As compared with placebo, regorafenib induced favorable progression-free survival rates at 24 weeks versus placebo in patients with Ewing sarcoma in the phase 2 REGOBONE study. Despite this, the trial failed to meet its primary end point of non-progression at 8 weeks, according to findings presented at the European Society of Medical Oncology Virtual Congress 2020.
As compared with placebo, regorafenib (Stivarga) induced favorable progression-free survival (PFS) rates at 24 weeks versus placebo in patients with Ewing sarcoma in the phase 2 REGOBONE study (NCT02389244). Despite this, the trial failed to meet its primary end point of non-progression at 8 weeks, according to findings presented at the European Society of Medical Oncology (EMSO) Virtual Congress 2020.1
Despite the negative results, lead author Florence Duffaud, MD, PhD, pointed out that Ewing sarcoma is a very aggressive disease and these data are enough to support exploration of regorafenib in combination with a PD-L1 or PD-1 inhibitor.
“Results indicate interesting activity of regorafenib for delaying disease progression in patients metastatic Ewing sarcoma after failure of prior conventional therapy,” said Duffaud, professor of oncology at the University of Medicine of Marseilles, France, and the head of the medical Oncology Unit at La Timone University Hospital in Marseilles. “Modest activity of regorafenib is nonetheless interesting to build upon for future combinations.”
Investigators recruited 41 patients into the phase 2, non-comparative, double-blind, placebo-controlled REGOBONE study (NCT02389244); 36 were eligible for efficacy. Thirteen patients were assigned to placebo while the remaining 23 were assigned to 160 mg daily oral regorafenib. Patients in both groups received best supportive care.
At least 14 patients had to be progression free at 8 weeks for the trial to be considered a success. Secondary endpoints included PFS and overall survival (OS).
Thirteen (56.6%; 95% CI, 37.5-not reached) patients in the regorafenib arm met the primary endpoint compared with 1 (7.7%; 95% CI, 0.4-not reached) in the placebo group. Five (21.7%) patients in the experimental arm had partial response and 11 (47.8%) had stable disease compared with 1 and 3 (23.1%), respectively, in the placebo arm.
PFS in the regorafenib group was 11.4 weeks (95% CI, 4.6-22.9) versus 3.9 weeks (95% CI, 3.3-7.3). Duffaud noted that the PFS advantage associated with regorafenib was stable. At 24 weeks, PFS rate in the experimental arm was 26% (95% CI, 11-45) compared with 8% (95% CI, 0-29) for placebo.
Ten patients in the placebo group crossed over to receive regorafenib after disease progression was confirmed. Six-month OS was 70% (95% CI, 47-84) in the regorafenib arm and 12-month OS was 39% (95% CI, 20-58) versus 54% (95% CI, 25-76) and 38% (95% CI, 14-63), respectively. The median PFS in the crossover group was superior to both the placebo group and the initial regorafenib group.
“The median PFS of 11.4 weeks with initial regorafenib and of 12.9 weeks [95% CI, 4.0-46.4] after crossover to open-label regorafenib despite rapid failure with placebo with a median PFS of 3.9 weeks [95% CI, 3.3-7.3] serves as confirmation of regorafenib impact,” Duffaud said.
At 12 weeks, PFS was 56% (95% CI, 20-80) in the crossover group compared with 43% (95% CI, 23-62) in the initial regorafenib arm. At 24 weeks, the PFS rate was 33% (95% CI, 8-62) in the crossover arm compared with 26% in the initial regorafenib arm.
Duffaud noted that these results are analogous to findings from the SARC024 trial of regorafenib. In that phase 2 trial, the median PFS was 3.6 months (95% CI, 2.0-7.6) in the regorafenib group versus 1.7 months (95% CI, 1.2-1.8) in the placebo group (HR, 0.42, P = .017). Three patients in the experimental group had objective response was observed in three patients treated with regorafenib compared with zero treated with placebo.2
Duffaud said safety results were consistent with previous findings. Twenty-three patients in the regorafenib arm and 14 in the placebo arm were evaluable for safety. Patients in the experimental arm received a median of 3 cycles of treatment (range, 1-54) compared with a median of 1 cycle in the placebo arm (range, 1-9).
Nine (39%) patients assigned to regorafenib required dose reductions and 8 (35%) required dose reduction for toxicity compared with 1 (8%) and zero, respectively, in the placebo arm.
Investigators recorded no transient discontinuation or drug-related serious adverse events (SAEs) in placebo arm. Eleven (48%) patients in the experimental arm required transient discontinuations and 7 (30.4%) experienced drug-related SAEs.
In findings published online in November 2018, 12 patients in the placebo group and 26 in the regorafenib group were evaluable for efficacy. Seventeen patients (65%; 95% CI, 47%) in the regorafenib group were non-progressive at 8 weeks compared with no patients in the placebo group.3
Regorafenib is a kinase inhibitor approved to treat patients with metastatic colorectal cancer and locally advanced, unresectable or metastatic gastrointestinal stromal tumor.4
1. Duffaud F. Results of the randomized, placebo (PL)-controlled phase II study evaluating the efficacy and safety of regorafenib (REG) in patients (pts) with metastatic relapsed Ewing sarcoma (ES), on behalf of the French Sarcoma Group (FSG) and UNICANCER. Presented at: European Society of Medical Oncology (EMSO) Virtual Congress 2020, held September 17, 2020 to September 21, 2020. Abstract #LBA68.
2. Davis LE, Bolejack V, Ryan CW, et al. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019;37(16):1424-1431. doi:10.1200/JCO.18.02374
3. Duffaud F, Mir O, Boudou-Rouquette P, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2019;20(1):120-133. doi:10.1016/S1470-2045(18)30742-3
4. Stivarga. Prescribing information. Bayer Healthcare. Revised February 2013. Accessed September 19, 2020. https://bit.ly/3mCrifs