Colorectal cancer (CRC) is a major cause of morbidity and mortality globally. More than 50% of patients can be expected to develop metastatic disease, and most of these patients will require palliative systemic therapy. The primary goal for patients who present with technically resectable liver metastases is definitely cure, with R0 resection as the primary goal. Consequently, any patient with limited liver and/or lung metastases should be considered a candidate for potential secondary resection as there are no criteria that allow physicians to distinguish between those patients for whom purely palliative treatment and those or whom potentially curative treatment is appropriate. Although survival times are slightly shorter for patients who undergo conversion therapy followed by surgery than for patients with initially resectable metastatic disease, they are far better than if resection is not carried out at all. First-line therapy commonly involves the doublet regimens of 5-fluorouracil, folinic acid, and either oxaliplatin or irinotecan. The addition of targeted therapies, such as bevacizumab (a pure anti-angiogenic agent which binds circulating VEGF-A), cetuximab, and panitumumab, to FOLFOX (5FU, oxaliplatin) or FOLFIRI (5FU, irinotecan) may be helpful to some patients in improving tumor response and ultimately overall survival. The cytotoxic triplet FOLFOXIRI (5FU, oxaliplatin, irinotecan) with or without bevacizumab may be an option in selected fit and motivated patients when cytoreduction (tumour shrinkage) is needed to undergo conversion therapy.

RAS mutations are found in about 50% of mCRC tumors. These mutations exclude affected patients from epidermal growth factor receptor (EGFR)-directed therapy. Besides their negative predictive value, RAS mutations may also carry distinct prognostic information. Modest studied the prognosis by RAS status of a total of 1239 mCRC patients from five randomized trials studying 2-CT. Actually, PFS and OS were significantly influenced by molecular subgroups. Multivariate comparison of Progression-Free Survival (PFS) and Overall Survival (OS) in patients with mutant tumors versus patients with non-mutated tumors revealed a negative prognostic effect of RAS mutations. Interestingly, the negative prognostic role of these mutations was consistently observed across different treatment regimens (subgroups of irinotecan- and oxaliplatin-treated patients as well as in bevacizumab- and non-bevacizumab-treated patients). Median PFS and OS were 10.3 vs. 9.5 months and 26.9 vs. 21.1 months in RAS-wildtype (and BRAF-wildtype) and RAS-mut patients, respectively. The TRIBE consortium reported that a 3-CT (FOLFOXIRI) combined with bevacizumab provided a significantly longer PFS (the primary end-point of the study) than did the 2-CT FOLFIRI plus bevacizumab . In the subgroup of RAS- and BRAF-wild-type patients, those in the FOLFOXIRI plus bevacizumab group reported a median PFS of 13.7 months (95% CI, 10.1-18.1) compared with 12.2 months (95%CI, 9.5-14.4) in the FOLFIRI plus bevacizumab group (HR 0.85, 95%CI 0.55-1.3).

Later on, the same group reported that FOLFOXIRI plus bevacizumab provided a significantly longer overall survival than the FOLFIRI plus bevacizumab group (HR 0.80, 95%CI 0·65-0·98; p=0·03) . Looking at survival by RAS status, Cremolini reported that median OS was 37.1 months (95%CI, 29.7-42.7) in the RAS- and BRAF-wild-type subgroup compared with 25.6 months (95%CI, 22.4-28.6) in the RAS-mut subgroup (HR 1.49, 95%CI, 1.11-1·99). Interestingly, median PFS was 13.7 months (95% CI 10.1-18.1) in the RAS-wild-type subgroup treated with FOLFOXIRI plus bevacizumab, while PFS data were not given for the RAS-mut patients . However, for these RAS-mut patients, it was possible to estimate the median PFS (i.e. 9.4 months) from the Kaplan-Meier curve which was provided.

Regorafenib is a small-molecule inhibitor of multiple membrane-bound and intracellular kinases. Beyond its well-known antiangiogenic properties, regorafenib has also less-known anti-proliferative activities in human colon cancer cell lines. Interestingly, regorafenib potently inhibits growth of patient-derived CRC xenografts alone and in combination with irinotecan . Regorafenib is approved for refractory mCRC patients, for locally advanced, unresectable or metastatic GIST patients and for HCC patients previously treated with sorafenib. The recommended dose is 160 mg (40 mg × 4 tablets) orally, once daily for the first 21 days of each 28-day cycle. Two phase III trials demonstrated a significant overall survival benefit for regorafenib over placebo in patients with mCRC who progressed on standard therapies . Two phase II trials studied the safety and efficacy profile of regorafenib when combined to chemotherapy in patients with mCRC . In vitro data indicate that both regorafenib and its metabolite M-2 inhibit glucuronidation mediated by UGT1A1 ( uridine 5'diphospho-glucuronosyl tranferase A1) and UGT1A9 (whereas M-5 only inhibits UGT1A1), hence triggering potential pharmacokinetic interactions. The study from Schultheis was designed to explore whether addition of regorafenib to FOLFOX or FOLFIRI could be feasible as a treatment of mCRC, in terms of safety and pharmacokinetic interactions of the various drug components of the regimen. Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m² bolus then 2400 mg/m² over 46 h, folinic acid 400 mg/m², and either oxaliplatin 85 mg/m² or irinotecan 180 mg/m².

On days 4-10, patients received regorafenib 160 mg orally once daily. Drug-related adverse events resulted in dose modification, dose interruption, or permanent discontinuation of study treatment in 31 (69%) patients overall (18 \[72%\] FOLFOX and 13 \[65%\] FOLFIRI).

Dose reduction or dose interruption of at least one of the chemotherapy components was observed in 52% of patients treated with FOLFOX and 65% of patients receiving FOLFIRI. A dose reduction of 5-fluorouracil due to AEs was necessary in 18% of administered cycles. 5-Fluorouracil administration was omitted in 8% of cycles. Oxaliplatin and irinotecan doses were reduced in 11% and 12% and interrupted in 11% and 5% of administered cycles, respectively. Actually, regorafenib had acceptable tolerability in combination with chemotherapy. The most frequent grade 3-4 AEs were: neutropenia (45%), Hand-Foot Skin Reaction (15%), diarrhea (10%), and hypophosphatemia (12%). Regarding pharmacokinetics, area under the curve (AUC) of irinotecan was significantly higher in cycle 2 (following regorafenib dosing) than in cycle 1 (before regorafenib dosing); the ratio of AUC values (cycle 2:cycle 1) was 1.28 (90% confidence interval \[CI\] 1.06 -1.54). Cmax of irinotecan was only slightly increased, and t½ (half-life) was unchanged. For SN-38 (metabolite of irinotecan), AUC was significantly higher in cycle 2 than in cycle 1 (ratio 1.44, 90% CI 1.12-1.85), while Cmax was unchanged. In line with the known elimination pathways of platinum and 5-fluorouracil, no pharmacokinetic interaction with regorafenib was seen . The study from O'Neil was designed to show whether the addition of regorafenib to FOLFIRI improves PFS (over a placebo-FOLFIRI arm) when given as second-line therapy for patients treated initially with oxaliplatin and fluoropyrimidine-based therapy. The regorafenib/FOLFIRI schedule that was used was the one proposed by Schultheis (i.e. standard FOLFIRI with irinotecan 180 mg/m² plus regorafenib 160 mg daily from day 4 to 10). The study met its primary endpoint of demonstrating that the addition of regorafenib to FOLFIRI prolongs PFS compared to FOLFIRI alone with a HR (Hazard Ratio) of 0.72. When looking at tumor response, authors found that regorafenib (combined to chemo) provided more partial responses than placebo plus chemo (35% vs. 19%, p= 0.045). The combination was very tolerable, with little increase in toxicity compared to the control chemotherapy regimen. Of note, regarding the top-3 reported severe (gr. 3-4) AEs, neutropenia, diarrhea, and hypophosphatemia were reported in 41%, 15%, and 14% of the patients, respectively (as compared to 30%, 5%, and 0% in the placebo group).

Actually, there is room to combine regorafenib with a chemo triplet such as FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) on the following conditions: controlling patients on UGT1A polymorphisms (at least UGT1A1), stepwise dose-escalation of irinotecan and regorafenib, mandatory granulocyte growth-factor injections.