Introduction: Conventional response parameters (eg, RECIST-defined objective response rate and progression-free survival [PFS]) do not fully recapitulate – either qualitatively or quantitatively – the true impact of targeted therapies on overall survival (OS) in mCRC; thus, novel metrics are required. In patients with RAS-wt mCRC, DpR – one such innovative response metric – has been shown to be induced effectively by first-line chemotherapy plus weekly cetuximab in the CRYSTAL, OPUS, and FIRE-3 studies. The present analysis evaluated the association between DpR and PFS and OS in the RAS-wt population from the Asia-Pacific, multicenter, nonrandomized, phase 2 APEC study.Methods: APEC enrolled 289 patients with KRAS-wt mCRC. Eligible patients received cetuximab once every 2 weeks plus investigator's choice of FOLFOX or FOLFIRI. Study treatment (either all drugs together or maintenance cetuximab in case of early withdrawal of chemotherapy) continued until disease progression, dose-limiting toxicity, or consent withdrawal. RAS status was assessed retrospectively by ion torrent next-generation sequencing on evaluable samples. DpR was defined as the extent of maximal tumor shrinkage (the sum of tumor diameters at the nadir divided by the sum of tumor diameters at baseline) and was expressed as a percentage.Results: Median PFS and OS in the RAS-wt population (n = 167) of APEC were 13.0 and 28.4 months, respectively; the best confirmed objective response rate was 64.7%, and 10.8% of patients underwent curative R0 resections. This study was not designed to formally assess efficacy differences between treatment subgroups; nevertheless, no major differences between patients receiving FOLFOX vs FOLFIRI were detected. There were no unexpected safety findings. The extent of tumor shrinkage was similar between the FOLFOX and FOLFIRI treatment subgroups; among patients whose disease did not progress, tumor size continued to decrease as the duration of treatment increased. 159 patients with RAS-wt mCRC were evaluable for DpR: median DpR was 62.2% (interquartile range [IQR], 39.1%–80.0%) in the overall DpR-evaluable population; in the FOLFOX plus cetuximab (n = 103) and FOLFIRI plus cetuximab (n = 56) treatment subgroups, median DpR was 62.2% (IQR, 40.0%–80.7%) and 62.5% (IQR, 38.1%–79.0%), respectively. The median time to tumor size nadir was 5.9 months (95% CI, 5.6–7.6 months) in the overall DpR-evaluable population; median time to nadir was 5.9 months (95% CI, 5.6–7.6 months) and 7.4 months (95% CI, 5.1–9.2 months) in the FOLFOX and FOLFIRI treatment subgroups, respectively. Notably, there appeared to be an association between the extent of DpR and time to nadir: patients experiencing a deeper response seemed to achieve maximal tumor shrinkage later than patients with a less deep response. Furthermore, the data suggest that there was a relationship between the extent of DpR and PFS/OS (Figure).Conclusion: These findings – obtained using a once-every-2-weeks dosing regimen – compare favorably to earlier subgroup analyses of analogous pivotal studies involving chemotherapy plus weekly cetuximab. DpR seems to be a sensitive indicator of response and is likely to be associated with PFS and OS. The phase 2 APEC study further suggests that patients with RAS-wt mCRC may benefit from an increased duration of treatment with FOLFOX or FOLFIRI plus cetuximab. Introduction: Conventional response parameters (eg, RECIST-defined objective response rate and progression-free survival [PFS]) do not fully recapitulate – either qualitatively or quantitatively – the true impact of targeted therapies on overall survival (OS) in mCRC; thus, novel metrics are required. In patients with RAS-wt mCRC, DpR – one such innovative response metric – has been shown to be induced effectively by first-line chemotherapy plus weekly cetuximab in the CRYSTAL, OPUS, and FIRE-3 studies. The present analysis evaluated the association between DpR and PFS and OS in the RAS-wt population from the Asia-Pacific, multicenter, nonrandomized, phase 2 APEC study. Methods: APEC enrolled 289 patients with KRAS-wt mCRC. Eligible patients received cetuximab once every 2 weeks plus investigator's choice of FOLFOX or FOLFIRI. Study treatment (either all drugs together or maintenance cetuximab in case of early withdrawal of chemotherapy) continued until disease progression, dose-limiting toxicity, or consent withdrawal. RAS status was assessed retrospectively by ion torrent next-generation sequencing on evaluable samples. DpR was defined as the extent of maximal tumor shrinkage (the sum of tumor diameters at the nadir divided by the sum of tumor diameters at baseline) and was expressed as a percentage. Results: Median PFS and OS in the RAS-wt population (n = 167) of APEC were 13.0 and 28.4 months, respectively; the best confirmed objective response rate was 64.7%, and 10.8% of patients underwent curative R0 resections. This study was not designed to formally assess efficacy differences between treatment subgroups; nevertheless, no major differences between patients receiving FOLFOX vs FOLFIRI were detected. There were no unexpected safety findings. The extent of tumor shrinkage was similar between the FOLFOX and FOLFIRI treatment subgroups; among patients whose disease did not progress, tumor size continued to decrease as the duration of treatment increased. 159 patients with RAS-wt mCRC were evaluable for DpR: median DpR was 62.2% (interquartile range [IQR], 39.1%–80.0%) in the overall DpR-evaluable population; in the FOLFOX plus cetuximab (n = 103) and FOLFIRI plus cetuximab (n = 56) treatment subgroups, median DpR was 62.2% (IQR, 40.0%–80.7%) and 62.5% (IQR, 38.1%–79.0%), respectively. The median time to tumor size nadir was 5.9 months (95% CI, 5.6–7.6 months) in the overall DpR-evaluable population; median time to nadir was 5.9 months (95% CI, 5.6–7.6 months) and 7.4 months (95% CI, 5.1–9.2 months) in the FOLFOX and FOLFIRI treatment subgroups, respectively. Notably, there appeared to be an association between the extent of DpR and time to nadir: patients experiencing a deeper response seemed to achieve maximal tumor shrinkage later than patients with a less deep response. Furthermore, the data suggest that there was a relationship between the extent of DpR and PFS/OS (Figure). Conclusion: These findings – obtained using a once-every-2-weeks dosing regimen – compare favorably to earlier subgroup analyses of analogous pivotal studies involving chemotherapy plus weekly cetuximab. DpR seems to be a sensitive indicator of response and is likely to be associated with PFS and OS. The phase 2 APEC study further suggests that patients with RAS-wt mCRC may benefit from an increased duration of treatment with FOLFOX or FOLFIRI plus cetuximab.

Aim/Background: ETS has been associated with improved long-term outcome in pts with KRAS/RAS-WT mCRC treated with first-line weekly cetuximab in the CRYSTAL, OPUS, and FIRE-3 studies. The present analysis evaluated the association between ETS and progression-free survival (PFS) and overall survival (OS) in the RAS-WT population from the Asia-Pacific, multicentre, nonrandomized, phase 2 APEC study. Methods: APEC enrolled 289 pts with KRAS-WT tumours. Eligible pts received cetuximab every other week + FOLFOX or FOLFIRI (investigator's choice). Study treatment continued until disease progression, dose-limiting toxicity or consent withdrawal. RAS status was assessed retrospectively by ion torrent next-generation sequencing on evaluable samples. ETS was categorized as ≥20% decrease in the sum of longest diameters of target lesions between baseline and 8 weeks after start of treatment. Results: Median PFS and OS in the RAS-WT population (n = 167) were 13.0 and 28.4 months, respectively; the best confirmed objective response rate was 64.7% and 10.8% of pts were converted for R0 resection. ETS, as defined above, occurred in 81.8% (130/159) of evaluable pts and was associated with longer PFS and OS (Table). Although this study was not designed to formally assess efficacy differences between treatment subgroups, there were no major differences between pts receiving FOLFOX vs FOLFIRI. There were no unexpected safety findings.Tabled 1RAS-WT, ETS-Evaluable PtsETS (n = 130)No ETS (n = 29)Total (n = 159)OS# of events (%)81 (62.3%)20 (69.0%)101 (63.5%)HR (95% CI)0.584 (0.357-0.954)-Median, mo (95% CI)30.3 (26.3-33.2)16.4 (10.3-31.2)28.5 (24.5-32.3)PFS# of events (%)90 (69.2%)19 (65.5%)109 (68.6%)HR (95% CI)0.721 (0.438-1.186)-Median, mo (95% CI)14.0 (11.2-14.9)7.5 (3.6-16.6)13.3 (11.1-14.8) Open table in a new tab Conclusions: ETS at 8 weeks appears to be associated with longer PFS and OS in RAS-WT pts receiving FOLFOX or FOLFIRI + cetuximab every other week in the phase 2 APEC study. These findings are comparable to earlier subgroup analyses of analogous pivotal studies involving weekly cetuximab. Clinical trial identification: NCT00778830 Disclosure: G.H. Cornelio: Merck KGaA: receiving research funding. L. Shen, B. Ma: Merck KGaA: received honoraria. T.J. Prince, R. S.c. Lim: Merck KGaA: consulting. F. Beier: employee of Merck KGaA, Darmstadt, Germany. S. Chatterjee: employee of Merck Serono, Mumbai, India. All other authors have declared no conflicts of interest.

Introduction: The Asia-Pacific, multicenter, non-randomized APEC study previously reported that the efficacy and safety profiles of cetuximab every 2 weeks combined with first-line FOLFOX or FOLFIRI in patients with KRAS wild-type metastatic colorectal cancer (mCRC) were similar to those reported in pivotal studies for either chemotherapy regimen plus weekly cetuximab (Cheng et al Ann Oncol 2013:24(S4);Abstract PD0028). This subgroup analysis of the APEC study investigated tumor response and progression-free survival (PFS) according to treatment in patients grouped by tumor EGFR expression status. Methods: Eligible patients received cetuximab administered every 2 weeks (day 1 of each cycle, 500 mg/m2) with, based on investigator's choice, either FOLFOX or FOLFIRI. Study treatment was continued until disease progression, the occurrence of unacceptable toxicity or withdrawal of consent. The primary endpoint was tumor response; assessed radiologically (RECIST 1.0) every 8 weeks, PFS was a secondary endpoint. EGFR expression was determined retrospectively by immunohistochemistry (IHC) using the Dako EGFR pharmDxtrade kit with a cutoff point of ≥5% of tumor cells exhibiting a staining intensity of at least 1+. Best overall objective response and PFS were determined according to treatment in patients grouped by whether tumors were EGFR detectable or EGFR undetectable. Results: Of the 289 patients in the intent to treat (ITT) population of the APEC study, tumor samples from 154 (53%) patients were available for EGFR IHC analysis, with the majority subsequently evaluable for EGFR expression status (147/154 [95%]). EGFR expression was detectable in 120 tumors (82%) and was undetectable in 27 tumors (18%) from the 147 evaluable patients. There were markedly more Caucasian (22/120 [18%] vs 0/27) and fewer Asian patients (97/120 [81%] vs 27/27 [100%]) in the EGFR detectable compared with the EGFR undetectable groups. Other baseline characteristics in these groups were comparable. Objective response rates (ORR, 58.8% vs 55.8%) and median PFS times (11.1 vs 11.1 months) were similar in the ITT compared with the EGFR evaluable populations, and also in the FOLFOX + cetuximab and FOLFIRI + cetuximab treatment groups in these populations (Table). In patients treated with FOLFOX + cetuximab, the ORR was 60.3% (47/78 patients) in the EGFR detectable group and 50.0% (8/16 patients) in the EGFR undetectable group. In patients treated with FOLFIRI + cetuximab, the ORR was 54.8% (23/42 patients) in the EGFR detectable group and 36.4% (4/11 patients) in the EGFR undetectable group. Median PFS times were generally comparable according to treatment in the EGFR detectable and EGFR undetectable groups (Table). Conclusion: In this retrospective subgroup analysis of APEC study patients, there were no major differences in ORRs and median PFS times between the subgroups of patients with EGFR detectable and EGFR undetectable tumors. Because of the small numbers of patients in some subgroups, no definite conclusions could be made with regard to EGFR expression as a clinically useful biomarker for the activity of chemotherapy plus cetuximab.