Colorectal cancer is one of the most prevalent and fatal types of cancer worldwide. Managing advanced colorectal cancer is still a difficult task despite notable improvements in cancer treatment. However, recent developments in immunotherapy have given new hope to patients with colorectal cancer. Dostarlimab, a novel immunotherapeutic agent, has demonstrated promising outcomes in the management of colorectal cancer [1].
Understanding colorectal cancer
Colorectal cancer affects the colon or rectum, parts of the large intestine. It typically starts as a polyp, a non-cancerous (benign) growth, which can turn into cancer over time. Polyps can be found through screening tests, allowing for their removal before they develop into cancer. Additionally, screening aids in the early detection of colorectal cancer, when therapy is most effective [1].
Currently, chemotherapy, surgery, and radiation therapy are used to treat colorectal cancer along with targeted therapy and immunotherapy to achieve better outcomes. Neo-adjuvant treatment and chemotherapy strategies have recently come to light as a cutting-edge approach for treating locally advanced colorectal cancer. The Food and Drug Administration (FDA) swiftly approved dostarlimab-gxly (Jemperli) for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer and solid tumors [2].
Understanding dostarlimab
Dostarlimab, also recognized as TSR-042 or Jemperli, is a monoclonal antibody that belongs to a class of drugs called immune checkpoint inhibitors. It targets the programmed cell death protein 1 (PD-1) receptor in immune cells. PD-1 is known to play a vital role in suppressing the immune response. PD-1 signaling is started upon its interaction with its ligands, PD-1 ligand-1 and -2 (PD-L1 and PD-L2). Since cancer cells have high levels of these PD-1 ligands, they can escape T-cell immune responses. The T-cell function can be recovered and cancer cell evasion from immune surveillance prevented by blocking the binding of PD-1 to its ligands. Dostarlimab inhibits PD-1 and reinvigorates the immune system, making it better able to identify and eliminate cancer cells [3].
Dostarlimab has been approved for use as a monotherapy in patients with recurrent or advanced solid tumors that have progressed during or after prior therapy and have microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) mutations. These patients have no other effective treatment options available in the United States. It is also approved for use in adult patients with dMMR (United States) or dMMR/MSI-H (European Union) recurrent or advanced endometrial cancer that has advanced on or after prior therapy with a platinum-containing schedule [4].
Real-world applications and success stories of dostarlimab
The safety and effectiveness of dostarlimab in colorectal cancer were studied in clinical trials including patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors. The high mutation rate of MSI-H or dMMR tumors makes them more amenable to immunotherapy. In the GARNET phase 2 clinical trial, the safety and effectiveness of dostarlimab were assessed in patients with advanced solid tumors, including colorectal cancer (ClinicalTrials.gov Identifier: NCT02715284).
The outcomes of the GARNET trial were highly encouraging. Dostarlimab showed persistent antitumor efficacy in patients with colorectal cancer. No additional safety signals were found, and the safety profile was controllable. The majority of side effects from treatments were mild and uniform among cohorts. The median time it took for a response to occur was also noteworthy, and several patients experienced prolonged remissions. These results imply that dostarlimab may be clinically useful for a subset of patients with advanced colorectal cancer [5].
Benefits and future perspectives
The emergence of dostarlimab as a colorectal cancer therapy option offers several benefits. Firstly, it offers a new therapeutic path for patients who have exhausted standard treatment options. Second, compared to conventional chemotherapy, dostarlimab's mechanism of action uses the patient's immune system to produce more long-lasting effects. Last but not least, dostarlimab has been shown to have a good safety profile and controllable adverse effects.
Even though dostarlimab has a lot of potentials, more studies and clinical trials are required to maximize its application and broaden its advantages. The effectiveness of the drug in various patient populations is being researched, along with combination therapy. Important research fields include the discovery of predictive biomarkers and the creation of methods to overcome resistance [3–5].
Does dostarlimab unlock new hope?
Dostarlimab signifies an important revolution in the treatment of colorectal cancer. Dostarlimab activates the immune system to target and eliminate cancer cells in patients with MSI-H or dMMR colorectal cancer by inhibiting the PD-1 pathway. Clinical trial findings showed significant responses and long-lasting remissions, giving hope to patients with advanced disease. Dostarlimab has the potential to fundamentally alter the way colorectal cancer is treated, leading to better patient outcomes and survival rates, even though additional research is still required.
References
1. 'What Is Colorectal Cancer? | CDC' [https://www.cdc.gov/cancer/colorectal/basic_info/index.htm]. (2023).
2. Ali, E. et al. 'Jemperli (Dostarlimab-gxly): An unprecedented cancer trial'. Ann Med Surg (Lond). (2022) 79, 104047. DOI: 10.1016/j.amsu.2022.104047.
3. Shuvo, P.A. et al. 'Dostarlimab: The miracle drug for the treatment of colorectal cancer'. Ann Med Surg (Lond). (2022) 81, 104493. DOI: 10.1016/j.amsu.2022.104493.
4. Patnaik, A. et al. 'Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose–escalation phase 1 trial'. Cancer Chemother Pharmacol. (2022) 89(1), 93–103. DOI: 10.1007/s00280-021-04358-3.
5. Berton, D. et al. 'Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study.'. JCO. (2021) 39(15_suppl), 2564–2564. DOI: 10.1200/JCO.2021.39.15_suppl.2564.
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