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  1. Resources for Information | Approved Drugs

FDA D.I.S.C.O.: First Tissue/Site Agnostic Approval Transcript


The D.I.S.C.O. hosts discuss the agency’s first approval of a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.


Sanjeeve Bala: Welcome back to the D.I.S.C.O. Today’s Drug Information Soundcast in Clinical Oncology from FDA’s Oncology Center of Excellence covers the accelerated approval of pembrolizumab, marketed as Keytruda, for the treatment of patients with any solid tumors that have progressed following prior treatment, based on the presence of specific molecular abnormalities. I’m Sanjeeve Bala, a medical oncologist and acting clinical team leader at FDA.

Abhi Nair: Hi, I’m Abhi Nair, an oncologist and medical officer here at the FDA. We’re excited to bring you information on an interesting new approval for patients with cancer.

SB: Yeah, Abhi, this approval has a number of interesting features that should have a meaningful impact in the clinic and select patients.

AN: So this is a supplemental approval for pembrolizumab, and most oncologists must be familiar with its existing indications for the treatment of a variety of malignant diseases, so let’s focus on the patient population for this new indication. Tell us about the indication before we dive into the molecular details.

SB: Abhi, this is the first approval in what we’re calling a “tissue agnostic” setting. That is, the indicated population is chosen by prior treatment history and a set of molecular markers instead of the conventional approach of using the histological tissue of origin. So this new indication is a long one, and it includes the names of the specific molecular defects thought to confer increased susceptibility to immuno-oncology approaches.

AN: I know it’s a long indication. What exactly are these molecular defects?

SB: In general, mismatch repair deficiency results in microsatellite instability, both of which can lead to an increased rate of new DNA mutations and therefore tumor-associated antigens. Pembrolizumab helps to dampen one of the tumor’s immune evasion signals, PD-1, and more tumor antigens may make the elicited immune response even stronger. Both MSI-High and deficient mismatch repair are frequently seen in colorectal cancers, but may also be found in a variety of other tumor types.

AN: I think we are ready to hear that new indication.

SB: OK, here goes: pembrolizumab is indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high or mismatch repair deficient solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options, or with microsatellite instability-high or mismatch repair deficient colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

AN: Sanjeeve, that sure is a mouthful.

SB: Yeah, I hear that a lot.

AN: And this is another accelerated approval, as noted in the label, which is based on a surrogate endpoint and requires confirmation. Can you tell us a little bit about the application?

SB: Sure, Abhi. The approval is based on data from 149 patients with microsatellite instability-high or mismatch repair deficient cancers who enrolled on one of five single-arm trials. Ninety patients had colorectal cancer, and 59 patients had one of 14 other cancer types.

AN: Now let’s talk about those endpoints that resulted in this unique approval.

SB: The objective response rate for all patients was 39.6%. Response rates were similar across all cancer types, including 36% in colorectal cancer and 46% across the other tumor types. Notably, there were 11 complete responses, with the remainder partial responses.

AN: Like the other immunotherapy approvals, duration of response was another important characteristic of the benefit with this trial.

SB: That’s right, Abhi. Responses lasted for at least six months in 78% of responders.

AN: And patients were prospectively identified with either biomarker?

SB: Most patients had MSI or MMR status determined prospectively by local testing. In other words, these were standard tests available in the community, and not FDA-approved companion diagnostics at this point, though these are in development.

AN: That’s great. So clinicians can keep an eye out for these patients if they’re refractory to other standard therapies.

SB: Exactly. Clinical awareness is important to identify those patients that may benefit from this immuno-oncology approach, since many of these tumor types did not previously have immunotherapy approvals. But importantly, patients should have experienced disease progression following prior treatments with standard therapies.

AN: Tell us about the types of patients that benefited here.

SB: In addition to colorectal cancer, there were multiple patients with responses with endometrial, biliary, gastric, pancreatic, and small intestinal sites of origin. The product label has a list of all of the tumor types identified with MSI-High or deficient mismatch repair, and the response rates for each type.

AN: Any unusual toxicities of this immunotherapy to watch out for?

SB: These toxicities are common to the PD-1 inhibitors. These include fatigue, pruritus, diarrhea, decreased appetite, rash, fever, cough, dyspnea, musculoskeletal pain, constipation, and nausea. They are also known to cause immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. The product label contains more detailed safety information, but basically, no new major safety signals were identified in these patients or with the approved dosing strategy.

AN: So to conclude, Sanjeeve, can you summarize the three take-home points from this D.I.S.C.O.?

SB: Abhi, clinicians should keep an eye out for patients with microsatellite instability-high and mismatch repair deficient tumors. These patients should have disease progression following standard therapies known to confer clinical benefit for their disease. The recommended dose is a flat dose of 200 mg intravenously every three weeks for adults. Detailed information can be found in the package insert at the FDA website.

SB: For a transcript with links to an in-depth look at the FDA analysis, and the multidisciplinary team of FDA experts who conducted the review, go to the FDA Oncology Center of Excellence website at www.fda.gov/OCE.

AN: Thank you Sanjeeve. Are there other FDA oncology drug approvals that you would like to hear about? Please leave us your questions and comments on Twitter @FDAOncologydisclaimer icon. We welcome your feedback. I’m Abhi Nair, and thank you for listening.

SB: And until next time at the D.I.S.C.O., I’m Sanjeeve Bala.

Acknowledgements and Additional Information:

For further information, see the FDA news release on this approval and the FDA notification to health care professionals.

This Drug Information Soundcast in Clinical Oncology was developed by Sanjeeve Bala, Abhilasha Nair, Steven Lemery, Leigh Marcus, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.

The FDA approval letter for this product approval is available on Drugs@FDA.

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