Prognostic Value of Early Objective Tumor Response (EOTR) to  First Line Systemic Therapy in Metastatic Colorectal Cancer (Mcrc): Individual Patient Data (IPD) Meta-Analysis of Randomized Trials from the ARCAD Database — ASN Events
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Prognostic Value of Early Objective Tumor Response (EOTR) to  First Line Systemic Therapy in Metastatic Colorectal Cancer (Mcrc): Individual Patient Data (IPD) Meta-Analysis of Randomized Trials from the ARCAD Database (#53)

Dirkje W Sommeijer 1 , Qian Shi 2 , Jeffrey Meyer 2 , Katrin M Sjoquist 1 , Paolo M Hoff 3 , Matthew T Seymour 4 , Jim Cassidy 5 , Richard Goldberg 6 , Jean-Yves Douillard 7 , J Randolph Hecht 8 , Herbert Hurwitz 9 , Christophe Tournigand 10 , Niall C Tebbutt 11 , Enrique Aranda 12 , John Souglakos 13 , Fairooz F Kabbinavar 8 , Benoist Chibaudel 14 , Aimery De Gramont 14 , Daniel J Sargent 2 , John Zalcberg 15
  1. AGITG & NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
  2. Mayo Clinics, Rochester, USA
  3. Hospital Sirio-Lianes, Sao Paulo, Brazil
  4. Cancer Research UK Clinical Centre, Leeds, UK
  5. Hoffmann La Roche, Nutley, UK
  6. Ohio State University Comprehensive Cancer Center, Columbus, USA
  7. ICO Centre Rene Gauducheau, St Herblain, France
  8. David Geffen School of Medicine at UCLA, Los Angeles, USA
  9. Duke University Medical Center, Durham, USA
  10. Hospital Henri Mondor, Creteil, France
  11. Austin Health and University of Melbourne, Heidelberg, Australia
  12. Medico Oncolo, Cordoba, Spain
  13. University of Crete, Heraklion, Greece
  14. Hospital Saint Antoine, Paris, France
  15. Peter McCallum Hospital, Melbourne, Australia

Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at  individual patient level, correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in patients with mCRC treated with first line chemotherapy with or without a targeted agent as a first step in surrogacy demonstration.

Methods: IPD from 13,949 patients enrolled on 15 randomized Phase III trials in  first line 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 patients, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in patients 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 patients were treated with targeted therapies or non-targeted therapies. Median PFS was 8.4 mo in patients with EOTR at 6 wk vs. 7.0 mo in patients without EOTR (p<.0001). 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 co-variates. Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR.

Conclusion: Early response measured at 6, 8 or 12 wk after starting first line treatment was a strong and independent predictor of both OS and PFS in patients with mCRC and warrants further consideration as a potential endpoint for future trials, particularly phase II trials.