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CHICAGO -- A year-long overall survival (OS) improvement with olaratumab (Lartruvo) in an early-phase soft-tissue sarcoma trial disappeared when the drug was tested in a larger phase III trial.

Among more than 500 doxorubicin-treated patients in ANNOUNCE, those randomized to olaratumab had a median OS of 20.4 months compared with 19.7 months for those on placebo (HR 1.05, 95% CI 0.84-1.30, P=0.69), reported William D. Tap, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"The control arm had the highest overall survival rate for doxorubicin in any phase III soft-tissue sarcoma clinical trial," Tap noted during the plenary session presentation at the American Society of Clinical Oncology (ASCO) annual meeting.

Median OS in the large leiomyosarcoma subgroup was not significantly different either (21.6 vs 21.9 months, respectively).

Prior data from a phase Ib/II open-label trial had shown an "unprecedented" 11.8-month improvement with olaratumab over placebo for advanced soft-tissue sarcoma patients (HR 0.46, 95% CI 0.30-0.71, P=0.0003), and a 16.1-month improvement in the leiomyosarcoma group, Tap said.

"These data were highly debated and scrutinized," he noted, but said that extensive subset analyses did not reveal any bias or meaningful imbalances that could have explained the results.

Based on this data, olaratumab from the FDA in 2016, which was contingent upon a confirmatory phase III trial (ANNOUNCE), and went on to receive accelerated, conditional, or full approval from regulatory agencies in more than 40 countries.

But in January 2019, Eli Lilly alerted regulatory agencies that the phase III trial failed to meet its primary endpoint -- they've since commenced plans to .

Olaratumab is a fully monoclonal antibody of immunoglobulin G class 1 that selectively binds to PDGFR-alpha. The drug demonstrated synergy with doxorubicin in sarcoma models, though its exact mechanism of action in the various types of soft-tissue sarcoma is unclear.

"Curiously, the survival in both studies seemed to be better in absence of the drug's target," noted ASCO invited discussant Jaap Verweij, MD, PhD, of Erasmus University in Rotterdam, the Netherlands. "If a drug seems to work in absence of its target, I would question the results and aim to find an explanation before embarking on a large trial."

In ANNOUNCE, exploratory analyses of PDGFR-alpha in the olaratumab group revealed an OS of 17.1 months in those with tumors expressing the target compared with 23.6 months for those whose tumors did not.

Verweij noted that toxicity in the combination arm was similar to single-agent doxorubicin, so patients exposed to olaratumab were not subjected to physical harm. Any grade adverse events in the trial were similar between the investigational and placebo groups for all-grade toxicity, grade 3/4 events, serious adverse events, treatment-emergent deaths, and treatment discontinuation.

[The] "flip side of the coin, however, for the accelerated approval is the financial burden to society," he said. "With sales on olaratumab in the third-quarter of 2018 reported to be $221 million, the total financial burden to society in the 2 years after conditional approval must have largely exceeded $1 billion, which at least in my humble opinion, seems to be a lot of expense for a drug without proven efficacy."

Lilly clarified that total worldwide sales for Lartruvo were $562 million through the first quarter of 2019.

Being a "little bit provocative," Verweij suggested that perhaps researchers should shift their focus away from adding drugs onto doxorubicin.

"We sadly have to conclude that, after decades, doxorubicin remains the standard of care for the lump group of soft tissue sarcomas," he concluded.

In an email statement, Anne White, president of Lilly Oncology, said the company pursued bringing olaratumab to market knowing the sarcoma community had seen no progress in more than four decades. "While only a portion of indications under the FDA's Accelerated Approval program fail to verify clinical benefit, it shows that the checks and balances of the clinical trial process works," she said.

Tap acknowledged that it's possible olaratumab has no activity in soft-tissue sarcomas, and that the phase Ib/II results were perhaps due to sample size, numerous histologies with disparate clinical behaviors, subsequent therapy, or even chance. It's also possible, he said, that the agent is active, and that outcomes were affected by the heterogeneity of the study population, trial design, and performance of the control arm.

From 2015 to 2016, the phase III, double-blind trial randomized 509 locally advanced or metastatic soft-tissue sarcoma patients to treatment with doxorubicin plus either olaratumab (n=258) or placebo (n=251).

The study was powered to evaluate OS in all patients as well as in the leiomyosarcoma subgroup (46.0%, with 18.5% uterine), and would be considered positive if either or both endpoints were met. Liposarcoma was the second-most common histology (17.9%), followed by pleomorphic sarcoma (12.6%). Patients with 26 other histologies comprised the remaining 23.6%.

Median patient age was 57, and roughly half had high-grade histology. The vast majority (82.9%) had metastatic disease and three-fourths had received no prior systemic therapy. Patients on olaratumab received fewer median doxorubicin infusions than the placebo group (6 vs 7), resulting in lower exposure to the cytotoxic agent (409 mg/m² vs 483 mg/m², respectively).

Progression-free survival was significantly worse with olaratumab in the total population. No significant differences were seen between overall response rates in either study group, but in the leiomyosarcoma subpopulation the rate of stable disease was significantly worse with olaratumab.

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