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
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.
1. Written informed consent for full study.
2. Documentation of tumor RAS mutation, wild-type homozygous, heterozygous status of
UGT1A1 gene. The status of UGT1A1 gene will be performed by the laboratory chosen by
3. Serum uracile < 16 ng/ml
4. Measurable disease, defined as at least one unidimensional measurable lesion on a CT
scan, according to RECIST version 1.1.
5. ECOG performance status ≤1.
6. Life expectancy of at least 3 months.
7. Adequate bone marrow, renal and liver functions as evidenced by the following
laboratory requirements within 7 days prior to study treatment initiation: Absolute
neutrophil count (ANC) ≥ 1,500/ mm3 without biologic response modifiers such as
granulocyte colony-stimulating factor (G-CSF), within 21 days before the start of
study treatment, Platelet count ≥ 100 000/mm3 , without platelet transfusion within 21
days before the start of study treatment ,Hemoglobin (Hb) ≥ 9 g/dL, without blood
transfusion or erythropoietin, within 21 days before the start of study treatment,
Serum creatinine ≤ 1.5 x upper limit of normal(ULN) Serum calcium ≥ LLN and ≤ 1.2 x
UNL ; Serum magnesium ≥ LLN and ≤ 1.2 x UNL ; Kalemia ≥ LLN, Glomerular filtration
rate as assessed by the estimated glomerular filtration rate (eGFR) ≥ 50 mL/min per
1.73 m2 calculated by the Modification of Diet in Renal Disease (MDRD) abbreviated
formula, Total bilirubin ≤ 1.5 x ULN, Alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of
their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with
liver involvement for their cancer and/or bone metastases).
8. Lipase ≤ 1.5 x ULN.
9. Adequate coagulation, as assessed by the following laboratory test results:
International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN,
Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, Note: Patients
on stable dose (dose has not been changed in at least 28 days) of anticoagulation
therapy will be allowed to participate if they have no sign of bleeding or clotting
and INR / PT and PTT / aPTT test results are compatible with the acceptable
benefit-risk ratio at the investigator's discretion. In such case, limits as noted
would not apply.
10. For women of reproductive potential, negative serum beta human chorionic gonadotropin
(β-HCG) pregnancy test obtained within 7 days before the start of study treatment.
Women not of reproductive potential are female patients who are postmenopausal or
permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy).
11. For women of childbearing potential and men, agreement to use an adequate
contraception for the duration of study participation and up to 4 months following
completion of therapy for women and 6 months for male patients. Females of
childbearing potential who are sexually active with a non-sterilized male partner must
use 2 methods of effective contraception. The investigator or a designated associate
is requested to advise the patient on how to achieve an adequate birth control.
Adequate contraception is defined in the study as any medically recommended method (or
combination of methods) as per standard of care.
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests and other study procedures.
13. Affiliation to the Social Security System.
1. Previous or concurrent cancer that is distinct in primary site or histology from
colorectal cancer within 5 years prior to study inclusion, except for curatively
treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder
tumors [Ta (noninvasive tumor), Tis (carcinoma in situ) and T1 (lamina propria
2. Discovery of metastases within 6 months after the termination of adjuvant
3. Previous treatment for metastatic disease. Radiotherapy within 28 days prior to first
dose of treatment.
4. Active cardiac disease including any of the following:
Congestive heart failure New York Heart Association (NYHA) class 2, Unstable angina
(angina symptoms at rest), new-onset angina (begun within the last 3 months),
Myocardial infarction less than 6 months before first dose of treatment, Cardiac
arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are
5. ECG with a QT/QTc interval higher than 450 ms for men and higher than 470 ms for women
6. Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure >
90 mmHg despite optimal medical management).
7. Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
within 6 months before start of treatment.
8;Persistent proteinuria of National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI-CTCAE V5) grade 3 (i.e. urinary protein ≥ 3.5 g/24 hrs) 9;Peripheral
neuropathy > grade1 (NCI-CTCAE v5). 10.Major surgical procedure, open biopsy, or
significant traumatic injury within 28 days prior to first dose of Treatment.
11.Ongoing infection >grade 2 (NCI-CTCAE v5). 12.Known history of human immunodeficiency
virus (HIV) infection. 13.Chronic hepatitis B or C infection (if hepatitis status cannot be
obtained from medical records, re-testing is required).
14.Seizure disorder requiring medication. 15.Symptomatic metastatic brain or meningeal
tumors. 16.Evidence or history of any bleeding diathesis, irrespective of severity. Any
hemorrhage or bleeding event ≥ grade 3 (NCI-CTCAE v5) within 4 weeks prior to the start of
17.History of organ allograft. 18.Non-healing wound, ulcer, or bone fracture.
19.Dehydration Grade 1 NCI-CTCAE v5). 20.Substance abuse, medical, psychological, or social
conditions that may interfere with the patient's participation in the study or evaluation
of the study results.
21.Known hypersensitivity to any of the study drugs, study drug classes, or any constituent
of the products.
22.Interstitial lung disease with ongoing signs and symptoms. 23.Concomitant intake of St.
John's wort. 24.Live attenuated vaccines are prohibited 10 days before the treatment,
during the treatment and 3 months after the termination of treatment 25.History of
gastrointestinal fistula or perforation 26.Inability to swallow oral medication. 27.Any
malabsorption condition. 28.Pregnant or breast-feeding subjects. 29.Any condition that, in
the opinion of the investigator, would interfere with the evaluation of study treatment or
interpretation of patient safety or study results.
30.Participation in another clinical study with an investigational product during the last
30 days before inclusion. 31.Patients who might be interconnected with or dependent on the
sponsor site or the investigator.
32.Legal incapacity or limited legal capacity.