Regorafenib Confers No PFS Benefit in Advanced Chordoma


Regorafenib did not show a benefit with progression-free survival in patients with advanced or metastatic chordoma.

Regorafenib (Stivarga) did not show a benefit with progression-free survival in patients with advanced or metastatic chordoma in phase 2 findings from the noncomparative REGOBONE study (NCT02389244) that were presented at the 2021 ESMO Congress.1

Investigators concluded that these findings show no benefit for regorafenib in patients with locally advanced or metastatic incurable chordoma. Furthermore, there is “no interesting activity” here to build on future combinations.

At 6 months, 40% (n = 6/14) of patients assigned to regorafenib were progression free (1-sided 95% CI, 20.6%). In the placebo arm, 2 of 5 patients were nonprogressive, for a progression-free rate (PFR) of 40% (1-sided 95% CI, 7.6). Regorafenib treatment would be deemed successful if at least 10 patients were progression-free at 6 months.

REGOBONE is a 5-arm, noncomparative study evaluating the efficacy and safety of regorafenib in patients with conventional high grade osteosarcoma, Ewing sarcoma of bone, intermediate or high-grade chondrosarcomas and chordomas and either bone or soft tissue metastatic CIC-rearranged sarcomas. Eligible adults had centrally confirmed locally advanced or metastatic chordoma without the possibility of cure and had progressive disease within 6 months of study entry.

Patients could have been treatment-naïve or received no more than 2 prior lines of therapy. All patients had ECOG performance score of 0 or 1.

Patients who received any prior treatment with a VEGFR inhibitor, had any other malignancy within 5 years, or had significant cardiovascular dysfunction were ineligible. Those who had undergone a major surgical procedure, open biopsy, or significant trauma within 28 days of enrollment were also excluded.

From March 2016 to February 2020, 27 patients with chordomas were enrolled onto the chordoma cohort. Sixteen patients were assigned to 160 mg regorafenib once daily for 21 days on a 28-day cycle plus best supportive care (BSC) until disease progression according to RECIST 1.1 criteria, intolerance or withdrawal of consent; 7 were assigned to placebo. Patients in the regorafenib arm who experienced disease progression could continue treatment if investigators determined the regorafenib was providing clinical benefit. Patients in the placebo arm crossed over to open-label regorafenib after objective tumor progression.

The primary end point was 6-month PFS rate, while main secondary end points were overall survival (OS) and safety. There was no formal statistical comparison between treatment groups.

The median age was 67.5 years (range, 33-85) in the experimental group and 54 years (range, 32-70) in the placebo group. Sixteen of the evaluable patients were men. Nine (56.2%) patients in the regorafenib group had an ECOG performance score of 1, as did 5 (71.4%) in the placebo group.

In the regorafenib group, 37.5% of patients had metastatic disease and 62.5% had locally advanced disease. Those numbers were 14.3% and 85.7%, respectively, in the placebo group.

At a median follow-up of 22.2 months, the median PFS was 8.2 months (95% CI, 4.5-12.9) and 10.1 months (95% CI, 0.8–not estimable) with regorafenib and placebo, respectively.

The median OS was 28.3 months in the experimental group but not reached with placebo. At 6 months, the OS rate was 88% (95% CI, 59%-97%) for regorafenib and 83% (95% CI, 27%-97%) for placebo. The 12-month OS rate was 88% (95% CI, 59%-97%) and 67% (95% CI, 19%-90%), respectively.

All patients in the placebo group had progressive disease, but only 4 (57%) crossed over. One patient withdrew consent, 1 died, and 1 was not eligible.

Twenty-five patients (n = 18 on regorafenib; n = 7 on placebo) were evaluable for safety. The most common grade 3 or higher regorafenib-related adverse events (AEs) during the double-blind period were hand-foot skin reaction (22.2%), hypertension (16.7%) and diarrhea (16.7%).

Two (11.1%) patients assigned to regorafenib had grade 3 or higher drug-related serious AEs. There was 1 incident each of pancreatitis and cholecystitis, and 1 patient developed pneumonia twice. There was one grade 3 or higher drug-related serious AE in the placebo group, which was a case of epilepsy.

No patient assigned to placebo discontinued treatment due to toxicity. Two (28.6%) had dose interruptions and 1 (14.3%) had a dose reduction.

Five (31.2%) discontinued treatment in the experimental group due to AEs. Eight (50.0%) had dose interruptions and 11 (68.8%) had dose reductions.

In findings from REGOBONE presented at the 2020 ESMO Virtual Congress, regorafenib improved 24-month PFS compared with placebo for patients with Ewing sarcoma but failed to meet the primary end point of non-progression at 8 weeks.2 At least 14 patients had to be progression free at 8 weeks for the trial to be considered a success. Thirteen (56.5%; 1-sided 95% CI, 37.5) patients in the regorafenib arm met the primary end point compared with 1 (7.7%; 95% CI, 0.4) in the placebo group.


  1. Duffaud F, Chabaud S, Chereau CM, et al. Results of the randomized, placebo (PL)-controlled phase II study evaluating the efficacy and safety of regorafenib (REGO) in patients (pts) with relapsed advanced or metastatic chordoma, on behalf of the FrenchSarcoma Group (FSG) and Unicancer. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA58.
  2. Duffaud F, Blay J-Y, Mir O, et al.. 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: 2020 ESMO Virtual Congress 2020; September 17- 21, 2020; virtual. Abstract LBA68.
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