Citations

TPS4136 Background: AGOC has a poor prognosis with no established standard treatment following failure of chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT). INTEGRATE (phase 2) demonstrated REG was highly effective in prolonging PFS across a range of AGOC pts, with a positive OS trend. Regional differences were found in magnitude of effect, but REG was effective in all regions/subgroups. The phase 3 INTEGRATE II will explore whether REG is effective in prolonging survival in patients overall, and in the Asian sub-population. Methods: International (Australia/New Zealand (NHMRC CTC); Canada (CCTG), Korea, Japan, Taiwan, USA (ACCRU)) randomised phase III, double-blind, placebo-controlled trial with 2:1 (REG:placebo)(PBO) randomisation and stratification by: Location of tumour, Geographic region, prior VEGF inhibitors. Eligible patients (histologically confirmed AGOC), with evaluable metastatic or locally advanced disease refractory to, or relapsed following second line CT, will receive best supportive care plus 160mg REG or matched placebo orally on days 1-21 of each 28 day cycle until disease progression or prohibitive adverse events. Primary endpoint is OS. Secondary endpoints: PFS, response rate, quality of life, safety, identification of prognostic/predictive biomarkers for study endpoints, and REG PK across geographical regions. 350 patients (50% from Asia) randomized in a 2:1 ratio will provide 90% power to detect a hazard ratio (HR) for OS of 0.67 with a 2-sided α of 0.05 assuming PBO median survival is 4.5 mos. The sample size accommodates 2 interim analyses undertaken at 1/3 and 2/3 of required events. As of January 2017, 12 of 28 planned ANZ sites are open, with 4 patients enrolled. Regulatory approval has been received for 12 Canadian sites, and 12 Korean sites. Korean recruitment is expected to commence in February 2017. Regulatory submissions are pending in Taiwan, Japan, and the USA. Clinical trial information: NCT02773524.

e15045 Background: BRAF V600E mutations are present in 7% of mCRC patients (pts) and portend a poor prognosis. Data guiding initial treatment decisions are limited. This study investigates the management approach and clinical impact of utilizing metastasectomy for pts with BRAF V600E mCRC. Methods: By using prospective clinical and molecular data from Mayo Clinic, pts with BRAF V600E mCRC were analyzed for clinical characteristics, treatment and survival outcomes. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: 164 pts with BRAF V600E mCRC were identified between 6/1999-8/2015. Complete follow up data were available for 52 pts. Median age of 65 years, 61% female, ECOG PS ≤ 1, 71% of pts had right sided tumors and 28% presented with liver limited metastasis. Only 7% (4/52) received FOLFOXIRI/BEV (average of 8 cycles). Peripheral neuropathy, pending BRAF status , and prior progression on FOLFOX, were the most common reasons documented for avoiding FOLFOXIRI/BEV. FOLFOX/BEV was the most common 1st line regimen used (32% of pts). Median overall survival (mOS) for all 52 pts was 25 months (mo) with median progression free survival (PFS) of 9.3 mo, reflecting worse survival when compared to BRAF wild-type control patients treated at Mayo Clinic (249 pts, mOS: 43 mo). With median follow up of 18.3 mo, 21 pts who underwent metastasectomy had improved OS (29.1mo vs. 22.7mo, HR = 0.33; CI: 0.12-0.78; p = 0.01) and PFS (13.6mo vs. 6.2mo, HR = 0.53, CI: 0.28-0.97; p = 0.03) when compared to the non-metastasectomy cohort, respectively. In multivariate analysis, metastasectomy remained statistically significant for improved survival outcomes (HR 0.52; 95% CI 0.07-1.02; p = 0.02). Median relapse-free survival after metastasectomy was 9.7 mo (95% CI, 5.5 mo-19.5 mo). Only 2 pts remain disease free at the time of last follow up, with 1 pt without recurrent disease for greater than 2 years (28.9 mo). Conclusions: The use of multimodality therapy incorporating metastasectomy for BRAF V600E mCRC is a critical component for enhanced survival outcomes.

e15030 Background: Deficiencies in the DNA mismatch repair (dMMR) system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI-H). MSI-H in mCRC is rare and its prognostic and predictive impact on outcome is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI-H in metastatic CRC prior to the immune therapy era. Methods: 75 MSI-H mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous) MSS mCRC pts were identified from 1268 mCRC who had MSI/MMR test results at Mayo Clinic Rochester between 1/1992 and 7/2016. A retrospective review was conducted by using data from electronic medical records (EMR). Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: In the MSI-H group, there were 39 male (52%) and 36 female (48%) pts. Median age at metastatic disease diagnosis was 54.7 years. 35 patients presented with stage IV CRC. Primary tumors location: 38 right side, 11 transverse colon, 15 left side, 11 rectum. The MSS group was well matched (3 mismatches for gender and 1 mismatch for metachronous metastatic disease). Median overall survivals (OS) were 28.1 and 37.4 months for MSI-H and MSS pts, respectively ( p= 0.098). 98.7% MSS pts and 94.7% MSI-H pts had Fluoropyrimidine-based chemotherapy for metastatic disease and there was no median OS difference between these two groups (37.4 vs. 32.3 months p= 0.91). 43 MSI-H and 39 MSS pts had metastasectomy including ablation ( p= 0.51) with longer median OS (82.0 and 69.9 months, p= 0.90) compared to pts without metastasectomy (13.9 and 19.7 months, p= 0.15). Age < 65, metastasectomy, asymptomatic metastatic lesions, BRAF wild type, and multiple metastasectomy were associated with better survival in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis ( p< 0.0001). Conclusions: MSI-H mCRC do not appear to have improved prognosis compared with MSS cancers, in fact, there is a trend toward inferior outcome. In both groups, metastasectomy including multiple metastasectomy should be considered to optimize OS.

TPS3624 Background: To improve survival for patients with mCRC, efforts are needed to identify and treat actionable genomic alterations. HER2 is amplified in approximately 5-8% of patients with KRAS and NRAS (RAS) wild-type mCRC. HER2 functions as an oncogenic driver and a mediator of EGFR antibody (Ab) resistance. Although prior studies have shown that anti-HER2 therapies are active in patients with HER2+ (HER2 IHC 3+ or HER2 amplified) mCRC, there are no HER2-directed therapies approved for these patients. Tucatinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of HER2, currently being developed to treat metastatic breast cancer. In HER2+ CRC patient derived xenograft models, tucatinib has substantial anti-tumor activity. The addition of the anti-HER2 monoclonal Ab trastuzumab augments tumor growth inhibition. Methods: This single-arm phase II study will test the combination of tucatinib and trastuzumab in patients with HER2+ mCRC. Eligible patients include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, and an anti-VEGF monoclonal Ab. Patients must have HER2+ disease by IHC, FISH, or NGS. Prior treatment with anti-HER2 targeting therapy is excluded. The primary objective is to assess the objective response rate for the combination. Secondary objectives are to evaluate the efficacy (PFS, OS, clinical benefit rate), safety, and tolerability of the combination. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if the combination eliminates HER2 amplified circulating tumor DNA. Subjects will receive tucatinib at a dose of 300mg by mouth daily, and trastuzumab will be administered every 3 weeks (8 mg/kg IV day 1 of cycle 1, then 6 mg/kg IV Q3 weeks). Response will be assessed every 3 cycles (9 weeks) per RECIST version 1.1. Both agents will be provided by the study. This study was initiated in February 2017. Recruitment is ongoing at 8 sites in the Academic and Community Cancer Research United (ACCRU) network. Clinical trial information: NCT03043313.

TPS3622 Background: BRAF mutations are found in ≈10% of mCRC cases. Pts with BRAFV600E mCRC have a poor prognosis, with shorter progression-free survival (PFS) and overall survival (OS) than pts with BRAFwt mCRC (Van Cutsem et al 2011; Modest et al 2012; Sorbye et al 2015). The benefits of combined BRAF + EGFR inhibition in mCRC have been demonstrated in vitro (Corcoran et al 2012; Prahallad et al 2012; Yang et al 2012), and preclinical evidence suggests that adding MEK signaling inhibition improves antitumor activity. Early clinical data indicate that BRAF + EGFR + MEK inhibition has greater activity than BRAF + EGFR inhibition in pts with BRAFV600E mCRC (Van Cutsem et al 2016). Our study will examine the combination of BINI (a MEK inhibitor) + ENCO (a selective BRAF kinase inhibitor) + CTX (an anti-EGFR antibody) and of ENCO + CTX in pts with BRAFV600E mCRC. Methods: BEACON CRC (NCT02928224) is enrolling pts with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. A safety lead-in phase (≈30 pts) will determine the safety and tolerability of oral ENCO 300 mg QD + oral BINI 45 mg BID + intravenous CTX 400 mg/m2 followed by 250 mg/m2 QW. In the phase 3 portion, ≈615 pts will be randomized 1:1:1 to triplet (ENCO + BINI + CTX), doublet (ENCO + CTX), or control (investigator’s choice of IRI/CTX or FOLFIRI/CTX) arms. Pts will be treated in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. The primary endpoint is OS (triplet vs control). Secondary endpoints include OS (doublet vs control), confirmed investigator-assessed objective response rate according to RECIST version 1.1 (triplet or doublet vs control; triplet vs doublet), PFS (triplet or doublet vs control), duration of response, time to response, pharmacokinetics, and pt-reported outcomes. Safety will be summarized using standard adverse event reporting. Clinical trial information: NCT02928224.

TPS3619 Background: Cancer stem cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapeutics, including 5-FU and irinotecan. Encouraging anticancer activity in advanced CRC was observed in a phase Ib/II (Bendell et al, GI ASCO 2017) study of 63 pts with disease control rate (DCR) of 93% (28/30) and overall response rate (ORR) of 33% (10/30) in FOLFIRI-naïve pts who have had an on-study RECIST evaluation. On the basis of these data, a phase III trial is being conducted in North America, Europe, Australia, and Asia. Methods: This study (ClinicalTrials.gov NCT02753127) will assess the efficacy of napabucasin+FOLFIRI vs FOLFIRI in pts with mCRC (n = 1250). Addition of bevacizumab (bev) is permissible per investigator choice. Pts must have failed 1 prior line of therapy with oxaliplatin and a fluoropyrimidine +/- bev for metastatic disease. Pts are randomized 1:1 to receive napabucasin 240 mg PO BID plus FOLFIRI bi-weekly, or FOLFIRI bi-weekly (bev may be added to FOLFIRI by investigator choice) and stratified by geography, time to progression on 1st-line therapy, RAS mutation status, bev as part of study treatment and primary tumor location. Treatment will continue until disease progression, or another discontinuation criterion. Primary endpoint is overall survival (OS) in the general study population (ITT) (HR 0.80 for OS improvement from 12.54 to 15.68 months); secondary endpoints include OS in the biomarker positive (biomarker+) population, progression free survival (PFS) in the ITT population, PFS in biomarker+ population, ORR and DCR in the ITT and in biomarker+ populations, safety and quality of life. Also, blood and tumor archival tissue will be assessed for PK and biomarker analyses. Global enrollment is underway. Clinical trial information: NCT02753127.

3559 Background: A Phase 3 clinical trial (RECOURSE) showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (mCRC) treated with standard chemotherapy and targeted-therapy drugs (Mayer et al. N Engl J Med 2015;372:1909-19). An expanded-access program (EAP) was started to provide access to FTD/TPI for patients with mCRC with similar eligibility and to further assess the safety of FTD/TPI in a “real-world” setting in US patients. Methods: Patients aged ≥18 years with refractory mCRC resistant to ≥2 regimens of standard chemotherapy with appropriate biologics and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to this open-label EAP. Patients received FTD/TPI 35 mg/m2twice daily for 5 days followed by 2 days’ rest repeated twice followed by 14 days’ rest over a 28-day treatment cycle until drug discontinuation. Sites reported duration of therapy, discontinuation due to disease progression, and adverse events (AEs) for each patient. Results: 549 patients were enrolled; 53.2% were male. Median duration of FTD/TPI therapy was 9.7 weeks, which was similar to US patients from RECOURSE (8.9). 10.2% of patients died during the study period, 9.7% due to disease progression. 76.1% of patients discontinued treatment due to disease progression and 4% discontinued due to AEs. Drug-related clinically significant AEs (all grades) are summarized in the table. Conclusions: Patients with refractory mCRC in this EAP had a similar exposure duration to that reported in US patients from RECOURSE, with no unexpected safety concerns. While gastrointestinal toxicity was lower in this population, this may be due to reporting of “significant” events. The clinical profile of FTD/TPI is confirmed in this larger, non-randomized “real-world” experience. Sponsorship: Taiho Oncology, Inc. Editorial Assistance: Complete HealthVizion. Clinical trial information: NCT02286492. [Table: see text]

3558 Background: Anti-programmed death-1 (PD-1) antibodies have been shown to be effective in the treatment of dMMR CRC. We describe an updated analysis from a cohort of 19 patients (pts) with dMMR CRC treated with pembrolizumab. Methods: Pts were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through January 2017. All pts with dMMR CRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR = CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: Nineteen pts were included in this analysis; median age at diagnosis was 48.6 years (range 25-93); 53% were female. Most primary tumors were right sided (n = 12; 63%), 6 (32%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Twelve (63%) pts received ≥2 lines of therapy prior to pembrolizumab (range 1-4). Five pts received 2 mg/kg every 3 weeks, 11 received 200 mg/day every 3 weeks and 2 pts received 10 mg/kg (1 every 2 weeks, the other every 3 weeks). The most common alterations identified were loss of MLH1 (11/15) and PMS2 (12/15); 4 pts had germline mutations (mut) identified. KRAS mut was identified in 6/16 pts and 2 pts had BRAF mut. Three pts had MLH1 hypermethylation. Median number of cycles of pembrolizumab was 8 (range 1-35+), with 13 (68%) pts receiving ≥6 cycles. DCR at first assessment was 68%, with 5% CR, 47% PR and 16% SD. Median follow-up from diagnosis was 29 months (95% CI 18-42). Median OS was 103 months (95% CI 85-103); 12-month OS was 89%. Median OS from PD-1 therapy was 16.1 months (95% CI 16-NR); 12-month OS from PD-1 therapy was 79%. Median PFS was NR (95% CI 5-NR); 12-month PFS was 54%. At time of analysis, 9 pts remain on PD-1 therapy; 5 pts have died; 3 have received subsequent therapy. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated pts.

3556 Background: To define and update survival rates and relapse patterns in patients (pts) with isolated advanced abdominal nodal metastasis secondary to colorectal cancer (CRC), treated with curative intent using aggressive trimodality therapy. Methods: Fifty-seven pts with isolated advanced abdominal lymph node metastasis (retroperitoneal and mesenteric) secondary to colorectal cancer received trimodality therapy defined as chemotherapy delivered in conjunction with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5-FU was the most common radiosensitizer used (66%, 38 pts). The median dose of EBRT was 50 Gy & the median dose of intraoperative radiotherapy was 12.5 Gy. End points included distant metastasis, toxicities, local failure within EBRT field, recurrence within the intraoperative radiotherapy field, and survival. Results: 49% of pts were male, median age 50.5 yrs. All patients had ECOG ≤ 1. 27 pts had primary right sided colon cancer, 16 left sided colon cancer and 14 rectal primaries. Median time from initial CRC diagnosis to development of abdominal lymph node metastatic disease was 24 months (95% CI, 23.5-45.1 months). 84% (48 pts) had paraaortic nodal metastases, 12% (7 pts) had mesenteric nodal metastases, and 3% (2 pts) had both. With a median follow up of 89.4 months, the median overall survival and 5-year estimated survival rate were 53.2 months (95% CI, 46.4-78.8 months) and 42%, respectively. Median progression free survival was 19.3 months (95% CI, 15.6-32.8 months). 21 (37%) pts never developed distant disease. Outcome was not affected by disease sidedness, rectal primary, or mutational profile. Treatment was well tolerated without any grade 3/4 toxicities. Conclusions: The use of trimodality therapy including EBRT with radiosensitizing chemotherapy, lymphadenectomy and IORT produces sustainable long-term survival in selected metastatic CRC pts presenting with isolated retroperitoneal/mesenteric nodal relapse.