The recent American Society of Clinical Oncology meeting featured a striking report from Memorial Sloan Kettering Cancer Center in New York in patients with rectal cancer. They identified a small subset of rectal cancer patients with a deficiency in DNA repair known as mismatch repair (MMR). MMR deficiency prevents cells from fixing the DNA wear and tear that occurs in our everyday life. This turns these patients into ideal candidates for immune therapy, the subject of this report.
With a 100% response rate in 12 of 12 patients, the PR value was off the charts but what did theses investigators really show?
The story began some years earlier when investigators at Johns Hopkins found that a tiny subset of colon cancer patients respond to immune therapy while the vast majority do not. The question being: “What distinguished the colon cancer patients who responded to immune therapy from those who did not?” Dung Le working with Bert Vogelstein solved the mystery showing that all the responders had MMR deficiency (Le, VT. NEJM, 2015).
It turns out that MMR deficiency leads to the massive expression of abnormal proteins on the surface of the cancer cells. These “neo-antigens” are “target-rich” and brilliantly sensitive to immune stimulation.
In the original Hopkins study fully 40% of heavily pre-treated patients responded.
The results were striking in that 12 of 12 patients had responses measured by magnetic resonance PET scan and endoscopic evaluation with some durable to 25 months without significant toxicity.
Putting the Sloan Kettering study in context, the100% response rate in 12 carefully selected, previously untreated patients receiving the immune stimulant, Dostarlimab (like pembrolizumab, nivolumab) is very encouraging but perhaps not entirely unexpected.
What can we learn from this observation? First, carefully selected patients can have brilliant responses to appropriate therapies.
In the past, all clinical therapies were administered to all comers and it was actually considered inappropriate to “cherry pick” your candidates. With the growing recognition that cancer patients are different, these investigators have thrown off the false premise that all cancers are created equal and begun to pre-select their candidates. This is a breakthrough and represents a new era of cancer medicine predicated on individual patient needs.
A second observation, however, is that the results, though extremely interesting, may not be very different from the original observations reported by Le, in 2015. After all patients in the original study had two or more prior chemotherapies, including radiation, all of which can down-regulate immune function. If 40% of heavily treated patients responded to these therapies, it is not that much of a leap to expect a higher percentage to respond to first line immune therapy and we will await the full data as it matures.
Most importantly the study shows that patients should receive the right treatment the first time and not wait for subsequent relapses to initiate appropriate interventions.
We pioneered the concept that each patient receives the right treatment the first time, every time. Immune therapies selected based on mismatch repair are an excellent example of the right treatment from the start.
Is it possible that other classes of therapies can be better utilized when we select candidates?
We believe that individual patient selection is to the advantage of all, from the patients who do better to the physicians to the insurers and finally the health care institutions who will see better outcomes, less side effects and more durable responses.
We applaud the investigators at Memorial Sloan Kettering for their excellent work and will await further follow up on these patients as they accrue more patients.
One final point is that this study was conducted in a small subset of rectal cancer patients who were very carefully selected and cannot be generalized to all rectal cancer or even other colon cancer patients, much less patients with other types of cancer.