. Conclusions: RET fusions represent extremely rate events in multiple cancers. RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted because RET is highly targetable with therapeutics. Citation Format: Jacob J. Adashek, Alexander Andreev-Drakhlin, Jason Roszik, Aakash P. Desai, Vivek Subbiah. The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1221.