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First-Line Treatment of Metastatic Colorectal Cancer: Interpreting FIRE-3, PEAK, and CALGB/SWOG 80405

  • Lower Gastrointestinal Cancers (AB Benson, Section Editor)
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Opinion statement

The advances made in the therapeutic management of colorectal cancer (CRC) over recent years with the addition of therapies targeting angiogenesis or cell proliferation have positioned bevacizumab, cetuximab, and panitumumab as accepted first-line treatments when combined with FOLFOX or FOLFIRI for RAS wild-type (WT) metastatic CRC. The question has been raised as to the choice of targeted therapy to maximize chances of an optimal outcome. Three studies, the phase III FIRE-3 (AIO KRK-0306), the phase II PEAK, and the recently presented phase III CALGB/SWOG 80405 trial, have addressed this issue face-on, directly comparing the addition of bevacizumab versus cetuximab or panitumumab to FOLFOX/FOLFIRI in terms of efficacy outcomes. None of these studies met their primary endpoint (response rate, progression-free survival or overall survival respectively), meaning we are no closer to being able to categorically define an optimal targeted treatment in the first-line setting for patients with advanced CRC. This led to reflection over study design and further analyses, raising a number of important issues. High-sensitivity analysis of the mutational status of exons identified a population with a “pure” non-RAS-mutated profile showing benefit with anti-epidermal growth factor receptor (anti-EGFR) combinations, particularly in the context of early and greater depth of response. Coherent with a personalized therapeutic approach, the importance of performing individual high-sensitivity extended RAS testing is unequivocal and is currently a requirement in many countries to identify this all-RAS WT population, thus limiting unnecessary exposure and expense in patients unlikely to respond. These three studies, particularly the CALGB/SWOG 80405 trial, mark an important milestone in the roadmap of metastatic CRC treatment, highlighting the need for close analysis to fully exploit the available data.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

  1. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA: Cancer J Clin. 2012;62(4):220–41.

    Google Scholar 

  2. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  3. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol : Off J Am Soc Clin Oncol. 2008;26(12):2013–9.

    Article  CAS  Google Scholar 

  4. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol : Off J Am Soc Clin Oncol. 2011;29(15):2011–9. The CRYSTAL trial granted the approval for prescribing FOLFIRI plus cetuximab in first metastatic chemotherapy line in RAS WT CRC.

    Article  Google Scholar 

  5. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34. The PRIME study constructed the necessary evidence for using FOLFOX plus panitumumab in first metastatic line in RAS WT patient. This trail was the first in considering as a pre-specified end point the analysis according KRAS exon 2 status.

    Article  CAS  PubMed  Google Scholar 

  6. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol : Off J Am Soc Clin Oncol. 2010;28(31):4697–705.

    Article  CAS  Google Scholar 

  7. Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.

    Article  CAS  PubMed  Google Scholar 

  8. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2007;25(13):1658–64.

    Article  Google Scholar 

  9. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2008;26(10):1626–34.

    Article  CAS  Google Scholar 

  10. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45.

    Article  CAS  PubMed  Google Scholar 

  11. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.

    Article  CAS  PubMed  Google Scholar 

  12. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.

    Article  CAS  PubMed  Google Scholar 

  13. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2008;26(14):2311–9.

    Article  CAS  Google Scholar 

  14. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2010;28(31):4706–13.

    Article  CAS  Google Scholar 

  15. Venook AND, Lenz HJ, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2015;32:5s. 2014 (suppl; abstr LBA3).

    Google Scholar 

  16. Heinemann V, Stintzing S. FOLFIRI with cetuximab or bevacizumab: FIRE-3-authors’ reply. Lancet Oncol. 2014;15(13):e583–4.

    Article  PubMed  Google Scholar 

  17. Tang PA, Bentzen SM, Chen EX, Siu LL. Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol : Off J Am Soc Clin Oncol. 2007;25(29):4562–8.

    Article  Google Scholar 

  18. Buyse M, Burzykowski T, Carroll K, Michiels S, Sargent DJ, Miller LL, et al. Progression-free survival is a surrogate for survival in advanced colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2007;25(33):5218–24.

    Article  CAS  Google Scholar 

  19. Shi Q, de Gramont A, Grothey A, Zalcberg J, Chibaudel B, Schmoll HJ, et al. Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database. J Clin Oncol : Off J Am Soc Clin Oncol. 2015;33(1):22–8.

    Article  Google Scholar 

  20. Venook AP, Tabernero J. Progression-free survival: helpful biomarker or clinically meaningless end point? J Clin Oncol : Off J Am Soc Clin Oncol. 2015;33(1):4–6.

    Article  Google Scholar 

  21. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

    Article  CAS  PubMed  Google Scholar 

  22. Stintzing SMD, Fischer von Weikerstha L, et al. Independent radiological evaluation of objective response rate, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population. Ann Oncol. 2014;2014:ii112–3. (suppl 2;abstr LBA O-0019). This is the FIRE-3 trial reference corresponding to the an oral presentation at the European Society of Medical Oncology congress on 2014.

    Google Scholar 

  23. Rivera FKM, Hecht R, et al. First-line treatment with modified FOLFOX6 (mFOLFOX6) + panitumumab (pmab) or bevacizumab (bev) in wild-type (WT) RAS metastatic colorectal carcinoma (mCRC): tumor response outcomes beyond RECIST. p. J Clin Oncol. 2015;33 suppl 3:abstr 660.

    Google Scholar 

  24. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2009;27(5):672–80.

    Article  CAS  Google Scholar 

  25. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72.

    Article  CAS  PubMed  Google Scholar 

  26. Venook AND, Lenz HJ, et al. CALGB/SWOG 80405: analysis of patients undergoing surgery as part of treatment strategy. Ann Oncol. 2014;25(5):1–41. This is the CALGB/SWOG 80405 trial reference corresponding to an oral presentation at the European Society of Medical Oncology congress on 2014.

    Google Scholar 

  27. Lenz HND, Innocenti F, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC). Ann Oncol. 2014;25(Supplement 5):v1–v41. This is the CALGB/SWOG 80405 trial reference corresponding to an oral presentation at the European Society of Medical Oncology congress on 2014.

    Google Scholar 

  28. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol : Off J Am Soc Clin Oncol. 2009;27(5):663–71.

    Article  CAS  Google Scholar 

  29. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol : Off J Am Soc Clin Oncol. 2012;30(15):1755–62.

    Article  CAS  Google Scholar 

  31. Primrose J, Falk S, Finch-Jones M, Valle J, O’Reilly D, Siriwardena A, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014;15(6):601–11.

    Article  CAS  PubMed  Google Scholar 

  32. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17.

    Article  PubMed  Google Scholar 

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Conflict of Interest

Elena Elez, Guillem Argilés, and Josep Tabernero declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Vall d’Hebron Institute of Oncology, P. Vall d’Hebron 119-129, Barcelona, 08035, Spain

    Elena Elez MD, PhD, Guillem Argilés MD & Josep Tabernero MD, PhD

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  1. Elena Elez MD, PhD
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  2. Guillem Argilés MD
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  3. Josep Tabernero MD, PhD
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Correspondence to Elena Elez MD, PhD.

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This article is part of the Topical Collection on Lower Gastrointestinal Cancers

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Elez, E., Argilés, G. & Tabernero, J. First-Line Treatment of Metastatic Colorectal Cancer: Interpreting FIRE-3, PEAK, and CALGB/SWOG 80405. Curr. Treat. Options in Oncol. 16, 52 (2015). https://doi.org/10.1007/s11864-015-0369-x

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