Cancer drug with accelerated approval fails Phase III trial

A Phase III trial of Lartruvo (olaratumab), which won accelerated approval for soft tissue sarcoma in 2016, has failed to meet the primary endpoints of overall survival (OS).

Lartruvo – a platelet-derived growth factor receptor alpha (PDGFR-α)-blocking antibody that specifically binds PDGFR-α and prevents receptor activation – in combination with doxorubicin previously showed a significant OS benefit in soft tissue sarcoma in a 133-patient, randomised Phase II trial; with a median OS of 26.5 months for the two-drug combination, compared with 14.7 months for doxorubicin alone.

These findings led to accelerated approval by the US Food and Drug Administration and conditional marketing authorisation by the European Medicines Agency for Eli Lilly and Company’s Lartruvo.

However, the Phase III trial – the ANNOUNCE study – did not confirm the clinical benefit of Lartruvo in combination with doxorubicin compared to doxorubicin alone, a standard of care treatment.

“Lilly was surprised and disappointed that Lartruvo did not improve survival for patients with advanced soft tissue sarcoma in this study,” said Anne White, president of Lilly Oncology. “Lilly is committed to helping people who have soft tissue sarcoma and we will carefully study the detailed data in an effort to better understand the different results between the two trials.”

The ANNOUNCE trial is a randomised, double-blind, Phase III study of Lartruvo in combination with doxorubicin, followed by Lartruvo monotherapy, versus doxorubicin plus placebo followed by placebo, in patients with advanced or metastatic soft tissue sarcoma.

The two primary endpoints are OS in the Intention-to-Treat (ITT) population and in the LMS sub-population. Patients with locally advanced, unresectable or metastatic soft tissue sarcoma not amenable to curative treatment were enrolled and were eligible with any prior number of treatment regimens, provided they had not previously received treatment with an anthracycline.

Lartruvo was administered at a loading dose of 20 mg/kg on days 1 and 8 of cycle 1 and 15 mg/kg on days 1 and 8 of all subsequent cycles, in combination with doxorubicin 75 mg/m² administered on day 1 of each cycle. Placebo was administered in combination with doxorubicin for 8 cycles. Lartruvo was continued as monotherapy until disease progression.

Key secondary endpoints were safety, progression-free survival, objective response rate, and patient-reported outcomes.

In a press statement, Lilly said they are working with global regulators to determine the appropriate next steps for the drug and promotion is being suspended.