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PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.

Background Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. Methods Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. Results Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. Conclusion One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA+), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA+ mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after next-generation androgen receptor–directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA+ identified by central plasma (n = 34), central tissue (n = 37), or local (n = 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA+ by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA+ mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.

Analyzing longitudinal cancer quality-of-life (QoL) measurements and their impact on clinical outcomes may improve our understanding of patient trajectories during systemic therapy. We applied an unsupervised growth mixture modeling (GMM) approach to identify unobserved subpopulations ("patient clusters") in the CO.20 clinical trial longitudinal QoL data. Classes were then evaluated for differences in clinico-epidemiologic characteristics and overall survival (OS).In CO.20, 750 chemotherapy-refractory metastatic colorectal cancer (CRC) patients were randomized to receive Brivanib+Cetuximab (n = 376, experimental arm) versus Cetuximab+Placebo (n = 374, standard arm) for 16 weeks. EORTC-QLQ-C30 QoL summary scores were calculated for each patient at seven time points, and GMM was applied to identify patient clusters (termed "classes"). Log-rank/Kaplan-Meier and multivariable Cox regression analyses were conducted to analyze the survival performance between classes. Cox analyses were used to explore the relationship between baseline QoL, individual slope, and the quadratic terms from the GMM output with OS.In univariable analysis, the linear mixed effect model (LMM) identified sex and ECOG Performance Status as strongly associated with the longitudinal QoL score (p 0.01). The patients within each treatment arm were clustered into three distinct QoL-based classes by GMM, respectively. The three classes identified in the experimental (log-rank p-value = 0.00058) and in the control arms (p 0.0001) each showed significantly different survival performance. The GMM's baseline, slope, and quadratic terms were each significantly associated with OS (p 0.001).GMM can be used to analyze longitudinal QoL data in cancer studies, by identifying unobserved subpopulations (patient clusters). As demonstrated by CO.20 data, these classes can have important implications, including clinical prognostication.

B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary. To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS. Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively. LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

Clinical trials have strict eligibility criteria, potentially limiting external validity. However, while often discussed this has seldom been explored, particularly across cancer types and at variable time frames posttrial completion. We examined comprehensive registry data (January 2014 to June 2019) for standard first-line treatments for metastatic colorectal cancer (CRC), advanced pancreatic cancer (PC), metastatic HER2-amplified breast cancer (BC) and castrate-resistant prostate cancer (CaP). Registry patient characteristics and outcomes were compared to the practice-changing trial. Registry patients were older than the matched trial cohort by a median of 2-6 years (all P =

3531 Background: Surgical resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether such benefit is consistently observed for BRAF V600E mutant (MT) and wild type (WT) mCRC. We conducted a retrospective analysis to explore the influence of BRAF mutation status on survival outcomes after metastasectomy. Methods: Data collected from two large prospective population databases in Australia (Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) and South Australian cancer registry). Overall survival (OS) and recurrence free survival (RFS) for BRAF MT and WT mCRC were evaluated by Kaplan-Meier method and compared by log-rank test. Results: 513 patients who had undergone metastasectomy were identified, 6% were BRAF MT. Median age 63. Metastasectomy rate was lower in BRAF MT (13 v 27%). In BRAF WT, 4% underwent resection of metastases (mets) in >1 organ at diagnosis and 5% had 3 or 4 metastasectomies versus none in BRAF MT. Median OS in BRAF MT v WT: 25.7 v 48.5 months (HR 1.95; 1.18-3.22). In a multivariate model adjusting for variables which were significant on univariate analysis, OS differences were not statistically significant. Right primary tumor, intact primary, >1 metastatic sites at diagnosis, non R0 resection, peritoneal mets and synchronous mets were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 v 19 months, p=0.09). Rate of downsizing was higher with triplet chemo than doublet +/- bevacizumab or doublet/EGFR in BRAF WT (50 v 30%) as well as MT (33 v 11%). Conclusions: Median OS was > 2 years in BRAF MT V600E after metastasectomy in this study consistent with an OS benefit. OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Presence of BRAF MT should not impact patient selection for metastasectomy.[Table: see text]

PURPOSE Metastatic colorectal cancers (mCRCs) assigned to the transit-amplifying (TA) CRCAssigner subtype are more sensitive to anti–epidermal growth factor receptor (EGFR) therapy. We evaluated the association between the intratumoral presence of TA signature (TA-high/TA-low, dubbed as TA-ness classification) and outcomes in CRCs treated with anti-EGFR therapy. PATIENTS AND METHODS The TA-ness classes were defined in a discovery cohort (n = 84) and independently validated in a clinical trial (CO.20; cetuximab monotherapy arm; n = 121) and other samples using an established NanoString-based gene expression assay. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) according to TA-ness classification were assessed by univariate and multivariate analyses. RESULTS The TA-ness was measured in 772 samples from 712 patients. Patients (treated with anti-EGFR therapy) with TA-high tumors had significantly longer PFS (discovery hazard ratio [HR], 0.40; 95% CI, 0.25 to 0.64; P < .001; validation HR, 0.65; 95% CI, 0.45 to 0.93; P = .018), longer OS (discovery HR, 0.48; 95% CI, 0.29 to 0.78; P = .003; validation HR, 0.67; 95% CI, 0.46 to 0.98; P = .04), and higher DCR (discovery odds ratio [OR]; 14.8; 95% CI, 4.30 to 59.54; P < .001; validation OR, 4.35; 95% CI, 2.00 to 9.09; P < .001). TA-ness classification and its association with anti-EGFR therapy outcomes were further confirmed using publicly available data (n = 80) from metastatic samples (PFS P < .001) and patient-derived xenografts ( P = .042). In an exploratory analysis of 55 patients with RAS/BRAF wild-type and left-sided tumors, TA-high class was significantly associated with longer PFS and trend toward higher response rate (PFS HR, 0.53; 95% CI, 0.28 to 1.00; P = .049; OR, 5.88; 95% CI, 0.71 to 4.55; P = .09; response rate 33% in TA-high and 7.7% in TA-low). CONCLUSION TA-ness classification is associated with prognosis in patients with mCRC treated with anti-EGFR therapy and may further help understanding the value of sidedness in patients with RAS/BRAF wild-type tumors.

PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

Background Two germ line Fc‐γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab‐treated chemotherapy‐refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods After germ line DNA genotyping, polymorphic relationships with survival were assessed using log‐rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results Of 592 wild‐type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P

248 Background: Quality indicators (QI) are essential to monitor the efficacy of cancer care and to guide quality improvement, however many are derived from ‘expert consensus’ and are not validated against outcomes. Moreover, the majority of oncological QI are defined in the surgical setting, with only a paucity of QI for the treatment of metastatic disease. We aimed to define and validate novel QI for metastatic colorectal cancer (mCRC) based on therapeutic approaches associated with a proven survival benefit. Methods: Data was analysed from TRACC, a multisite Australian registry collecting prospective demographic, tumour, treatment and outcome data for mCRC. We identified all patients diagnosed across 11 hospitals and explored variation by site with regards to patient and tumour characteristics, first-line chemotherapy administration and resection of oligometastatic disease. Log-rank testing and Kaplan-Meier curves compare overall survival (OS) between sites, and Pearson correlation was used to assess associations with each QI. Results: We examined data from 3132 patients diagnosed with mCRC between July 2009 – April 2021. Median age was 66 years (range 62 – 71 years by site), ECOG 0-1 81% (range 69 – 96% by site), and Charlson Comorbidity Index ≤2 43% (33 – 59% by site). Multivariate analysis confirmed association of known adverse prognostic factors with inferior OS (poor ECOG, right sided primary, KRAS or BRAF mutation, all p 2 = 0.851), rate of liver resection (9.8 – 23.2% by site) was moderately correlated (R2 = 0.523), and rates of active treatment with first-line chemotherapy (63 - 90% by site) were weakly correlated (R2 = 0.209). Other proposed QI such as rates of lung metastases resection or chemotherapy administration in the elderly showed significant variation by site, but did not correlate with survival. Conclusions: There is significant variation in OS for patients with mCRC in these Australian hospitals, with major differences in treatment approaches. Treatment strategies known to improve survival outcomes, such as triplet FOLFOXIRI chemotherapy and resection of liver metastases, may be potential QI to benchmark and track quality improvement over time. Further analysis will determine the impact of baseline patient populations between sites, and to correlate these QI with other quality measures.

e18723 Background: Chemotherapy at the end of life (CEOL) is widely accepted as an indicator of aggressive care. However, the evidence is limited primarily to single-centre experiences, with no consensus regarding acceptable benchmarks for CEOL, nor how this may be changing over time and with novel treatment options. We describe ‘real world’ CEOL in two large, multisite Australian registries of metastatic colorectal cancer (mCRC) and both locally advanced and metastatic pancreatic cancer (PC). Methods: Data was analysed from the TRACC and PURPLE registries, two large prospective multisite Australian cancer registries collecting prospective demographic, tumour, treatment and outcome data for mCRC and PC respectively. We identified all decedents between May 2009 and November 2020, determined the proportion who died within 14 or 30 days of chemotherapy (14D / 30D), or within 30D after a new line of therapy, defined as the first cycle of a new treatment regimen. Using univariate analysis, we compared baseline demographic and clinicopathological variables and trends over time. Results: 1505 mCRC and 602 PC decedents were identified. 20.9% of decedents (21.6% mCRC and 19.3% PC) received chemotherapy within 30D, and 11.5% within 14D (12.3% mCRC and 9.6% PC). There were lower rates of 30D CEOL after the first cycle of a new line of therapy (4.3% mCRC and 5.7% PC). Rates of CEOL decreased over the study period for mCRC (median rate of initial 3-year period 28% versus 15% in last 3-year period), but remained largely static for PC (18.9% versus 17.9%). 30D CEOL was more likely with palliative than curative intent treatment (mCRC OR 1.6, 95% CI 1.14-2.25, p = 0.007, PC OR 5.3, 95% CI 1.6-17.8), and advanced rather than local disease in PC (PC OR 2.59, 95%CI 1.6-4.1, p < 0.001). There was a trend towards CEOL and poorer performance status (ECOG) across all groups, only significant for 30D CEOL mCRC (OR 1.51, 95% CI 1.04-2.2). There was no association between CEOL and patient age, gender, Charlson comorbidity score or lines of therapy. Conclusions: Real-world rates of CEOL are higher in our cohorts of mCRC and PC patients than historical benchmarks but comparable to contemporary reports, which may be due to a wider array of available active treatments. Overall rates are decreasing over time for mCRC but static for PC, which may reflect the poorer overall survival for PC and lack of new effective therapies. The lower rates of death after new lines of therapy may signify that CEOL is more likely with existing treatment regimens and that clinicians are less likely to initiate a new chemotherapeutic regimen at EOL.

80 Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was granted accelerated approval by the US Food and Drug Administration for patients with BRCA+ mCRPC based on results from the phase 2 TRITON2 study (NCT02952534). The TP53 tumor suppressor gene is among the most frequently mutated genes in human cancers, including mCRPC, and alterations in TP53, PTEN, and RB1 are associated with poor prognosis in patients with prostate cancer and other tumor types. We present data on co-occurring alterations in patients with BRCA+ mCRPC treated with rucaparib in TRITON2. Methods: Patients had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy and were treated with rucaparib 600 mg BID. Tissue and/or cell-free DNA extracted from plasma samples were profiled comprehensively for genomic alterations using Foundation Medicine, Inc., next-generation sequencing assays. Objective response rate (ORR) was assessed per modified Response Evaluation Criteria in Solid Tumors and Prostate Cancer Working Group 3 criteria by independent radiologic review of patients with measurable disease. Prostate-specific antigen (PSA) response rate (≥50% decrease from baseline) was assessed in all patients. Results: Tissue and/or plasma samples were available for 114/115 patients with BRCA+ mCRPC (visit cutoff date: Dec. 23, 2019). Among patients with BRCA+ mCRPC who had samples available for comprehensive genomic profiling, 36.8% (42/114) had a co-occurring alteration in TP53. Deleterious alterations in PTEN were observed in 34.2% (39/114) of patients, 44% (17/39) of which were homozygous deletions of PTEN. RB1 loss was observed in 12.3% (14/114) of patients and was seen more frequently in patients with measurable disease (18.0%, 11/61) than in patients with non-measurable disease (5.7%, 3/53). Although patients with and without TP53 mutations had generally similar baseline demographics and disease characteristics, visceral disease was more prevalent in patients with TP53 mutations (54.8%; 23/42) than in those without them (29.2%; 21/72). Similar ORR and PSA response rates were seen in patients with BRCA+ mCRPC with or without TP53 mutation, with a non-significant trend towards lower response rates in patients with co-occurring TP53 alterations. Conclusions: Results from TRITON2 showed antitumor activity for rucaparib in patients with BRCA+ mCRPC associated with or without co-occurring alterations in TP53. Demographics and additional efficacy analyses in genomic subgroups with co-occurring alterations in TP53, PTEN, and RB1 will be reported. Clinical trial information: NCT02952534. [Table: see text]

71 Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. In Australia, TAS-102 was initially made available locally through patients self-funding, later via an industry sponsored Medicine Access Program (MAP) and then via the Pharmaceutical Benefits Scheme (PBS). This study aims to investigate the efficacy and safety of TAS-102 in real world Australian population. Methods: A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to all TRACC patients and those enrolled in the registration study (RECOURSE). Results: Across 13 sites, 107 patients were treated with TAS-102 (non-PBS n = 27, PBS n = 80), The median number of patients per site was 7 (range: 1-17). The median age was 60 years (range: 31-83), compared to 67 for all TRACC patients and 63 for RECOURSE. Comparing registry TAS-102 and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 39% vs 49% were RAS wild type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median clinician assessed progression-free survival was 3.3 compared to RECIST defined PFS of 2 months in RECOURSE study, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths in the real-world series, where TAS102 dose at treatment initiation was at clinician discretion. In the RECOURSE study there was a 4% febrile neutropenia rate and one treatment-related death. Conclusions: TRACC registry patients treated with TAS102 were younger than both TRACC patients overall and those from the RECOURSE trial. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS. However overall survival outcomes achieved with TAS102 in real world patients were comparable to findings from this pivotal trial with an acceptable rate of major adverse events.

84 Background: The optimal management of isolated distant lymph node metastases (IDLNM) in metastatic colorectal cancer (mCRC) is not clearly established. Small case series and prior data from the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry support the use of radical treatment with curative intent (local resection, chemo-radiation or stereotactic radiotherapy), which may lead to better outcomes in mCRC patients with IDLNM. Aims: This study investigates the clinical characteristics and outcomes of mCRC patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. Methods: Clinical data were collected and reviewed from the TRACC registry, a prospective, comprehensive registry for mCRC from multiple tertiary hospitals across Australia from 01/07/2009 to 30/06/2020. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with other organ metastases. Fisher exact test was used for significance tests and Kaplan Meier curves for survival analyses. Results: Of 3408 mCRC patients with a median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC with other organ metastases, patients with IDLNM were younger (mean age: 62.1 vs 65.6 years, p=0.0200), more likely to have metachronous disease (57.0% vs 38.9%, p=0.0005), be KRAS wild-type (74.6% vs 53.9%, p=0.0012) and BRAF mutant (12.9% vs 6.2%, p=0.0100). There was no overall survival difference between with IDLNM and those with other organ metastases (median OS 27.24 vs 25.92 months, p=0.2300). Twenty-four patients (25.8%) with IDLNM received treatment with curative intent, with a trend towards improved overall survival compared to those with other organ metastases treated with curative intent (73.5 vs 62.7 months, p=0.8200). Amongst mCRC patients with IDLNM, those who received treatment with curative intent had a significantly better overall survival than those treated with palliative intent (73.5months vs 23.2 months, p=0.0070). Conclusions: Our findings suggest that there are differences in the patterns of presentation of IDLNM and other organ metastases. Radical treatment with curative intent options should be considered for mCRC patients with IDLNM where appropriate.

Advanced esophagogastric cancers are aggressive malignancies with an extremely poor prognosis. Palliative chemotherapy remains disappointing, with median survival of

e16048 Background: Bevacizumab remains the dominant biologic treatment option for RAS mutant (RASmt) metastatic colorectal cancer (mCRC). While the health economic impact of bevacizumab in the RASmt subpopulation may deviate from its use in the general mCRC population, this has never been investigated. This study uses the power of real-world data to assess the cost-effectiveness of doublet chemotherapy with compared to without bevacizumab (ChemBev and ChemOnly, respectively) for first-line treatment of RASmt mCRC, while accounting for subsequent treatment in second and third line. Methods: Data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was analyzed to populate a discrete event simulation of three treatment lines, surgery of primary tumor and metastases, hospitalizations following serious adverse events, and best supportive care. Imbalance in baseline patient and disease characteristics was corrected for in all analyses using inverse probability weights. Costs were included from an Australian public payer perspective in Australian dollars (AUD). All health and economic outcomes were discounted at 5% per year. Results: Of the 507 included RASmt mCRC patients that started first-line treatment in the 2010 – 2017 time period, 345 received ChemBev and 162 ChemOnly. The corrected median time on first-line treatment was 7.1 months (95% confidence interval: 6.4 – 8.0) for ChemBev and 4.1 months (3.5 – 5.1) for ChemOnly. Time on second- and third-line treatment was comparable between the groups. Corrected overall survival was 22.6 months (21.7 – 24.0) for ChemBev and 14.3 months (12.1 – 21.7) for ChemOnly. In terms of the health economic impact, mean life years were 1.9 for ChemBev and 1.5 for ChemOnly, and mean costs were AUD 93,025 and AUD 44,929 per patient, respectively. The resulting incremental cost-effectiveness ratio (ICER) of ChemBev compared to ChemOnly was AUD 149,317 per life-year gained (LYG). Conclusions: In contrast to results from clinical trials, overall survival was substantially longer for patients who received bevacizumab, which can possibly be attributed to an imbalance between groups despite correction for known prognostic factors. At an ICER of AUD 149,317 per LYG, the economic burden of upfront treatment with bevacizumab was found to be substantial and consistent with estimates for the general mCRC population. This is mainly caused by the duration of first-line treatment, which was significantly longer for ChemBev.

e16072 Background: The KRASG12C mutation is present in 3% of colorectal cancer and is of particular interest given the recent development of specific targeting drugs. Previous data suggest KRAS (all) mutations may impact prognosis. Here we assess the clinical features and outcomes of real world patients with KRASG12C mutant metastatic colorectal cancer (mCRC) to explore any clinicopathologic associations and prognostic impact. Methods: Patients diagnosed with mCRC between January 2011 and December 2018 were included in this prospective mCRC registry. Patients with BRAF mutations, unknown or unspecified KRAS variants were excluded. Clinicopathologic features, treatment and overall survival (OS) were compared for RAS wildtype (RASWT) and KRASG12C mutant patients, and between KRASG12C and other (RASother) mutations. Results: Of 1308 patients analysed, 674 (52%) were RASmut, of whom 56 (8.3%) were KRASG12C. More patients with KRASG12C were female compared to RASother and RASWT (Table). No differences were observed in primary tumor location, number of metastatic sites and distribution of metastases. The proportion of patients undergoing metastasectomy was similar between KRASG12C and RASother, and KRASG12C and RASWT. There was no difference in the proportion of patients receiving systemic therapy. RASWT patients received more lines of therapy. Median OS was similar between KRASG12C, RASother, and RASWT: 31.7 vs 29.2 vs 31.8 months respectively (P = 0.545). Conclusions: KRASG12C mutations were observed in 4.3% of mCRC patients and in 8.3% of RAS mutant cases. Patients with KRASG12C have comparable clinical features to RASWT or RASother mCRC. Treatment and survival were also similar between groups. KRASG12C does not appear to be prognostic, but may be an important predictive biomarker as promising targeted therapies continue to be developed. [Table: see text]

178 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]

159 Background: There is conflicting evidence regarding benefit of perioperative chemotherapy (p-chemo) for metastatic colorectal cancer (mCRC) patients (pts) undergoing resection of metastases (mets). Aims: To describe use of and outcomes from p-chemo in mCRC pts who underwent resection of isolated liver or lung mets. Methods: Pts were identified from the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a multi-centre registry of mCRC pts. P-chemo was defined as chemotherapy within 12 weeks of surgery. Multivariate (MV) analysis using a Cox proportional hazards model was undertaken. Results: 371 pts were identified. Median age was 64 (27 – 90), 169 (45%) had de novo stage IV disease, 96% were ECOG 0-1. 284 (77%) had liver-only and 87 (23%) lung-only mets. 242 (65%) pts received p-chemo (58 pre-op alone, 134 post-op alone, 50 both). 62 (19%) pts also received a biologic agent (47/62 pre-op). Median age was 68 and 61 years in no p-chemo and p-chemo groups, respectively (p

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.

Background: The phase 2 TRITON2 (NCT02952534) study is evaluating the poly(ADP-ribose) polymerase inhibitor rucaparib in mCRPC patients with a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or 1 of 12 other DNA damage repair (DDR) genes who have progressed on prior androgen receptor-directed therapy and 1 taxane-based therapy. Here we present results from central genomic screening of plasma and tissue samples for TRITON2. Methods: Plasma samples were profiled for genomic alterations (GAs) in 70 genes and tumor tissue FFPE samples for GAs in 395 genes by Foundation Medicine, Inc., using next-generation sequencing (NGS) assays. Deleterious alterations included frameshift, nonsense, and deleterious missense mutations, protein-truncating rearrangements, and (for tissue samples) homozygous loss. Tissue samples included both archival and more recent specimens, whereas plasma samples were collected at the time of disease progression on prior therapy. Results: As of July 2, 2018, 359 plasma samples from patients with mCRPC were screened for deleterious GAs in a DDR gene. Of the plasma samples, 96% (343/359) were successfully sequenced for a comprehensive genomic profile. The most commonly altered genes were AR (49%) and TP53 (48%). Deleterious GAs were detected in BRCA1 (2%), BRCA2 (10%), ATM (15%), CDK12 (6%), or other DDR genes (6%). GAs in the MAPK pathway were observed in 5% of plasma samples. Additionally, 738 tissue samples from primary prostate cancer tumors (78%) or metastases (22%) were profiled. Only 66% of tissue samples (487/738) were sequenced successfully, highlighting the challenges associated with NGS of predominantly archival prostate tissues (median sample age, 2.5 years [range, 4 days to 21 years]). The most commonly altered genes were TP53 (38%), PTEN (33%), ERG-TEMPRSS2 fusions (28%), AR (15%), and MYC (9%). Deleterious GAs were observed in BRCA1(2%), BRCA2 (9%), ATM (7%), CDK12 (7%), or other DDR genes (5%), as well as in the PI3K/AKT (41%), Wnt (11%), MAPK (5%), and mismatch repair (3%) pathways. Further, GAs in the DDR, PI3K/AKT, and Wnt pathways were observed at a higher rate in metastatic (42%, 40%, and 15%, respectively) than in primary prostate tissues (32%, 34%, and 12%, respectively). Updated and expanded genomic analyses and plasma-tissue concordance analyses will be presented. Conclusions: Genomic NGS profiling of plasma and FFPE tumor tissue samples successfully identified patients with GAs in a DDR gene for the evaluation of rucaparib in mCRPC. The plasma assay is convenient for patients and has a low NGS failure rate, whereas the tumor tissue assay has a higher failure rate but can detect more alteration types. Taken together, these data highlight the strengths and limitations of tissue and plasma testing to identify GAs for targeted therapies in mCRPC. Citation Format: Foad Green, Jeremy D. Shapiro, Ray McDermott, Josep Maria Piulats, Alison Reid, Peter Ostler, Jingsong Zhang, David Campbell, Dominique Spaeth, Ivor Percent, Arif Hussain, Andrew D. Simmons, Tony Golsorkhi, Simon P. Watkins, Andrea Loehr, Simon Chowdhury, Wassim Abida. Comprehensive genomic profiling of >1000 plasma and tumor tissue samples from metastatic castration-resistant prostate cancer (mCRPC) patients gives insight into targeted treatment strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 727.

5031 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic alteration in BRCA ( BRCA1 or BRCA2) or 1 of 13 other DNA damage repair genes. Here we present analyses of tumor genomics and baseline clinical characteristics in mCRPC patients with a deleterious alteration in BRCA. Methods: Plasma (baseline) and tissue (archival or baseline) samples from patients with a deleterious alteration in BRCA were analyzed using Foundation Medicine next-generation sequencing assays. The alterations and zygosity of the alterations that were detected, as well as the somatic/germline status from Color Genomics testing, were summarized. Associations between genomic alterations, DNA yield, allele frequency, and baseline clinical characteristics were investigated. Results: Results are shown in the Table for a cohort of 40 BRCA2 and 5 BRCA1 patients enrolled in TRITON2 (Abida W et al. Presented at ESMO 2018. Abst 793PD). A biallelic alteration was observed in 21 of the 22 BRCA2 patients (95%) for whom alteration zygosity could be determined. Among the 5 BRCA1 patients, 1 alteration was monoallelic and 4 were of unknown zygosity. Co-occurring alterations in cancer-related or DNA damage repair genes were observed in many patients with BRCA alterations. At baseline, cell-free DNA (cfDNA) yield correlated positively with the sum of target lesions (STL; P= 0.04), but not with prostate-specific antigen (PSA) levels ( P= 0.86). No correlation was observed between allele frequency of the BRCA alteration baseline STL ( P= 0.68) or PSA levels ( P= 0.97). Conclusions: Patients with a BRCA mutation enrolled in TRITON2 demonstrate a profile of genomic alterations consistent with that of prior studies of patients with mCRPC. Plasma cfDNA profiling showed a correlation between baseline cfDNA yield and measurable tumor burden, but not baseline PSA. Clinical trial information: NCT02952534. [Table: see text]

e18061 Background: The wide range of possible combinations and sequences available for mCRC treatment presents a major challenge to clinicians, who need to determine the optimal approach for an individual patient or patient subset. In the absence of clinical trial evidence, real world data are an increasingly valuable resource that can be utilized not only to understand treatment patterns and outcomes in routine practice, but also to define an optimal treatment strategy for individual patients across multiple lines of therapy. Methods: Real world data from an Australian mCRC registry were used to develop an interactive data visualization tool that displays treatment variation, customizable to different levels of detail and specific patient subsets, based on patient and disease characteristics. Next, a discrete event simulation model was developed to predict progression-free (PFS) and overall survival (OS) for first line palliative treatment with doublet chemotherapy alone or with bevacizumab, based on data of 867 patients that were treated accordingly. Results: Of 2694 Australian patients enrolled, 2057 (76%) started 1st line treatment with chemotherapy and/or a biologic agent, 1087 (40%) and 428 (16%) received 2nd and 3rd line therapy, respectively. Combined, these 3 lines of treatment accounted for 733 unique sequences. After recoding treatment to the most intensive chemotherapy and the first exposed biologic, 472 unique sequences remained. In exploratory analyses, the simulation model estimated that median 1st line PFS (95% CI) of 219 (25%) patients could be improved from 175 (156, 199) to 269 days (247, 293) by targeting a different treatment. Conclusions: This was an initial exploration of the potential for data visualization and simulation modeling to inform understanding of practice in mCRC and to guide clinical decision making. Such tools allow clinicians and health system providers to define variation in practice patterns and to identify opportunities to improve care and outcomes. Ultimately, the aim is to improve the delivery of personalized cancer care, where other applications such as conditional survival and cost-effectiveness analyses may be useful.

623 Background: Patients with metastatic colorectal cancer (mCRC) arising from a right sided colorectal cancer (RC) have an inferior survival versus patients with a left sided colorectal cancer (LC). Previous analyses have suggested that multiple factors contribute. Methods: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry has prospectively captured comprehensive data on consecutive mCRC patients since 2009. For this analysis LC were defined as primary tumors at or distal to the splenic flexure and included rectal cancers. We analysed patient, tumor, treatment and outcome data. Results: Of 2306 patients enrolled from July 2009–March 2018, median age 67 years (range 18–100), 1559 (67.6%) had a LC. Patients with a RC were older (median 71 vs 65 years, p < 0.001), more likely to be female (50.2% vs 36.9%, p < 0.001) and to have a Charlson score ≥ 3 (67.5% vs 54.6%, p < 0.001). More common in RC, where tested, were BRAF mutations (22.3% vs 7.2%, p < 0.001) and deficient mismatch repair (6.4% vs 1.5%, p < 0.001), but not RAS mutations. Peritoneal metastases were more frequent in RC (29.7% vs 14.9%, p < 0.001). RC patients were more likely to have their primary tumor resected (77.9% vs 70.6%, p < 0.001) and to receive less first-line chemotherapy (72.2% vs 78.7%, p = 0.001). Progression-free survival on first-line systemic therapy was inferior for RC patients (8.1 vs 10.8 months, HR 1.38, p < 0.001). Median overall survival (OS) for all RC patients was inferior (19.6 vs 27.5 months, HR 1.44, p < 0.001). Primary side remained a significant factor for OS in multivariate analysis. Conclusions: Our data confirms the poor prognosis associated with RC, contributed to by multiple factors. However, primary side remains significant even when adjusting for these, indicating the existence of further as yet undefined differences. [Table: see text]

INTRODUCTION: Colorectal cancer (CRC) and its treatments can cause distressing sequelae. We conducted a multicenter randomized controlled trial aiming to improve psychological distress, supportive care needs (SCNs), and quality of life (QOL) of patients with CRC. The intervention, called SurvivorCare (SC), comprised educational materials, needs assessment, survivorship care plan, end-of-treatment session, and three follow-up telephone calls. METHODS: At the end of treatment for stage I-III CRC, eligible patients were randomized 1:1 to usual care (UC) or to UC plus SC. Distress (Brief Symptom Inventory 18), SCNs (Cancer Survivors' Unmet Needs measure), and QOL (European Organization for Research and Treatment of Cancer [EORTC] QOL questionnaires C30 and EORTC CRC module CR29) were assessed at baseline and at 2 and 6 months (follow-up 1 [FU1] and FU2, respectively). The primary hypothesis was that SC would have a beneficial effect on distress at FU1. The secondary hypotheses were that SC would have a beneficial effect on (a) SCN and QOL at FU1 and on (b) distress, SCNs, and QOL at FU2. A total of 15 items assessed experience of care. RESULTS: Of 221 patients randomly assigned, 4 were ineligible for the study and 1 was lost to FU, leaving 110 in the UC group and 106 in the SC group. Patients' characteristics included the following: median age, 64 years; men, 52%; colon cancer, 56%; rectal cancer, 35%; overlapping sites of disease, 10%; stage I disease, 7%; stage II, 22%; stage III, 71%. Baseline distress and QOL scores were similar to population norms. Between-group differences in distress at FU1 (primary outcome) and at FU2, and SCNs and QOL at FU1 and FU2 were small and nonsignificant. Patients in the SC group were more satisfied with survivorship care than those in the UC group (significant differences on 10 of 15 items). CONCLUSION: The addition of SC to UC did not have a beneficial effect on distress, SCNs, or QOL outcomes, but patients in the SC group were more satisfied with care. IMPLICATIONS FOR PRACTICE: Some survivors of colorectal cancer report distressing effects after completing treatment. Strategies to identify and respond to survivors' issues are needed. In a randomized controlled trial, the addition of a nurse-led supportive care package (SurvivorCare) to usual posttreatment care did not impact survivors' distress, quality of life, or unmet needs. However, patients receiving the SurvivorCare intervention were more satisfied with survivorship care. Factors for consideration in the design of subsequent studies are discussed.

Background Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are “wild type”). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a “quadruple wild type” tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent. Methods and design ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with “quadruple wild type” or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer. Discussion This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the “quadruple wild type”, which may ‘superselect’ for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups. Trial registration Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808, registered 16 August 2012.

Purpose RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype. Patients and Methods Patients with chemotherapy-refractory KRAS G13D mutation–positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m2 loading dose and then 250 mg/m2 once per week with or without irinotecan 180 mg/m2 once every 2 weeks. The primary end point was 6-month progression-free survival; secondary end points were response rate, overall survival, quality of life, and toxicity. Results Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar; toxicities were higher with combination therapy. Conclusion In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.

633 Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.

Purpose National Cancer Institute of Canada Clinical Trials Group CO.17 demonstrated the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab improves overall and progression-free survival in patients with advanced, chemotherapy-refractory colorectal cancer (CRC), particularly in patients with wild-type KRAS tumors. This article reports the health-related quality-of-life (HRQL) outcomes from CO.17. Patients and Methods Patients (N = 572) with pretreated EGFR-detectable advanced CRC were randomly assigned to cetuximab and best supportive care (BSC) or to BSC alone. HRQL primary end points assessed by the EORTC QLQ-C30 were physical function (PF) and global health status (GHS); mean changes from baseline to 8 and 16 weeks were assessed. Post hoc analysis by KRAS mutation status was performed. Results Questionnaire compliance was 94% at baseline, but it declined differentially (67% v 47% for cetuximab v BSC at 16 weeks). PF change scores were −3.9 for cetuximab and −8.6 for BSC (P = .046) at 8 weeks and were −5.9 and −12.5 for cetuximab and BSC, respectively, (P = .027) at 16 weeks. GHS change scores were −0.5 and −7.1 (P = .008) at 8 weeks and were −3.6 and −15.2 (P = .008) at 16 weeks for cetuximab and BSC, respectively. In patients who had tumors with wild-type KRAS status, cetuximab resulted in less PF deterioration at 8 weeks (−0.7 v −7.2; P = .11) and 16 weeks (−3.4 v −13.8; P = .008) compared with BSC. Patients with wild-type status who received cetuximab experienced improved GHS at 8 weeks, whereas patients who received BSC alone deteriorated (3.2 v −7.7; P = .002). Cetuximab preserved GHS at 16 weeks (−0.2 v −18.1; P < .001). No significant differences were noted between study arms for patients with mutated KRAS tumors. Conclusion Cetuximab offers important HRQL and survival benefits for pretreated patients with advanced, wild-type KRAS CRC.

Background: Hormone-refractory prostate cancer (HRPC) is associated with a poor prognosis and has historically been considered relatively chemoresistant. Emerging data demonstrate clinical benefit with the use of docetaxel in HRPC, culminating in two recent published phase III studies demonstrating survival benefit. Currently, docetaxel is registered but not reimbursed for HRPC in Australia. Aim: To retrospectively review prostate-specific antigen (PSA) response rate, and survival following the use of docetaxel for metastatic HRPC. Methods: Retrospective audit of the use of docetaxel for HRPC from 1 January 2001 to 1 April 2004 in three medical oncology practices. Demographic data, baseline PSA, ECOG (Eastern Cooperative Oncology Group) Performance Status, sites of disease, number of cycles received and PSA response rates were collected. Results: Thirty five patients (median age, 71 years; range, 50–88) had an ECOG status of 0 (eight), 1 (20) and 2 (seven). The mean duration from initial prostate cancer diagnosis to start of docetaxel was 5.4 years (range, 0.2–13.5 years). The mean baseline PSA doubling time, available for 29/35 patients, was 1.9 months (range, 0.4–4.9). The median number of metastatic sites was 1 (range, 1–4): bone (34 patients), lymph nodes (10), liver (seven) and lung (seven). Twelve patients were chemotherapy naive; 23 had received prior chemotherapy (21/23 received mitoxantrone). Twenty patients received docetaxel three times weekly; 15 were on weekly schedules. Their mean dose density was 23 mg/m2/week. Patients received an average of 3.2 months of treatment (range, 0.2–11.8). There were 170 recorded toxicities, 13 of which were grade 3–4, and two likely treatment-related deaths (sepsis). Twelve patients (34%) had >50% PSA response (four were chemotherapy naive); of these 12 responders, seven patients had a >75% PSA response (four chemotherapy naive). Median survival from start of docetaxel was 8 months with 37% alive at 12 months and 23% alive at 24 months. Conclusion: Docetaxel is active in HRPC (in both chemotherapy naive and exposed patients) with a predictable toxicity profile. More research is warranted to identify predictors of response and toxicity.

The aim of this phase II study was to assess the feasibility and efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-fluorouracil (CI 5FU) sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. Patients with inoperable cancer in the pancreatic head or body without metastases were given gemcitabine at 1000 mg m(-2) weekly for 3 weeks followed by a 1-week rest and a 6-week period of radiotherapy and concurrent CI 5FU (200 mg m(-2) day(-1)). The defined target volume was treated to 54 Gy in 30 daily fractions of 1.8 Gy. After 4 weeks' rest, gemcitabine treatment was re-initiated for three cycles (days 1, 8, 15, q28). Forty-one patients were enrolled. At the end of radiotherapy, one patient (2.4%) had a complete response and four patients (9.6%) had a partial response; at the end of treatment, three patients (7.3%) had a complete response and two patients (4.9%) had a partial response. Median survival time was 11.7 months, median time to progression was 7.1 months, and median time to failure of local control was 11.9 months. The 1- and 2-year survival rates were 46.3 and 9.8%, respectively. Treatment-related grade 3 and 4 toxicities were reported by 16 (39.0%) and four (9.8%) patients, respectively. Sixteen out of 41 patients did not complete the planned treatment and nine due to disease progression. This approach to treatment of locally advanced pancreatic cancer is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomised trial.

Purpose: Two germline Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A;Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximab-related outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR. Experimental Design: DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism–treatment arm interaction term. Results: Somatic KRAS status was wild-type for exon 2 in 153 (52%) of 293 patients, from whom tumor DNA was available. For FCGR2A H/H, a genotype–treatment interaction for KRAS wild-type patients was observed for OS (P = 0.03). In KRAS wild-type patients carrying FCGR2A H/H, cetuximab (vs. no cetuximab) improved survival substantially, with adjusted HRs (aHR) of 0.36 (OS) and 0.19 (PFS) and absolute benefits of 5.5 months (OS; P = 0.003) and 3.7 months (PFS; P = 0.02). In contrast, patients carrying FCGR2A R alleles (H/R or R/R) had aHRs of only 0.78 (OS; 2.8-month benefit) and 0.53 (PFS; 1.6-month benefit). No relationships were found for rs396991 (FCGR3A). Conclusions: In the CO.17 trial, cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes. Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles. Clin Cancer Res; 22(10); 2435–44. ©2016 AACR.

699 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by Vmax and Km). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m2 for V, 2.5 ± 0.3 mg/h/m2 for Vmax, and 101.0 ± 0.05 mg/L/m2 for Km. Grouped into quartiles, Vmax and Km were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of Vmax was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p< 0.001), while the median OS was 11.6 ms in the highest Km quartile vs. 6.9 ms in the lowest Km quartile ( p< 0.001). When compared to the quartile with the combination of highest Vmax and lowest Km, pts in the quartile with the lowest Vmax and highest Km had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p< 0.001). Pts in the lower Vmax and higher Km quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.

3572 Background: Cetuximab (cet) increases survival in RAS wild-type (WT) metastatic colorectal cancer (mCRC) in first-line and chemorefractory patients (pts). Adding irinotecan (iri) to cet in refractory pts who had progressed on iri increased response and delayed progression in the BOND trial, which was conducted prior to recognition that RAS mutations are predictive of EGFR-inhibitor (EGFR-I) resistance. Subsequent trials in chemorefractory pts used single agent EGFR-I as standard. In the era of biomarker selection, the benefit of continuing iri versus single agent EGFR-I had not been resolved. Methods: ICECREAM is a randomised phase II trial evaluating cet v cet + iri in chemotherapy-refractory mCRC, stratified for KRAS G13D mutation (previously reported) or no mutations in KRAS, NRAS, BRAF and PI3KCA (Quad WT ). EGFR-I naïve, ECOG PS 0-1 pts, progressing within 6 months of iri and refractory (or intolerant) to fluoropyrimidine and oxaliplatin were randomised to cet 400mg/m2 IV loading then 250mg/m2 weekly +/- iri 180mg/m2q2 wks. The primary endpoint was progression-free survival at 6 months (6m PFS); secondary endpoints were response rate (RR), overall survival (OS), toxicity and quality of life (QOL). Results: From Nov 2012 to June 2016, 48 Quad WT pts were recruited: 2 ineligible (not iri-refractory, BRAF mutation) wre not included for analyses and a further 2 not evaluable for response. Characteristics were balanced between cet (n = 21) v cet-iri (n = 25), except for sex (male 62 v 72%) and primary site (left 95 v 68%). 6m PFS rate was 14% v 41%; HR 0.39 (95% CI: 0.20–0.78, p = 0.008). RR was 10% (2 PR) v 36% (1 CR, 8 PR); p = 0.04. Toxicities were higher with cet-iri; at least one grade 3/4 adverse event in 50 v 23%. No differences in global or specific QOL were seen. Conclusions: The AGITG ICECREAM trial confirms a significant synergy for the addition of iri to cet and improved PFS in Quad WT chemorefractory mCRC, echoing data in molecularly unselected pts. Clinical trial information: ACTRN12612000901808.

3555 Background: There is minimal data on the efficacy and improvement of quality of life (QoL) of these targeted therapies, like cetuximab, in elderly CRC patients (≥70yo). We analyzed outcomes from two randomized phase III clinical trials from the Canadian Clinical Trials Group, CO.17 and CO.20. Methods: CO.17 and CO.20 were retrospectively analyzed. CO.17 compared cetuximab (CETUX) with best supportive care (BSC), CO.20 compared CETUX + brivanib (BRIV) with CETUX + placebo. Key eligibility criteria were similar between each trial. Patients were dichotomized by age (≥70yo/ < 70yo) for comparisons. Outcomes included overall survival (OS), progression free survival (PFS), adverse events (AEs), and QoL deterioration. In CO.17, only patients with wild type K-RAS were included in analysis. Multivariate analysis with Cox regression controlled for additional variables. Results: 980 patients were included in this analysis. 257 (26.2%) were ≥70yo at the time of enrollment. In CO.17, OS and PFS were similar between young and elderly patients treated with CETUX (OS 9.7m vs 8.0m, p = 0.45; HR 0.73 95%CI 0.39-1.37). Compared to the BSC arm, elderly patients treated with CETUX had a non-significant increase in OS (8.0m vs 5.1m, p = 0.11). In patients treated with CETUX, grade 3/4 AEs were similar between age groups, however elderly patients had a faster deterioration in global QoL than younger patients (3.6m vs 5.7m p = 0.046). In CO.20, younger patients had longer OS than elderly (9.2m vs 7.6m, p = 0.02; HR 0.81 95% 0.68-0.97, p = 0.02). AEs in the BRIV+CETUX arm were higher in the elderly than young (88% vs 77%, p = 0.03). Both young and elderly treated with BRIV+CETUX had more rapid decreases in global QoL than the CETUX arm. Conclusions: Age was neither prognostic nor predictive of response to targeted therapy in the single agent CO.17 trial. In CO.20, age conferred a worse prognosis. Elderly patients who are eligible for clinical trials may garner similar survival benefits as younger patients with single agent therapy, but may not derive the same improvement in QoL.

682 Background: Patients (pts) with metastatic colorectal cancer (mCRC) arising from a right sided colon cancer (RCC) have an inferior survival versus pts with a left sided primary (LCC). Previous analyses have suggested that multiple factors contribute. Methods: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry has prospectively collected data on consecutive mCRC pts at 32 sites (Australia and Hong Kong) from July 2009. LLC were defined as those distal to the splenic flexure. We analysed patient, tumour, treatment and outcome data. Results: Of 1763 patients, median age 67 years (range 18 – 100), 1201 patients (68.1%) had a LCC. RCC were more common in pts ≥ 70 years old (53.9% vs 38.5%, p < 0.01) and females (50.7%, p < 0.01). Where tested, KRAS (50.9% vs 41.5%, p < 0.01) and BRAF (19.1% vs 6.4%, p < 0.01) mutations were more common in RCC. Where tested, dMMR was more common in RCC (11.0% vs 3.2%, p < 0.01). Pts with a RCC more often had peritoneal metastases (25.9% vs 12.5%%, p < 0.01) and were less likely to have liver metastases (69.8% vs 77.9%, p < 0.01) or resection of metachronous metastases (31.8% vs 43.6%, p < 0.01). LCC more commonly received chemotherapy in the 1st (86.1% vs 80.3%, p = 0.02) and 2nd (49.7% vs 43.0%, p = 0.04) line setting. There was no difference in ECOG performance status or co-morbidity for LCC vs RCC. Overall survival for pts with a RCC was 20.6 months vs 27.9 months for LCC L-sided tumours (HR 1.395, p < 0. 0001). Conclusions: Our data confirms that pts with mCRC arising from a RCC have an inferior survival. This appears multifactorial due to associations with adverse clinical and molecular features, metastatic pattern, and less therapy, some of which are related. A multivariate analysis is being performed.

785 Background: Resection of metastases with curative intent is an integral component of mCRC management. However, relapse rates are high and identifying patients most likely to benefit from this approach is of considerable importance. Among patients with mCRC, mutations (mt) in RAS and BRAF genes portent a worse prognosis. Our hypothesis, therefore, is that patients harbouring these mutations may have a higher relapse rate after resection of metastases. We also wished to analyse clinical predictors of relapse, including site of metastases. Methods: We interrogated the TRACC database of patients undergoing resection with curative intent who had mutation status available. The frequency of RAS and BRAF mt was established and their association with clinical parameters determined. Relapse free (RFS) and overall survival (OS), from the date of resection, was estimated for the mt and wild type (wt) groups using the Kaplan Meier method. Multivariate analysis is planned to investigate factors associated with RFS, including stage of the primary tumour, synchronous metastases, site and number of metastases, CEA, peri-operative chemotherapy use, site of the primary (left v right) and RAS and BRAF mutation status. Results: 188 patients were identified. 89 were KRAS/BRAF wt, 92 KRAS mt and 7 BRAF mt. 40% had presented with metastatic disease and 27% had a right sided primary. 76%, 22% and 2% underwent resection of liver, lung or both metastases. Microscopic resection margin was involved in 6%. Resection was performed prior to any chemotherapy in 48%. No difference was seen in relapse free or overall survival between the mt and wt groups. Conclusions: We found no difference in relapse free or overall survival by mutation subgroup suggesting this should not influence suitability for curative intent resection, but analyses is planned on a much larger cohort once data is available. A multivariate analysis, adjusting for important prognostic variables, is planned.

BACKGROUND The authors combined cisplatin and carboplatin together with cyclophosphamide to maximize platinum dose intensity in patients with advanced epithelial ovarian cancer (AOC). METHODS The authors treated 26 consecutive, newly diagnosed patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III/IV AOC with carboplatin, 600 mg/m2, on Day 1; cyclophosphamide, 250 mg/m2, on Day 1; and cisplatin, 100 mg/m2, on Day 8 every 4 weeks with or without pretreatment with amifostine (range, 740-1140 mg/m2). Platinum dose intensity was estimated using a 4:1 conversion for equipotent doses of cisplatin and carboplatin for expression as cisplatin dose equivalents (CDE). RESULTS The mean administered CDE was 49.4 mg/m2/week, which was 79% of the planned dose. Hematologic toxicity was severe, with FIGO Grade 3-4 anemia in 81% of patients, Grade 3-4 neutropenia in 92% of patients, and Grade 4 thrombocytopenia in 96% of patients. Eleven patients (42%) were admitted to the hospital for febrile neutropenia and there was 1 toxic death. Sensory neuropathy ≥ Grade 2 occurred in 10 patients (38%), ototoxicity ≥ Grade 2 occurred in 18 patients (69%), and 6 patients (23%) required long term hearing aids. Elevations in serum creatinine ≥ Grade 2 occurred in 7 patients (27%) and ≥ Grade 2 hypomagnesemia was noted in 23 patients (88%). Other Grade 3 toxicities were nausea (42%), emesis (38%), fatigue (15%), mucositis (4%), and respiratory toxicities (4%). Twenty-two of 26 patients (85%) had a clinical response (19 with a complete response [CR] and 3 with a partial response). Pathologic CR was demonstrated in 10 of 26 patients (38%) and residual microscopic disease in 4 of 26 patients (15%) for a total pathologic response rate of 53%. The median progression free survival was 13.5 months and the median overall survival was 37.2 months at a median potential follow-up of 79.3 months. Three of 26 patients remained free of disease at 66, 71, and 103 months, respectively. CONCLUSIONS Although dose intensive combination platinum treatment combined with cyclophosphamide in patients with AOC is active, it also is associated with substantial toxicity. Cancer 1998;83:1980-1988. © 1998 American Cancer Society.

Background: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy–refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. Methods: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment–biomarker interaction. Results: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status (‘co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P

BACKGROUND The CO.20 trial randomized patients with K-RAS wild-type, chemotherapy-refractory, metastatic colorectal cancer to receive cetuximab (CET) plus brivanib alaninate (BRIV) or CET plus placebo (CET/placebo). METHODS Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 at baseline and at 2, 4, 6, 8, 12, 16, and 24 weeks until disease progression. Predefined coprimary QoL endpoints were time to deterioration (first worsening from baseline of ≥ 10 points) on the Physical Function (PF) and Global (GHS) scales. RESULTS Of 750 randomized patients, 721 (358 of whom received CET/BRIV) were assessable for QoL. QoL compliance and baseline PF and GHS scores did not differ by treatment arm. The median time to deterioration was 1.6 months versus 1.1 months for GHS (P = .02) and 5.6 months versus 1.7 months for PF (P

Purpose The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. Patients and Methods Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m2 intravenous loading dose followed by weekly maintenance of 250 mg/m2 plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS). Results A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively. Conclusion Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.

Background: This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer. Methods: Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2:1 to also receive intravenous trebananib 10 mg kg(-1) once weekly (OW) (Arm A) or placebo OW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS). Results: One hundred and forty-four patients were randomised (Arms A/B, n = 95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P = 0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P = 0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade >= 3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%). Conclusion: Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.