GSK has updated updated long-term results from the Memorial Sloan Kettering Cancer Center (MSK)-supported GSK-supported Phase II collaborative study evaluating dostarlimab as a first-line treatment, as an alternative to surgery, for locally rectal cancer. advanced with deficiency of the mismatch repair system (dMMR). The trial showed an unprecedented 100% clinical complete response (cCR) rate in 42 patients who completed treatment with dostarlimab, defined as pathologic complete response or no evidence of tumors as assessed by magnetic resonance imaging, endoscopy, and digital rectal examination. . A sustained complete clinical response was observed in the first 24 patients evaluated with a median follow-up of 26.3 months (95% CI: 12.4-50.5).
These late-breaking data were presented orally (abstract LBA3512) during the 2024 annual meeting of the American Society of Clinical Oncology (ASCO), which took place from May 31 to June 4 in Chicago. The data presented today reinforce findings previously presented at the ASCO 2022 meeting and published simultaneously in The New England Journal of Medicine.1
Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, said: “The data showing no evidence of disease in 42 patients is remarkable. These results bring us one step closer to understanding the potential of dostarlimab in this curative intent setting for patients with locally advanced rectal cancer with dMMR We hope to evaluate dostarlimab in certain types of colorectal cancer in our ongoing registration studies AZUR-1 and AZUR-2.”
The current standard of care (SoC) for patients with locally advanced rectal cancer with dMMR/microsatellite instability high (MSI-H) involves initial treatment with chemotherapy plus radiation, followed by surgery to remove the tumor along with parts of the intestine and/or or surrounding tissue. This results in initial positive results for most patients, but almost a third will experience a relapse in other organs of the body (distant metastasis).2 Furthermore, surgery and chemoradiotherapy associated with standard treatment can lead to long-term adverse effects that have a significantly negative impact on quality of life, including bowel, urinary and sexual dysfunction, secondary cancers and infertility.1
“These findings demonstrate the potential of dostarlimab as a novel treatment for locally advanced rectal cancer with dMMR, leading to complete and durable tumor regression without the need for life-altering treatment As a physician, I have witnessed firsthand the debilitating impact of standard cancer treatment. of rectum dMMR and I am excited about the potential of dostarlimab in these patients.
The safety and tolerability profile of dostarlimab was consistent with the known safety profile of the drug. No grade 3 or higher adverse events were reported in this trial.
Dostarlimab is not approved anywhere in the world for the initial treatment of locally advanced rectal cancer with dMMR. GSK is advancing studies evaluating dostarlimab in patients with advanced/metastatic stages of dMMR/MSI-H colorectal cancer through its AZUR clinical trial program. AZUR-1 is a globally registered, multicenter, open-label Phase II clinical trial investigating the efficacy and safety of dostarlimab as monotherapy, as a replacement for chemotherapy, radiation and/or surgery, for treatment-naïve patients with cancer. of locally advanced rectum with dMMR/MSI-H. The goal of the AZUR-1 trial is to confirm the findings of the GSK-supported collaborative study in locally advanced rectal cancer with dMMR led by Dr. Cercek at MSK. AZUR-2 is a Phase III trial evaluating the efficacy of perioperative dostarlimab compared to standard treatment in participants with untreated dMMR/MSI-H T4N0 or stage III (resectable) colon cancer.
About dMMR/MSI-H rectal cancer
Rectal cancer is a form of cancer that begins in the rectum, the final section of the large intestine, and is often classified as part of a group of cancers called colorectal cancer.3 Colorectal cancer is the third most diagnosed cancer in the world.4 In the US, it is estimated that approximately 46,220 people are diagnosed with rectal cancer annually.5 Approximately 5-10% of all rectal cancers are dMMR/MSI-H, meaning they contain abnormalities that affect the proper repair of DNA when it is copied in a cell.6 Mismatch repair system deficiency is a biomarker that has been shown to predict response to immune checkpoint blockade with PD-1 therapy.7.8 Tumors with this biomarker are most commonly found in endometrial, colorectal, and other gastrointestinal cancers, but can also be found in other solid tumors.9.12
About JEMPERLI (dostarlimab)
It is an antibody that blocks the programmed cell death 1 (PD-1) receptor by binding with high affinity to said receptor and blocking its interaction with the PD-L1 and PD-L2 ligands.eleven
It was discovered by AnaptysBio and licensed to TESARO, Inc. based on an exclusive collaboration and license agreement signed in March 2014. Under this agreement, GSK is responsible for the research, development, marketing and manufacturing of dostarlimab, as well as as cobolimab (GSK4069889), a TIM-3 antagonist.
Important information about dostarlimab in the EU
Indication
It is indicated: in combination with carboplatin and paclitaxel for the treatment of adult patients with newly diagnosed or relapsed advanced endometrial cancer with mismatch repair system deficiency (dMMR)/microsatellite instability high (MSI-H) and who They are candidates for systemic therapy.
as monotherapy for the treatment of adult patients with relapsed or advanced dMMR/MSI-H endometrial cancer who have progressed on or after prior platinum-based treatment.
see the EMA reference information on dostarlimab for a complete list of adverse reactions and all important safety information in the EU.
References:
1. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med 2022; 386: 2363-76.
2. Smith JJ, et al. Rectal Cancer Consortium. Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer. 2015 Oct 23;15:767. doi:10.1186/s12885-015-1632-z. PMID: 26497495; PMCID: PMC4619249.
3. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660.
4. SEER Explorer. SEER Explorer Application. Accessed April 19, 2024. Available at https://seer.cancer.gov/statistics-network/explorer/.
5. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. Doi:10.3322/caac.21820.
6. Cercek A, et al. Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy. Clin Cancer Res. 2020 Jul 1;26(13):3271-3279. doi: 1158/1078-0432.CCR-19-3728. Epub 2020 Mar 6. PMID: 32144135; PMCID: PMC7348681.
7. Le DT, et al. PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
8. Marabelle A, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair deficient cancer: results from the Phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10.
9. National Cancer Institute at the National Institutes of Health. Definition of mismatch repair deficiency. Accessed April 19, 2024. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mismatch-repair-deficiency.
10. Lorenzi M, et al. Epidemiology of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in solid tumors: a structured literature review. J Oncol. 2020. doi.org/10.1155/2020/1807929.
eleven. Zhao P, et al. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12(1):54. doi:10.1186/s13045-019-0738-1.
12. Laken H, Kehry M, Mcneeley P, et al. Identification and characterization of TSR-042, a novel anti-human PD-1 therapeutic antibody. European Journal of Cancer. 2016;69, S102. doi:10.1016/s0959-8049(16)32902-1.
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