First Cancer Drug for Genetic Defect, Not Tumor Type

Zosia Chustecka  

May 24, 2017

The latest approval of a cancer drug by the US Food and Drug Administration (FDA) changes the paradigm of cancer treatment — the new indication specifies a genetic defect without any mention of tumor types. It allows the drug to be used in any cancer that harbors the specified genetic defect, wherever the tumor appears in the body.

This is an important first for the cancer community. Dr Richard Pazdur


"This is an important first for the cancer community," said 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.

"Until now, the FDA has approved cancer treatments based on where in the body the cancer started — for example, lung or breast cancers. We have now approved a drug based on a tumor's biomarker without regard to the tumor's original location."

The new approval is for the immunotherapy pembrolizumab (Keytruda, Merck & Co), which is already approved for use in several different tumor types, including melanoma and lung cancer.

But this latest approval covers the use of pembrolizumab in tumors that have microsatellite instability-high (MSI-H) or are mismatch repair deficient (dMMR).

These defects are found most commonly in colorectal, endometrial, and gastrointestinal cancers but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland, and other places, the agency notes.

Approximately 5% of patients with metastatic colorectal cancer have MSI-H or dMMR tumors, it adds.

All patients with advanced cancer who have had at least one standard therapy should be tested. Dr Dung Le

"All patients with advanced cancer who have had at least one standard therapy should be tested to see if their tumor harbors these genetic defects," Dung Le, MD, an oncologist at the Johns Hopkins Bloomberg-Kimmel Institute, Baltimore, Maryland, told Medscape Medical News. "And if the patient is found to have this defect, the next step is to try pembrolizumab."

Pembrolizumab is the drug that has the approval, but Dr Le says that she would also expect similar responses with other immunotherapies with the same mode of action, programmed cell death-1 inhibition. 

"This is a paradigm shift — now we are not looking at where the tumor started, what organ it is in, but we are looking across all tumor types — and we are bringing a treatment to patients with all types of tumors, many of whom were thought not to respond to immunotherapy," Dr Le commented

Tests for defects in mismatch repair are already widely available, costing around $300 to $600. "These tests are available everywhere, because they are already in use for identifying Lynch syndrome," Dr Le commented.  

The genetic defects, MSI-H and dMMR, interfere with the usual process of DNA repair inside cells, which results in unchecked cellular growth, a hallmark of cancer. It also results in a lot of mutations, and these tumors often have T cells infiltrating them, which make them a good target for immunotherapy, Dr Le explained in an interview.

Dr Le was the principal investigator on the first trial to show that tumors with MSI respond to immunotherapy with pembrolizumab (the Keynote 16 trial, an investigator initiated study for which Merck just provided the drug).

The results from that trial showed that patients with colorectal cancer with normal DNA repair (microsatellite stable) had zero response to pembrolizumab, whereas those with MSI and deficient DNA repair had a 50% response rate, she said. In addition, about 20% had stable disease.

This is much higher than has been seen with immunotherapy in other tumor types, where fewer than 20% patients respond, she added.

But the trial also included patients with any solid tumor and MSI, and these patients also showed the 50% response rate and 20% stable disease results.

"So it's not just colorectal cancer," Dr Le told Medscape Medical News. "We think these defects are found in about 4% of all advanced cancers," she said.

We think these defects are found in about 4% of all advanced cancers. Dr Dung Le


These defects seem to occur in all solid tumors, and the finding that all tumors with this defect respond in a similar way is new, Dr Le emphasized. It is also unique, as this has not been found with other genetic mutations and defects.

For example, BRAF-mutated melanoma responds very well to treatment with a BRAF inhibitor, as does thyroid cancer, but BRAF-mutated colorectal cancer does not have any response. It seems that different molecular circuitry is involved, with different bypass mechanisms, she added, and seems to be "hit or miss."

This is the first pan-tumor marker, and the fact that the FDA approved the drug for use in children as well as adults shows "how strong the biology is," she commented.

Accelerated Approval

The new indication for pembrolizumab is for use of the drug in adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having MSI-H and dMMR. This indication covers patients with solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as patients with colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This indication received priority review and an accelerated approval, based on  tumor response rates and durability of response; confirmatory trials are in progress, which will provide data on survival and clinical benefits.

The data used for approval come from five uncontrolled single-arm studies conducted in patients with MSI-H or dMMR solid tumors, the agency notes. In some of these trials, patients were required to have MSI-H or dMMR cancers, whereas in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began.

A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial, and other gastrointestinal cancers.

Pooled results from these trials show that of the 149 patients who received pembrolizumab, 39.6% had a complete or partial response; for 78% of those patients, the response lasted for 6 months or more.

The FDA notes that common side effects of pembrolizumab include fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. The drugs can also cause serious immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dose of pembrolizumab in adults is 200 mg (in children the dose is 2 mg/kg, up to a maximum of 200 mg), and the drug is administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

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