Olaratumab for STS Disappoints in Phase III

Two years after receiving accelerated approval from the FDA as a first-line therapy with doxorubicin for patients with advanced or inoperable soft-tissue sarcoma (STS), olaratumab's (Lartruvo; Eli Lilly) potential has not held up in the phase III ANNOUNCE trial. At least for now, the company has no plans to continue promoting the anti-PDGFRα antibody.

“The sarcoma community is reeling from this outcome,” says Gary Schwartz, MD, chief of hematology and oncology at NewYork-Presbyterian/Columbia University Irving Medical Center, who participated in the trial. “We'd had great confidence that this combination was here to stay and ANNOUNCE's findings would merely confirm what we'd already seen with the phase II trial.”

In that study, for which Schwartz was an author, 133 patients were randomly assigned to receive olaratumab plus doxorubicin, or doxorubicin alone (Lancet 2016;388:488–97). The difference in median overall survival (OS) between the arms was sizeable: 26.5 months versus 14.7 months. Olaratumab showed particularly impressive activity in patients with leiomyosarcoma, a common form of STS originating in smooth muscle;responses were also seen across all other subtypes evaluated. This prompted the FDA to grant accelerated approval to olaratumab in December 2016—a much-cheered decision, given that doxorubicin had been the mainstay for the last 40 years.

“The data were so positive, it's hard to fathom why olaratumab did not meet expectations in phase III,” Schwartz says. Eli Lilly will present the full data from ANNOUNCE at an upcoming medical conference; for now, the key disclosure is that no significant differences in median OS were observed between study arms—for either the entire trial population or the leiomyosarcoma cohort.

One possible reason for this lack of survival benefit is that “the control arm really overperformed,” Schwartz notes. The median OS for patients given only doxorubicin was “considerably longer than historical data have shown, which was surprising. I can't explain what might account for it.” As well, there was no crossover from the control arm to the combination arm if the disease progressed, so “you have to wonder what, if any, subsequent therapies these patients received may have boosted their survival,” he adds. Trabectedin (Yondelis; Janssen) and eribulin (Halaven; Eisai) are possibilities.

“Alternatively, it may be that our supportive-care measures are just that much better over the past 3 years, and this was sufficient to improve survival with doxorubicin alone,” he suggests.

To Schwartz, a retrospective analysis attempting to tease out the reasons for olaratumab's disappointing performance is warranted. That said, although a phase II trial evaluating olaratumab combined with gemcitabine and docetaxel for advanced STS is ongoing, he thinks Eli Lilly may elect to abandon further development of the drug. “At least when combined with doxorubicin, it'll die by itself, whether or not the FDA withdraws approval—which should happen, given how the accelerated program is meant to work.”

Global collaborations to explore expanding olaratumab's use beyond advanced or inoperable disease—for instance, as adjuvant therapy for patients with localized STS at high risk of developing metastases—will probably also be reconsidered, Schwartz adds. At Columbia, he and his colleagues were gearing up to evaluate an immunotherapy regimen for STS—a CD40 agonist, with olaratumab–doxorubicin as the backbone—but they'll now revise their study protocol.

ANNOUNCE's results are all the more frustrating because of the complexity of STS, which comprises more than 60 known subtypes, each histologically and biologically different. However, “it is what it is,” Schwartz says, “and we'll just have to go back to the drawing board because there's a desperate need for new therapies.” –Alissa Poh

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