Frontline FOLFOXIRI Plus Bevacizumab Effective in Metastatic Colorectal Cancer

The combination of FOLFOXIRI plus molecular targeted therapies, including bevacizumab (Avastin), was effective as a first-line treatment in metastatic colorectal cancer (mCRC), according to findings from a retrospective study recently published inOncotarget.^1,2

Among 55 patients, the overall response rate (ORR) was 69%. That included a complete response (CR) in 7 patients and a partial response (PR) in 30 patients. The disease control rate was 98%, with stable disease (SD) in 16 patients.

“A stratified analysis of the molecular target therapy regimens indicated that the response rate tended to be higher in patients receiving anti-EGFR antibodies than in those treated with anti-VEGF antibodies, although the patients who received the anti-EGFR antibodies tended to have a higher incidence of skin toxicities and hypomagnesaemia,” wrote the authors, led by Takatsugu Ogata, MD, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan. “The median PFS and median OS did not significantly differ between patients treated with anti-EGFR antibodies and those with anti-VEGF antibodies.”

Ogata et al examined the outcomes of 55 patients with metastatic colorectal cancer who had been treated at 2 institutions in Japan with first-line therapy consisting of FOLFOXIRI (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, and oxaliplatin) plus bevacizumab, ramucirumab, cetuximab, or panitumumab. They collected a variety of data for each patient, including tumor located on the left or right, RAS/BRAFstatus, UGT1A1status, primary resection, prior adjuvant therapy, liver metastasis, lung metastasis, peritoneal dissemination, stage at diagnosis, and the efficacy and safety of the therapeutic antibodies during treatment.

The investigators followed the FOLFOXIRI protocol as described in the TRIBE trial: a 60-minute infusion of irinotecan at a dose of 165 mg/m², and a 120-minute infusion of oxaliplatin at a dose of 85 mg/m²combined with a concomitant 120-minute infusion of leucovorin at a dose of 200 mg/m², followed by a 48-hour continuous infusion of fluorouracil to a total dose of 3200 mg/m², repeated every 2 weeks.³

Additionally, the targeted therapies were dosed as follows: bevacizumab, 5 mg/kg; ramucirumab, 8 mg/kg; and panitumumab at 6 mg/kg. Cetuximab was given at 400 mg/m²as the initial dose, followed by 250 mg/m²in subsequent treatments.

After completing initial therapy, patients received maintenance treatment with fluorouracil, leucovorin, and molecular target drugs until disease progression. CT was used to assess tumors every 8 weeks until disease progression. When tumor shrinkage was observed, conversion therapy was recommended.

The patients’ median age was 60 years (range, 33−74; Interquartile Range, 52−65). A majority of patients (69%, n = 38) received anti-VEGF antibodies, while 31% (n = 17) received anti-EGFR antibodies.

In patients treated with anti-EGFR antibodies, the primary tumor location was on the left side in 14 patients (25%) and on the right side in 3 patients (5%). Among patients who received anti-VEGF antibodies, the primary tumor was located on the left side in 26 patients (47%) and on the right side in 12 patients (22%).

With a median follow-up of 18.4 months, the median PFS was 11.0 months. The PFS did not significantly differ between the anti-EGFR antibodies and anti-VEGF antibodies arms (13.1 months vs 10.3 months; HR, 3.12;P= 0.143).

Additionally, PFS did not differ significantly based on tumor location. Patients with left-sided tumors had a PFS of 11.5 months, while those with right-sided tumors had a PFS of 8.4 months (HR, 1.32;P= 0.460).

The authors used multivariable analyses to determine which factors were associated with PFS. They found that the HR of liver metastasis and PFS was 4.37 (1.80—10.6;P= 0.001). The HR of peritoneal dissemination and PFS was 0.27 (0.10—0.70;P= 0.007), while the HR of tumor location associated with PFS was 4.23 (1.58—11.3;P= 0.004).

The median OS was 41.9 months. The authors found that OS did not differ significantly based on the antibodies used and the tumor location. By treatment group, the OS was not reached vs 36.7 months (HR, 2.65;P= 0.115. By tumor location, OS was 41.8 months vs not reached (HR, 1.13;P= 0.815).

When Ogata et al performed multivariable analyses of OS, they found thatBRAFstatus was significant, with HR of 13.1 (P= 0.003). Liver metastasis and OS had HR of 5.16 (P= 0.031), while progressive disease (PD) during induction phase was associated with OS (HR, 12.5;P= 0.004). “Moreover, if classified by primary location and antibodies, the FOLFOXIRI plus anti-EGFR antibodies tended to be more effective than the FOLFOXIRI plus anti-VEGF antibodies in left-sided primary tumors,” they wrote.

                                          

Leukopenia and neutropenia were the most common adverse events (AEs) of any grade, experienced by 44 patients each (80%). Slightly more than half the study patients developed moderate to severe neutropenia, the most common grade 3 and 4 AE (28 patients, 51%). The median number of days until the worst neutropenia occurred was 39 days (range, 9—161 days).

The authors analyzed the BRAFstatus in 45 patients and found that 3 patients, all female, were positive forBRAFV600Emutation. Two of these patients had the primary tumor located on the right side. Two patients received bevacizumab and 1 patient received cetuximab. The median depth of response in patients withBRAFV600Emutation was -24% (range, -38 to 7).

When Ogata et al compared the median PFS in patients withBRAFV600Emutation to those without, they found that PFS tended to be somewhat shorter in those with the mutation (8.2 months vs 11.0 months; HR, 2.79;P= 0.093). However, these patients experienced significantly shorter OS than patients without the mutation: (12.9 months vs 41.9 months; HR, 5.82;P= 0.003).

The authors noted that, in both tumor locations, anti-EGFR antibodies were associated with higher overall response rates as compared to those associated with anti-VEGF antibodies. “Furthermore, the depth of response was also higher using anti-EGFR antibodies,” Ogata et al wrote. “However, the number of patients was too small to perform a combined analysis of primary locations and antibodies. A prospective study will be needed to support this type of analysis.”

References:

1. Ogata T, Satake H, Ogata M, et al. Safety and effectiveness of FOLFOXIRI plus molecular target drug therapy for metastatic colorectal cancer: A multicenter retrospective study.Oncotarget. 2019;10(10):1070-1084.
2. Ogata T, Satake H, Ogata M, et al. The safety and efficacy of FOLFOXIRI plus molecular target therapy as a first-line treatment for metastatic colorectal cancer: A multicentre retrospective study.Ann Onc. 2018;29(suppl_8):viii150-viii204. 10.1093/annonc/mdy281
3. Loupakis F, Cremolini C, Masi G, et al. Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer.N Engl J Med. 2014;371:1609-1618.