VHIO-authored Comment: extending the promise of combinatorial immunotherapy in metastatic colorectal cancer


Barcelona, June 10th, 2022. In an invited Comment article recently published online first in The Lancet Oncology (1) , co-authors Elena Élez and Iosune Baraibar, Medical Oncologists and Clinical Investigators of VHIO’s Gastrointestinal & Endocrine Tumors Group, first discuss the rationale and results of the phase II AtezoTRIBE multicenter, open-label, randomized, controlled clinical trial, that also published ahead of print in the latest issue of this journal (2).

Based on the promising data from updated overall survival and molecular subgroup analyses of patients in the phase III TRIBE study (3) , the AtezoTRIBE investigators sought to establish if the addition of immunotherapy, atezolizumab, could enhance the efficacy of first-line triplet FOLFOXIRI plus bevacizumab in previously untreated mCRC.

“This phase II study enrolled patients with both microsatellite instable and microsatellite stable tumors. Importantly, it was designed prior to the approval of pembrolizumab for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer, based on the results of the phase III KEYNOTE-177 trial,” observes Elena Élez, corresponding author of this invited article.

Now published (2), results from the AtezoTRIBE study suggest that atezolizumab in combination with first-line FOLFOXIRI plus bevacizumab improves progression free-survival in this patient population, with consistent toxicity profiles previously reported for each strategy alone.

In their brief discussion of opportunities versus possible limitations of AtezoTRIBE and KEYNOTE-177 (4),  VHIO’s Elena Élez and Iosune Baraibar call for the timely development of novel strategies to extend the benefits of immune-based approaches either as monotherapy or in combination, to a larger population of patients including those with microsatellite stable and microsatellite instable tumors, as well as patients presenting proficient mismatch repair status.

Identifying predictive biomarkers beyond microsatellite status

The second half of their Comment article centers on an additional unmet clinical need; the  seeking out robust biomarkers of response beyond microsatellite classification.

“The AtezoTRIBE investigators propose Immunoscore IC assay and tumor mutation burden as potential markers of response. This approach could however be limited due to the unique, intrinsic tumor biology of colorectal cancer, which differs from other tumor types,” notes co-author Iosune Baraibar.

“Genomic-driven biomarker strategies are key to advancing essential insights into the molecular mechanisms mediating cancer drug response, and rely on the comprehensive analysis of those patients who derive most benefit from these novel combinatorial therapies,” adds Iosune Baraibar.

Drawing on the results from the AtezoTRIBE trial, our authors highlight certain factors that could limit the accurate identification of mechanisms underlying improved response. Regarding the higher and more durable  response rates observed in patients who received nivolumab with FOLFOX chemotherapy in the  CheckMate 9XE study, results of which were recently reported at the 2022 ASCO Gastrointestinal Cancers Symposium (5),  the molecular drivers of this activity have not yet been elucidated.

“As we collectively seek to improve outcomes for patients with metastatic colorectal cancer, efforts aimed at developing new immunotherapy-containing approaches must go hand in hand with a deeper understanding of response characteristics based on robust biomarkers,” says Elena Élez.

“The promise of immunotherapy is currently restricted to patients presenting deficient mismatch repair or microsatellite instability. We must continue to work together to extend the promise of immune-based strategies to all mCRC patients,  covering each mutational status,” she concludes.


  1. Elez E, Baraibar I. Immunotherapy in colorectal cancer: an unmet need deserving of change. Lancet Oncol. 2022 May 27:S1470-2045(22)00324-2.
  2. Antoniotti C, Rossini D, Pietrantonio F, Catteau A, Salvatore L, Lonardi S, Boquet I, Tamberi S, Marmorino F, Moretto R, Ambrosini M, Tamburini E, Tortora G, Passardi A, Bergamo F, Kassambara A, Sbarrato T, Morano F, Ritorto G, Borelli B, Boccaccino A, Conca V, Giordano M, Ugolini C, Fieschi J, Papadopulos A, Massoué C, Aprile G, Antonuzzo L, Gelsomino F, Martinelli E, Pella N, Masi G, Fontanini G, Boni L, Galon J, Cremolini C; GONO Foundation Investigators. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2022 May 27:S1470-2045(22)00274-1.
  3. Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D’Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15.
  4. André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218.
  5. Heinz-Josef Lenz, Aparna Raj Parikh, David R. Spigel, Allen Lee Cohn, Takayuki Yoshino, Mark D. Kochenderfer, Elena Elez, Spencer H. Shao, Dustin A. Deming, Regan C. Holdridge, Timothy Larson, Eric Chen, Amit Mahipal, Antonio Ucar, Dana Cullen, Edwina S Baskin-Bey, Jean-Marie Ledeine, Amy Hammell, Josep Tabernero. Nivolumab (NIVO) + 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6)/bevacizumab (BEV) versus mFOLFOX6/BEV for first-line (1L) treatment of metastatic colorectal cancer (mCRC): Phase 2 results from CheckMate 9X8. J. Clin. Oncol. 2022;40(4_suppl):8-8. doi:10.1200/JCO.2022.40.4_suppl.008.


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