
Luis Diaz, Jr., Head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering.
Two years ago at the annual meeting of the American Society of Clinical Oncology, researchers from Johns Hopkins wowed an audience with results from a recent immunotherapy clinical trial. People with a type of colorectal cancer that bore a genetic abnormality called mismatch repair (MMR) deficiency fared surprisingly well when treated with the immunotherapy drug pembrolizumab (Keytruda®). In fact, 62% of them responded to the treatment.
The result was remarkable because colorectal cancer patients typically do not benefit from this type of immunotherapy, called an immune checkpoint inhibitor. None of the other colorectal cancer patients in the study responded at all.
Experts celebrated the findings as bolstering an emerging concept in the field of immuno-oncology, that the more DNA mutations a cancer cell has, the higher the likelihood it will be recognized by the immune system as foreign and killed.
MMR-deficient cells have lots of mutations — 1,700 on average compared with just 70 in a typical cancer cell. That’s because the mismatch repair pathway is a major way that cells fix DNA base-pair mistakes that occur during DNA replication, which cells must do each time they divide.
The Hopkins-led trial eventually enrolled people with a dozen different cancer types that all shared this genetic defect. Together, the results showed that the potential for an excellent response to immunotherapy was not unique to MMR-deficient colorectal cancer. It held true for all of the MMR-deficient cancers, regardless of their tissue origin.
These striking results served as the basis for the Food and Drug Administration’s approval of pembrolizumab for advanced MMR-deficient cancers last month. This was a landmark event in oncology. It represents the first time that a drug has been approved on the basis of a specific genetic profile rather than where the cancer originated.
“It’s a shift in how we develop anti-cancer therapeutics,” says Luis Diaz, Jr., a medical oncologist at Memorial Sloan Kettering. Dr. Diaz was the principal investigator on this trial when he was a professor of medicine at Johns Hopkins. He recently moved from Hopkins to Memorial Sloan Kettering to assume a new role here as Head of the Division of Solid Tumor Oncology.
“It’s not only a pan-tumor approval for adult tumors, it also includes pediatric tumors. So it’s agnostic to both age and tumor type,” he says.
Science Behind the Study
In a new paper published in Science, Dr. Diaz and his colleagues report in detail on the results of the clinical trial. Among the 86 people in the trial, there were 12 different types of cancer. More than half of the participants (46 patients) had an objective response to pembrolizumab, a PD-1-blocking drug. That means their disease became smaller. Of these 46, 21% (18 patients) had a complete response, meaning the cancer vanished. The disease control rate, or the percentage of people whose disease either remained stable or improved, was 77% (66 patients). Responses were often durable.
These are impressive results for a cancer clinical trial, and even more impressive for an immunotherapy trial. Typically, a smaller fraction of people responds to a single-drug immunotherapy.
In fact, the number of people who had a complete response is probably higher than reported. This is because what looks like cancer on an imaging scan might actually be the battle scars left after the immune system has done its work.
“We biopsied patients at 20 weeks who appeared to have residual disease on their scans. What we found was that the majority of these ‘tumors’ were just scar tissue,” Dr. Diaz explains.
In addition to reporting on the trial’s results, Dr. Diaz and colleagues delve into the underlying cause of immune responses to MMR-deficient cancers. For three patients who had a good response to pembrolizumab, the team analyzed the genetic attributes of both the tumor tissue (which had been removed prior to treatment and archived) and the immune cells circulating in the blood. They found that T cells specific for particular neoantigens — the fragments of altered proteins produced from mutated DNA — were present in the tumor before treatment, and these cells rapidly and dramatically increased in the blood following treatment.
As the authors note, these results support the hypothesis that the large number of neoantigens present in MMR-deficient tumors makes them responsive to immune checkpoint blockade therapy. This approach is often likened to releasing the brakes on immune cells, allowing them to attack cancer. Side effects of these drugs can include autoimmune reactions, caused when the immune system attacks normal tissues in the body.
Back to topA Telling Observation
Dr. Diaz notes that the inspiration for the MMR study goes back to a clinical trial that his Hopkins colleagues Suzanne Topalian and Drew Pardoll conducted. The results of that study were published in 2012. In the trial, a single colorectal cancer patient had a dramatic response to the PD-1-blocking drug nivolumab (Opdivo®). The patient was subsequently found to have Lynch syndrome, an inherited form of mismatch repair deficiency. Dr. Diaz surmised that the high mutational burden in this patient made the cancer more recognizable to his immune system.
“So then it was off to the races,” Dr. Diaz says. “I knew we had to conduct a trial.”
They did, and based on the trial’s early results, the FDA granted the approach a Breakthrough Therapy designation in October 2015. Final approval of pembrolizumab for MMR-deficient tumors came in May 2017.
Dr. Diaz notes that the trial never would have happened without the groundbreaking work of many researchers, including several at MSK, who established the promise of immunotherapy as a cancer treatment. “Jedd Wolchok and his colleagues really helped define that immune checkpoint inhibitors could be a potent class of anticancer drugs,” Dr. Diaz says. “We wouldn’t be here today without his work.”
Around the same time that Dr. Diaz and his group were conducting their study, Dr. Wolchok and MSK researchers Timothy Chan and Alexandra Snyder Charen showed that mutational burden was an important variable influencing immunotherapy responses in lung cancer and melanoma.
And in 2008, it was work by immunologist James Allison (then at MSK) and MSK physician-scientist Neil Segal, in collaboration with cancer biologist Bert Vogelstein at Hopkins, that established mutant proteins could create neoantigens recognizable by the immune system.
Back to topA Big Impact
Dr. Diaz notes that about 60,000 people a year will be eligible for this immunotherapy on the basis on their mutation profile. He estimates that about 4% of all cancers are likely to be MMR deficient.
Witnessing the dramatic effect of immunotherapy on people with MMR-deficient tumors who had otherwise run out of options has made him optimistic about the power of this approach to make a profound difference in people’s lives. He notes that a couple of the patients were in hospice when they enrolled in the study and are still alive today.
“I feel lucky to be a part of this breakthrough,” he says.
Back to topComments
Robert Cawley
Jun 23, 2017 • 3:00 PM
Memorial Sloan Kettering
Jun 26, 2017 • 12:36 PM
In reply to WILL THIS WORK IN A CANCER… by Robert Cawley
Dear Robert, if your genomic analysis shows that your tumor has a mismatch repair deficiency then this may be an appropriate treatment for you. We recommend that you discuss it with your oncologist. If you’d like to have an consultation with an expert at MSK, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.
Donald J. Redwine
Aug 1, 2017 • 12:20 PM
Memorial Sloan Kettering
Aug 1, 2017 • 12:28 PM
In reply to Would keytruda work on… by Donald J. Redwine
Karen Sandvick
Sep 16, 2017 • 1:31 PM
Memorial Sloan Kettering
Sep 17, 2017 • 10:27 PM
In reply to My 30 year old nephew has… by karen sandvick
Frank Finkelstein
Oct 10, 2017 • 11:57 AM
Memorial Sloan Kettering
Oct 10, 2017 • 12:18 PM
In reply to Would this be an option for… by Frank Finkelstein
Dear Frank, we recommend that you discuss this with your doctor. If you would like to arrange for a consultation at MSK, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.
Carl Winget
Oct 14, 2017 • 7:02 AM
Memorial Sloan Kettering
Oct 16, 2017 • 10:41 AM
In reply to I have signet ring cancer,… by Carl Winget
Dear Carl, we’re sorry to hear about your diagnosis. If you would like to speak to an MSK expert to find out what treatments may be available, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.
Kurt Schilling
Jan 29, 2018 • 6:30 AM
A friend from the UK has been diagnosed with a fairly advanced (multiple sites) neuroendocrine cancer. T A colon biopsy has shown poorly differentiated neuroendocrine cancer that is fast proliferating (K67 index exceeds 75%) and high grade and her docs think is a MANEC type. Do you think she should get the analysis done to determine if it has mismatch repair deficiency and therefore a candidate for PD-1 based therapy?
Memorial Sloan Kettering
Jan 30, 2018 • 8:00 AM
In reply to A friend from the UK has… by Kurt Schilling
Dear Kurt, we’re sorry to hear about your friend’s diagnosis. We recommend that she discuss this with her medical team. If she would like to arrange for a medical records review with MSK doctors, she can go to https://www.mskcc.org/experience/become-patient/international-patients/… for more information. Thank you for your comment, and best wishes to you and your friend.
Carl Winget
Feb 8, 2018 • 3:31 PM
Memorial Sloan Kettering
Feb 8, 2018 • 5:29 PM
In reply to I sent a comment on Oct 14… by Carl Winget
Dear Carl, we’re sorry to hear about your misdiagnosis. We do not have any trials specifically for signet ring cell carcinoma, but depending on the mutations in your tumor, you may qualify for immunotherapy or targeted therapy. If you would like to make an appointment to learn more, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment, and best wishes to you.
WILL THIS WORK IN A CANCER CALLED THYMOMA THAT HAS SPREAD TO MY LUNGS. tHE ORIGINAL TUMOR THAT WAS 85% RESECTED HAS SHOWN NO SIGNS OF LIFE BUT THERE ARE SEVERAL NODULES THAT HAVE STARTED TO GROW IN MY LUNGS. ALSO MY GYNOME REPORT SHOWED A HIGH MUTATION RATE