Metastatic colorectal cancer "beyond surgery".

At the advanced training course in clinical oncology in St. Gallen, there was also a symposium on colorectal carcinoma, among other topics. In an overview, Prof. Dr. med. Ralf-Dieter Hofheinz, Mannheim, presented the current therapy options and addressed the new ESMO recommendations published in 2016. Finally, he made a suggestion for a possible algorithm.

“It has long been known that chemotherapy in first-line non-resectable metastatic colorectal cancer (mCRC) leads to improved survival and quality of life. Even over further lines of therapy, we can conclude that active therapy is superior to best supportive care in mCRC,” said Prof. Ralf-Dieter Hofheinz, MD, Interdisciplinary Tumor Center, University Medical Center Mannheim, Germany, in an introductory review of therapeutic advances in recent years. “After more than a decade of experience with bevacizumab, it is also evident that its addition to chemotherapy provides a significant, albeit circumscribed, benefit in terms of overall survival. A survival benefit can be achieved with antiangiogenic treatment even beyond progression” [1].

Mutation status plays a central role in treatment decisions: currently, it is known that in addition to KRAS exon 2 [2], rarer mutations in exon 3 and 4 of the KRAS gene and mutations in exon 2, 3, and 4 in the NRAS gene can cause tumor resistance to anti-EGFR drugs. RAS mutations overall have been identified as negative predictive biomarkers of anti-EGFR therapy in mCRC in several studies [3]. Without such mutations (all-RAS wild-type), an overall survival benefit of more than five months is found, add the anti-EGFR antibody panitumumab to chemotherapy according to FOLFOX4 regimen. The same is true for other chemotherapy background, namely FOLFIRI, and for its “sister antibody” cetuximab: In the CRYSTAL trial [4], extended RAS analysis (i.e., all-RAS wild-type) found a median OS benefit of approximately eight months with the addition of cetuximab, compared with the FOLFIRI regimen alone.

New ESMO guidelines under the microscope

The predictive value of BRAF mutation, i.e., whether patients with RAS wild type and BRAF mutation benefit less from anti-EGFR treatment than those with BRAF wild type, is debated in studies [5]. What is certain is that patients with BRAF mutation achieve a median overall survival of eleven (FOLFIRI) or 19 months (FOLFOXIRI) with chemotherapy and bevacizumab, depending on the regimen [6]. Since there is no benefit from anti-EGFR therapy and more intensive chemotherapy leads to better outcomes, the new ESMO guideline [7] provides triplet chemotherapy with/without bevacizumab but no therapy with anti-EGFR antibodies for patients with mCRC and BRAF mutation in whom the goal is cytoreduction (shrinkage) or disease control (control of progression).

According to the ESMO guideline [7], individuals in whom the goal is cytoreduction or disease control should also have a re-evaluation/response survey every two or two to three months, regardless of molecular profile. If there is progression, you move to the second line. If the goal is still cytoreduction, one should continue therapy – if, on the other hand, the goal is (newly) disease control, there is also the option of active maintenance therapy or pause. The AIO-KRK-0207 trial [8] looked to see if, after six months of induction combination chemotherapy with bevacizumab, a watch-and-wait strategy or bevacizumab alone was non-inferior to standard maintenance therapy with fluoropyrimidine plus bevacizumab. It took 6.9 months (fluoropyrimidine plus bevacizumab), 6.1 months (bevacizumab), and 6.4 months (watch&wait) for each type of therapy to fail, the primary endpoint (TFS). Re-induction of the original therapy after first progression was necessary in only 19%, 43%, and 46% in the above order – thus the primary endpoint TFS, defined as progression after reinduction, turned out to be clinically irrelevant. “Although the noninferiority of the watch-and-wait strategy versus fluoropyrimidine plus bevacizumab was not formally demonstrated in the trial, it seems reasonable to pause after six months of therapy given the small differences,” he said.

Tumor localization decisive

Excitement was generated last year by the finding, including from a retrospective analysis of FIRE-3 and CRYSTAL data [9], that primary tumor location has prognostic value. The survival benefit of cetuximab plus FOLFIRI (versus bevacizumab plus FOLFIRI) was found only in mCRC patients with all-Ras wild-type and left-sided tumors (38.3 vs. 28 months, p=0.002) – but not in those with right-sided tumors (18.5 vs. 15 months, p=0.28). In CRYSTAL, also only patients with left-sided tumors benefited from cetuximab plus FOLFIRI (versus FOLFIRI alone). Associated survival values were 28.7 vs. 21.7 months (p=0.002) and 18.3 vs. 23 months (p=0.76). CALGB and PRIME analyses presented at ESMO 2016 reached similar conclusions. “So in that respect, the new ESMO guideline is already outdated again,” Prof. Hofheinz said. “Of course, the left-right distinction is a cane, albeit a quite workable one, as tumors actually differ relevantly in their microsatellite instability (MSI), BRAF, and CpG island methylator phenotype (CIMP) status depending on their location. Right-sided KRAS wild-type tumors are more often MSI- and CIMP-high (hypermethylation) and BRAF-mutated. However, this does not mean that these characteristics are never found in left-sided tumors, they are just less frequently present – so determining BRAF status, as recommended in the ESMO guidelines, remains reasonable.”

Sequence Studies

According to a phase III trial, the addition of panitumumab to FOLFIRI in the second-line setting (after fluoropyrimidine with/without bevacizumab) is again superior to chemotherapy alone, particularly for all-RAS wild-type tumors [10]. Is this an argument for the use of such antibodies in the second line? “This is where we need sequence studies to answer the question more precisely,” he said. “In recent years, four analyses have attracted attention in this regard.”

RAS wild-type patients with a first-line anti-EGFR antibody (FIRE-3) benefit more from second-line therapy with antiangiogenic agents than patients with a reverse sequence [11].
The SPIRITT study [12] concludes that comparable efficacy is achieved with bevacizumab and panitumumab added to FOLFIRI in the second-line setting (after oxaliplatin-based chemotherapy and bevacizumab) – this in patients with KRAS exon 2 wild-type.
In patients with RAS wild-type and progression after bevacizumab and chemotherapy, continuing therapy with bevacizumab and cross-over chemotherapy beyond progression results in a numerical but not statistically significant prolongation of progression-free and overall survival-this compared with cetuximab and cross-over chemotherapy in the second-line setting [13].

Also, in a study presented at ASCO 2016 by Shitara K et al. [14] there is no significant survival difference between panitumumab and bevacizumab (added to FOLFIRI) in the second-line setting in patients with KRAS exon 2 wild-type mCRC (after first-line oxaliplatin chemotherapy and bevacizumab).

“Looking over the data, one can hypothesize that second-line anti-EGFR antibodies (after chemo plus bevacizumab) are no longer performing as convincingly in these groups, and continuing anti-VEGF therapy appears to be just as effective,” Prof. Hofheinz noted. “This may be contrary to expectations, but the data from randomized trials are relatively clear in that regard – even though they are rather small studies.”

Triplet vs. doublet

Results from TRIBE [6] showed an advantage in progression-free and overall survival for the triplet combination FOLFOXIRI over the doublet combination FOLFIRI (each given in the first-line setting and together with bevacizumab). In the phase II study CHARTA [15] presented at ESMO 2016, the results were confirmed at least in trend: A similar extension of PFS from 9.76 to 12 months (TRIBE 9.7 to 12.1 months) was found under the triplet combination. However, this difference was not significant. “It also showed the toxicity is greater – but quantum leaps, as you might expect, are not observed,” the expert explained. Neutropenia and diarrhea should be kept in mind. The regimen is particularly suitable for younger fitter patients (corresponding to the sample of CHARTA).

Algorithm

“If you put all the information you just heard together, a possible algorithm in mCRC ‘beyond surgery’ can be created,” the expert explained. Figure 1 provides a corresponding overview.

Source: 27th Physician Continuing Education Course in Clinical Oncology, February 16-18, 2017, St. Gallen.

Literature:

Hofheinz RD, et al: Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials. Gastroenterol Res Pract 2016; 2016: 9189483. DOI: 10.1155/2016/9189483.
Amado RG, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008 Apr 1; 26(10): 1626-1634.
Douillard JY, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013 Sep 12; 369(11): 1023-1034.
Van Cutsem E, et al: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015 Mar 1; 33(7): 692-700.
Rowland A, et al: Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer 2015 Jun 9; 112(12): 1888-1894.
Cremolini C, et al: 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): 1306-1315.
Van Cutsem E, et al: ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016 Aug; 27(8): 1386-1422.
Hegewisch-Becker S, et al: Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2015 Oct; 16(13): 1355-1369.
Tejpar S, et al: Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncol 2016 Oct 10. DOI: 10.1001/jamaoncol.2016.3797 [Epub ahead of print].
Peeters M, et al: Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer. Clin Cancer Res 2015 Dec 15; 21(24): 5469-5479.
Modest DP, et al: Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer. J Clin Oncol 2015 Nov 10; 33(32): 3718-3726.
Hecht JR, et al: SPIRITT: A Randomized, Multicenter, Phase II Study of Panitumumab with FOLFIRI and Bevacizumab with FOLFIRI as Second-Line Treatment in Patients with Unresectable Wild Type KRAS Metastatic Colorectal Cancer. Clin Colorectal Cancer 2015 Jun; 14(2): 72-80.
Hiret S, et al: Bevacizumab or cetuximab plus chemotherapy after progression with bevacizumab plus chemotherapy in patients with wtKRAS metastatic colorectal cancer: a randomized phase II study (Prodige 18 -UNICANCER GI). J Clin Oncol 2016; 34(suppl; abstr 3514).
Shitara K, et al: A randomized multicenter phase II study of FOLFIRI plus either panitumumab (Pmab) or bevacizumab (Bmab) as second-line treatment for wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) with exploratory biomarker analysis by liquid biopsy: WJOG6210G. J Clin Oncol 2016; 34(suppl; abstr 3567).
Schmoll HJ, et al: LBA22 – FOLFOX / Bevacizumab (Beva) +/- Irinotecan in advanced colorectal cancer (CRC): A randomized phase II trial (AIO CRC 0209, CHARTA). Annals of Oncology 2016; 27(6): 1-36. 10.1093/annonc/mdw435.