FDA Approves Olaratumab for Soft Tissue Sarcoma

The FDA has granted an accelerated approval olaratumab in combination with doxorubicin for the treatment of patients with advanced soft tissue sarcoma who are not good candidates for radiotherapy or surgery.

Richard Pazdur, MD

The FDA has granted an accelerated approval to the PDGFRα antagonist olaratumab (Lartruvo) in combination with doxorubicin for the treatment of patients with advanced soft tissue sarcoma (STS) who are not candidates for radiotherapy or surgery, based on an improvement in overall survival (OS) in the phase II JGDG study.

In the pivotal trial, the combination of olaratumab with doxorubicin reduced the risk of death by 48% compared with doxorubicin alone for patients with advanced STS (HR, 0.52; 95% CI, 0.34-0.79, P <.05). Median OS in the intent-to-treat population (n = 129) was improved by 11.8 months with the olaratumab combination versus doxorubicin alone. The median OS was 26.5 months with the combination versus 14.7 months with doxorubicin alone.

"For these patients, Lartruvo, added to doxorubicin, provides a new treatment option," Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and acting director of the FDA’s Oncology Center of Excellence, said in a statement. "This is the first new therapy approved by the FDA for the initial treatment of soft tissue sarcoma since doxorubicin’s approval more than 40 years ago."

In the open-label phase II JGDG study, 133 patients with advanced STS were randomized to olaratumab plus doxorubicin (n = 66) or doxorubicin alone (n = 67). Of those enrolled, 129 received at least 1 dose of treatment (64, olaratumab combination; 65, doxorubicin). Patient characteristics were well balanced between the arms and all patients had not received prior treatment with an anthracycline before entering the study.

The median age of patients in the combination arm was 58.5 years, and most had an ECOG performance status of 0 to 1 (94%). Eighty-eight percent of patients were positive for PDGFRα. Thirty-six percent and 40% of patients had leiomyosarcoma, in the combination and monotherapy arms, respectively. Other common histologies in the olaratumab and control arms, respectively, included undifferentiated pleomorphic sarcoma (15% vs 21%, respectively) and liposarcoma (12% vs 22%).

By blinded independent review, median progression-free survival (PFS) was 8.2 versus 4.4 months for the olaratumab combo and doxorubicin alone, respectively (HR, 0.67; 95% CI, 040-1.12; P = .1208). By investigator assessment, median PFS was 6.6 months with olaratumab plus doxorubicin compared with 4.1 months with doxorubicin alone (HR, 0.67; 95% CI, 0.44-1.02; P = .0615).

By independent assessment, the objective response rate was 18.2% in the combination arm versus 7.5% in the doxorubicin arm. The complete response (CR) rate to the olaratumab combination was 4.5% and the partial response rate was 13.6%. The CR rate was 1.5% in the doxorubicin arm.

In the olaratumab arm, patients received a median of 7 infusions of doxorubicin (range, 1-8), 16.5 infusions of olaratumab (range, 1-83), and 5 infusions of olaratumab monotherapy post-combination (range, 1-68). In the doxorubicin arm, patients received a median of 4 infusions (range, 1-8) with 30 patients going on to receive olaratumab post-progression for a median of 4 infusions (range, 1-60). Following the study, 67% of those in the olaratumab group received subsequent therapy compared with 49% of those in the doxorubicin alone arm.

The most commonly reported all-grade adverse events (AEs) in the olaratumab group versus chemotherapy, respectively, were nausea (73% vs 52%), fatigue (69% vs 69%), musculoskeletal pain (64% vs 25%), mucositis (53% vs 35%), vomiting (45% vs 19%), diarrhea (34% vs 23%), and headache (20% vs 9%). The most common all-grade hematologic AEs were lymphopenia (77% vs 73%), neutropenia (65% vs 63%), thrombocytopenia (63% vs 44%), and hyperglycemia (52% vs 28%). Febrile neutropenia was experienced by 13% of patients treated with olaratumab versus 12% of those in the doxorubicin alone group.

"Lartruvo represents an important step forward in soft tissue sarcoma treatment," principal investigator of the JGDG trial William D. Tap, MD, chief of the sarcoma medical oncology services at Memorial Sloan Kettering Cancer Center, said in a statement. "We are pleased with this approval, which will provide patients with a treatment option that offers new hope in their battle against this difficult disease."

Based on the positive phase II data, the olaratumab/doxorubicin combination is being compared with doxorubicin alone in the ongoing phase III ANNOUNCE trial (NCT02451943). Results from this study will act as confirmatory data for the accelerated indication. Prior to the approval, the FDA had granted olaratumab a breakthrough therapy designation.

Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488-497.