CAN DOSTARLIMAB BE LABELLED AS A CURE FOR RECTAL CANCER?

–Dr Roma Patil, Intern

Bangalore Medical College and Research Institute

Dostarlimab, also known as Jemperli, which was approved for the treatment of advanced or recurrent endometrial cancer in 2021, has proven to be a potential cure for rectal cancer in a recent study conducted at Memorial Sloan Kettering Hospital.

Dostarlimab is a humanised monoclonal antibody directed against human cell surface receptor PD-1(programmed death-1). Upon administration, it binds to and inhibits PD-1 and it’s downstream signalling pathways, which helps the body destroy cancer cells through activation of T cells . In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer, and it was approved for its treatment in April 2021. This drug has a good safety profile, as compared to the standard chemo-radiotherapy as it has minimal complications such as fatigue, diarrhoea, nausea and very rarely anaemia, rash, hypothyroidism, increase in ALT, amylase and lipase levels.

Colorectal cancer is the third most commonly diagnosed cancer in both men and women. About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder. The remaining 10 to 30% of patients have a family history of CRC that suggests hereditary contribution, common exposures or shared risk factors or a combination of both. The two most common causes of hereditary CRC are FAP(Familial Adenomatous Polyposis), due to germline pathogenic variants in the APC gene, and Lynch syndrome(previously called Hereditary Nonpolyposis Colorectal Cancer- HNPCC), due to germline pathogenic variants in DNA Mismatch Repair genes. Locally advanced rectal cancer(LARC) is a subset of rectal cancer commonly defined as T3 or T4 primary tumours or nodal metastases (T3-4 and/or N+) or Stage II (cT3-4N0) or Stage III (cT1-4, N1-3) tumour.

As metastatic mismatch repair deficient colorectal cancer was found to respond to PD-1 blockade, in this study, they thought of using Dostarlimab for another stage(LARC) of rectal cancer patients. So this class of drugs has been used before to treat colorectal cancer.

Twelve patients with Mismatch repair deficient, stage 2 or 3 rectal adenocarcinoma were administered only Dostarlimab every 3 weeks for 6 months. This was to be followed by standard chemo-radiotherapy and surgery. The primary end points of the study were;

1. Clinical complete response 12 months after completion of dostarlimab therapy or 
2. Pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy
3. Overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.

In a never heard before study result, all 12 patients with Mismatch repair deficient, locally advanced rectal cancer who were treated with Dostarlimab alone for 6 months, had a complete response, with no evidence of tumour on any diagnostic test after 6 months following treatment with Dostarlimab.

This hallmark study which has received laurels from doctors and researchers around the globe, has opened up a new chapter for cancer treatment and has bought about immense hope for cancer patients worldwide. However since the prevalence of Mismatch repair deficient LARC is just 1-3% and the current study needs a longer follow up period, the world still awaits a solid answer to this dreaded disease. Dostarlimab, though a leap forward in cure for rectal cancer, still needs to leave footprints. Nevertheless it marks the beginning of many more panacea for cancer.

It is breakthrough studies like this that push healthcare professionals to go beyond the normal standard of care and discover drugs that patients across the globe need. It is studies like this that make patients cry “happy tears”. Dostarlimab, which already has “star” in its name, is a promising drug for the treatment of cancer.

References:

1. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, El Dika IH, Segal N, Shcherba M, Sugarman R, Stadler Z, Yaeger R, Smith JJ, Rousseau B, Argiles G, Patel M, Desai A, Saltz LB, Widmar M, Iyer K, Zhang J, Gianino N, Crane C, Romesser PB, Pappou EP, Paty P, Garcia-Aguilar J, Gonen M, Gollub M, Weiser MR, Schalper KA, Diaz LA Jr. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022 Jun 23;386(25):2363-2376. doi: 10.1056/NEJMoa2201445. Epub 2022 Jun 5. PMID: 35660797.
2. https:///wiki/Dostarlimab
3. Genetics of Colorectal Cancer (PDQ®)–Health Professional Version was originally published by the National Cancer Institute.”
4. Ostwal V, Pande NS, Engineer R, Saklani A, deSouza A, Ramadwar M, Sawant S, Mandavkar S, Shrirangwar S, Kataria P, Patil P, Shetty O, Ramaswamy A. Low prevalence of deficient mismatch repair (dMMR) protein in locally advanced rectal cancers (LARC) and treatment outcomes. J Gastrointest Oncol 2019;10(1):19-29. doi: 10.21037/jgo.2018.10.01
5. Oronsky, B., Reid, T., Larson, C., & Knox, S. J. (2020). Locally advanced rectal cancer: The past, present, and future. Seminars in Oncology. doi:10.1053/j.seminoncol.2020.02.001 
6. Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET—a phase I, single-arm study. Journal for ImmunoTherapy of Cancer 2022;10:e003777. doi: 10.1136/jitc-2021-003777
7. Meillan N, Vernerey D, Lefèvre JH, Manceau G, Svrcek M, Augustin J, Fléjou JF, Lascols O, Simon JM, Cohen R, Maingon P, Bachet JB, Huguet F. Mismatch Repair System Deficiency Is Associated With Response to Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer. Int J Radiat Oncol Biol Phys. 2019 Nov 15;105(4):824-833. doi: 10.1016/j.ijrobp.2019.07.057. Epub 2019 Aug 9. PMID: 31404579.
8. Bailey and Love Short Practice of Surgery- 27^th Edition
9. Caldwell, C., Johnson, C.E., Balaji, V.N. et al. Identification and Validation of a PD-L1 Binding Peptide for Determination of PDL1 Expression in Tumors. Sci Rep 7, 13682 (2017). https://doi.org/10.1038/s41598-017-10946-2
10. Cercek, A. et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2201445 (2022)