The FDA Oncologic Drugs Advisory Committee’s March 20 review of two investigational sarcoma treatments played out like a tale of two efficacy stories.

It was the best of times for GlaxoSmithKline PLC’s Votrient (pazopanib), with ODAC voting 11-2 that the tyrosine kinase inhibitor had a favorable risk/benefit profile in patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Pazopanib demonstrated a statistically significant 65% improvement in progression-free survival, with a median benefit of three months, in its pivotal trial. Although many panel members deemed this benefit to be marginal, the majority nevertheless found it to be clinically significant.

Ridaforolimus had the disadvantage of following pazopanib at ODAC’s review of the two drugs for sarcoma indications.

For Merck & Co. Inc. and Ariad Pharmaceuticals Inc.’s Taltorvic (ridaforolimus), the ODAC meeting proved to be the worst of times. The committee voted 13-1 that the drug did not have a favorable risk/benefit profile in patients with metastatic STS or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy.

Ridaforolimus had the disadvantage of following pazopanib at ODAC’s review of the sarcoma drugs. The mTOR inhibitor could not overcome a slimmer median PFS benefit measured only in weeks. Furthermore, its toxicity profile, particularly when viewed in the context of a maintenance setting, led committee members to worry they would be doing more harm than good by giving it to patients with stable disease.

Pazopanib’s PFS Benefit “Marginal” But Enough

Sarcomas are a heterogeneous group of solid tumors; although they arise from a common mesenchymal precursor, each subtype has distinctive clinical and pathological features. Patients are treated with sequential chemotherapies, although only doxorubicin is FDA approved in STS. Use of currently available therapies is based on limited data.

Even in patients with responsive disease, chemotherapy is usually discontinued after a predefined number of cycles due to toxicities. There are no drugs approved for use in the STS maintenance setting.

Pazopanib was approved for renal cell carcinoma in 2009. Complicating GSK’s bid for a supplemental indication in sarcoma, however, was the pivotal trial’s failure to demonstrate a significant advantage in overall survival Also see "Merck, GSK Sarcoma Drugs Bring Different Efficacy Stories To FDA Panel Review" - Pink Sheet, 16 March, 2012..

ODAC members struggled to understand the clinical significance of a median three-month PFS advantage, particularly given the absence of a survival benefit or evidence of symptom improvement.

However, ODAC’s sarcoma experts said they believed a three-month benefit was clinically meaningful for STS patients, who have limited treatment options and poor prognoses.

“This is a drug I would like to have in my armamentarium,” temporary voting member Lee Helman, National Cancer Institute, said. Although he would have preferred to have seen a stronger efficacy signal, Helman nevertheless urged the committee to view pazopanib in context with other currently used treatments, which have high toxicities and generally lack efficacy data from randomized, controlled trials.

“It’s a little step, but it’s a little step in a field that’s had nothing,” Helman said. “My worry is if this is not good enough, at this point it will be 20 years before another randomized study in sarcoma is done.”

“I think that the benefit, though marginal, is real,” temporary voting member Ephraim Casper, Memorial Sloan-Kettering Cancer Center, said. When viewed in the context of current second-line and later therapies, “it sounds like it’s a good thing.”

Committee Chairman Wyndham Wilson, NCI, said he was struck that some patients appeared to experience a highly durable effect, as evidenced by the 14% of patients in the pazopanib arm who were still on therapy after one year, compared with 1% in the placebo arm. “That seems to me to be a very meaningful number,” he said.

A Pathway To Accelerated Approval?

Despite the majority’s positive endorsement, committee members nevertheless said they would like to see more studies to examine pazopanib’s efficacy in early disease as well as symptom improvement. Safety issues in the Phase III STS trial, such as myocardial dysfunction and pneumothorax, also warranted further investigation.

Although GSK is seeking full approval in STS, FDA Office of Hematology and Oncology Products Director Richard Pazdur suggested the agency could instead grant accelerated approval and require a confirmatory study in an earlier disease setting and have that trial look at symptom benefit using a patient-reported outcomes instrument.

Some committee members found Pazdur’s suggestion appealing.

“We’ll accept interim markers for accelerated approval in patients who have a rare disease where it seems it wouldn’t be feasible to get an overall survival benefit. So this fits the marker, except for the fact that it’s full approval and not accelerated approval,” committee member Mikkael Sekeres, Cleveland Clinic, said. “I’d be much more comfortable with this if it were accelerated approval, where we had some guarantee from the sponsor that there would be a follow-up study that would adequately measure patient-reported outcomes or have enough patients to measure overall survival.”

Ridaforolimus’ Maintenance Setting Proves Problematic

In contrast to pazopanib, the accelerated approval option was never discussed during the ridaforolimus review.

In the pivotal trial, ridaforolimus was associated with a statistically significant 26% improvement in PFS, although this translated into a median benefit of only two weeks, according to FDA’s analysis. As with pazopanib, there was no overall survival benefit.

Merck’s primary analysis showed a 28% PFS improvement and a median benefit of three weeks. However, the company argued that medians underestimate PFS benefit. The sponsor presented alternative analyses, deemed exploratory by FDA, suggesting the benefit was closer to six weeks.

Even these more upbeat analyses were insufficient to sway committee members, who deemed the benefit too slim given the drug’s toxicities, which include pneumonitis, renal failure, infections and hyperglycemia. Committee members also cited concerns that patients would be taken off chemotherapy, which could be more beneficial, and put onto ridaforolimus.

NCI’s Wilson said the PFS benefit, no matter which way the data were cut, amounted to relatively modest numbers.

Committee member Ralph Freedman, M.D. Anderson Cancer Center, was bothered by the number of patients that had to stop study drug due to adverse events. “It doesn’t fit with the concept of a maintenance treatment,” he said.

[Editor’s note: The original version of this story reported that almost 50% of patients on ridaforolimus permanently discontinued study drug due to adverse events. This figure was based on FDA’s presentation at the meeting, which listed the figure as 48%. The agency later confirmed to “The Pink Sheet” that 48 was the total number of patients who discontinued drug; the percentage was 14%.]

Committee member Deborah Armstrong, Johns Hopkins University, said the evidentiary threshold should be higher in the maintenance setting. “I don’t think we saw the same kind of robust improvement in progression-free survival, and I frankly think that the negative outcomes, the toxicities, the going off trial … because of adverse events really zeroed out …the potential for benefit.”

Tale Of Two Sarcoma Drugs: ODAC Gives Nod To GSK’s Votrient, Thumbs Down On Merck/Ariad’s Taltorvic

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