MAESTRO Trial Shows Evofosfamide Provides Little Benefit in STS

MAESTRO Trial Shows Evofosfamide Provides Little Benefit in STS

Laura Hansen, PhD

The results from MAESTRO, a phase III trial examining evofosfamide in advanced pancreas cancer patients, show the treatment offers little-to-no advantage to both patients with pancreatic cancer and soft tissue sarcoma (STS) were presented at an oral session at the ASCO Gastrointestinal Cancers Symposium.

The results were announced at an oral session1 during the 2016 ASCO Gastrointestinal Cancer Symposium, held in San Francisco in late January.

In an announcement made by Threshold Pharmaceuticals, Inc, the developer of the drug, evofosfamide failed two phase III clinical trials, one studying its possible efficacy in pancreatic cancer and one in advanced STS. Both trials were conducted in collaboration with Merck KGaA.

Evofosfamide is thought to preferentially release anticancer agents in oxygen-scarce regions of the tumor.

In the pancreatic cancer trial, the experimental drug narrowly failed to show a statistically significant advantage over gemcitabine in its primary endpoint of overall survival (OS) (8.7 vs 7.6 months, P = .0589).

A phase II trial of published in 2015 found that while progression-free survival (PFS) was increased in those who received evofosfamide (5.6 vs 3.6 months, P =.005), there was no statistically significant advantage in OS.2

Sponsors for the study believed the phase III trial could show an advantage despite the results from the phase II study, due to problems with the design of the phase II study.

“Patients on the control arm could crossover to get evofosfamide once they had progressed. This confounded the survival results in the phase II (ie, the control arm performed better with the patients who subsequently got evofosfamide). There was no crossover in the Phase III,” explained Laura Hansen, PhD, senior director of corporate communications, Threshold, in an interview with Targeted Oncology.

Results from the STS trial (TH-CR-406/SARC021) have not yet been released, though survival among patients in the evofosfamide arm was decreased compared with those in the control arm (HR: 1.06), according to a statement by Threshold.3 The decrease is said not to be statistically significant.

No Statistically Significant Differences

In the MAESTRO study, 693 patients with unresectable locally advanced or metastatic pancreatic cancer were randomized to gemcitabine plus either 340 mg/m2 of evofosfamide or placebo. Patients in the study had no prior chemotherapy or systemic therapy, according to the abstract. Treatment continued until disease progression.

One-year survival was improved in the experimental arm (34.2% vs 29.8%), according to the slide. However, there were no differences in OS in any subgroup of patients, other than Asian patients, according to the ASCO press release. Among the 65 Japanese and Korean patients in the experimental arm, median OS was 12 months, compared with 8.5 months in 58 Asian patients in the control arm.

While data from the sarcoma trial have not been released, 640 patients were randomized to doxorubicin or doxorubicin plus evofosfamide (300 mg/m2). The patients had either prior surgery or radiation, but not chemotherapy, and the trial did not use a placebo, according to Mark Agulnik, MD, associate professor of medicine, Northwestern University Feinberg School of Medicine in Chicago, principal investigator on MAESTRO.

While patients who received evofosfamide did worse, there was no statistically significant difference, or disadvantage, in one arm or the other, he added. Agulnik discredited the theory that study design could have played a result in the outcome.

“The results are the results. It’s very difficult to imagine that a non-blinded study would have disadvantaged the evofosfamide arm. The fact that it was not blinded would be a criticism of the trial, but it would not have affected OS in this situation,” he said.

Evofosfamide continues to be investigated for conditions like non—small cell lung cancer. However, while Threshold will not be pursing further development of the drug in soft tissue sarcoma and pancreatic cancer, KGaA Merck is recruiting patients for a Japanese trial of the drug in soft tissue sarcoma, according to clinicaltrials.gov

Trials Challenged by Rapidly-Evolving Standards of Care

“From large phase III clinical trials in soft tissue sarcoma over the last several years, OS does look higher than previously reported,” said Agulnik. “Patients typically survive for 16 to 18 months, which is better than what we traditionally saw in prior trials, where it was closer to the 12- to 15-month mark.”

Agulnik added that much of the credit for increased survival goes to treatments recently approved by the FDA, such as pazopanib and trabectedin, the latter of which was approved in October 2015.

Investigators in the MAESTRO study attributed the negative results in both the pancreatic cancer and STS trials in part to unexpectedly strong results in the control arms. 

“If you go back to the statistical assumptions, [OS] was on track in the combination arm. However, the [patients in the] placebo arm performed better than the initial assumptions,’” which predicted a median OS duration of 6.5 months in the control group,” said Eric Van Cutsem, MD, PhD, professor of internal medicine, University of Leuven in Belgium, and coordinating investigator for MAESTRO, in an ASCO press release.4

Van Cutsem also said more patients in the control arm than in the treatment arm received second-line therapy after progression (23.1% vs 16.4%), according to the press release.

References

1. Eric Van Cutsem E, Lenz H, Furuse J, et al. Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: Primary analysis of the randomized, double-blind phase III MAESTRO study.J Clin Oncol. 34, 2016 (suppl 4S; abstr 193)
2. Borad, M, Reddy S, Bahary N, et al. Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer.J Clin Oncol. Published Ahead of Print on December 15, 2014 as 10.1200/JCO.2014.55.7504 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.55.7504 DOI: 10.1200/JCO.2014.55.7504
3. Threshold press release. Threshold pharmaceuticals announces its two phase 3 studies evaluating evofosfamide did not meet primary endpoints. Dec. 7, 2015. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=945765 Accessed Jan. 26, 2016.
4. ASCO Press Release. MAESTRO trial of evofosfamide/gemcitabine in PDAC fails to improve OS,” January 23, 2016. http://gicasym.org/maestro-trial-evofosfamidegemcitabine-pdac-fails-improve-os Accessed Jan. 26, 2016.