Phase III Results Show S-1 and Irinotecan/Bevacizumab Noninferior to Standard First-Line Treatments for mCRC

Irinotecan plus bevacizumab (Avastin) with a fluoropyrimidine proved to be a noninferior treatment option compared to the standard regimens of either mFOLFOX6, CapeOX, or FOLFIRI for patients with metastatic colorectal cancer (mCRC), according to findings from the phase III TRICOLORE trial.

In this open-label, multicenter, randomized, noninferiority trial, investigators sought to discover if an S-1 and irinotecan plus bevacizumab regimen would be noninferior to other standards of care in the first-line setting of mCRC in terms of progression-free survival (PFS).

S-1 is an oral fluoropyrimidine comprised of a combination of tegafur, a prodrug of 5-fluorouracil (5-FU), and the modulators gimeracil and oteracil potassium. Previous studies have shown that S-1 plus irinotecan is noninferior as a second-line treatment for mCRC compared with FOLFIRI. Additionally, promising outcomes were seen in 2 prior phase II trials evaluating 3-week and 4-week regimens of S-1 combined with irinotecan plus bevacizumab as a first-line treatment regimen for patients with mCRC.

Between June 2012 and September 2014, investigators enrolled 487 patients from 53 institutions in Japan over the age of 20 who had unresectable mCRC with an ECOG performance status of 0 or 1, and adequate oral intake and organ function. They also had to have histologically confirmed colorectal adenocarcinoma. The study required that participants were not previously treated with either chemotherapy or radiotherapy.

After randomization, 2 patients were deemed not to have colorectal adenocarcinoma, and 1 patient withdrew consent. These patients were excluded from the primary analysis. The remaining participants were randomized into 2 groups, with 243 in the control arm and 241 in the experimental arm.

Patient characteristics were similar between the 2 groups. The control arm included 143 males (58.8%) and 100 females (41.2%), while the experimental arm included 151 males (62.7%) and 90 females (37.3%) The majority of patient in both groups—205 patients (84.4%) in the control arm and 204 patients in the experimental arm—had an ECOG performance status of 0. The remainder of patients—38 patients (15.6%) in the control arm and 37 patients (15.4%) in the experimental arm—had an ECOG performance status of 1.

In the control arm, patients received either mFOLFOX6 or CapeOX. In the mFOLFOX6 arm, patients were given bevacizumab (5 mg/kg) by infusion on day 1 of each 2-week cycle, followed by infusion of oxaliplatin (85 mg/m²) plus leucovorin (200 mg/m²), 5-FU bolus (400 mg/m²), and a continuous infusion of 5-FU (2400 mg/m²).

The CapeOX arm received bevacizumab at a dose of 7.5 mg/kg, with an infusion of oxaliplatin (130 mg/m²), capecitabine (1000 mg/m²) twice orally from day 1 to 15, followed by a 7-day rest period.

Patients in the experimental arm were administered treatment on either a 3-week or 4-week schedule. The 3-week cycle included bevacizumab (7.5 mg/kg) by infusion on day 1, followed by irinotecan (150 mg/m²), and S-1 (40 mg/m²) orally 2 times daily for days 1 to 15, followed by a 7-day rest period.

The 4-week cycle included a lower dose of bevacizumab (5 mg/kg), which was followed by irinotecan (100 mg/m²) and S-1 (40 mg/m²) twice daily for days 1 to 15, followed by 2 weeks of rest.

The primary endpoint for this study was PFS, and secondary endpoints included overall survival (OS), time to treatment failure (TTF), response rate, adverse events (AEs), quality of life (QOL), quality-adjusted life years (QALYs), cost effectiveness, and biomarker analysis.

There was a median follow-up period of 32.4 months (range, 1.5-46.6). PFS events occurred in 426 (88%) of the 484 patients. The median PFS in the control arm was 10.8 months (95% CI, 9.6-11.6), while the experimental arm had a median PFS of 14.0 months (95% CI, 12.4-15.5) (HR, 0.84; 95% CI, 0.70-1.02).

The median TTF was 7.7 months (95% CI, 7.1-8.2) in the control arm and 9.6 months (95% CI, 8.2-11.0) in the experimental arm (HR, 0.71; 95% CI, 0.59-0.85;P= .0002). The response rate of target lesions was found at 70.6% in the control arm and 66.4% in the experimental arm. A curative resection rate of 8.6% was also found in the control arm, with a 12.4% rate in the experimental arm.

Overall, there were 218 deaths (45%). A median survival time was found in the control and experimental arms at 33.6 months (95% CI 29.8—40.1) and 34.9 months (95% CI 31.9–42.4), respectively (HR, 0.86; 95% CI, 0.66-1.13;P= .2841).

AEs of grade 3 or higher, including leukopenia, neutropenia, febrile neutropenia, thromboembolism, or diarrhea, were more common with the experimental arm. However, grade 3 or higher sensory neuropathy, hand-foot syndrome, or paralytic ileus were found at higher rates in the control arm. The overall rate of grade 3 or higher AEs was 64.9% in the control arm compared with 58.6% with the S-1 combination regimen.

One treatment-related death was observed among patients receiving the CapeOX regimen and 4 among patients who received the S-1 experimental regimen.

The rate of AEs observed in the experimental arm was similar to what had been found with this regimen in previous studies. The study authors noted that diarrhea occurred in 13.4% of patients in the experimental arm, similar to what’s been reported for patients receiving FOLFIRI plus bevacizumab as a first-line treatment (10%-14%).

While AEs seemed noninferior for either arm, peripheral neuropathy was more common in higher grades within the control arm.

“Furthermore, peripheral neuropathy is usually prolonged, interfering with the daily lives of patients and reducing their quality of life,” the study authors wrote.

Peripheral neuropathy was noted in 92.1% of patients in the control arm, ultimately affecting their QOL. The QOL was analyzed with FACT-GOG-Nxt scores, showing more favorable results in the experimental arm.

Overall, S-1 and irinotecan plus bevacizumab proved to be noninferior to the standard of mFOLFOX6 or CapeOX plus bevacizumab. However, superiority of this regimen was not proven.

With a median PFS of 3.2 months longer in the experimental arm and a more favorable QOL, the study authors commented that they “consider S-1 and irinotecan plus bevacizumab to be an effective first-line therapy for mCRC and believe that it can be included as one of the recommended standard regimens.”

Results from a post-hoc analysis suggested more favorable toxicity results in patients with a creatinine clearance (CCr) of &ge;70 ml/min at enrollment. Patients with a CCr of &ge;70 ml/min experienced grade &ge;3 diarrhea at an incidence of 11.5% compared with 19.6% cases of grade &ge;3 diarrhea in patients with a CCr of <70&thinsp;ml/min in the experimental arm.

This led the study authors to believe that the regimen could be less beneficial in elderly patients with decreased renal function. &ldquo;On the other hand, non-elderly patients might benefit from aggressive S-1 and irinotecan plus bevacizumab regimens,&rdquo; they noted.

Reference:

Yamada Y, Denda T, Gamoh M, et al. S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer (TRICOLORE): a randomized, open-label, phase III, noninferiority trial.Ann Oncol.2018;29(3):624-631. doi: 10.1093/annonc/mdx816.