ABSTRACT

1. Prognostic value of early objective tumor response (EOTR) to 1stline systemic therapy in metastatic colorectal cancer (mCRC) Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database Dirkje W Sommeijer1, Qian Shi2, Jeffrey P Meyer2, Katrin M Sjoquist1, Paulo M Hoff 3, Matthew T Seymour4, James Cassidy5, Richard Goldberg6, Jean-Yves Douillard7, J. Randolph Hecht8, Herbert Hurwitz9, Christophe Tournigand10, Niall C Tebbutt11, Enrique Aranda12, John Souglakos13, Fairooz F Kabbinavar8, Benoist Chibaudel15, Aimery de Gramont15, Daniel J Sargent2, John Zalcberg16 –For the ARCAD Group 1AGITG and NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; 2 Mayo Clinic, Rochester, MN, USA; 3Centro de Oncologia, Hospital Sirio-Lianes-Sao Paulo, Sao Paulo, Brazil; 4Cancer Research UK Clinical Centre, Leeds, UK; 5Hoffmann La Roche, Nutley, UK; 6Ohio State University Comprehensive Cancer Center, Columbus, USA; 7ICO Centre René Gauducheau, St Herblain, France; 8David Geffen School of Medicine at UCLA, Los Angeles, USA; 9Duke University Medical Center, Durham, USA; 10Hospital Henri Mondor, UPEC, Creteil, France; 11Austin Health and University of Melbourne, Heidelberg, Australia; 12Medico Oncolo, Córdoba, Spain; 13Medico Oncolo, Córdoba, Spain; 14University of Crete, School of Medicine, Heraklion, Greece; 15Hospital Saint Antoine, Paris, France; 16 Peter McCallum Hospital, Melbourne, Australia ABSTRACT METHODS RESULTS FINDINGS Figure 1: Kaplan-Meier Estimates for OS and PFS by EOTR at 6, 8 and 12 weeks CONSORT Diagram Background EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC1-6and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1stline mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values <0.01 were considered statistically significant to account for multiple comparisons. Results Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p<.0001, HR 0.66, 95% CI 0.56-0.78, c 0.55) or non-targeted therapies (p<.0001, HR 0.63, 95% CI 0.56-0.70, c 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p<0.0001) after adjusting for age, gender, performance status and location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.48-0.54, CS 0.60) vs. EOTR. Conclusions Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials. • Patient Characteristics • 13,949 patients from 15 trials were included • Age: 14% < 50; 27% 50 – 59; 34% 60 – 69; 25% ≥ 70 • ECOG PS: 52% 0; 43% 1; 5% 2+ • Gender: 61% male; 39% female • 37% lung involvement; 79% Liver involvement • Regimen: 43% targeted; 57% non-targeted • Median follow: 16.6 months • Response Endpoints • EOTR (Primary) –any objective response (CR or PR) at 6, 8, and 12 weeks from randomization • EOTR endpoints at different time points, i.e. EOTR6, EOTR8, and EOTR12, were analyzed using protocol-specified tumor assessment frequency • Overall tumor response (Secondary) • Best objective response –CR or PR within initial 26 weeks treatment • Confirmed response –CR or PR which was confirmed at least 4 weeks later during treatment up to 26 weeks • Long-term outcomes • OS – Time from randomization to death due to any cause • PFS – Time from randomization to 1st PD or death due to any cause. • Statistical Methods • Univariate and multivariate Cox model, stratified by treatment arms with landmark approach was used to assess the prognostic values of response endpoints in terms of long-term outcomes • C statistics were reported for model prediction comparisons among response endpoints • Median OS and PFS were significantly longer in patients with an EOTR at 6, 8, and 12 weeks as compared to patients without an EOTR (Figure 1) • Hazard ratios for survival were similar whether patients were treated with targeted or non-targeted therapies in univariate models (Figure 2) • The prognostic value of EOTR at 6, 8, an 12 weeks remained significant after adjusting for age, gender, performance status and lung/liver metastatic disease • Overall tumor response however provided better prediction of OS at the individual patient level • *Not included in EOTR endpoints, but included in overall response endpoints • **EOTR12 studies included 5 EOTR6 studies and 1 EOTR8 study (OPTIMOX2, see Table 1) * ** Table 1: Studies Included DISCUSSION Figure 2: Association between Response Endpoints and Outcomes • EOTR warrants further consideration as a potential surrogate endpoint to detect early signals for future trials, particularly randomized phase II studies • The second step in the surrogacy evaluation of EOTR in patients with mCRC will be the assessment of correlation between EOTR and OS/PFS at trial level7 REFERENCES OBJECTIVES 1. H. Piessevaux et al. Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial). Annals of Oncology, 2009 2. W. De Roock et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Annals of Oncology, 2008 3. U.R. Mansmann et all. Improved early prediction of individual prognosis for patients with mCRC: Joint modeling of tumor shrinkage with volume data for PFS and OS. ASCO, 2012,Journal of Clinical Oncology 30, Abstract 3603 4. Suzuki et al. The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy. Annals of Oncology, 2012 5. A. Grothey et al. Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. Journal of Clinical Oncology, 2008 6. H. Piessevaux et al. Early tumor shrinkage and long-term outcome in metastatic colorectal cancer (mCRC): Assessment of predictive utility across treatment arms in the CHRYSTAL and OPUS studies. ASCO 2011, Journal of Clinical Oncology, Abstract 3572 7. Q. Shi and D. Sargent. Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials. International Journal of Clinical Oncology, 2009 • To determine, at the individual patient level, the correlation between early tumor response and long-term outcomes in patients with mCRC treated with 1st line chemotherapy with or without a targeted agent. • This analysis will be the first step in the surrogacy evaluation of early tumor response endpoints in patients with mCRC. Abbreviations: IRI, irinotecan; OX, oxaliplatin; LV, leucovorin; Bev, bevacizumab; Cap, capecitabine; Pmab, Pamtumumab; WT, wild type; MT, mutated; NT, non-targeted; ANG, Anti-angiogenic regimen; EGFR, Anti-EGFR regimen; #.Protocol-specified tumor measurement frequency.## HORG: Publication indicates every 8 weeks, however, data shows every 12 weeks; *Treatment grouping was according to the 1st cycle of the treatment