Background

The AIO KRK-0110 study compares a sequential application of FP+ BEV followed by IRI+ FP+ BEV at first progression (arm A) vs. initial FP+ IRI+ BEV (arm B) in patients (pts) with untreated mCRC.

Methods

The primary efficacy-endpoint was time-to-failure of strategy (TFS). The non-inferiority margin was a 90% confidence interval of a hazard ratio (HR) of 0.8 (Power 70%, α = 0.05). Secondary endpoints of the study included response rate, progression-free survival (PFS), overall survival (OS), efficacy in molecular subgroups and quality of life (EORTC QLQ C30).

Results

The full analysis set (FAS) consists of 421 pts (212/209 Arm A/B), median age was 71 years. The primary endpoint (TFS) was not met (HR: 0.86 (0.73-1.02)). Concerning TFS, patients with RAS/BRAF wild-type (WT) mCRC appeared to have significant benefit from initial irinotecan while this was not observed in patients with mutant (MT) RAS or BRAF. A Cox model interaction test for study arm and RAS-status was significant (P = 0.03). PFS and OS were consistent with TFS (see table for details). Objective response rate favored the initial irinotecan-arm (36.8% vs 53.6%, P = 0.005). Quality of life (global health, physical functioning, etc) was not substantially different between both study arms at baseline and end of treatment.

Conclusions

In this trial comprising a more elderly population, non-inferiority for TFS of initial FP+ BEV as compared to FP+ IRI+ BEV was not shown. In detail, sequential therapy was inferior in pts with RAS/BRAF-WT mCRC and cannot be recommended. However, sequential bevacizumab-based therapy could be discussed as an option in elderly pts with RAS MT mCRC. Conclusions on BRAF mutant tumors are limited by sample size.Table:

486O

Clinical trial identification

NCT01249638

Legal entity responsible for the study

Hospital of the University of Munich (LMU)

Funding

Roche

Disclosure

D. P. Modest: Honoraria/Advisory Boards: Amgen, Merck, Roche, Bayer, Servier, MSD, BMS. Research Grants: Amgen, Merck, Roche. Travel Support: Merck, Amgen, Servier, Bayer, BMS. L. Fischer von Weikersthal: Honoraria: Pfizer. Consulting or Advisory Role: Roche-Peru. Travel, accommodations, expenses: Pfizer, Roche-Peru, AMtene. T. Decker: Travel, accommodations, expenses: Novartis Pharma KK. U. Vehling-Kaiser: Consulting or Advisory Role: Gilead Sciences, MSD, Lilly, Abbvie, Roche Pharma AG, AMtene. U. Graeven: Honoraria: Sanofi, Bayer, Boehringer Ingelheim, Roche-Peru, AMtene. Consulting or Advisory Role: Baxalta, Servier. Travel, accommodations, expenses: Sanofi, Merck Inc. I. Schwaner: Consulting or Advisory Role: Abbvie, Merck Inc., Janssen Corp, Roche-Peru. Travel, accommodations, expenses: Novartis Pharma KK, Roche-Peru. A. Jung: Consulting or Advisory Role: Biocartis, AstraZeneca, Merck Inc., Roche-Peru, AMtene. Speakers\' Bureau: AstraZeneca, Merck Inc., Roche-Peru. Travel, accommodations, expenses: Biocartis, AstraZeneca, Merck Inc., Roche-Peru, AMtene. S. Stintzing: Consulting or Advisory Role: Merck KGA, Roche, Sanofi, Bayer, Amgen, Boehringer Ingelheim, Lilly. Travel, accommodation, expenses: Merck KGA, Roche, Sanofi, Bayer, Amgen, Lilly, Sirtex Medical. Honoraria: Merck KGaA, Roche, Bayer, Amgen, Sanofi, Lilly, Sirtex Medical. VV. Heinemann: Consulting or Advisory Role: Merck, Am., Roche, Sanofi, Boehringer Ingelheim, Celgene, Sirtex Medical, Bax. Travel, accommodation, expenses: Merck, Am., Roche, Sirtex Medical, Bax. Honoraria: Merck, Am., Roche, Sanofi, Celgene, Sirtex Medical, Bax. Research Funding: Merck, Am., Roche, Sanofi, Celgene, Boehringer Ingelheim, Sirtex Medocal, Int.Gen, Taiho, Bayer. All other authors have declared no conflicts of interest

Background

Sym004, a mixture of 2 anti-EGFR monoclonal antibodies (mAbs), was shown to be active in a prior P1/2 trial in refractory mCRC. Due to its unique mode of action, Sym004 was developed for overcoming of acquired resistance to anti-EGFR antibodies.

Methods

254 patients (pts) were entered to an open label, multinational, 3-arm (1:1:1) RP2S comparing 2 regimens (12 mg/kg [A] or 9 mg/kg loading dose followed by 6 mg/kg [9/6; B]) of weekly Sym004 vs investigator choice (IC) of 5-FU, capecitabine, or best supportive care [C]. Standard eligibility criteria were used; pts were to be refractory to chemotherapy and have responded to, and progressed on anti-EGFR mAb-based therapy; RAS exon 2 wild type in tumour archival sample. The study was designed to detect a 3-month (M) improvement in overall survival (OS) (6 vs 9 M) between either Arm A or B and Arm C.

Results

Demographic and baseline parameters were well balanced. The Sym004 adverse event (AE) profile was typical although frequency/severity of dermatologic AEs and hypomagnesemia was higher and GI AEs appeared lower than with approved anti-EGFR mAbs. Arm B was better tolerated than Arm A. OS in the ITT population and exploratory subgroups are presented. The primary outcome of the study was negative due to unexpected outcomes of Arm C. Arm B (9/6 mg dose) was not only better tolerated over 12/6 mg (Arm A), but also was associated with improved survival. Biomarker-specific analyses evaluating pts with double-negative (DN) (no RAS mutant allele frequency >20% in circulating tumor [ct]DNA; no BRAF V600E) or triple-negative (TN) (DN + no EGFR extracellular domain mutation in ctDNA) mCRC demonstrated markedly prolonged survival and established the 9/6 regimen as well-tolerated and active in DNmCRC (OS increased 3.5 M) and TNmCRC (OS increased 5.5 M).Table: 478O

Conclusions

Although the study was negative in ITT population, treatment with Sym004 was associated with remarkable response when compared with any 4th-line treatment of mCRC. The promising results in the molecularly selected population provide guidance to design a pivotal ctDNA-guided pivotal trial in EGFR inhibitor refractory mCRC.

Clinical trial identification

NCT02083653 or EMR200637-002

Legal entity responsible for the study

Symphogen

Funding

Symphogen

Disclosure

J. Tabernero: Advisory boards: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, Takeda. F. Ciardiello: Advisory boards: Roche, Merck, Lilly, BMS, Pfizer, Amgen, Bayer. C. Montagut: Advisory boards: Amgen, Bayer, Merck Serono, Sanofi, Symphogen. C. Ding, T. Tuxen Poulsen, M. Kragh, I.D. Horak: Employee of Symphogen. S. Kopetz: Advisory boards: Amgen, Merrimack, Bayer, Sanofi, Array BioPharma, Genentech, Molecular Match, Symphogen, Guardant Health, EMD Serono, Merck. V. Zagonel: Advisory boards: Celgene, Bayer, Roche, Amgen, Novartis, Pfizer. J. Bennouna: Honoraria: Roche, Boehringer Ingelheim, AstrZeneca, Shire, MSD, BMS; consulting or advisory role: Roche, Boehringer Ingelheim, AstraZeneca, Shire, MSD, BMS. S. Siena: Advisory boards: Amgen, Roche, Bayer, Merck-Serono, Sanofi, Merrimack. A. Falcone: Advisory boards and research grants to Institution: Amgen, Merck, Roche, Bayer, Servier, Lilly, Sanofi. All other authors have declared no conflicts of interest.

Background

CMS is a transcriptome-based classification of colorectal cancer (CRC) with prognostic implications, but its association with treatment outcomes, especially in the metastatic setting, remains unknown. We investigated whether CMS classification was predictive of bevacizumab treatment benefit using data from the phase 3 MAX trial. MAX previously reported progression-free survival (PFS) benefit for the addition of bevacizumab (B) to chemotherapy (capecitabine (C) +/- mitomycin (M)) in first line treatment of metastatic CRC.

Methods

Archival tumours from 256 patients (54% of trial population) were available for gene expression profiling using Almac Xcel microarray. Tumours were classified into CMS groups 1 to 4 using previously published methods. We correlated CMS groups with PFS in the MAX trial. The predictive value of CMS was demonstrated as the interaction between CMS and bevacizumab treatment, assessed by Cox proportional hazards model.

Results

After data quality control, primary tumours from 239 patients (51% of trial population) were suitable for survival analysis. Distribution of CMS groups were CMS1 18%, CMS2 48%, CMS3 12%, CMS4 23%. Hazard ratios (HR)(95% CI) of PFS in C vs CB+CBM arms for CMS 1,2,3 and 4 were 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25) respectively (test for interaction between CMS and treatment, p = 0.03). CMS remained a significant independent predictor of PFS after adjustment for prognostic factors in a multivariate analysis (p = 0.04).

Conclusions

In metastatic CRC, CMS 2 and 3 subtypes preferentially benefit from the addition of bevacizumab to chemotherapy, compared to CMS 1 and 4. Validation of these findings in independent cohorts is required. Once validated, CMS classification could be used to guide patient selection for bevacizumab therapy.

Legal entity responsible for the study

Olivia Newton-John Cancer Research Institute, Australia

Funding

Olivia Newton-John Cancer Research Institute, Australia and Australian Gastrointestinal Trials Group (AGITG)

Disclosure

P. Wirapati: Funding: Roche, Bayer and Sanofi for research in predictive biomarker for colorectal cancer. T.J. Price, N. Tebbutt: Advisory boards: Roche All other authors have declared no conflicts of interest.

Background

There are conflicting results concerning the prognostic value of the methylator phenotype (CIMP+ for “CpG island methylator phenotype”) in non-metastatic colon cancer (CC) patients (pts). We studied this phenotype in stage III CC pts having undergone R0 resection, characterized for MSI, RAS and BRAF mutation status and treated with adjuvant FOLFOX-based treatment.

Methods

Tumor samples of 1910 pts enrolled in the PETACC-8 adjuvant phase 3 trial were analysed. The method used was methylation-specific PCR where CIMP⁺ status was defined by methylation of at least three of the five following genes: IGF2, CACNA1G, NEUROG1, SOCS1 and RUNX3. Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after relapse (SAR) was assessed by Cox model and adjusted for prognostic factors (including MSI, BRAF and RAS mutation status) and treatment arm (FOLFOX or FOLFOX plus cetuximab). CIMP status was analyzed according to treatment efficacy.

Results

Determination of CIMP status was successful in 1870 pts (98%): 275 (14.7%) tumors were classified CIMP⁺. Compared to CIMP^- pts, CIMP⁺ pts were significantly older (p = 0.002), with more frequently women (p = 0.04). CIMP⁺ tumors were more frequently right-sided (p < 0.0001)), with histopathology grade 3-4 (p < 0.0001), pN2 (p = 0.001), MSI (p < 10e-4), BRAF mutated (p < 0.0001) and RAS wild-type (p < 0.0001). In multivariate analysis, CIMP⁺ status was associated with shorter OS (HR: 1.4; 95% CI 1.02 – 1.9; p = 0.04) and SAR (HR: 1.8; 95% CI 1.2 – 2.6; p < 0.0004); but DFS was not significantly different between CIMP⁺ and CIMP^– pts (HR: 1.1; 95% CI 0.8 1.5; p = 0.34). Theses results were independent of the treatment received. No benefit or detrimental effect of cetuximab was observed in CIMP⁺ patients for OS and DFS.

Conclusions

In a large clinically and molecularly well defined stage III CC population treated with standard adjuvant therapy, methylator phenotype is a prognostic biomarker for OS and SAR. However, no impact of CIMP status on DFS was observed. Finally, we did not find any predictive value of the CIMP status for the efficacy of FOLFOX versus FOLFOX plus cetuximab.

Clinical trial identification

PETACC8 Trial (EuDRACT number: 2005-003463-23)

Legal entity responsible for the study

FFCD

Funding

Merck, Sanofi

Disclosure

J. Taieb: Consulting or/and advisory boards: Merck KGaA, Sanofi, Roche Genentech, Pfizer, Amgen. J. Tabernero: Consulting or/and advisory boards: Amgen, ImClone Systems, Lilly, Millennium, Novartis, Roche/Genentech, Sanofi, Celgene, Chugai Pharma, Taiho Pharmaceutical, Boehringer Ingelheim, Merck KGaA. J-F. Seitz: Grants for consultancy: Celgene, Lilly, Merck, Novartis Oncology, Pfizer, Sanofi, Roche; grants: Roche; payments for development of educational presentations: Amgen, Lilly; travel grants: Ipsen Pharma, Merck. T. Aparicio: Personal grants consultancy: Pierre Fabre; grants: Roche, Amgen; payments for development of educational presentations: Novartis Oncology, Pfizer, Sanofi, Roche; travel grants: Ipsen Pharma, Novartis Oncology, Sanofi, Roche. G. Folprecht: Consulting or/and advisory boards: Merck KGaA, Roche/Genentech, Sanofi-Aventis, Bayer, Lilly, Servier, BMS. C. Lepage: Personal grants for board membership: AAA; grants: Novartis; travel grants: Ipsen Pharma, Amgen, Bayer. J.F. Emile: Honoraria: Amgen, Merck KGaA. P. Laurent-Puig: Consulting or/and advisory boards: Sanofi, Merck KGaA, Amgen, Roche, Genomic Health, Myriad Genetics, Pfizer. All other authors have declared no conflicts of interest.