Hubbard, Joleen M.

3532 Background: Colorectal cancer with dMMR display heterogeneity in the extent of intratumoral T-cell infiltration which may explain their variable responsiveness to PD-1 blockade. We examined the association of intratumoral CD3+ and CD8+ T-cell densities (TCD) with objective response rate (ORR) and response duration in patients with dMMR mCRCs receiving pembrolizumab (PEM). Methods: Record review was performed on 12 patients with dMMR mCRC treated with PEM (200 mg intravenously every 3 weeks) after failure of prior chemotherapy [median no. of regimens was 1 (range 1-4)] between 01/2015 and 12/2017. CD3+ and CD8+ TCDs were analyzed in the primary tumor core (CT) and at the invasive margin (IM) by immunohistochemistry and automated image analysis to determine density score (0 to 100) for each T-cell subtype and compartment (Ventana Medical Systems, Inc.). Patients were categorized as 1) responders [CR (complete response) + PR (partial response)] vs. non responders [SD (stable disease) + PD (progressive disease)] per RECIST version 1.1, and 2) by duration of response (< or > 12 months). Results: Median follow-up post PEM was 19.5 (9-41) months. Responders included 2 CR and 5 PR; non-responders included 4 SD and 1 PD. The ORR and median time to response were 58.3% (7/12) and 12 weeks (range 9-40), respectively. CD3+ and CD8+ TCD scores were higher in responders vs. in non-responders as well as in patients who had disease control for > 12 months; differences were greatest for CD8+ CT (Table). Conclusions: Among patients treated with PEM, data suggest higher intratumoral CD3+ and CD8+ TCDs in responders versus non-responders and in those with a longer duration of disease control. If confirmed, TCDs may potentially predict responsiveness to PD-1 blockade in dMMR mCRCs. [Table: see text]

3524 Background: In mCRC, induction combination chemotherapy with targeted agents is considered the mainstay of treatment. This is typically followed by maintenance therapy vs. observation which had been examined in various trials. However, it remains unclear how best optimize maintenance strategy. We aim to evaluate comparative effectiveness to support best maintenance strategy. Methods: We searched PubMed, Embase, and Cochrane CENTRAL for randomized controlled trials (RCT) evaluating different maintenance strategies in previously untreated mCRC patients (pts): observation (obs), bevacizumab (bev), fluoropyrimidine (FP), FP+bev, or continuing induction regimen (CTX). Outcomes of interest included OS and PFS. The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White’s multivariate meta-regression to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Results: Twelve trials at low risk of bias (5540 pts) were included. Network meta-analysis shows no benefit of CTX over obs in terms of PFS (HR 0.7; 95% CI 0.46-1.09) and OS (HR 0.95; 95% CI 0.85-1.07). Compared to obs, maintenance therapy shows PFS benefit (HR 0.58; 95% CI 0.43-0.77) with only a trend in OS (HR 0.91; 95% CI 0.83-1.009). All maintenance strategies (FP, FP+bev, and bev) show significant improvement in PFS over obs. On SUCRA analysis, maintenance treatment (FP or FP+bev) has the highest likelihood of achieving better PFS (67.1% for FP and 99.8% for FP+bev) and OS (81.3% for FP and 73.2% for FP+bev). Conclusions: A maintenance strategy with at least a FP with or without the addition of bevacizumab is preferred. However, given the lack of a clear OS benefit, obs is an acceptable alternative. Optimal maintenance strategies should be dependent on factors including patient preferences, cost and toxicities. [Table: see text]

3101 Background: PDO is a promising translational tool that recapitulates the biology and drug response of donor cancer patient. However, an unmet need is to have PDO drug-screening data available for treatment decision making in clinic. We conducted a pilot study to determine whether PDO testing results will be available at critical treatment decision points in metastatic GI cancer patients. Methods: Metastatic GI cancer patients undergoing core-needle biopsy were eligible. Tumor cells isolated from ≤4 fresh biopsy tissues were grown in a Matrigel-based culture. PDO response to anti-cancer drugs were evaluated; and when available, correlated with donors’ clinical response to the same agent(s). PDO response was defined as IC50 < 0.1 × published Cmax of the drug clinically; stable as IC50 between 0.1 to 10 × Cmax. Radiographic response was per RECIST criteria. Results: We enrolled 27 refractory metastatic GI cancer patients (9 colorectal [CRC], 9 pancreas, and 9 biliary tract). Median lines of therapy were 4, 2, and 2; the success rate of organoid establishment was 89%, 44%, and 55%, respectively. The median time from biopsy to availability of drug-testing data was 64 days (range: 24 to 93 days). The median time from biopsy to next CT re-staging in donors was 64 days. The established PDOs shared histological and genomic features with donor clinical tissue. PDO and clinical responses to the same agent(s) were correlated in 2 CRC donors including (1) BRAFV600E-mutated PDO responded to vemurafenib + panitumumab, as did the donor who had partial response (PDO drug-testing data were available 55 days post-biopsy, 23 days prior to restaging scan); (2) KRAS/FGF-dual amplified PDO had stable disease status to regorafenib, as did the biopsied lesion from the donor (73 days post-biopsy, 5 days post-scan). Conclusions: We showed the feasibility of completing PDO drug sensitivity testing in metastatic GI cancer patients within a short time that could impact clinical decision making, particularly in CRC. PDO drug response showed correlation with clinical response. With further refinement, PDO can be a powerful tool for personalizing cancer therapy in metastatic GI cancer patients.

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.

619 Background: Regorafenib (at a starting dose of 160 mg/day, rego 160), regorafenib (with a weekly dose escalation, rego 80+) and TAS-102, are suggested treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these 3 strategies. Methods: We searched PubMed, Embase, and Cochrane CENTRAL, for randomized controlled trials evaluating TAS 102 or regorafenib in refractory mCRC patients who progressed on/intolerant of previous oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included OS and PFS. The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White’s multivariate meta-regression to pool evidence from direct and indirect comparisons. Results: Six trials (3 of regorafenib and 3 of TAS-102) at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to BSC in terms of PFS (Rego 160: HR = 0.4, CI 0.26 to 0.63; TAS-102: HR = 0.46, CI 0.40 to 0.52) and OS (Rego 160: HR = 0.67, CI 0.48 to 0.93; TAS-102: HR = 0.67, CI 0.57 to 0.80). Network analysis showed that there was no difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR = 0.44, CI 0.23 to 0.84) and PFS (HR = 0.37, CI 0.21 to 0.66). There was a numerical advantage for Rego 80+ compared to TAS-102 and Rego 160 (see table). Conclusions: Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. [Table: see text]

TPS532 Background: Recent studies have shown that FGFR2 fusions may represent recurrent (prevalence ~10-15% in larger cohorts) driver events amenable to therapeutic targeting in patients with advanced, intrahepatic cholangiocarcinoma. Methods: This single arm pilot study (NCT02265341) is being conducted at 3 centers (Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester; enrollment initiated December 2014). Next-generation sequencing based assays and a FISH-break apart assay are used to identify tumors with FGFR2 fusions. Patients must additionally have histologically/cytologically confirmed cholangiocarcinoma, ECOG performance score 0-2, measurable disease, preserved hematologic/renal and hepatic function and absence of cardiac events/stroke in the preceding 6 months. Ponatinib is administered at 45 mg once daily. Patients will be treated until disease progression, intolerable toxicity or patient decision to not pursue further therapy. The primary objective of the study is to estimate the clinical benefit rate (defined as composite of partial response rate, complete response rate and stable disease rate ≥ 4 months; as defined by RECIST criteria v1.1). Secondary endpoints include estimation of progression-free survival, overall survival, CA19-9 response rate (defined as > 50% reduction from baseline) and evaluation of the overall adverse event profile of ponatinib in this patient population. Translational objectives include serial circulating DNA (ct-DNA) monitoring, target knockdown assessments in tumor tissue (p-FGFR2, p-FRS2, p-Akt and p-ERK) and evaluation of mechanisms of resistance through comparison of baseline and progression biopsy samples using multi-platform sequencing (exome, RNA-Seq and methyl-Seq). Additionally, quality of life assessments will be evaluated using EORTC-QLQ-C30 and BIL21 tools. A total of 30 patients will be enrolled into the study (12 of 30 patients have been enrolled). The trial is designed using an underlying assumption of clinical benefit rate (CBR) of 5% with significance level of 0.15 and 80% power to detect a 20% CBR. Clinical trial information: NCT02265341.