Dr. Luis Diaz: Marrying Cancer Genomics with Immunotherapy

“It worked better than our wildest dreams,” Dr. Diaz said of a therapeutic approach that uses a tumor biomarker to identify patients likely to respond to immunotherapy.

A cancer diagnosis comes with a multitude of stressors, but patients with rare cancer types face an additional burden: a paucity of effective treatments. This means that if the treatments available to them fail, these patients may be left with few options.

This was the case for Adrienne Skinner, who in 2013 was diagnosed with ampullary cancer, a rare intestinal malignancy that accounts for less than 1 percent of the cancers diagnosed each year in the United States. After her cancer stopped responding to chemotherapy, Adrienne knew that her options were limited. She could try a different chemotherapy regimen, but it had little chance of success. And finding a clinical trial for a rare cancer like hers was tough.

Fortunately for Adrienne, researchers at the time were recruiting patients for a new type of trial that wasn’t specific to any one cancer type. Instead, they were testing a therapy in patients whose cancers had a particular genetic feature, a biomarker, that was found in Adrienne’s ampullary cancer.

“It was really quite a different kind of trial,” Adrienne recalled. “It was addressing the problem on a genetic basis.” 

The trial was led by AACR member and leader Luis A. Diaz, Jr., MD, FAACR, a physician-scientist at Memorial Sloan Kettering Cancer Center and formerly of Johns Hopkins University (JHU).

Dr. Diaz and colleagues, who began this research at JHU, were testing an immune checkpoint inhibitor called pembrolizumab, which is a type of immunotherapy that works by targeting the immune-suppressing protein PD-1 on the surface of immune cells. By binding this protein, pembrolizumab effectively releases the immune system’s “brakes,” allowing it to mount an attack against a patient’s cancer. 

The trial found that pembrolizumab worked extraordinarily well for patients like Adrienne whose cancers had a certain genetic signature associated with defects in DNA repair. 

These results led the U.S. Food and Drug Administration (FDA) to issue its first ever tumor-agnostic drug approval, making pembrolizumab available for patients with any cancer type—even rare ones that seldom receive new drug approvals—as long as their cancers contained this genetic signature.

The landmark approval was the culmination of years of research from Dr. Diaz and others. We’ll review some of the seminal findings that led to this historic moment.

A lone responder to anti-PD-1 immunotherapy

On September 4, 2014, pembrolizumab received its first approval for certain patients with advanced melanoma. It was the second immune checkpoint inhibitor to be approved by the FDA and the first to target PD-1. The approval was based on the results of a clinical trial in which 24 percent of patients with advanced melanoma responded to the treatment.

Additional clinical trials demonstrated that anti-PD-1 immune checkpoint inhibitors benefited patients with other cancer types as well, with responses observed in a significant portion of patients with lung, renal, and prostate cancers. 

However, out of the 33 patients with colorectal cancer who received an immune checkpoint inhibitor across two clinical trials, only one experienced a clinical response.

This led researchers, including Dr. Diaz, to ask—What was different about this patient?

Mismatch repair deficiency presents a vulnerability

Dr. Diaz hypothesized that this patient’s tumor may have had microsatellite instability, a genetic signature associated with defects in a process known as mismatch repair. This defect prevents cancer cells from properly repairing DNA, leading to the accumulation of mutations that can stimulate the immune response. Genetic testing of the patient’s colorectal tumor revealed that it did, indeed, have high levels of microsatellite instability, a trait termed microsatellite instability-high, or MSI-H.

Shortly after, researchers from JHU reported that colorectal tumors with microsatellite instability due to defects in mismatch repair had high levels of immune cells and immune-stimulating proteins in the surrounding microenvironment, consistent with prior reports. Importantly, they found that these tumors also had dramatic upregulation in the expression of immune-suppressing proteins, which prevented the surrounding immune cells from mounting an effective antitumor response. 

Based on these findings, which were published in January 2015 in the AACR journal Cancer Discovery, researchers proposed that the subset of colorectal tumors with deficient mismatch repair might be susceptible to immune checkpoint inhibition. Blocking the immune-suppressing activity of PD-1, they reasoned, could allow immune cells to clear the tumors.

Targeting mismatch repair-deficient colorectal cancers

This hypothesis was tested in a clinical trial led by Dr. Diaz that evaluated pembrolizumab in patients with either mismatch repair-deficient or mismatch repair-proficient colorectal cancer. In trial results published in the May 2015 issue of The New England Journal of Medicine, Dr. Diaz and colleagues reported that patients whose colorectal cancers were deficient in mismatch repair were more likely to respond to treatment and less likely to have disease progression or death. 

Interestingly, the benefits of pembrolizumab for patients with mismatch repair-deficient tumors were not restricted to colorectal cancer: Seven patients with other mismatch repair-deficient cancer types also had superior responses to pembrolizumab in this trial. 

Could mismatch repair deficiency make any tumor, regardless of cancer type, susceptible to immune checkpoint inhibition?

A tumor-agnostic approach shows promise

To answer this question, Dr. Diaz and colleagues tested pembrolizumab in a larger group of patients with mismatch repair-deficient cancers that had progressed after prior therapy. Adrienne was one of the 86 patients enrolled in the trial after her ampullary cancer stopped responding to chemotherapy.

Dr. Diaz and colleagues reported in Science that over three-quarters of the trial’s patient population, which encompassed 12 different cancer types, had some level of disease control in response to pembrolizumab. Eighteen patients, including Adrienne, experienced complete remission.

A routine biopsy revealed that her tumor was gone. 

“I go in for this biopsy, and when I come to, the surgeon comes over to me and says, ‘If somebody hadn’t told me you have ampullary cancer, I wouldn’t have known because there’s nothing in there’,” she recalled.

“We were taking patients who were in hospice and pulling them out,” Dr. Diaz emphasized. “They had this genetic signature, and their tumor melted away within one or two weeks [of treatment].

“It worked better than our wildest dreams.”

Similarly impressive results were observed among patients with mismatch repair-deficient tumors enrolled in other clinical trials.

Based on the groundbreaking results seen in five clinical trials, including Dr. Diaz’s, the FDA approved pembrolizumab for the treatment of advanced, progressive cancer that has mismatch repair deficiency and/or contains the MSI-H genetic signature—regardless of where in the body it originated. 

The historic approval, rendered on May 23, 2017, was the agency’s first to be tumor-agnostic. Since then, three additional cancer therapies, larotrectinib, entrectinib, and dostarlimab, have received tumor-agnostic approvals. 

What’s next?

While the tumor-agnostic approval of pembrolizumab revolutionized cancer treatment, there are lingering questions and opportunities for improvement. 

One path Dr. Diaz is interested in is using immune checkpoint inhibitors to treat patients with earlier stages of disease—before the cancer has spread to other organs. To that end, Dr. Diaz recently evaluated an immune checkpoint inhibitor in patients with locally advanced MSI-H rectal cancer. Amazingly, all 12 patients in the trial had complete responses to the therapy, according to results published in The New England Journal of Medicine in June 2022.

Another opportunity Dr. Diaz is exploring is inducing microsatellite instability in tumors with intact mismatch repair. As presented at the AACR Annual Meeting 2022, and detailed in a recent post on the AACR’s Cancer Research Catalyst blog, Dr. Diaz and colleagues found that treating patients with a combination of DNA-damaging agents caused microsatellite instability in mismatch repair-proficient tumors, making the tumors susceptible to immune checkpoint inhibition. 

The power of collaboration

Reflecting on the seminal findings that led to pembrolizumab’s tumor-agnostic indication, Dr. Diaz remarked on the importance of passion and teamwork in driving progress. 

“I’ve had the good fortune of being part of unbelievably great teams, and I’m very proud of what we’ve accomplished,” he said, noting that the “infectiousness of passion” within these teams allowed a simple idea to develop into a new treatment paradigm that is impacting patients’ lives.

“I don’t think there’ll be one cure to cancer,” he added. “It’s going to take multiple passionate efforts by scientists all around the world coming together and finding solutions to problems that we haven’t been able to solve yet.”