Complete response in 12 Out of 12 Patients with Rectal Carcinoma using Immunotherapy

On June 5, published by Cercek et al. in The New England Journal of Medicine, a small trial of 12 patients with stage 2-3 rectal cancer was treated with the PD-1 inhibitor, dostarlimab.   Amazingly, they reported that 12 out of 12 had a complete response. Clearly very exciting and goes with my feeling that most cancer patients need to be allowed to be treated with Immunotherapy, especially if other treatments have failed. There is one special consideration in the study; the patients had what is known as a mismatch repair deficient tumor. What is mismatch repair? It is the ability to fix incorrectly inserted bases of DNA that occur during the copying of the DNA. If this process does not function correctly, more DNA errors will accumulate. The more errors, the more different the cancer DNA will be from normal cells. This gives the immune system more targets, making cancer more receptive to Immunotherapy. Unfortunately, like many other cancers, mismatch deficiency is in the minority of colorectal cancer, 15% or less. Certainly, it is essential to identify patients with mismatch deficiency and consider Immunotherapy. That is undoubtedly a common practice in evaluating the biopsy of a tumor. There are also other aspects beyond mismatch repair, such as tumor mutational burden and other mutations associated with DNA repair. Also, in some cases, certain medications can be used to block DNA repair, potentially increasing the potential to respond to Immunotherapy.

There are a few questions that arise from this trial. One question is whether dostarlimab is superior to Opdivo or Keytruda, even though all are in the same class of drugs as PD-1 inhibitors. The results seemed similar in prior trials where dostarlimab and Keytruda were used. We may see more head-to-head trials to answer this question in the future. The next question is what can be done to make the majority of patients who don’t have mismatch deficiency respond as well. Though there are many complex aspects of the immune response, one key one is to increase the immune cell infiltration into cancer. One technique is injecting immune agents into the tumor that calls the immune cells to the tumor. This now alerts the immune cells to cancer and can increase the ability to respond to other Immunotherapy. This is a way to equalize the playing field for patients who don’t have mismatch repair to be more like those who do.

Certainly, this study further demonstrates to the public what we in the scientific community already knew, that it is possible to have incredible responses with Immunotherapy. And we know the playbook and can expand this out to the majority of other cancers. That is precisely what we are doing with our patients, bringing the treatments of the future to them today.

By Dr. Jason Williams