Highlights
- •53% of mCRC patients treated with upfront doublets/triplet + bev receive a 3rd line.
- •RAS/BRAF wild-type patients achieve more likely a 3rd line versus RAS/BRAF mutants.
- •In 3rd line, RAS/BRAF wild-type patients reach longer disease control with anti-EGFRs.
- •Regorafenib and Tas-102 show modest efficacy, and chemotherapy re-challenge is frequent.
- •The pronounced funnel effect in BRAF mutants endorses early blockade of BRAF + EGFR.
Abstract
Background
The availability of new drugs in the chemo-refractory setting opened the way to the
concepts of treatment sequencing in mCRC. However, the impact of later line options
in the therapeutic route of metastatic colorectal cancer (mCRC) patients and the attrition
rate across subsequent lines of therapy are not well established.
Methods
We performed a pooled analysis of treatments administered after the 2nd disease progression
in 1187 mCRC patients enrolled in the randomized phase III TRIBE and TRIBE2 studies,
where upfront FOLFOXIRI/bev was compared with FOLFOX or FOLFIRI/bev. Per each line,
we assessed the attrition rate, treatment choices and clinical outcomes.
Results
625 (53%), 326 (27%) and 136 (11%) patients received a systemic treatment after the
2nd, 3rd and 4th disease progression, respectively. PFS and objective response rate
decreased along each line. RAS/BRAF wild-type patients received more likely a 3rd line (75%) compared with RAS (66%, p = 0.005) and BRAF (66%, p = 0.11) mutants. In 3rd line, 67% of RAS/BRAF wild-type patients received anti-EGFRs, achieving longer PFS with respect to other
therapies (6.4 vs 3.9 months, p = 0.02). A trend towards longer 3rd line OS was observed
in TRIBE patients (9.9 vs 7.2 months, p = 0.05).
Conclusions
A relevant attrition rate across subsequent lines of therapy is evident, and more
pronounced in RAS and BRAF mutated patients, thus highlighting the relevance of the choice of the upfront treatment.
The efficacy of anti-EGFR agents among RAS/BRAF wild-type patients unexposed to anti-EGFRs is higher than other options. The reintroduction
of chemotherapy remains frequent in clinical practice.
Trial registration
Clinicaltrials. gov Identifiers NCT00719797, NCT02339116.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.Ann Oncol. 2016; 27: 1386-1422https://doi.org/10.1093/annonc/mdw235
- Colon cancer, version 2.2021, NCCN clinical practice guidelines in Oncology.J Natl Compr Cancer Netw. 2021; 19: 329-359https://doi.org/10.6004/jnccn.2021.0012
- First-line chemotherapy for mCRC—a review and evidence-based algorithm.Nat Rev Clin Oncol. 2015; 12: 607-619https://doi.org/10.1038/nrclinonc.2015.129
- Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.N Engl J Med. 2014; 371: 1609-1618https://doi.org/10.1056/NEJMoa1403108
- Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial.Lancet Oncol. 2020; 21: 497-507https://doi.org/10.1016/S1470-2045(19)30862-9
- Individual patient data meta-analysis of FOLFOXIRI plus bevacizumab versus doublets plus bevacizumab as initial therapy of unresectable metastatic colorectal cancer.J Clin Oncol. 2020; JCO2001225https://doi.org/10.1200/JCO.20.01225
- Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial.Ann Oncol. 2015; 26: 724-730https://doi.org/10.1093/annonc/mdv012
- Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.J Clin Oncol. 2012; 30: 3499-3506https://doi.org/10.1200/JCO.2012.42.8201
- Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.Lancet Oncol. 2013; 14: 29-37https://doi.org/10.1016/S1470-2045(12)70477-1
- Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO.Br J Cancer. 2021; 124: 183-190https://doi.org/10.1038/s41416-020-01089-9
- Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.Lancet Oncol. 2013; 14: 1077-1085https://doi.org/10.1016/S1470-2045(13)70154-2
- First-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS-BRAF wild-type metastatic colorectal cancer elderly patients: the PANDA study.J Clin Oncol. 2020;https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4002Date accessed: December 4, 2021
- Pembrolizumab in microsatellite-instability-high advanced colorectal cancer.N Engl J Med. 2020; 383: 2207-2218https://doi.org/10.1056/NEJMoa2017699
- FDA approval summary: pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma.Clin Cancer Res. 2021; 27: 4680-4684https://doi.org/10.1158/1078-0432.CCR-21-0557
- The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer.ESMO Open. 2021; 6: 100145https://doi.org/10.1016/j.esmoop.2021.100145
- Encorafenib, binimetinib, and cetuximab in BRAF V600e-mutated colorectal cancer.N Engl J Med. 2019; 381: 1632-1643https://doi.org/10.1056/NEJMoa1908075
- FDA approves encorafenib for colorectal cancer.National Cancer Institute. 2020;https://www.cancer.gov/news-events/cancer-currents-blog/2020/fda-encorafenib-cetuximab-metastatic-colorectalDate accessed: December 4, 2021
- The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy.ESMO Open. 2021; 6: 100031https://doi.org/10.1016/j.esmoop.2020.100031
- Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.Lancet Oncol. 2016; 17: 738-746https://doi.org/10.1016/S1470-2045(16)00150-9
- Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study.J Clin Oncol. 2018; 36: 536-542https://doi.org/10.1200/JCO.2017.75.3780
- Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018; 378: 731-739https://doi.org/10.1056/NEJMoa1714448
- Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2015; 16: 619-629https://doi.org/10.1016/S1470-2045(15)70156-7
- Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.Lancet. 2013; 381: 303-312https://doi.org/10.1016/S0140-6736(12)61900-X
- Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in asian patients with previously treated metastatic colorectal cancer: the TERRA study.J Clin Oncol. 2018; 36: 350-358https://doi.org/10.1200/JCO.2017.74.3245
- Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review.Ann Oncol. 2018; 29: 835-856https://doi.org/10.1093/annonc/mdy038
- Regorafenib or rechallenge chemotherapy: which is more effective in the third-line treatment of metastatic colorectal cancer?.Cancer Chemother Pharmacol. 2019; 83: 115-122https://doi.org/10.1007/s00280-018-3713-6
- Chemotherapy rechallenge or reintroduction, regorafenib, and TAS-102 for metastatic pretreated colorectal cancer patients: a propensity score analysis of treatment beyond the second line (PROSERpINA Study).Ann Oncol. 2019; 30: iv37-i38https://doi.org/10.1093/annonc/mdz155.138
- Clinical practice patterns in chemotherapeutic treatment regimens for metastatic colorectal cancer.Clin Colorectal Cancer. 2016; 15: 135-140https://doi.org/10.1016/j.clcc.2015.10.003
- Treatment of patients with metastatic colorectal cancer in a real-world scenario: probability of receiving second and further lines of therapy and description of clinical benefit.Clin Colorectal Cancer. 2017; 16: 372-376https://doi.org/10.1016/j.clcc.2017.03.019
- A retrospective observational study to estimate the attrition of patients across lines of systemic treatment for metastatic colorectal cancer in Canada.Curr Oncol. 2019; 26: e748-e754https://doi.org/10.3747/co.26.4861
- Systemic therapy for metastatic colorectal cancer: patterns of chemotherapy and biologic therapy use in US medical Oncology practice.J Oncol Pract. 2010; 6: 301-307https://doi.org/10.1200/JOP.2010.000072
- Radiologic assessment of response to therapy: comparison of RECIST Versions 1.1 and 1.0.Radiographics. 2011; 31: 2093-2105https://doi.org/10.1148/rg.317115050
- KRASG12C inhibition with sotorasib in advanced solid tumors.N Engl J Med. 2020; 383: 1207-1217https://doi.org/10.1056/NEJMoa1917239
- Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.Lancet Oncol. 2022; 23: 115-124https://doi.org/10.1016/S1470-2045(21)00605-7
- Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation.Ann Oncol. 2014; 25: 404-408https://doi.org/10.1093/annonc/mdt547
- Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation.Ann Oncol. 2018; 29: 1800-1806https://doi.org/10.1093/annonc/mdy197
- 383O MAYA trial: temozolomide (TMZ) priming followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite stable (MSS), MGMT silenced metastatic colorectal cancer (mCRC).Ann Oncol. 2021; 32: S530-S531https://doi.org/10.1016/j.annonc.2021.08.905
- Pembrolizumab in MMR-proficient metastatic colorectal cancer pharmacologically primed to trigger dynamic hypermutation status: the ARETHUSA trial.J Clin Oncol. 2019; 37: TPS2659https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.TPS2659Date accessed: November 6, 2021
Article info
Publication history
Published online: May 17, 2022
Accepted:
April 16,
2022
Received in revised form:
April 11,
2022
Received:
February 11,
2022
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
