Regorafenib Dose-Escalation Superior to Standard Dosing in mCRC

Tanios Bekaii-Saab, MD

Weekly dose-escalation of regorafenib (Stivarga) may become the new standard dosing for patients with refractory metastatic colorectal cancer (mCRC) being treated with the multikinase inhibitor. Results from the regorafenib dose optimization study (ReDOS) presented at the 2018 World Congress on GI Cancer established that the strategy of escalating regorafenib from 80 mg to 160 mg per day was superior to starting at a dose of 160 mg per day.

Of the 54 patients enrolled in the dose-escalation experimental arm, 43% initiated the third cycle of therapy, compared to only 24% of the 62 patients in the control arm (P = .0281). These results met the primary endpoint of the study, which was proportion of patients who initiate a third cycle in the escalation arm versus the control arm. The superiority of the experimental arm over the control arm was also a prime consideration, noted ReDOS lead author Tanios Bekaii-Saab, a professor of medicine at Mayo Clinic.

“There is a need to optimize the dose of regorafenib in patients with refractory mCRC that allows maintenance of the observed benefits while improving the tolerability profile,” said Bekaii-Saab. "There is no supportive data to teach us about how to use different dosing strategies with regorafenib.”

Patients enrolled in the dose-escalation arm began at an 80 mg starting dose in week 1, then were escalated to 120 mg in week 2, and ended at 160 mg in week 3. Patients enrolled in the control arm received regorafenib at 160 mg for 21 days.

While regorafenib has been shown to improve survival in trials of patients with mCRC, toxicities such as palmar-plantar erythrodysesthesia syndrome (PPES) and fatigue often occur within the first 2 to 3 weeks. To examine this aspect of regorafenib therapy, there was a secondary randomization in each arm to evaluate preemptive control of PPES with clobetasol versus reactive treatment of PPES with clobetasol.

Overall survival (OS) was a secondary endpoint on this study. The experimental arm was superior to the control arm in terms of survival, but it was not statistically significant as an endpoint, Bekaii-Saab said.

The median OS in the experimental arm was 9 months (95% CI, 6.8-13.4) compared with 5.9 months (95% CI, 5.3-12.4) in the control arm (HR, 0.65; 95% CI, 0.39-1.08; P = .0943). The 6-month OS rate was 66.5% in the escalation arm compared with 49.8% in the control arm. The 12-month rates were 34.4% and 26.7%, respectively.

The median OS in patients in the experimental arm who were able to initiate cycle 3 was 11.0 months (95% CI, 5.8-NE) versus 12.4 months (95% CI, 7.7-12.4) in the control arm (HR, 1.23; 95% CI, 0.33-4.58; P = 0.7566).

“If you are able to get those patients to cycle 3 and they were able to continue, then the survival was close to a year, regardless of the dose strategy used. Although more patients were able to get to cycle 3 on the dose-escalation strategy,” Bekaii-Saab said.

The other secondary endpoint was progression-free survival (PFS). Median PFS for patients in the experimental arm was 2.5 months (95% CI, 1.9-4.0), compared with 2.0 months (95% CI, 1.8-2.4) in the control arm (HR, 0.89; 95% CI, 0.59-1.33; P = 0.5534).

While the 6-month PFS rate of 12.2% in the escalation arm was superior to the 11.8% rate in the standard arm, the 12-month PFS rate favored the standard arm, at 5.9% versus 2.4%.

Data for ReDOS were initially reported at the 2018 Gastrointestinal Cancers Symposium. In March, the NCCN updated its CRC guidelines to recommend this weekly dose-escalation strategy of regorafenib based off that report. Regorafenib has been FDA-approved since 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 with an anti-EGFR therapy if KRAS wild-type.

“When you look at the overall quality of life (QoL), there did not seem to be any deterioration of the QoL on the escalating dose,” said Bekaii-Saab. “Overall, there were less toxicities on the dose escalating arm compared to the standard dose when it comes to fatigue, PPES, and hypertension.”

Rates of fatigue and hypertension during cycle 1 were more favorable in the experimental arm, with patients who received preemptive clobetasol experiencing less grade 2/3 PPES in cycles 1 and 2. In the preemptive arm, 28% of patients experienced PPES in cycle 1 and 13% experienced PPES in cycle 2, while 35% of patients who received reactive clobetasol in cycle 1 experienced PPES, and 34% experienced PPES in cycle 2.

Numerically, there were fewer grade 2/3 toxicities when clobetasol was applied preemptively as opposed to reactively. This was more pronounced during cycle 2, where a higher percentage of toxicities occurred across the board. This is not an established part of the dose-escalation strategy moving forward though, because QoL did not seem to correlate, Bekaii-Saab said. Although, there were more QoL parameters that were favorable in the experimental arm overall.

“The dose-escalation strategy did not appear to compromise QoL, unlike the standard dose administration," said Bekaii-Saab. "We think that these results potentially establish a new standard for optimizing regorafenib dosing through a dose-escalation strategy and a preemptive strategy with clobetasol may decrease the risk of PPES, warranting further investigation.”

Bekaii-Saab said that further data on the plasma pharmacokinetic analysis of regorafenib will be presented at a future meeting.

Beakii-Saab T, Ou F, Anderson A, et al. Regorafenib Dose Optimization Study (ReDOS): Randomized phase II trial to evaluate escalating dosing strategy and pre-emptive topical steroids for regorafenib in refractory metastatic colorectal cancer (mCRC) — An ACCRU Network study. Ann Oncol. 2018;29 (suppl 5; abstr O-014).