FDA is eyeing the powerful class of immune-checkpoint inhibitors as the focus for a real-world, clinical practice study.

At the June 16 FOCR/Alexandria Summit meeting on real-world evidence, Office of Hematology and Oncology Products Director Richard Pazdur said the agency has suggested that PD-1 inhibitor product sponsors make the drugs available to patients who have refractory cancers with tumors that have high rates of microsatellite instability (MSI-high) and no standard therapy.

Microsatellite instability is a marker of tumor mutation burden. There have been impressive response rates reported with the checkpoint inhibitors in MSI-high patients with colon cancer and other tumor types, Pazdur said.

In return for giving the drug to MSI-high patients, product sponsors could require that practitioners report back any data on toxicities not included in labeling and provide X-rays for those patients who respond to treatment, Pazdur said. If the results from such a pragmatic clinical trial were positive, "we would then consider basically a site-agnostic indication" for MSI-high tumors, he said.

Such a study was proposed as a pilot project in the FOCR/Alexandria Summit meeting brief, which notes that studies evaluating the link between MSI-high and immune-checkpoint blockade are ongoing.

Determining whether this type of pilot is feasible would require a retrospective analysis of existing databases to address outstanding questions, such as testing and treatment patterns in cancers with evidence of mutational burden, the brief states. "Once all the necessary components are identified, building a prospective trial would depend on scoping (i.e., cancer type, study size, etc.), optimizing the biomarker and test use, and ultimately defining mechanisms to measure efficacy."

Merck & Co. Inc., which markets the PD-1 inhibitor Keytruda (pembrolizumab), is one of the companies in discussions with FDA about a study in patients with MSI-high tumors. Eric Rubin, VP and therapeutic area head for oncology early development, said after the meeting that Merck is interested in the proposed study because it ultimately would benefit patients but is still discussing the concept.

The other PD-1 inhibitor on the market is Bristol-Myers Squibb Co.'s Opdivo (nivolumab). The company said it is collaborating with FDA on innovative ways to expedite immuno-oncology drug development in a variety of tumor types and would disclose details at the appropriate time.

Genentech Inc. markets the PD-L1 inhibitor Tecentriq (atezolizumab). Genentech said it is aware that FDA has discussed the study proposal with sponsors of PD-1/PDL-1 inhibitors, but the company has not had any formal discussions with the agency on this topic.

A Question Of Fairness

The PD-1 study idea was raised during a panel discussion on endpoints (see related story, Also see "Clinical Trial Endpoints May Not Fit Real-World Studies" - Pink Sheet, 27 June, 2016.).

Rubin questioned the fairness of companies coming to FDA with retrospective data analyses after earlier product sponsors have done much of the clinical data collection legwork.

"If you're a company and you're doing a prospective, classical, randomized clinical trial, you invest in that effort and then another company comes along and says we're just going to do real-world retrospective data analysis, how would you view that," Rubin asked Pazdur. "In a sense it doesn't seem quite fair. I guess there is a potential for that type of scenario."

"There is a potential," Pazdur responded, adding, "Life is unfair."

"If we could actually leverage that clinical trial data [and show] that for this class of drugs it definitely does work … if other companies wanted to come in with a supplemental indication on that basis that would be fine," Pazdur said.

FDA officials noted generally that for real-world evidence to support a labeling expansion, drugs would have to have large effects to overcome the "noise" from more loosely structured studies (see related story, Also see "Real-World Evidence May Find A Home On Breakthrough Pathway" - Pink Sheet, 27 June, 2016.).

FDA, PD-1 Inhibitor Sponsors Discussing Real-World Study

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