NCCN Recommends Regorafenib Dose Escalation in Metastatic CRC

Tanios Bekaii-Saab, MD

The NCCN has updated its colorectal cancer (CRC) guidelines, recommending a weekly regorafenib (Stivarga) dose-escalation strategy beginning at 80 mg and ending at 160 mg for previously treated patients with metastatic CRC (mCRC).

The new dosing scheme calls for a starting dose of 80 mg/daily on days 1 to 7, escalating to 120 mg/daily on days 8 to 14, and concluding with 160 mg/daily on days 15 to 21. For subsequent cycles, the NCCN recommends 160 mg of regorafenib on days 1 to 21 every 28 days.

The updated results are based on findings from ReDOS, a phase II regorafenib dose optimization study comparing the dose escalation regimen with the standard dose of 160 mg of regorafenib daily. The median overall survival (OS) was 9.0 months in the dose-escalation arm versus 5.9 months in the standard arm (P = .0943).

The 6-month OS rate was 66.5% (95% CI, 53.8-82.2) in the escalation arm versus 49.8% (95% CI, 37.2-66.8) in the standard arm. Twelve-month OS also favored the dose escalation arm, at 34.4% versus 26.7%.

Additionally, the median progression-free survival (PFS) favored dose escalation (2.5 vs 2.0 months). The 6-month PFS was 12.2% (95% CI, 5.4-27.5) in the escalation arm versus 11.8% (95% CI, 5.2-26.6) in the standard arm. However, the 12-month PFS rate favored the standard arm, at 5.9% versus 2.4%.

Regorafenib was approved by the FDA in 2012 for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy, and, if KRAS wild-type, with an anti-EGFR therapy.

The approval was based on the phase III CORRECT trial, in which the median OS was 6.4 months in the regorafenib group versus 5.0 months in the placebo group (HR, 0.77; 95% CI, 0.64-0.94; one-sided P = .0052). Patients in the regorafenib arm received the treatment at 160 mg orally once daily for 3 weeks of every 4-week cycle.

Tanios Bekaii-Saab, MD, professor of medicine, Mayo Clinic, presented ReDOS at the 2018 Gastrointestinal Cancers Symposium in January. In an Interview with OncLive, he called the findings “practice changing.”

“The most important aspect of this study is that now we have another option, and I think it is a preferred option, of how to administer regorafenib,” said Bekaii-Saab. “As we get more confirmatory studies, [we might want] to consider regorafenib a little earlier if we want to get the full benefit of the agent rather than wait until the end when the patient is literally about to go to hospice. A dose-escalation strategy would make more sense now than the standard 160 mg. We have to become more proactive about how we place our drugs and how to optimize the dose-escalation strategy for regorafenib.”

In ReDOS, 54 patients were assigned to dose escalation and 62 were assigned to standard dosing. All patients had an ECOG performance status of 0 (37.1%) or 1 (62.9%). Four patients (7.4%) in the escalation arm had local recurrence, 37 (68.5%) had resected disease, and 13 (24.1%) had unresected disease compared with 1 (1.6%), 44 (71.0%), and 17 (27.4%) in the standard arm, respectively.

The median age was 61 (range, 53-68) and a majority of patients were male (61.2%). The percentage of patients with KRAS mutated or wild-type tumors was nearly identical (46.6% vs 44.0%).

The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated a third. Patients in the dose escalation arm were more likely to meet that endpoint (43% vs 24%; P = 0.281).

Investigators noted that toxicity was more favorable in the dose-escalation arm, and quality-of-life parameters were improved as well.

“Another finding that was very intriguing was the quality of life. The quality of life of patients, when you use the dose-escalating strategy from 80 mg to 120 mg to 160 mg was not compromised…it was a straight line,” Bekaii-Saab said. “Whereby, with the higher standard dose of 160 mg, we see a drop in the quality of life that readjusts as you readjust the dose of the medication. That difference was consistent across every parameter that was included in the quality of life.”

Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36(suppl 4S; abstr 611).