Unprecedented, But Puzzling, Results in Advanced Sarcoma

Nick Mulcahy

June 14, 2016

An investigational targeted therapy extends the life of patients with unresectable and metastatic soft tissue sarcoma by nearly a year, according to phase 2 clinical trial results published online June 9 in the Lancet.

"Seeing these results is remarkable because we have never seen anything like that in our disease. It is encouraging and hopeful," said lead author William Tap, MD, from the Memorial Sloan Kettering Cancer Center in New York City, in an interview with Medscape Medical News.

Dr Tap pointed out that the results need confirmation from a larger study, the phase 3 ANNOUNCE trial, which is currently underway.

A lot more needs to be learned about how exactly olaratumab (Eli Lilly), a selective platelet-derived growth factor (PDGF)-alpha inhibitor, works in these cancers, he said. The antibody drug binds to and blocks the PDGF-alpha receptor on the surface of select cancer cells, and possibly in the tumor microenvironment.

"We don't truly understand the mechanism of action," said Dr Tap. He and his team wanted to determine whether specific patient populations that fall under the umbrella of soft tissue sarcoma are "driving the results," and how that might be explained mechanistically.

In their phase 2 randomized trial of 133 patients, median overall survival was longer with the combination of olaratumab plus doxorubicin than with doxorubicin monotherapy (26.5 vs 14.7 months; hazard ratio [HR], 0.46; P = .0003).

Soft tissue sarcoma comprises a rare and diverse group of solid tumors for which doxorubicin, either alone or in combination, is a first-line standard of care for advanced disease, and has been for 40 years.

No other drug, either in combination with doxorubicin or used alone, has been found to improve survival better than doxorubicin monotherapy, the researchers note.

Median progression-free survival — the primary end point — was 6.6 months with the doxorubicin combination and 4.1 months with doxorubicin monotherapy (HR, 0.67; P = .0615). The difference met the predefined primary end point.

However, the difference in progression-free survival was just 2.5 months, whereas the difference in overall survival was 11.8 months.

This outcome "is as much promising as puzzling," Winette van der Graaf, MD, from the sarcoma unit of the Royal Marsden NHS Foundation Trust in London, United Kingdom, writes in an accompanying comment.

In this trial of "all-comers" with soft tissue sarcoma, the overall survival benefit "is so much longer than expected based on the gain in progression-free survival," Dr van der Graaf told Medscape Medical News in an email.

She agrees with Dr Tap that the findings "need confirmation in a larger study." But she also has some concerns.

Specifically, Dr van der Graaf notes that it "is not easy to interpret" the exact effect of various poststudy treatments, including local treatments, that were allowed upon disease progression in both groups.

Furthermore, she says that differences in "the pace of progression before start of treatment might have affected the results because no specific time period in which progression [to advanced disease] should have occurred before patients entered the study was defined and only the group with shorter history of disease showed a significant increase in overall survival."

Dr van der Graaf agrees with the researchers that an indepth understanding of PDGF receptors "is still relatively scarce in sarcomas." She also suspects that finding a predictive biomarker will be "complex" and probably not "universal" across all soft tissue sarcomas.

But she could be rooting for olaratumab because of the "desperate need of patients with soft tissue sarcomas for new active drugs."

Another type of sarcoma, gastrointestinal stromal tumor, has seen great improvement in survival from treatment with multitargeted tyrosine kinase inhibitors (that target KIT or PDGF-receptor mutated tumors).

Novel systemic treatments in soft tissue sarcomas are challenging because there are more than 70 different histologic subtypes.

Subtypes of soft tissue sarcoma differ in overall survival (measured from the start of the first systemic treatment for advanced disease), from 9.3 months in undifferentiated pleomorphic sarcoma to 24.4 months in leiomyosarcomas, Dr van der Graaf reports.

Another drug, pazopanib (Votrient, Novartis), a multitargeted tyrosine kinase inhibitor, is also directed at PDGFR-alpha (as well as PDGFR-beta and vascular endothelial growth-factor receptors 1, 2, 3, and other targets).

Pazopanib was approved by the US Food and Drug Administration (FDA) for metastatic soft tissue sarcomas in 2012 on the basis of trial data showing that the agent was associated with a significant 3-month advantage in median progression-free survival over placebo, and a nonsignificant gain in median overall survival of 1.8 months.

The approval of pazopanib was the first in decades for soft tissue sarcomas.

In January, eribulin (Halaven, Eisai) was approved by the FDA for use in the treatment of unresectable or metastatic liposarcomas, after being the first drug to show an improvement in overall survival in this disease. The indication is in patients who have received previous chemotherapy that contained an anthracycline drug.

In 2015, the chemotherapy trabectedin (Yondelis, Janssen) was approved for the treatment of two types of soft tissue sarcoma — unresectable or metastatic liposarcoma and leiomyosarcoma — in patients who had previously received an anthracycline-based chemotherapy regimen. That approval was granted on the basis of a significant improvement in progression-free survival, but not overall survival.

Study Details and Toxicity

In the phase 2 trial, the combination and monotherapy groups were well balanced in terms of histologic types, including leiomyosarcoma (36% vs 40%), undifferentiated pleomorphic sarcoma (15% vs 21%), and liposarcoma (12% vs 22%).

All patients received doxorubicin alone 75 mg/m² on day 1 of each 21-day cycle for up to eight cycles. In addition, 66 patients were randomly assigned to receive olaratumab 15 mg/kg intravenously on days 1 and 8. The other 67 patients served as the control group.

The cumulative dose of doxorubicin is above the threshold generally deemed to be safe, Dr van der Graaf observes, so the cardioprotective drug dexrazoxane was added to the treatment regimens.

But Dr Tap explained that sarcoma clinicians in the United States are accustomed to working with the higher dosage.

"There are a lot of people in our community who really feel comfortable pushing the dose of [doxorubicin] with close cardiac monitoring," he said.

Normally, the drug is administered in six cycles (at 75 mg/m²), but he and his team used it for eight cycles, Dr Tap acknowledged.

This is an "important caveat" about the study and the findings, he explained.

Overall, there was more toxicity in the combination group.

Adverse events that were more frequent in the combination group than in the monotherapy group, including neutropenia (58% vs 35%), mucositis (53% vs 35%), nausea (73% vs 52%), vomiting (45% vs 18%), and diarrhea (34% vs 23%).

Febrile neutropenia of grade 3 or higher was similar in the combination and monotherapy groups (13% vs 14%).

Dr Tap and his team highlight the fact that the overall survival benefit was achieved "without an increase in serious toxicity, despite a higher cumulative exposure to doxorubicin."

This study was funded by Eli Lilly. Dr Tap reports financial relationships with Eli Lilly and other pharmaceutical companies. Dr van der Graaf reports financial relationships with Lilly, Novartis, and GlaxoSmithKline (makers of pazopanib). A number of the study authors report relationships with industry or are employees of Eli Lilly, as detailed in the publication.

Lancet. Published online June 9, 2016. Abstract, Comment

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