FDA’s First Site-Agnostic Drug Approval Marks a Paradigm Shift in Regulatory Criteria

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Richard Pazdur, MD

Richard Pazdur, MD

IN MAY, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda) for patients with solid tumors that have the microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) biomarker, which disrupts the ability of cells to repair DNA. The approval is the first for a cancer drug based on a tumor’s specific genetic features rather than its location in the body. 

Previously approved in the treatment of advanced-stage melanoma, non–small cell lung cancer, head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma, pembrolizumab—which blocks the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway—is now FDA-approved for patients with any solid tumor that has progressed following prior treatment and who have no appropriate alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer that has advanced following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. 

The FDA granted accelerated approval for this new indication of pembrolizumab based on results from five uncontrolled, single-arm clinical trials. In some of these trials, patients were required to have MSI-H– or dMMR-based cancers, and in other trials, a subgroup of patients were identified as having MSI-H cancers by testing tumor samples after treatment began. 

A total of 15 cancer types were identified among the 149 patients enrolled across the 5 clinical trials. The most common cancers were colorectal, endometrial, and other gastrointestinal cancers. According to Richard Pazdur, MD, Acting Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and Director of the FDA’s Oncology Center of Excellence (OCE), the review of pembrolizumab for this indication was based on overall response rate and durability of response. Of the 149 patients who received pembrolizumab in these studies, 39.6% had a complete or partial response. For 78% of those patients, the response lasted 6 months or longer. 

The ASCO Post talked with Dr. Pazdur about the significance of the first FDA approval of a “site-agnostic” therapy, the likelihood of more such therapies being approved, and how the newly launched Oncology Center of Excellence is expediting evaluation of new drugs, biologics, and medical devices in the treatment of cancer. 

New Way to Define and Treat Cancer 

How significant a change in the FDA drug evaluation process is the approval of pembrolizumab as the first tumor-agnostic agent in the treatment of solid tumors? 

This new indication represents a shift in our evaluation of therapies. The approval moves us away from the strict disease-site indication, such as breast, colon, or lung cancer, to a site-agnostic indication. It changes how we may define cancer—the disease is no longer being solely determined by its site of origin or pathologic diagnosis. It is now defined by the presence of a specific biomarker. 

When we heard about patients with refractory colon cancer, cholangiocarcinomas, endometrial carcinomas, esophageal carcinomas, and small bowel cancers and observed clinically meaningful responses to pembrolizumab with substantial durations, we worked proactively with the drug sponsor to develop this new indication. These patients had either largely ineffective treatment options or no options available. 

I put myself in the position of a potential patient. If I had one of these cancers and had exhausted all therapies, I would want my tumor tested for this biomarker. And if it was positive, I certainly would want this drug because, while not all patients responded to this therapy, those who did experienced obvious benefit. 

Tumor Location and Response to Treatment 

Doesn’t tumor location still influence its response to treatment? 

We examined the response rate from the patients with refractory colon cancer compared to those with other disease sites enrolled in these studies, and the response rates were similar. Small numbers of patients were enrolled in these clinical trials, and there are overlapping confidence intervals surrounding the point estimates of the response rates. I cannot make the statement that we would have seen a differential response based on tumor location. 

Approving Drugs Based on Tumor Biomarker 

Are more biomarker-based drugs on their way to FDA approval? 

We are open to working with drug sponsors on site-agnostic indications based on a strong scientific rationale and robust clinical results. We also consider whether other effective therapies are available. Patients entered on the pembrolizumab clinical trials had few or no satisfactory available options. 


dMMR = mismatch repair–deficient; MSI-H = microsatellite instability–high.
  • KEYNOTE-016 (NCT01876511 on
  • KEYNOTE-164 (NCT02460198)
  • KEYNOTE-012 (NCT01848834)
  • KEYNOTE-028 (NCT02054806)
  • KEYNOTE-158 (NCT02628067)

If a situation exists where there is effective therapy available, a randomized trial may be necessary to determine the benefit of the new drug against the existing therapy. That was not the situation for this approval. The new indication clearly states that pembrolizumab was given accelerated approval for patients with solid tumors that had progressed following prior treatment and for whom there were no satisfactory alternative treatment options. 

Unlike other accelerated drug approvals, we did not ask for a randomized study to be performed as a postmarketing requirement. This request would not have been feasible due to the small number of patients as well as the lack of a reasonable standard treatment. Alternatively, we requested that more data be collected in different cancer types with the MSI-H biomarker. 

Pembrolizumab had already been approved in the advanced setting for the treatment of several cancers. We had an understanding of the drug’s safety profile and knew that it was clearly an active drug in multiple disease settings, where some randomized trials demonstrated survival advantages. 

Changing How Cancer Is Treated 

Some drugs targeting tumor-driving gene defects do not work universally. How will approval for site-agnostic drugs change the way cancer is treated? 

There is not a one-stop solution for every clinical situation. For a drug directed toward a specific biomarker, the level of activity and benefit may depend on the disease site. For example, although BRAF and MEK inhibitors have shown activity in BRAF-mutated melanoma and lung cancer, we did not see activity with these inhibitors as single agents in BRAF-mutated colorectal cancer. The story of site-agnostic indications is still unfolding, and, therefore, we can’t make a dogmatic statement that this first site-agnostic approval is going to be the pathway for all biomarker-identified populations. 

“This new indication represents a shift in our evaluation of therapies. The approval moves us away from the strict disease-site indication …to a site-agnostic indication.”
— Richard Pazdur, MD

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We have to consider the scientific rationale supporting the claim and the expected results in terms of response rate and duration. We then put this information into the context of existing therapies for the given patient population. 

Expediting Cancer Drug Approval 

The Oncology Center of Excellence (OCE) was launched earlier this year. How is the Center changing the way cancer drugs and medical products are approved? 

The OCE leverages the combined skills of the scientists and reviewers at the FDA with expertise in drugs, biologics, and medical devices under one regulatory umbrella. It facilitates an active exchange among the various centers and offices across the agency, including the Center for Drug Evaluation and Research, the Center for Biologics Evaluation Research, and the Center for Devices and Radiological Health. 

We have launched several scientific programs, are engaged in collaborative reviews of drugs and devices among the centers, and have many more meetings to interact with the centers to discuss products. This provides us with an integrated approach in the clinical evaluation of oncology therapies. 

The ultimate goal of the OCE is to expedite the development of oncology and hematology therapies and medical devices, to provide patients with cancer more and better treatment options. 

DISCLOSURE: Dr. Pazdur is Acting Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and Director of the FDA’s Oncology Center of Excellence. ■