Grothey, Axel

497 Background: As activating RAS mutations have been shown to predict lack of benefit from anti-EGFR therapies in advanced CRC, NCCN guidelines recommend testing for KRAS exon 2 and non-exon 2 mutations; however, these alterations are thought to explain only a subset of de novo resistance to targeted therapy. In a large set of CRC assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we assessed the frequency of less common KRAS short insertions that may predict failure of anti-EGFR therapy. Methods: 4,422 CRC cases were assayed with CGP performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 650X for at least 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were identified, including base pair substitutions, insertions/deletions, copy number alterations, and rearrangements. Pertinent available prior molecular testing results and clinical history was reviewed for selected cases. Results: Out of 4,422 CRC cases analyzed, KRAS short variants were identified in 50.9% of cases. A majority of cases contained a KRAS alteration at either codon G12 (35.5%) or G13 (9.1%), while alterations at codons Q61 or A146 were identified in 2.2% and 3.1% of cases, respectively. KRAS insertions were identified in 8 ( < 0.5%) cases. All KRAS insertions identified fell within codons 9-13, and 6/8 cases harbored V9_G10 insertions. Out of 6 patients with prior KRAS testing results available, 5 (83%) were negative by previous testing. Conclusions: CGP identifies KRAS insertions within or adjacent to hotspot regions in CRC cases which have previously tested negative for KRAS mutations. Given the importance of KRAS alterations in predicting lack of response to anti-EGFR therapies in CRC, accurate detection of these alterations in the course of clinical care is essential for effective treatment. CGP offers the possibility of identifying KRAS insertions that may impact efficacy of anti-EGFR targeted therapy and should be considered when previous focused testing for KRAS mutations is negative.

535 Background: Prior ARIES analyses showed that BV-treated mCRC patients (pts) receiving chemotherapy (CT)/biologics + BV within 2 months (mo) after 1st progressive disease (PD) had longer post-progression survival (PPS) than pts receiving only CT/biologics. The present analysis evaluated whether this effect of BV was consistent when used with common 2L CT regimens— irinotecan- (iri-) and oxaliplatin- (ox-) based—in mCRC pts exposed to 1L BV in ARIES. Methods: ARIES enrolled mCRC pts receiving 1L CT + BV. No tx regimens or assessments were protocol specified. This analysis evaluated 1L BV-treated mCRC pts who had PD, survived ≥2 mo after PD, and received 2L iri- or ox-based tx. PPS was estimated by Kaplan-Meier methods. Cox regression was used to estimate hazard ratios (HRs), while adjusting for covariates (eg, 1L time to progression). Results: Of 1550 1L pts in ARIES, 1074 had 1st PD and survived ≥2 mo after PD. Of these 1074, 390 and 114 received 2L iri- and ox-based tx, respectively, ± BV ( table ). Baseline characteristics were generally similar between groups. The incidence of targeted adverse events (TAEs) was as expected and similar between the BV and No BV groups over time. In pts receiving 2L iri- or ox-based CT tx, PPS in BV-treated pts was longer compared to those not on BV. Analyses may be limited by small pt numbers in some groups. Conclusions: Consistent with prior ARIES analyses, the continued use of BV after 1st PD was associated with prolonged PPS regardless of the 2L CT backbone used. [Table: see text]

111 Background: Trastuzumab in combination with chemotherapy is recommended for advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2) overexpression. Despite this recommendation, an informal pilot survey suggested that many oncologists do not include HER2 testing as part of routine practice to identify patients most likely to benefit from adding trastuzumab to chemotherapy. Methods: An interactive online educational activity was developed to provide expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer. Pre- and post-education surveys were administered as part of the activity to measure changes in participant competence. In addition, 3 months after completing the educational activity, participants were sent another follow-up survey by email to assess changes in practice. Results: To date, pre-and post-education surveys have been obtained for 122 oncologists and 3-month follow-up surveys obtained from 14 oncologists. In the pre-education survey, only 46% said they were testing all of their patients with advanced gastric or GE cancer for HER2 overexpression. However, immediately after participating in the educational intervention, this proportion increased to 93%. Importantly, a follow-up survey indicated that HER2 testing of all patients with advanced gastric or GE cancer was now part of routine practice for 79% of those surveyed. A final analysis of pre- and post-education and 3-month follow-up surveys will be presented. Conclusions: Expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer provided through an interactive online educational intervention substantially improved oncologist competence and practice patterns.

In the past decade, significant advances have been made in the treatment of advanced colorectal cancer. Multiple cytotoxic agents and targeted therapies have been approved for management of metastatic colorectal cancer, leading to improvement of median overall survival in clinical trials to more than 30 months. Of note, before the introduction of biologics into treatment algorithms for metastatic colorectal cancer, median survival in phase III trials never exceeded 24 months. In 2016, the most common treatment approach in first line is a combination of chemotherapy with a biologic agent. The choice of therapy is influenced by patient factors (eg, age, comorbidities), tumor characteristics (eg, overall tumor burden, pattern of metastatic spread, mutation signature), potential adverse effects of therapy, and goals of treatment. The choice between irinotecan- or oxaliplatin-based cytotoxic chemotherapy regimen is primarily based on differential toxicity profile because they have similar efficacy. Currently, three biologic agents—bevacizumab, cetuximab, and panitumumab—are approved for first-line treatment of metastatic colorectal cancer. For patients with mutant RAS and likely mutant BRAF V600E tumors, bevacizumab is the only biologic agent that can be used in conjunction with cytotoxic chemotherapy. The choice of anti–epidermal growth factor antibody or anti–vascular endothelial growth factor antibody in RAS wild-type tumors is based on the specific clinical scenario. Recently, some clinical and molecular biomarkers have emerged that may help in decision making. In this review, we discuss the role of biologics in the management of first-line treatment of metastatic colorectal cancer.

480 Background: COs associated with varying Tx patterns in mCRC pts are poorly understood because patterns diverge from the randomized trials (RCT). The RCTs of BV (Avastin) plus chemotherapy (CT) in mCRC pts continued BV until progressive disease (PD), even if CT was stopped/changed. Some RCTs of BV+CT in mCRC show ∼50% of pts stopping Tx early for reasons other than PD with possible lessening of benefit. It is unclear if this is due to use of a particular CT regimen or other practice pattern. While the beneficial effect of post-PD BV Tx has been shown in ARIES (HR 0.52 BBP vs No BBP) [A Cohn, ASCO 2010], the effect of stopping BV or CT before PD is unclear. ARIES, a community based observational study with a large cohort of 1st line BV-treated mCRC pts, will assess the COs associated with different 1st line Tx patterns (BV and CT) based on real world practice. Methods: ARIES enrolled mCRC pts receiving first- or second-line CT+BV. No Tx regimens or assessments are protocol specified. Data are collected prospectively at baseline (BL) and quarterly. Analyses included first-line pts with PD. Tx patterns of pts initially treated with FOLFOX/BV or FOLFIRI/BV are described and preliminary COs (PFS and OS) are estimated from K-M curves. Tx duration is calculated from enrollment date. Results: As of 2/5/10, 1,548 first-line mCRC pts enrolled (median follow up = 21 m); 1,133 pts had PD. Of 1,133 pts with PD, most had FOLFOX/BV (63%) or FOLFIRI/BV (16%) as first CT. BL characteristics were similar, but the FOLFOX/BV group had more stage 4 pts (74%). Main reasons for stopping BV include AE, max benefit achieved and CT holiday. Tx patterns and COs are in the table. Conclusions: ARIES first-line mCRC pts treated with FOLFOX/BV or FOLFIRI/BV had similar Tx patterns and COs despite the common opinion that they may differ in tolerability and possibly effectiveness. Additional analyses will assess the impact of stopping BV and/or CT before PD. [Table: see text] [Table: see text]