Michael Offin

Capturing Genomic Evolution of Lung Cancers through Liquid Biopsy for Circulating Tumor DNA

Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumors dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA) analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors.

Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK , ROS1 , and ALK fusion-positive solid tumors

Entrectinib is a potent small-molecule tyrosine kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1, and ALK. The consolidated results of 2 Phase I trials demonstrated activity in tyrosine kinase inhibitor-naïve patients along with substantial intracranial activity. In ROS1-rearranged lung cancers, entrectinib results in durable disease control and prolonged progression-free survival. The drug is well tolerated and has a safety profile that includes adverse events mediated by on-target tropomyosin-related kinase A/B/C inhibition.

Abstract 1826: Oncogenic KRAS mediates resistance to MET targeted therapy in non-small cell lung cancer (NSCLC) with MET mutations that induce exon14 skipping

Mutations in MET that induce skipping of exon 14 and lead to reduced ubiquitin ligase-mediated turnover of this receptor tyrosine kinase (RTK) are detected in 3-4% of non-small cell lung cancer (NSCLC), approaching the prevalence of ALK-rearranged lung cancers. Preclinical and clinical studies have revealed that MET exon14 alterations are actionable oncogenic drivers that are amenable to therapy with MET kinase inhibitors such as crizotinib. However, similar to most kinase-driven cancers, despite initial benefit, acquired resistance to therapy is inevitable. Next-generation sequencing (MSK-IMPACT 468 gene panel) was performed on samples from 81 NSCLC patients with MET exon14 alterations, including 7 with paired pre- and post-treatment tumor samples. A concurrent KRAS G12 mutation was identified in 5 patients. In 4 of these patients, the KRAS mutation was present prior to receiving crizotinib. The KRAS mutation was acquired post-crizotinib in the remaining patient. These findings implicate KRAS activation as a potential mechanism of acquired resistance. Using isogenic and patient-derived in vitro and in vivo models harboring MET exon14 skipping alteration, we confirmed that the KRAS mutation results in constitutive activation of RAS/ERK signaling and cells expressing both MET exon14 skipping and KRAS mutations are refractory to MET inhibition. Dual inhibition of MET and MEK with crizotinib and trametinib, respectively, has an additive effect in cell line and xenograft models. Whereas concurrent KRAS mutation is an extremely rare event in EGFR- and ALK-driven NSCLC, our findings confirm KRAS mutation as a recurrent mechanism of primary or secondary resistance to MET-directed therapies in lung cancers harboring MET exon14 alterations. We provide a new potential therapeutic strategy for NSCLC patients with both MET exon14 alterations and KRAS mutations. Citation Format: Ken Suzawa, Michael D. Offin, Christopher Kurzatkowski, Daniel Liu, Morana Vojnic, Roger S. Smith, Marissa Mattar, Inna Khodos, Elisa de Stanchina, Joshua K. Sabari, William W. Lockwood, Alexander E. Drilon, Marc Ladanyi, Romel Somwar. Oncogenic KRAS mediates resistance to MET targeted therapy in non-small cell lung cancer (NSCLC) with MET mutations that induce exon14 skipping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1826.

Evolution of a chemosensitive core-binding factor AML into an aggressive leukemia with eosinophilic differentiation

Key Points Core-binding factor AML can evolve from good-risk disease into aggressive disease through the gain of additional genomic aberrations. In this unique case, an AML patient died of hypereosinophilic syndrome with solid organ infiltration of differentiated eosinophils.

PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers

Background MET exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced MET exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized. Patients and methods Patients with MET exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was carried out and TMB was calculated by estimation from targeted next-generation sequencing panels. Results We identified 147 patients with MET exon 14-altered lung cancers. PD-L1 expression of 0%, 1%-49%, and ≥50% were 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers was lower than that of unselected non-small-cell lung cancers (NSCLCs) in both independently evaluated cohorts: 3.8 versus 5.7 mutations/megabase (P < 0.001, n = 78 versus 1769, cohort A), and 7.3 versus 11.8 mutations/megabase (P < 0.001, n = 62 versus 1100, cohort B). There was no association between PD-L1 expression and TMB (Spearmans rho=0.18, P = 0.069). In response-evaluable patients (n = 24), the objective response rate was 17% (95% CI 6% to 36%) and the median progression-free survival was 1.9 months (95% CI 1.7-2.7). Responses were not enriched in tumors with PD-L1 expression ≥50% nor high TMB. Conclusion A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.