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Purpose:BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.Patients and Methods:We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.Results:Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification.Conclusions:The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.

The VEGF-A monoclonal antibody bevacizumab is currently recommended for first-line treatment of all metastatic colorectal cancer (mCRC) patients. Cost-benefit ratio and side-effects however necessitate patient selection. A large retrospective yet nonrandomized study showed that patients with loss of chromosome 18q11.2-q12.1 in the tumor and treated with bevacizumab have 3 months improved median progression-free (PFS) and overall survival (OS) benefit compared to patients without this loss and/or treatment modality. Implementation for loss of chromosome 18q11.2-q12.1 as a marker in clinical practice mandates evidence in a randomized controlled trial for bevacizumab. Of the trials with randomization of chemotherapy vs chemotherapy with bevacizumab, the AGITG-MAX trial was the only one with tumor materials available. Chromosome 18q11.2-q12.1 copy number status was measured for 256 AGITG-MAX trial patients and correlated with PFS according to a predefined analysis plan with marker-treatment interaction as the primary end-point. Chromosome 18q11.2-q12.1 losses were detected in 71% of patients (181/256) characteristic for mCRC. Consistent with the nonrandomized study, significant PFS benefit of bevacizumab was observed in patients with chromosome 18q11.2-q12.1 loss (P =.009), and not in patients without 18q loss (P =.67). Although significance for marker-treatment interaction was not reached (Pinteraction =.28), hazard ratio and 95% confidence interval of this randomized cohort (HRinteraction = 0.72; 95% CI = 0.39-1.32) shows striking overlap with the nonrandomized study cohorts (HRinteraction = 0.41; 95% CI = 0.32-0.8) supported by a nonsignificant Cochrane χ2 test (P =.11) for heterogeneity. We conclude that post hoc analysis of the AGITG-MAX RCT provides supportive evidence for chromosome 18q11.2-q12.1 as a predictive marker for bevacizumab in mCRC patients.

Purpose: To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods: In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively. Conclusions: Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

Background Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). Methods/design INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator’s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. Discussion INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. Trial registration INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most colorectal cancers. A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in colorectal cancer cells. Nevertheless, these drugs do induce expression of proapoptotic factors, suggesting they may prime colorectal cancer cells to undergo apoptosis. As histone deacetylase inhibitors (HDACis) induce expression of multiple proapoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in colorectal cancer cell lines and patient-derived tumor organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor–induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by combining an HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT; KRASG12C, BRAFV600E colorectal cancer cell lines, respectively. These findings identify a series of ERK/MAPK genotype-tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer.

Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1–4 was detected in 8%–19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.

PURPOSE The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer. METHODS Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763). RESULTS A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) v 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% v 37.3% and 23.4% v 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; P = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% v 65.5% (HR, 1.02) and OS of 73.5% v 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis. CONCLUSION The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.

Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4–6, 6–8 and 8–10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.

118 Background: Anti-VEGF is widely used in the treatment (trt) of metastatic colorectal cancer (mCRC). Only studies with bevacizumab (BEV) have shown survival benefit (bnf) in first line trt. The magnitude of bnf might differ based on the metastatic (met) site and the chemotherapy regimen (CTR) with which BEV is partnered. ARCAD database contains individual patient data (IPD) of randomized trials that evaluated BEV+ CT. In this pooled analysis, we aimed to evaluate BEV bnf in mCRC with lung metastases (mets) either as single or multiple sites. Methods: IPD from four trials (AVF2107g, N016966, AVF2192g, AGITG) comparing CT +/- BEV were pooled. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method and prognostic value of lung mets was evaluated by stratified Cox models according to number and type of met sites and CTRs, oxaliplatin or irinotecan (OX/IRI) based. The predictive bnf of BEV was evaluated by interaction test (int) between trt and lung mets status in subgroups and considered as significant (sig) with a P < 0.1. Results: 2728 patients (pts) with known met sites and survival data were pooled. 1020 pts had single met site, 133 had only lung mets. 1708 pts had multiple met sites, 1008 had lung mets. Pts characteristics were well balanced. Sig OS bnf of BEV was observed in the whole population. In pts subgroup according to the presence or absence of lung mets, sig bnf of BEV were observed with a non-sig int ( Pint=.590). Non-sig bnf of BEV was observed in pts with single site regardless of met site (lung or no lung) or CTR. Sig bnf of BEV was observed in pts with multiple sites without lung mets whatever the CTRs. While sig bnf of BEV was observed in pts with multiple sites with lung mets, we found a sig int between BEV and OX/IRI-based regimens ( Pint=.022). The bnf of BEV was observed with IRI-based regimen but not in OX-based regimen. The bnf of BEV appears greater in multiple sites without lung mets than with lung mets with a sig stratified log-rank test ( PLRT

LBA294 Background: AGOC has limited options after second-line therapy. Regorafenib (Rego), an oral multi-targeted tyrosine kinase inhibitor (TKI) targeting angiogenic, stromal and oncogenic receptor TKs, prolonged progression free survival (PFS) versus placebo (PBO) across all regions/subgroups in the INTEGRATE phase 2 randomised trial (JCO 2016 43(23):2728-2735). INTEGRATE IIa was designed to examine if Rego improves overall survival (OS). Methods: Double-blind placebo-controlled phase 3 trial comparing Rego + best supportive care (BSC) vs PBO + BSC using 2:1 randomisation, stratified by tumour location (GO junction vs gastric), geographic region (Asia vs rest of world), prior VEGF inhibitors (Y/N). Eligibility criteria: histologically/cytologically confirmed AGOC, evaluable metastatic/locally advanced disease, failure/intolerance of ≥ 2 prior lines of therapy with a platinum agent + fluoropyrimidine. Primary objective: OS in the whole study population. OS among Asian sub-population is a key secondary objective. Target of at least 221 events from 250 patients provides 80% power to detect an OS hazard ratio (HR) of 0.67. Pooled OS analysis incorporating INTEGRATE phase 2 data is also planned. Secondary endpoints include PFS, objective response rate, safety and quality of life. Results: 251 patients enrolled (Oct16 - Sep21) from 5 countries:157 from Asia (Korea, Taiwan, Japan);169 Rego and 82 PBO. After 238 events, median OS (in months) for Rego vs PBO was 4.5 vs 4.0 (HR 0.70 [95%CI: 0.53 to 0.92]; p = 0.011) in the whole study population, with a 12 mo survival of 19% vs 6%. Median PFS was 1.8 v 1.6 (HR = 0.52; [95%CI: 0.40-0.69]; p = < .0001). After pre-planned adjustment for multiplicity, there were no statistically significant differences across regions (Asia versus non-Asia) or other pre-specified subgroups. Pooled analysis median OS was 5.0 v 4.1 (HR 0.69 [95% CI:0.56 to 0.87]; p = 0.001). Rego toxicity was similar to previously reported. Conclusions: Rego improves survival compared with PBO in advanced refractory AGOC, offering a new treatment option. This result creates a therapeutic platform for combination studies. INTEGRATE IIb is an ongoing international randomised Phase 3 trial in pre-treated patients with AGOC comparing Rego + nivolumab to standard chemotherapy (NCT0487936). Clinical trial information: NCT02773524 .

84 Background: Colorectal cancer (CRC) survivorship is rising. Few studies have considered shared follow up (FU) care (SC) between oncologists and primary care providers (PCPs). SCORE is the first large RCT of SC for CRC survivors. Aim: to compare SC with usual care (UC) for CRC survivors. Primary objective: assess the effect of SC vs UC on the EORTC QLQ-C30 Global Health Status/Quality of Life (GHQ-QoL) scale to 12 months (mo). Secondary objectives: assess the effect of SC vs UC on QoL; pt perceptions of care; costs; clinical care processes (CEA tests, recurrences); and feasibility (recruitment, completion rate). Methods: Pts had stage I-III CRC, completed all treatments within 3 mo, spoke English, had a PCP, and no prior cancer. After pt consent, PCP could opt out. Pts were randomised 1 to 1 to SC or UC. SC replaced 2 routine oncologist visits with PCP visits and included a survivorship care plan, concerns checklist and management guidelines for the PCP. PCPs were asked to request CEA tests at 3 and 9 mo visits. Pts completed measures at baseline (BL) and at 6 and 12 mo FU. An estimate of the difference (diff) between groups on GHQ-QoL to 12 mo was obtained from a mixed model for repeated measures (MMRM). The test of non-inferiority was performed by evaluating the lower limit of the two-sided 95% confidence interval (CI) for the estimated diff (SC–UC) against a pre-specified non-inferiority margin (NIM) of -10 points. All randomised pts with available data were included in the primary analysis. Per-protocol population (PPP) comprised all randomised pts with ≥ 1 post-BL questionnaire (6 +/or 12 mo) and, for SC, ≥ 1 of the PCP visits. Results: 150 pts were randomised to SC (N=74) or UC (N=76); 11 PCPs declined. Median age 63 years, 39% women, 24% had radiotherapy. Primary: colon (59%), rectum (32%), overlapping (9%). 138/150 (92%) had BL and ≥1 post-BL GHQ-QoL score. 65/74 (88%) of SC pts attended 3- and/or 9-mo PCP visit. The mean (SD) GHQ-QoL scores at baseline / 6 mo / 12 mo were: 69 (18.7) / 69 (21.2) / 72 (20.2) for SC versus 68 (20.0) / 73 (15.1) / 73 (17.2) for UC. The MMRM mean estimate of GHQ-QoL across the 6 mo and 12 mo FU was 69 for SC and 73 for UC, mean diff -4.0 (95% CI: -9.0 to 0.9). The lower limit of the 95% CI did not cross the NIM. For the PPP (N=130/150), mean diff was -5.0 (95% CI: -10.1 to 0.2). No clear evidence of between group diffs on other C30 scales (accounting for multiplicity). At 12 mo, most popular preferences for FU were: SC for 40/63 (63%) in the SC group, similar preferences for SC 22/62 (35%) and ‘Hospital-based care with the doctors that treated the cancer’ 22/62 (35%) in UC. CEA completion was 89% at 3 and 83% at 9 mo in SC; 63% and 68% in UC. 5 recurrences in SC and 6 in UC arms. Conclusions: SCORE was highly feasible with high participation and retention, few PCPs declined. Compared to UC, pts having SC had non-inferior QoL. Adherence to CEA testing was higher in SC. Pts exposed to SC prefer this model of FU. Cost and implementation analyses will follow. Clinical trial information: ACTRN12617000004369 .

The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumor organoids in vitro,and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only pro-apoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor-induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in CRCs, by combining a HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT ; KRASG12C , BRAFV600E CRC cell lines respectively. These findings identify a series of ERK/MAPK genotype tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer. Citation Format: Laura J. Jenkins, Ian Y. Luk, Walter D. Fairlie, Erinna F. Lee, Michelle Palmieri, Kael L. Schoffer, Tao Tan, Irvin Ng, Natalia Vukelic, Sharon Tran, Janson Tse, Rebecca Nightingale, Zakia Alam, Fiona Chionh, George Iatropoulos, Matthias Ernst, Shoukat Afshar-Sterle, Jayesh Desai, Peter Gibbs, Oliver M. Sieber, Amardeep S. Dhillon, Niall C. Tebbutt, John M. Mariadason. Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B014.

Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine, median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm, 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine, 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

248 Background: Most individual treatments for advanced cancer are associated with modest survival benefits. The time spent in pursuing these treatments can be substantial. We have previously developed a pragmatic and patient-centered metric of these time costs, which we term ‘’time toxicity’’, as any day with physical healthcare system contact. This includes outpatient visits (e.g., for bloodwork, scans, infusions, urgent care), emergency room visits, and overnight stays in a healthcare facility. Herein we sought to assess time toxicity in a completed RCT. Methods: We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions vs supportive care alone in 572 patients with advanced colorectal cancer. CO.17 recruited participants in Canada, Australia and New Zealand. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 vs 4.6 months, p = 0.005). Subsequent analyses reported that OS benefit was restricted to and significantly more in patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing treatment, follow-up, and resource utilization forms. We considered a day without physical healthcare contact as a ‘’home day’’. Thus, for a patient, OS was time toxic days + home days. We compared medians of time measures across arms, and stratified results by K-ras status. Results: In the overall population, median time toxic days were higher in the cetuximab arm (28, vs 10, p < 0.001), although median home days were not statistically different (140, vs 121, p = 0.09). The proportion of time toxic days (time toxic days/OS) were significantly more with cetuximab (18%, vs 6%, p < 0.001). Of the 28 time toxic days in the overall cetuximab arm, 14 (50%) were protocol-related (e.g., scheduled infusions etc). Stratified results are in the table. Conclusions: Time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS-benefit with cetuximab, home days were statistically similar across arms. In the K-ras-mutated group, cetuximab was associated with numerically similar OS but more time toxic days. In the K-ras-wild type group, cetuximab was associated with higher home days. Thus, time toxicity data need not always be sobering. Time toxicity measures can supplement traditional survival endpoints in RCTs to guide patient-oncologist decision-making. Cooperative group RCTs are well positioned for such analyses. Clinical trial information: NCT00079066. [Table: see text]

Background Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. Methods PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided. Results Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P < .001) but not for right-sidedness. Conclusions The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.

3583 Background: There are limited treatment options for patients with metastatic colorectal cancer (mCRC) who have progressed on standard therapies. A personalised approach to guide treatment selection would maximise efficacy whilst minimising unnecessary toxicity. Patient derived tumour organoids (PDTO) are self-organizing three-dimensional in vitro models cultured from a fresh tumour biopsy. Drug sensitivity testing on PDTO models have the potential to guide personalised treatment in this clinical setting. Methods: FORECAST-1 is a feasibility study, sponsored by the Australian Gastro-Intestinal Trials Group, of PDTO-based drug sensitivity testing for 30 patients with mCRC that have failed ≥two lines of therapy. Established PDTOs underwent drug sensitivity screening including regorafenib, TAS102, oxaliplatin, irinotecan, 5FU, gemcitabine, pemetrexed and temozolomide. Patients underwent treatment at clinician’s discretion, with clinical response correlated with PDTO response. Results: Between September 2020 and December 2021, 30 patients were enrolled in the study with a median age of 59 years (range 36-71). All patients were ECOG 0-1 and eight patients had received prior TAS102 treatment. Fresh tumour biopsies were obtained from liver (N = 17), soft tissue/peritoneal metastases (N = 5), lung (N = 3), lymph node (N = 2), primary colon (N = 1), brain (N = 1) and bone (N = 1). 20/30 (67%) of patients had successful drug sensitivity screening performed at a median PDTO age of 62 days (range 42-128), nine PDTO cultures failed, and one is still undergoing culture. 15/17 (88%) of PDTO cultures obtained from a fresh liver biopsy were successfully cultured to drug sensitivity testing. 14/20 (70%) of PDTOs that underwent drug sensitivity testing identified therapies with intermediate to high likelihood of clinical response, including regorafenib (N = 7), TAS102 (N = 5), gemcitabine (N = 4), oxaliplatin (N = 3), irinotecan (N = 1), 5FU (N = 1) and temozolomide (N = 1). Subsequent anti-cancer treatment received by patients after study enrolment included TAS102 (N = 7), FOLFOX (N = 3), FOLFIRI+EGFR-inhibitor (N = 2), FOLFIRI (N = 2), regorafenib (N = 1), capecitabine (N = 1) and an immunotherapy based clinical trial (N = 2). As of February 2022, 11 patients remain on active anti-cancer therapy and 17 patients have died. Conclusions: Improving therapeutic selection in refractory mCRC patients remains an area of high clinical need. Two-thirds of patients achieved PDTO establishment to allow drug sensitivity testing in a timely manner. Of these further potentially efficacious treatments were able to be successfully identified. Methods to accelerate PDTO culture and drug testing are being pursued to increase the feasibility of a planned prospective study of PDTO sensitivity informing patient management. Clinical trial information: ACTRN12620001353987.

The EGFR/RAS/MEK/ERK signalling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumour organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically this effect was mediated through induction of the BH3-only pro-apoptotic proteins BIM and BMF. Importantly, we demonstrate that this treatment paradigm can be tailored to specific MAPK genotypes in CRCs, by combining HDACi with EGFR, KRASG12C or BRAFV600 inhibitors in KRAS/BRAFWT; KRASG12C, BRAFV600E CRC cell lines respectively. These findings identify a novel ERK/MAPK genotype-targeted treatment paradigm for colorectal cancer.

Meta-analysis based on individual participant data (IPD) is a powerful methodology for synthesizing evidence by combining information drawn from multiple trials. Hitherto, its principal application has been in questions of clinical management, but an increasingly important use is in clarifying trials methodology, for instance in the selection of endpoints, as discussed in this review. In oncology, the Aide et Recherche en Cancerologie Digestive (ARCAD) Metastatic Colorectal Cancer Database is a leader in the use of IPD-based meta-analysis in methodological research. The ARCAD database contains IPD from more than 38 000 patients enrolled in 46 studies and continues to collect phase III trial data. Here, we review the principal findings of the ARCAD project in respect of endpoint selection and examine their implications for cancer trials. Analysis of the database has confirmed that progression-free survival (PFS) is no longer a valid surrogate endpoint predictive of overall survival in the first-line treatment of colorectal cancer. Nonetheless, PFS remains an endpoint of choice for most first-line trials in metastatic colorectal cancer and other solid tumors. Only substantial PFS effects are likely to translate into clinically meaningful benefits, and accordingly, we advocate an oncology research model designed to identify highly effective treatments in carefully defined patient groups. We also review the use of the ARCAD database in assessing clinical response including novel response metrics and prognostic markers. These studies demonstrate the value of IPD as a tool for methodological studies and provide a reference point for the expansion of this approach within clinical cancer research. SL was supported by the US National Cancer Institute Cancer Center Support Grant, award number: P30CA008748. AS was supported by AIRC, grant number IG2018. We thank our ARCAD colleagues Daniel G Haller, MD, for guidance and helpful revisions to the text, and Lama Sharara, PhD, Director General of ARCAD, for expertly coordinating this multi-author review. We also thank the many ARCAD members who commented on this article at the outline stage. AIRCFondazione AIRC per la ricerca sul cancro [IG2018]

Background SCOT was an international, randomized phase 3 trial of 3 months vs 6 months of adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine in patients with colorectal cancer. We sought patients’ preferences for 3 months vs 6 months of adjuvant chemotherapy in the SCOT trial. Methods SCOT participants from Australia and New Zealand completed a validated questionnaire (at 3 and 18 months) to elicit the minimum survival benefits judged necessary to make an extra 3 months of adjuvant chemotherapy worthwhile, based on their experience. Standardized hypothetical scenarios used the following baseline survivals (with 3 months of chemotherapy): life expectancies (LE) of 5 years and 15 years and 5-year survival rates (5YS) of 65% and 85%. Results Of the 160 participants, 82 were assigned 3 months adjuvant chemotherapy, and 78 were assigned 6 months. Adjuvant chemotherapy was FOLFOX in 121 (75.6%) and XELOX in 39 (24.4%). Preferences varied substantially and did not differ according to treatment group. The median survival benefits judged necessary to make the extra 3 months of chemotherapy worthwhile were an extra 3 years beyond a LE of 5 years; 3 years beyond a LE of 15 years; 15% beyond a 5YS of 65%; and 5% beyond a 5YS of 85%. Preferences were similar at 3 months and 18 months. Preferences were not predicted by participants’ baseline characteristics. Conclusion Preferences varied substantially, and the benefits many required to warrant an extra 3 months of adjuvant chemotherapy were larger than the benefits of an extra 3 months of chemotherapy calculated in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) meta-analysis.

Importance Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies. Objective To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers. Design, Setting, and Participants The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research. Interventions Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events. Main Outcomes and Measures The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1. Results Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events. Conclusions and Relevance This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti–programmed cell death protein 1 (anti–PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response. Trial Registration ClinicalTrials.gov Identifier:NCT02923934

Purpose: To assess the efficacy and safety of dual antiangiogenesis agents, bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer (mCRC). Patients and Methods: This open-label phase II study enrolled patients with unresectable mCRC with no prior systemic treatment. All patients received bevacizumab 7.5 mg/kg 3-weekly and trebananib 15 mg/kg weekly. The primary endpoint was disease control [stable disease, partial response (PR), or complete response (CR)] at 6 months (DC6m). Secondary endpoints included toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers in plasma angiogenesis–related proteins, tumor gene expression, and plasma antibodies to tumor antigens were examined. Results: Forty-five patients were enrolled from four Australian sites. DC6m was 63% [95% confidence interval (CI), 47–77]. ORR was 17% (95% CI, 7–32), comprising of seven PRs. Median duration of response was 20 months (range, 10–48 months). Median PFS was 8.4 months and median OS 31.4 months. Grade 1–2 peripheral edema and joint-related symptoms were common. Overall incidence of grade 3–4 adverse events (AE) of any type was 33% (n = 15). Expected AEs of bevacizumab treatment did not appear to be increased by the addition of trebananib. Conclusions: In a first-line mCRC population, the dual antiangiogenic combination, bevacizumab plus trebananib, without chemotherapy, was efficacious with durable responses. The toxicity profile of the combination was manageable and did not exceed that expected with bevacizumab +/− chemotherapy. Exploratory biomarker results raise the hypothesis that the antiangiogenic combination may enable the antitumor immune response in immunotolerant colorectal cancer.

575 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A 4th cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for Phase 1b expansion. Results: Fifty patients were enrolled (N=25, Phase 1a and N=25, Phase 1b) and received up to 13 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (>10%) are fatigue (N=14), LFT/transaminase abnormalities (N=15), vision abnormalities (N=10), injection site pain (N=13), dehydration (N=7), nausea (N=7). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N=6) and retinal toxicity (N=8) both occurring after prolonged treatment and requiring dose reduction or discontinuation. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 1/29 (3%) achieving a complete remission 13/29 achieving partial responses (45%) and 10/29 achieving stable disease at 8 weeks (35%). PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Sixteen subjects are in survival follow-up. Median OS is 10.1 months and is not final. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. A vision screening program will be used in future studies to mitigate retinal toxicity. Clinical trial information: NCT03412799.

101 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p

Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab, and everolimus. Patients and Methods: Patients with KRAS exon 2 wild-type (WT) mCRC following failure of fluoropyrimidine-based therapy received i.v. irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14-day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using the Kaplan–Meier method, and results were analyzed as intention to treat. A preplanned exploratory biomarker analysis was performed. Results: Forty-nine patients were enrolled. Dose level 1 (irinotecan 200 mg/m2, panitumumab 6 mg/kg, and everolimus 5 mg alternate day) was declared the MTD with no dose-limiting toxicities in six patients. Forty patients were treated at dose level 1: median age, 60 years (37–76); 65% male; 45% and 52.5%, respectively, with Eastern Cooperative Oncology Group values of 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhea (23%), mucositis (18%), rash (13%), fatigue (8%), dehydration (5%), neutropenia (20%), febrile neutropenia (8%), hypomagnesemia (20%), and hypokalemia (8%). Grade 4 toxicities were hypomagnesemia (5%) and neutropenia (3%). RR was 48%, and stable disease was 43%. Median progression-free survival (PFS) was 5.6 months, and median overall survival (OS) was 10.8 months. Twenty-five patients were RAS/RAF WT and had an RR of 60%, median PFS of 6.4 months, and OS of 11.8 months. Conclusions: The toxicity of the panitumumab, irinotecan, and everolimus regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination. Clin Cancer Res; 24(16); 3838–44. ©2018 AACR.

BACKGROUND: Advanced biliary tract cancers (BTCs) have a poor prognosis and limited treatment options. This exploratory phase II study aimed to evaluate the activity of the mTOR inhibitor everolimus in advanced BTC and explore prognostic biomarkers. METHODS: Patients with advanced BTCs, who had not received chemotherapy for advanced disease, were enroled to receive everolimus (10 mg daily). The primary endpoint was disease control rate (DCR) at 12 weeks. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events. Activation status of the RAS and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathways was assessed by DNA sequencing and immunohistochemistry on archival tumour tissue. RESULTS: The study enroled 27 patients and the DCR at 12 weeks was 48%. Median PFS was 5.5 months (95% confidence interval (CI): 2.1–10.0 months) and median OS was 9.5 months (95% CI: 5.5–16.6 months). DCR at 12 weeks was significantly worse for gall bladder carcinoma compared to other anatomical sites, and there was a trend towards a worsened PFS and OS. Treatment was well tolerated. KRAS (12%) and PIK3CA mutations (12%) were uncommon. Immunohistochemical staining for PI3K/AKT/mTOR pathways did not significantly correlate with outcome. CONCLUSION: In unselected patients, everolimus demonstrated clinical activity as first-line monotherapy in advanced BTC.

Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K-Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback-mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP-competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K-Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.

Summary Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers., Graphical Abstract, Highlights • BTC cell lines harbor similar genomic alterations to primary tumors • Transcriptomic profiling of BTC cell lines identified two molecular subtypes • MAPK signaling is activated in BTC via multiple mechanisms • BTC lines with deregulated ERBB2 or FGFRs respond to specific targeted therapies, Biological Sciences; Genetics; Genomics; Cancer

4127 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A fourth cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for phase 1b expansion. Interim Results: Fifty patients were enrolled (N=25, phase 1a and N=25, phase 1b) and have received up to 12 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (>10%) are fatigue (N=15), LFT/transaminase abnormalities (N=15), vision abnormalities (N=6), injection site pain (N=13), dehydration (N=7), diarrhea (N=7) and nausea (N=6). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N= 6) and retinal toxicity (N=6) both occurring after prolonged treatment and requiring dose reduction or discontinuation. There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 12/28 evaluable patients achieving partial responses (43%) and 11/28 achieving stable disease at 8 weeks (39%). Nine subjects are ongoing. PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Median OS has not been reached. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. Retinal toxicity that occurred in some subjects is under investigation. Clinical trial information: NCT03412799.

3575 Background: Pts with mCRC frequently receive ≥1 sequential treatment TL. Approximately 50%-60% of pts receive second-line (L2) and 20%-30% third-line (L3) regimens in routine practice. We investigated the pts clinical/tumor characteristics and their prognostic impact across TL. Methods: Data from 37,560 pts enrolled in 48 randomized trials (34 in first (L1), 9 in L2, and 5 in L3) were analyzed. Candidate variables (VAR) measured at enrollment were sex, age, body mass index, performance status (PS), bilirubin, hemoglobin (Hb), platelets (Pl), derived white blood cells-to-absolute neutrophil counts ratio (WBC/ANC), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), primary tumor location, and number and location of metastatic sites (MS). Missing data were imputed. VAR with significant value at all TL were selected to construct a prognostic score of overall survival (OS) in training set (TS, n=30,050; 80%). For each TL, the score was calculated as the sum on the estimations of the VAR’ coefficients from the common multivariate model; Cox’s model was used to define risk groups. The discrimination capability was assessed using the Harrell’s C-index. External validation was done in the validation set (VS, n=7,510; 20%). Results: A total of 26,974 pts in L1, 7,693 pts in L2 and 2,893 pts in L3 were analyzed. The following characteristics increased continuously over TL: ≥2 MS (57%, 72%, 82%), lung metastases (50%, 74%, 91%), lymph nodes metastases (51%, 61%, 80%), KRAS mutation (37%, 47%, 51%) and elevated ALP (46%, 52%, 61%). BRAF mutation decreased (9%, 7%, 5%). In L1 vs L3 trials, 70% vs 89% of patients had primary tumor resection, 10% vs 80% had at least one metastasectomy and 31% vs 78% had a late metachronous (>12 months) metastasis. 7 independent VAR were retained in the prognostic score (PS, Hb, Pl, WBC/ANC, LDH, ALP, and the number of MS); four pt groups with significantly different prognoses were defined (table). This score remained valid when excluding pts with PS 2. Third-line oral drugs (vs placebo) and subsequent line (L2/L1 or L3/L2) were effective in all prognostic groups. Conclusions: Clinical/tumor pt characteristics significantly varied over subsequent TL in patients included in randomized trials. The same prognostic model using practical clinical and biological variables can be used in all TL.[Table: see text]

e15571 Background: Many patients with metastatic colorectal cancer (mCRC) that have failed standard first- and second-line therapies remain fit and eager for further treatment. Therapeutic options include two agents with proven but modest survival benefit, a clinical trial of an investigational agent, rechallenge with agents successfully used in earlier lines of treatment, or agents that have shown some activity in non-randomised phase II studies. Patient derived tumouroid (PDT) are self-organizing three-dimensional in vitro models cultured from a fresh tumour biopsy. They potentially represent a robust personalized model for real-time drug sensitivity testing to determine optimal anti-cancer therapies for individual patients. Methods: FORECAST-1 is an observational, non-randomized study to determine the feasibility of PDT based drug sensitivity screening for patients with mCRC that have failed at least two lines of therapy. Once established, PDTs undergo drug sensitivity screening including agents regorafenib, trifluridine/tipiracil (TAS102), oxaliplatin, irinotecan, 5-fluorouracil (5FU), erlotinib (a surrogate EGFR-inhibitor), gemcitabine, pemetrexed and temozolomide. Patients are treated at clinician discretion, with clinical response to be correlated with PDT response. Results: Since September 2020 we have enrolled 18 of a planned 30 patients, median age 55 years (range 44 – 81). 17 patients were ECOG 0-1. Four patients had received prior TAS102 treatment. Biopsies were obtained from liver (n = 6), soft tissue/peritoneal metastases (5), lung (2), lymph node (2), primary (1), brain (1) and bone (1). Drug sensitivity testing has been performed on seven PDTs at a median of 62 days from biopsy (range 42 – 128), one PDT culture has failed. A standardised reporting template has been developed. Treatments received by patients to date include TAS102 (n = 5), regorafenib (2), FOLFOX (3), FOLFIRI (1) FOLFIRI plus EGFR-inhibitor (1), capecitabine plus bevacizumab (1) and an immunotherapy-based clinical trial (1). Four patients did not receive further anti-cancer therapy post enrolment, and one patient is yet to commence further systemic therapy. Conclusions: Enrolment to this feasibility study has been rapid demonstrating this to be an area of clinical need. PDTs have been successfully established from a high proportion of patients, but with variable growth rates. Methods to accelerate PDT culture and drug testing are being pursued to increase the feasibility of a planned prospective study of PDT sensitivity informing patient management. Clinical trial information: ACTRN12620001353987.

Purpose We evaluated the activity of regorafenib, an oral multikinase inhibitor, in advanced gastric adenocarcinoma. Patients and Methods We conducted an international (Australia and New Zealand, South Korea, and Canada) randomized phase II trial in which patients were randomly assigned at a two-to-one ratio and stratified by lines of prior chemotherapy for advanced disease (one v two) and region. Eligible patients received best supportive care plus regorafenib 160 mg or matching placebo orally on days 1 to 21 of each 28-day cycle until disease progression or prohibitive adverse events occurred. The primary end point was progression-free survival (PFS). Final analysis included data to December 31, 2014. Results A total of 152 patients were randomly assigned from November 7, 2012, to February 25, 2014, yielding 147 evaluable patients (regorafenib, n = 97; placebo, n = 50). Baseline characteristics were balanced. Median PFS significantly differed between groups (regorafenib, 2.6 months; 95% CI, 1.8 to 3.1 and placebo, 0.9 months; 95% CI, 0.9 to 0.9; hazard ratio [HR], 0.40; 95% CI, 0.28 to 0.59; P < .001). The effect was greater in South Korea than in Australia, New Zealand, and Canada combined (HR, 0.12 v 0.61; interaction P < .001) but consistent across age, neutrophil-to-lymphocyte ratio, primary site, lines of chemotherapy, peritoneal metastasis presence, number of metastatic sites, and plasma vascular endothelial growth factor A. A survival trend in favor of regorafenib was seen (median, 5.8 months; 95% CI, 4.4 to 6.8 v 4.5 months; 95% CI, 3.4 to 5.2; HR, 0.74; P = .147). Twenty-nine patients assigned to placebo received open-label regorafenib after disease progression. Regorafenib toxicity was similar to that previously reported. Conclusion In this phase II trial, regorafenib was effective in prolonging PFS in refractory advanced gastric adenocarcinoma. Regional differences were found, but regorafenib was effective in both regional groups. A phase III trial is planned.

Background: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer. Methods: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy. Results: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34–64%) in the chemotherapy arm and 58% (95% CI 42–72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively. Conclusions: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

4588 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with first and second line chemotherapy resulting in modest survival benefits. Immunotherapy using single agent anti-PD-1 therapy has also shown low activity with an objective response rate (ORR) of less than 10%. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell carcinoma. To date, no trials in BTC pts with ipi/nivo therapy have been reported. Methods: 39 pts with metastatic BTCs were enrolled into the CA 209-538 clinical trial for rare cancers. Patients received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for 4 doses, followed by nivo 3mg/kg q 2 weekly. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers including PD-L1 expression and tumour mutation burden. Results: 39 pts with BTC were enrolled and 33 pts (85%) had received at least one prior line of systemic treatment (0-2 lines). The ORR was 24% and the CBR 45% with the median duration of response not been reached (range 2-26+months). Responses were observed in 3/14 intrahepatic, 1/10 extrahepatic, 0/2 unspecified cholangiocarcinoma and 5/13 gallbladder ca pts. None of the responding pts had a microsatellite instable tumour. 2 pts with durable partial responses were subsequently rendered surgically free of disease. Median OS and PFS were 6.1 and 3.1 months respectively. 22 (56%) pts experienced an immune –related adverse event (irAE) with grade3/4 irAEs being observed in 8 (20%) pts. Conclusions: Combination immunotherapy with ipi/nivo demonstrates significant clinical activity in a subset of patients with advanced microsatellite stable BTC. The response rate compares favourably to clinical trials investigating single agent anti-PD-1 therapy. Clinical trial information: NCT02923934 .

TPS271 Background: Pan added to combination chemotherapy is established first-line therapy for RAS and BRAF wild type mCRC. Elderly patients are not well represented in clinical trials and may be more suited to treatment protocols with lower toxicity risks; FU plus bevacizumab (bev) is commonly used. Treatment related efficacy, toxicity, impact on quality of life and other outcomes of pan based regimens in an elderly population have not been well studied. Methods: A prospective non-comparative randomized phase 2 study. Australian Clinical Trials Registry Number: ACTRN 12618000233224. Main inclusion criteria include: Untreated patients aged 70 years or older; RAS and BRAF wild type; ECOG performance 0-2. Randomisation 1:1, stratified by primary tumour side, performance status, number of metastatic sites; to pan 6mg/kg 2 weekly or panitumumab plus FU 400 mg/m² bolus; leucovorin 200mg/m²; FU 2400mg/m² 48 hour infusion 2 weekly. Primary endpoint is 6-month progression-free survival (PFS). Sample size is 80 patients based on expected 6-month PFS rate of 73% with FU and bev. Using the method of Metha-Cain, if 24 or more patients are progression free at 6 months, the one sided 95% confidence interval includes 73% and we declare similar activity. Secondary endpoints include overall survival; toxicity and overall treatment utility, a composite measure of treatment benefit based on radiology, clinical progress, toxicity and patient reflection of the impact of treatment on their daily lives. Patients undergo a comprehensive health assessment at baseline and limited health assessment at 4 months. Physical activity trackers are worn for 2 weeks at treatment commencement and again at week 16. Tumour tissue and blood samples (at baseline, cycle 3 day 1 and at 24 weeks) will be collected for translational research. First site opened in June 2018. Twelve patients have been recruited to date from 9 sites in Australasia. Eighteen sites were open as at September 2019. Clinical trial information: 12618000233224.

710 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens, N=4) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the safety, tolerability, PK, and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. Safety and tolerability were evaluated by clinical and laboratory assessments. PK was evaluated on day 1 of cycle 1. Efficacy was assessed by CA19-9 levels, objective response as assessed by RECIST criteria, progression-free survival (PFS) and overall survival (OS). Results: Fifteen patients have been enrolled in 3 cohorts (1: N=4, 2: N=7, 3: N=4) and received up to 6 cycles of treatment (7 subjects are ongoing in cohorts 2 and 3). The most common adverse events related to SBP-101 are fatigue (N=4), nausea (N=2) and injection site pain (N=2). There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. One patient in cohort 2 developed grade 3-4 reversible liver enzyme elevation. PK parameters in cohort 1 were below the limits of detection at most time points, but plasma Cmax and AUC0-t were measurable in cohorts 2 and 3. In those cohorts, CA19-9 levels decreased 76-95% in 7 of 8 evaluable subjects (1 additional subject TBD), with 5 patients achieving partial responses (4 ongoing) and 1 achieving stable disease. Median PFS and OS have not yet been reached. Conclusions: Preliminary results suggest SBP-101 is well tolerated when administered with G and A. Signals of efficacy support continued development of SBP-101 in combination first-line treatment for PDA. Clinical trial information: NCT03412799.

Purpose: Patients with left-sided colon tumours have better survival and respond differently to biologics compared with patients with right-sided tumours. Left-sided colon tumours and rectal cancers are often grouped together. Herein, we examined the clinicopathological differences and outcomes between left-sided colon and rectal cancers.Patients and methods: Data from 2879 metastatic colorectal cancer patients enrolled on six first-line clinical trials during 2004–2010 were pooled. Patients were included if the primary tumour origin was clearly defined. Progression-free survival (PFS) and overall survival (OS) were compared in the two groups after adjusting for patient and tumour characteristics, metastatic sites and the first-line regimen.Results: In total, 1374 patients with metastatic left-sided colon cancer and 1505 patients with metastatic rectal cancers were evaluated. Left-sided colon cancer patients were more likely to be female (40.1% versus 32.6%; P < 0.0001) and older (31.0% ≥ 70 years versus 25.8%; P = 0.0033) compared with rectal cancers patients. Patients with left-sided colon cancer had higher rates of liver metastases (80.9% versus 72.3%, P < 0.0001) but lower rates of lung metastases (34.2% versus 53.8%, P < 0.0001). KRAS mutations were slightly less frequent among left-sided tumours (34.8% versus 40.5%; P = 0.0103). Patients with left-sided tumours had approximately similar PFS (median 7.4 versus 6.9 months; hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.87–1.03; P = 0.1998) and OS (median 17.4 versus 16.6 months; HR 0.99, 95% CI 0.91–1.07; P = 0.7597) compared with rectal cancer patients.Conclusion: The site of tumour origin within the left side was not prognostic of outcomes. Moreover, neither bevacizumab nor cetuximab impacted, differently, the findings of the comparisons in outcomes between patients with left-sided colon tumours or rectal cancers.

Background: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. Methods: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). Results: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). Conclusion: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Background:Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database. Methods:Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (50% vs 50% vs

Purpose CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). Patients and Methods Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 (111In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days. Results Nineteen patients were enrolled. 111In-CS-1008 uptake in tumor was observed in only 12 patients (63%). 111In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. 111In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti–CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with 111In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor–5 expression in archived tumor samples did not correlate with 111In-CS-1008 uptake (P = .5) or tumor response (P = .6). Conclusion Death-receptor–5 imaging with 111In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC.

Right- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab.Reanalyzing NCIC CO.17 trial (cetuximab versus best supportive care [BSC]), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS).Patients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 [0.79-1.44], p = 0.67) or OS (HR 0.96 [0.70-1.31], p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 [0.18-0.45], p0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 [0.42-1.27], p = 0.26), [interaction p = 0.002].In refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.

Purpose Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Methods Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2 statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. Results Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. Conclusion In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

Contains fulltext : 154417pub.pdf (Publisher’s version ) (Closed access) BACKGROUND: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. METHODS: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. RESULTS: Patients with low expression of VEGF-D (0, 1thorn) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CBthornCBM), 0.21; 95% CI, 0.08-0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13-0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2thorn PFS HR, 0.67; 95% CI, 0.45-1.00; OS HR, 0.82; 95% CI, 0.52-1.30; VEGF-D 3thorn PFS HR, 0.77; 95% CI, 0.50-1.17; OS HR, 1.28; 95% CI, 0.79-2.09) (P interaction o0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. CONCLUSIONS: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.

Lessons LearnedThese negative phase II results for parsatuzumab highlight the challenges of developing an agent intended to enhance the efficacy of vascular endothelial growth factor inhibition without the benefit of validated pharmacodynamic biomarkers or strong predictive biomarker hypotheses. Any further clinical development of anti-EGFL7 is likely to require new mechanistic insights and biomarker development for antiangiogenic agents.BackgroundEGFL7 (epidermal growth factor-like domain 7) is a tumor-enriched vascular extracellular matrix protein that supports endothelial cell survival. This phase II trial evaluated the efficacy of parsatuzumab (also known as MEGF0444A), a humanized anti-EGFL7 IgG1 monoclonal antibody, in combination with modified FOLFOX6 (mFOLFOX6) (folinic acid, 5-fluorouracil, and oxaliplatin) bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC).MethodsOne-hundred twenty-seven patients were randomly assigned to parsatuzumab, 400 mg, or placebo, in combination with mFOLFOX6 plus bevacizumab, 5 mg/kg. Treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months, with the exception of oxaliplatin, which was administered for up to 8 cycles.ResultsThe progression-free survival (PFS) hazard ratio was 1.17 (95% confidence interval [CI], 0.71–1.93; p = .548). The median PFS was 12 months for the experimental arm versus 11.9 months for the control arm. The hazard ratio for overall survival was 0.97 (95% CI, 0.46–2.1; p = .943). The overall response rate was 59% in the parsatuzumab arm and 64% in the placebo arm. The adverse event profile was similar in both arms.ConclusionsThere was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line mCRC.

Background ALK, ROS1, and NTRK fusions occur in 0.2% to 2.4% of colorectal cancers. Pioneer cases of metastatic colorectal cancer (mCRC) patients bearing rearrangements who benefited from anti-ALK, ROS, and TrkA-B-C therapies have been reported previously. Here we aimed at characterizing the clinical and molecular landscape of ALK, ROS1, and NTRK rearranged mCRC. Methods Clinical features and molecular characteristics of 27 mCRC patients bearing ALK, ROS1, and NTRK rearranged tumors were compared with those of a cohort of 319 patients not bearing rearrangements by means of Fisher's exact, χ2 test, or Mann-Whitney test as appropriate. Overall survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was adopted in the multivariable analysis. Deep molecular and immunophenotypic characterizations of rearranged cases, including those described in The Cancer Genome Atlas database, were performed. All statistical tests were two-sided. Results Closely recalling the "BRAF history," ALK, ROS1, and NTRK rearrangements more frequently occurred in elderly patients (P = .02) with right-sided tumors (P < .001) and node-spreading (P = .03), RAS wild-type (P < .001), and MSI-high (P < .001) cancers. All patients bearing ALK, ROS1, and NTRK fusions had shorter overall survival (15.6 months, 95% confidence interval [CI] = 0.0 to 20.4 months) than negative patients (33.7 months, 95% CI = 28.3 to 42.1 months), both in the univariate (hazard ratio [HR] = 2.17, 95% CI = 1.03 to 4.57, P < .001) and multivariable models (HR = 2.33, 95% CI = 1.10 to 4.95, P = .02). All four evaluable patients with rearrangements showed primary resistance to anti-epidermal growth factor receptor agents. Frequent association with potentially targetable RNF43 mutations was observed in MSI-high rearranged tumors. Conclusions ALK, ROS1, and NTRK rearrangements define a new rare subtype of mCRC with extremely poor prognosis. Primary tumor site, MSI-high, and RAS and BRAF wild-type status may help to identify patients bearing these alterations. While sensitivity to available treatments is limited, targeted strategies inhibiting ALK, ROS, and TrkA-B-C provided encouraging results.

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.

Purpose: Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular BRAF, PIK3CA, and PTEN. Experimental Design: Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment–biomarker interaction. Results: A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61). Conclusions: In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size. Clin Cancer Res; 20(3); 744–53. ©2013 AACR.

Tumor biomarkers to more accurately predict a patient's response to a given therapy are much needed in oncology practice. For metastatic colorectal cancer the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab is now commonly included in first-line therapy regimens and has led to modest but significant improvements in patient outcomes compared with chemotherapy. Given the modest gains there is a pressing need for predictive biomarkers to better identify patients who would benefit from this targeted therapy. We used a multiplex protein assay to determine the tumor expression levels of the proangiogenic proteins IL-6, IL-8, bFGF, PDGF-BB and VEGF-A in formalin-fixed paraffin-embedded tumors from the MAX clinical trial patients with available tissue samples. Patients were dichotomized into "low" vs. "high" expression subgroups based on median baseline levels to correlate with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). "Low" tumor VEGF-A level was predictive of better ORR for bevacizumab [ORR (low) 53% vs. (high) 19%, interaction p = 0.03] but not for PFS [hazard ratio, HR (low) 0.73 vs. (high) 0.62, interaction p = 0.68] in the comparison of capecitabine (C) versus C and bevacizumab (CB) and CB plus mitomycin (M). When analyzed as a dichotomized variable, "high" VEGF-A was prognostic for shorter PFS (unadjusted HR 1.34, p = 0.06; adjusted HR 1.55, p = 0.008). The other four proteins were neither predictive of bevacizumab benefits nor prognostic for ORR, PFS or OS. "Low" tumor VEGF-A was associated with longer PFS after adjustment for other baseline factors. Proangiogenic proteins were not predictive of benefit with bevacizumab for PFS.