Citations

2534 Background: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were derived from an international collaborative effort supported by data from clinical trials (16 studies, 9147 patients) on cytotoxic chemotherapy (CT), providing a standard tool for response assessment. RECIST’s role has been questioned for TCA. Using a pooled individual patient database (IPD) from clinical trials performed by industry and cooperative groups, we assessed whether modifications to RECIST are required to evaluate antitumor activity of TCA. Methods: Data were collected from phase 2 and 3 clinical trials testing TCA in solid tumors. To study the occurrence of mixed responses, the variability of response of lesions within patients was studied. Furthermore, response was correlated with survival through landmark analyses and time dependent Cox models. Results: Clinical data were obtained from 23,259 patients, mainly with lung (36%), colorectal (28%) or breast cancer (11%). 15,620 patients (67%) received a TCA, mainly transduction or angiogenesis inhibitors, either as single agent (37%) or combined with other TCAs (7%) or CT (56%); 28% received CT only and 5% best supportive care or placebo. Within-patient variability reduced as the number of lesions used for response assessment increased, and did so similarly for TCAs (+/- CT) and CT. Mixed responses seemed to occur similarly across these treatment categories as well. Landmark analyses showed improving overall survival by % tumor shrinkage and a clear distinction between the effect of tumor shrinkage and progressive disease (PD) according to RECIST 1.1. This was confirmed by time dependent analysis. In addition target lesion growth showed no marked improvement in overall survival prediction over and above the other components of RECIST 1.1 PD (new lesions, non-target PD), regardless of treatment (TCA, CT or both) received. Similar results were seen focusing on major tumor types and classes of TCA. Conclusions: Using a large IPD dataset we demonstrated that RECIST 1.1 performs equally well for response assessment of TCA as for CT. No modifications are required.

9065 Background: BRG is a potent and selective ALK inhibitor with preclinical and clinical activity against wild-type ALK and a broad range of mutants associated with clinical CRZ resistance, including G1202R. Herein we examine the association between BRG efficacy and ALK mutation status using plasma specimens from the initiation of BRG treatment (baseline [BL]) and the end of BRG treatment (EOT) in CRZ-resistant ALK+ NSCLC pts enrolled in the BRG Ph1/2 or pivotal Ph2 (ALTA) trials. Methods: Plasma samples were analyzed using the Resolution Bioscience ctDx Lung Panel v3.0. BRG activity was described using the confirmed objective response rate (cORR) (RECIST v1.1). Data are reported as of May 31, 2016 for the Ph1/2 (NCT01449461) and ALTA (NCT02094573) trials. Results: Of 291 CRZ-resistant ALK+ NSCLC pts enrolled in the Ph1/2 (N = 69) and ALTA (N = 222) trials, evaluable plasma samples were obtained from 67 pts at BL. cORR to BRG in these pts was 49% (33/67). An ALK fusion was detected in plasma in 45% (30/67) of these pts (cORR 57% [17/30]), of whom 33% (10/30) had secondary ALK mutations (cORR 50% [5/10]) and 67% (20/30) did not (cORR 60% [12/20]). Best responses in pts with secondary ALK mutations were: 2 CR (ALK amplification [Amp] copy number [CN] = 10; T1151M); 3 PR (L1196M; E1408V; Amp CN = 6); 4 SD (L1196M; E1419K; F1174C; C1156Y+S1206F+G1269A); 1 PD (T1151R+C1156Y+E1161D+F1174L). Of 67 pts with evaluable plasma at BL, 35 discontinued BRG therapy, of whom 20 had evaluable samples collected at EOT. No new mutations were detected at EOT in 75% (15/20) of pts. Complex mutation patterns were associated with resistance in the remaining 25% (5/20): High-level ALK-Amp (CN = 58); ALK-Amp (CN = 14)+MET-Amp (CN = 6); ALK-S1206F+S1206C+Amp (CN = 6); ALK-G1202R+L1196M+L1198Q; ALK-G1202R+BRAF-V600E+KRAS-G12D. Conclusions: ALK fusions were detected in plasma in < 50% of CRZ-resistant ALK+ NSCLC pts. BRG had substantial activity in ALK fusion–positive pts with a range of CRZ-resistance mutations. Neither primary nor secondary resistance to BRG was associated with any single plasma ALK mutation. The therapeutic implications of complex secondary resistance patterns associated with BRG require further exploration. Clinical trial information: NCT01449461, NCT02094573.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Abstract Introduction Voyager-V1TM is derived from VSV, a bullet-shaped negative sense RNA virus with very low human seroprevalence; it is engineered to selectively replicate in and kill human cancer cells. Voyager-V1 encodes the human IFNβ gene to boost antitumoral immune responses and the thyroidal sodium iodide symporter NIS gene to permit noninvasive imaging of virus spread. FIH studies are underway via both IV and IT routes. Here we report safety and preliminary correlative data from the FIH IT study. Methods and objectives This is a classical 3+3 phase 1 design, using escalating single IT viral doses from 3 x 106 to 3 x 109 TCID50 into one target lesion. The primary objective is safety and tolerability, monitored by committee. Other objectives include PK by RT-PCR for viral genomes, serum IFNβ levels, Tc-99m SPECT/CT imaging to monitor virus infection in injected lesions, peripheral blood immunophenotyping with 11-color flow cytometry for activation markers on T cells, T-regs, NK cells, and MDSCs, and serial biopsies to assess the tumor microenvironment (TME). IHC was performed on tumor biopsies for CD3, CD8, CD4, FoxP3, CD68, PD-1 and PDL-1 pre and post treatment in non-injected and injected lesions. CD45 staining is ongoing. Results Dose level 3 is ongoing (n=8+). No DLTs have been observed to date. Most patients were male (75%), white (100%), with ECOG PS1 (75%) and a median of &gt;6 lines of prior systemic therapy. AEs (in 63% patients) reported as related to study drug were mild-moderate, short-lived, and consisted of G1 fever, chills, hot flashes, nausea, vomiting, hyperhidrosis and G2 fatigue. Most patients had some mild AEs (pain, bruising, subclinical pneumothorax) related to biopsy and IT injection procedures and one had an SAE related to biopsy (G2 pneumothorax). There was no difference in incidence, intensity or duration of related AEs between dose levels so far. In patients analyzed to date, at the first three dose levels of 3 x 106, 1 x 107 and 3 x 107 TCID50 (n=7), viremia and serum IFNβ were below levels of detection after IT injection. There is evidence in all patients of an increase in PD-1 expression on CD4 and CD8 T cells, suggesting T cell activation post- single virus injection. One patient at dose level 2 had increased CD4 and CD8 T cells in the peripheral blood. TME analysis revealed increased infiltration of CD3 and CD8 cells in tumors of some patients. In addition, there are changes in numbers of FoxP3 and CD68 positive cells in the injected lesions compared to the pre-treatment and non-injected lesion. Two patients at dose level 3, one with an injected adrenal metastasis of colorectal cancer and another with a chest wall lesion from a head of pancreas primary, have positive SPECT/CTs on days 3-15 showing viral replication in tumor plus concomitant lymphocyte/neutrophil trafficking in the periphery. Conclusions IT injection of a single dose of the novel oncolytic virotherapy Voyager-V1 has proven safe at doses up to 3 x 107 TCID50. There was evidence of T cell activation with increased PD-1 expression in peripheral blood lymphocytes after a single IT injection. Tumor biopsies indicate increased lymphocyte infiltration. Two patients at the highest dose tested show signs of viral replication in the injected lesion plus evidence of systemic impact on leukocyte populations. Citation Format: Steven Powell, Manish R. Patel, Jaime R. Merchan, Timothy P. Cripe, James Strauss, Rosa M. Diaz, Nandakumar Packiriswamy, Bethany A. Brunton, Deepak Upreti, Rehan Khan, Lukkana Suksanpaisan, Rianna Vandergaast, Stephen J. Russell, Alice S. Bexon, Kah Whye Peng. Preliminary correlative and clinical data from a first-in-human (FIH) study of the intratumoral (IT) oncolytic virotherapy, Voyager-V1, in patients with solid tumors [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 CT051.