Bryan Johnson

Next-generation sequencing (NGS) has enabled genome-wide personalized oncology efforts at centers and companies with the specialty expertise and infrastructure required to identify and prioritize actionable variants. Such approaches are not scalable, preventing widespread adoption. Likewise, most targeted NGS approaches fail to assess key relevant genomic alteration classes. To address these challenges, we predefined the catalog of relevant solid tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics analysis of >700,000 samples. To detect these variants, we developed the Oncomine Comprehensive Panel (OCP), an integrative NGS-based assay [compatible with <20 ng of DNA/RNA from formalin-fixed paraffin-embedded (FFPE) tissues], coupled with an informatics pipeline to specifically identify relevant predefined variants and created a knowledge base of related potential treatments, current practice guidelines, and open clinical trials. We validated OCP using molecular standards and more than 300 FFPE tumor samples, achieving >95% accuracy for KRAS, epidermal growth factor receptor, and BRAF mutation detection as well as for ALK and TMPRSS2:ERG gene fusions. Associating positive variants with potential targeted treatments demonstrated that 6% to 42% of profiled samples (depending on cancer type) harbored alterations beyond routine molecular testing that were associated with approved or guideline-referenced therapies. As a translational research tool, OCP identified adaptive CTNNB1 amplifications/mutations in treated prostate cancers. Through predefining somatic variants in solid tumors and compiling associated potential treatment strategies, OCP represents a simplified, broadly applicable targeted NGS system with the potential to advance precision oncology efforts.

Abstract Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. Experimental Design: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. Results: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. Conclusions: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.

8009 Background: Vandetanib (V) is a once-daily oral agent that selectively inhibits VEGFR, EGFR and RET signaling. Three randomized Phase II studies of V in advanced NSCLC have demonstrated improved progression-free survival (PFS) with V: V300 mg vs gefitinib (6474IL0003) and V100 mg ± docetaxel (D) vs D (6474IL0006) in previously treated NSCLC; V300 mg ± paclitaxel (P) and carboplatin (C) vs PC (6474IL0007) in 1st-line NSCLC. However, in 6474IL0007, V300 mg monotherapy was inferior to PC in terms of PFS. An exploratory analysis of the potential relationship between baseline VEGF levels and PFS was investigated in patients (pts) from these 3 studies. Methods: Two baseline plasma samples were collected from 163/168 pts (6474IL0003) and 44/83 pts (6474IL0006). Two baseline serum samples were collected from 144/181 pts (6474IL0007). Mean baseline VEGF levels were determined for each pt by ELISA. High baseline VEGF values were above the immunoassay reference range for healthy subjects (>115 pg/mL in plasma, >707 pg/mL in serum) and low baseline VEGF values were within this reference range. Results: In 6474IL0003, pts with low baseline VEGF had a lower risk of disease progression when treated with V vs gefitinib (HR = 0.55, 95% confidence interval [0.35, 0.86]). Conversely, pts with high baseline VEGF had similar benefit from both agents (HR = 1.03 [0.60, 1.75]). In 6474IL006, pts with low baseline VEGF had a lower risk of disease progression when treated with V100 mg + D vs D (HR = 0.25 [0.09, 0.68]), whereas disease progression was similar in both treatment groups for pts with high baseline VEGF (HR = 0.95 [0.25, 3.61]). In 6474IL0007, pts with low baseline VEGF had a lower risk of disease progression when treated with V300 mg vs PC (HR = 0.72 [0.38, 1.38]) whereas those with a high baseline VEGF progressed more quickly when treated with V300 mg vs PC (HR = 1.62 [0.88, 2.98]). There was no evidence that pts with low or high baseline VEGF had differential benefits when treated with V300 mg + PC vs PC (HR = 0.77 [0.42, 1.40] {low}; HR = 0.66 [0.31, 1.43] {high}). Conclusions: These exploratory analyses suggest low baseline levels of circulating VEGF may be predictive of PFS advantage in pts with NSCLC receiving V300 mg monotherapy vs gefitinib or PC, or V100 mg in combination with D vs D alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology AstraZeneca Oncology AstraZeneca Oncology AstraZeneca Oncology