The results of a recent study published in the New England Journal of Medicine, PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer, aroused astonishment worldwide. The reason is that a complete response to therapy was achieved in all patients treated with the PD-1 blocker dostarlimab in the trial. Also, within the follow-up period (between 6 and 25 months, magnetic resonance imaging (MRI) and endoscopic examinations could not detect any recurrence or progression. [1]
Study Objective and Methods
The study aims to evaluate the overall response to therapy with the PD-1 inhibitor dostarlimab alone or in combination with chemotherapy and radiotherapy.
In the evaluation, classification into the categories “complete remission”, “partial remission”, and “stable disease” will take place. According to the study design, endoscopic control and MRI of the rectal region are prerequisites for the classification as complete remission.
A total of 30 participants with Stage I and II dMMR colorectal cancer will be treated with dostarlimab in the ongoing Phase II study. All but one patient’s lymph nodes have already been affected. Of the 18 patients enrolled in the study to date, with an average age of 54 years, 78% percent are already in tumor stage T3 or T4. All patients had dMMR and BRAF V600E wild-type tumors; the median tumor mutation burden was 67 mutations per million bases. In addition, most participants suffered from large, highly space-occupying tumors. As a result, the standard treatment for most would have consisted of a combination of surgery, chemotherapy, and radiation.
Participants in the study will receive intravenous treatment with 500mg of the antibody dostarlimab every three weeks for six months. The current status of the disease is continuously monitored by imaging and endoscopy. If complete remission is not achieved in the study participants, chemotherapy or radiotherapy will be administered, and surgery will be performed if the disease progresses.
However, this case had not occurred in participants to date, as complete remission was observed in all cases when dostarlimab was administered. [1]
Evaluation of the study
Colorectal carcinoma is one of the most common cancers, with 60,000 new cases and 25,000 deaths in Germany each year. [2] Worldwide, a diagnosis of colorectal carcinoma affects more than 1.9 million people. But only 12 to 15% of these rectal cancers are classified as dMMR by biomarker status. A dMMR /deficient MMR) is defined as defective DNA mismatch repair due to which mismatch errors accumulate. As a result, microsatellites begin to vary in length. Statistically, this particular form of colorectal cancer is more likely to affect patients with right-sided, poorly differentiated, and/or mucinous adenocarcinoma. [3] Likewise, the rate of MSI-H patients is very low at 2%. Patients with MSI-H/dMMR status have, according to recent studies, a good prognosis in the early stage, but if metastases have already spread, the prognosis is rather poor. [4]
However, in this small target group with MSI-H/dMMR, checkpoint inhibition can be considered very effective.
Whether inhibition of PD-1 in the future and targeted therapies can replace chemotherapy or a combination of chemo- / and radiotherapy cannot be said with certainty yet. Therefore, further studies are mandatory here, especially with follow-up over a longer period.
Nevertheless, the results published so far are very impressive and show that patients with cancer can benefit greatly from personalized and targeted therapy.
References
[1] Andrea Cercek, M.D., Melissa Lumish, M.D., Jenna Sinopoli, N.P., Jill Weiss, B.A., Jinru Shia, M.D., Michelle Lamendola-Essel, D.H.Sc., Imane H. El Dika, M.D., Neil Segal, M.D., Marina Shcherba, M.D., Ryan Sugarman, M.D., Ph.D., Zsofia Stadler, M.D., Rona Yaeger, M.D., et al.: PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. The New England Journal of Medicine 2022; 10.1056/NEJMoa2201445 NEJM
[2] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394–424 PubMed
[3] Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in Patients With Metastatic DNA Mismatch Repair-Deficient or Microsatellite Instability-High Colorectal Cancer (CheckMate 142): An Open-Label, Multicentre, Phase 2 Study. Lancet Oncol (2017) 18(9):1182–91. doi: 10.1016/S1470-2045(17)30422-9 PubMed
[4] Gelsomino F, Barbolini M, Spallanzani A, Pugliese G, Cascinu S. The Evolving Role of Microsatellite Instability in Colorectal Cancer: A Review. Cancer Treat Rev (2016) 51:19–26. doi: 10.1016/j.ctrv.2016.10.005 PubMed
