Regorafenib Shows ‘Clinically Meaningful’ Activity For Metastatic Osteosarcoma

Patients with progressive metastatic osteosarcoma may respond to second- or later-line treatment with regorafenib

medwireNews: Patients with recurrent, metastatic and/or unresectable osteosarcoma who have received one or two prior lines of chemotherapy may benefit from treatment with the oral multikinase inhibitor regorafenib, suggest phase II trial findings published in The Lancet Oncology.

While emphasizing that the double-blind, placebo-controlled study is statistically non-comparative, the French investigators say their progression-free survival (PFS) results point to “clinically meaningful antitumour activity” in adult patients.

“Regorafenib might have an important therapeutic role as an agent complementary to standard cytotoxic chemotherapy in the therapeutic armamentarium against osteosarcoma”, write Florence Duffaud, from Hôpital La Timone in Marseille, and co-authors.

Median PFS was 16.4 weeks for the 26 patients who were randomly assigned to receive regorafenib 160 mg/day for 21 of 28 days versus 4.1 weeks for the 12 placebo-treated patients.

Overall, 65% of the regorafenib group were free from progression at week 8 versus none of the controls, and this difference was maintained over time, the researchers say, with 12- and 24-week PFS rates in the regorafenib-treated patients of 62% and 35%, respectively.

Two patients in the control arm died before crossover to regorafenib therapy but the remaining 10 patients began regorafenib after disease progression. Their median PFS was 19.4 weeks, which the investigators believe “further serves as confirmation of the clinical activity of regorafenib.”

Median overall survival (OS) in the regorafenib arm was 11.3 months versus 5.9 months for the controls.

Acknowledging that the cross-over trial design “compromises the ability to assess the clinical effect–if any–on overall survival”, the researchers observe that the confidence intervals of the OS curves are “large and overlap each other”, but the duration is similar to the OS findings for earlier multikinase inhibitor studies in metastatic osteosarcoma.

“While still regrettably short-lived, we believe that these overall survival durations are both clinically meaningful for patients and might potentially add to any other benefits derived from other conventional agents available to treat osteosarcoma in this relapsed and refractory setting”, they write.

Safety analysis shows that treatment-related serious adverse events occurred in around a quarter of the 29 patients given regorafenib versus none of the 14 placebo-treated patients. During the double-blind phase, grade 3 or more severe treatment-related side effects in the regorafenib and control groups included hypertension (24 vs 0%), hand–foot skin reactions (10 vs 0%), fatigue (10 vs 3%), hypophosphataemia (10 vs 0%) and chest pain (10 vs 0%).

Writing in a linked comment, Dominique Heymann, from the Université de Nantes in France, says the findings “highlight the potential therapeutic value of regorafenib in cases of recurrent and unresectable osteosarcoma for which there are currently very few therapeutic options and a pressing medical need.”

The commentator recommends deeper investigation to determine the precise actions of single and multitargeted receptor tyrosine kinase (RTK) inhibitors in patients with metastatic osteosarcoma.

“Pertinent screening of patients with recurrent unresectable osteosarcoma on the basis of their RTK profiling could help to prevent the development of drug resistance, and thus define the therapeutic alternatives”, Dominique Heymann suggests. 

“By increasing the homogeneity of the population studied, this type of screening will also improve the chances of success of large phase 3 clinical trials which, as recommended by the authors, should be set up at the European and international levels.”



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; Advance online publication 23 November 2018. S1470-2045(18)30742-3

Heymann D. Metastatic osteosarcoma challenged by regorafenib.   Lancet Oncol; Advance online publication 23 November 2018.

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