Options for second-line treatment in metastatic colorectal cancer (mCRC) are multiple but the best one is not yet clear. Also, the value of predictive and prognostic factors is evolving but still need more clarifications. Kras status has proved to be a strong predicting factor of response to anti-EGFR agents. Determination of Kras status is mandatory before starting cetuximab and panitumumab. However the prognostic value of Kras is still a point of debate. The available data states that the KRAS has no general prognostic value, but may have modest predictive effect with oxaliplatin- versus irinotecan-based treatment.
For Kras mutant patients, targeted therapy options are limited to anti-VEGF agent (bevacizumab) in first-line , and options become limited for second-line treatment, especially if new targeted therapy is not available (e.g. regorafenib). However, in Kras wild patients, the use of anti-angiogenic agents or anti-EGFR agents is relevant. Data has shown that the KRAS status does not predict clinical benefit from the addition of bevacizumab to chemotherapy in the first line setting. Using bevacizumab plus chemotherapy beyond first progression has been investigated in many trials. In the BEBYP study (1) the use of bevacizumab as second-line beyond progression had led to improve progression-free survival (PFS) and overall survival (OS).
In a recently published phase III trial, ML18147 (2), bevacizumab in second-line beyond progression has also led to improvement in PFS and OS. In this study, subgroup analysis by KRAS status has shown that the efficacy of bevacizumab as second-line treatment beyond progression is independent of the Kras status. In this subgroup analysis, the median PFS was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [p < 0.0001; HR = 0.61; 95% confidence interval (CI): 0.49–0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (p = 0.0027; HR = 0.70; 95% CI: 0.56–0.89) for mutant KRAS. The median OS was 15.4 and 11.1 months (p = 0.0052; HR = 0.69; 95% CI: 0.53–0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (p = 0.4969; HR = 0.92; 95% CI: 0.71–1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed in term of PFS and OS. It has to be mentioned that evaluating the response according to the KRAS status was an exploratory analysis in that study. The KRAS data were collected from local and/or from a central laboratories. No adjustment was made for multiplicity, so the analyses were not powered to detect statistically significant differences.
In the second-line setting, the data is available for Kras wild patients who failed on first-line oxaliplatin-based treatment. In the EPIC trial, cetuximab added to irinotecan had led to improvement in PFS (4.0 versus 2.6 months; HR = 0.70) and response rate (RR) (16.4% versus 4.2%) (3). The absence of survival advantage can be partly due to crossover as half of the control patients received cetuximab as post-trial therapy. The addition of panitumumab to irinotecan based treatment as second line also had led to improvement in PFS and RR but not in OS (4). In the same setting, there is no relevant data for the use of anti-EGFR agents with oxaliplatin in patients who failed on irinotecan-based first-line treatment. This is also clear in the NCCN guideline (version 3, 2013), in which there is no recommendation of combing anti-EGFR agents with oxaliplatin as subsequent therapy after failure on irinotecan based therapy. Using anti-angiogenic agents as second-line with oxaliplatin or irinotecan-based treatment either upfront or beyond progression was associated with improvement in OS (5).
In the era of evolving options of treatment as well as the presence of some predictive and prognostic factors, stating the best sequence of treatment is required to give the best response in each line of treatment.
What is the best sequence of treatment as first- and second-line in non-resectable mCRC, in both KRAS wild and mutant status?
- Masi G, Loupakis F, Salvatore L, et al. A randomized phase III study evaluating the continuation of Bevacizumab (bv) beyond progression in metastatic colorectal cancer (mCRC) patients ( pts) who received bv as part of first-line treatment: results of the BEBYP trial by the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol 2012; 23(Suppl 9): ixe9 (abstract LBA17).
- Kubicka S, Greil R, Andre T, et al. Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings. Ann Oncol 2013; 24(9):2342-9.
- Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 2311–2319.
- Peeters M, Price TJ, Cervantes A, 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 2010; 28: 4706–4713.
- Jitawatanarat P, Wee W. Update on antiangiogenic therapy in colorectal cancer: aflibercept and regorafenib. J Gastrointest Oncol 2013; 4(2):231-8.
The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.