Jemperli (Dostarlimab) First Immunotherapy Approved for Recurrent or Advanced Mismatch Repair-Deficient Endometrial Cancer

December 2021 Twelfth Annual Payers' Guide - FDA Approvals
Loretta Fala
Medical Writer

Endometrial cancer (the most common type of uterine cancer) begins when malignant cells grow and multiply in the tissues of the endometrium (ie, inner lining of the uterus).1 In the United States, endometrial cancer is the most common gynecologic malignancy, and its prevalence is increasing, currently accounting for 7% of all cancers affecting women.1,2

Approximately 66,570 new cases of uterine cancer, including endometrial cancer, are diagnosed annually (median age at diagnosis, 63 years). Furthermore, nearly 13,000 American women are estimated to die from endometrial cancer in 2021.3

Endometrial cancer is associated with high rates of mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) abnormalities.4 Approximately 25% to 30% of patients with advanced endometrial cancer have dMMR tumors, a genetic abnormality that affects intracellular DNA repair.4,5 Patients with dMMR endometrial cancer may be at a higher risk for disease recurrence than patients without this dMMR biomarker.6 The National Comprehensive Cancer Network guidelines on uterine neoplasms recommend that patients with recurrent or advanced endometrial cancer be tested for the dMMR and the MSI-H biomarkers.7

Approximately 75% of endometrial cancer cases are diagnosed early and can be treated successfully with surgery.2,4 The treatment options for patients with recurrent or advanced endometrial cancer that progresses after a platinum-containing regimen, however, are limited.2,5 Recently, a novel immunotherapy was approved for the treatment of this patient population.

Jemperli First Immunotherapy Approved for dMMR Endometrial Cancer

On April 22, 2021, the US Food and Drug Administration (FDA) approved dostarlimab-gxly (Jemperli; GlaxoSmithKline), a new monoclonal antibody and a programmed cell death 1 (PD-1) inhibitor, for the treatment of adult women with recurrent or advanced endometrial cancer that has progressed during or after a platinum-containing chemotherapy regimen in patients with the dMMR genetic abnormality, as determined by an FDA-approved test.5

“Today’s approval of Jemperli is evidence of the FDA’s progress in applying precision medicine to expand treatment options for patients with cancer,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “This immunotherapy was specifically studied to target dMMR endometrial cancer and leverages scientific knowledge surrounding the mechanism of immunotherapy response in this unmet medical need population,” Dr Pazdur added.5

The FDA granted dostarlimab, a new monoclonal antibody, an accelerated approval, based on the tumor response rate and the durability of response, as well as a breakthrough therapy designation.5,8 The continued approval of dostarlimab may be contingent upon confirmatory trials to verify its clinical benefits.8

Mechanism of Action

Upregulation of the PD-1 ligands PD-L1 and PD-L2 occurs in some tumors. Binding of the PD-1 ligands to the PD-1 receptor that is expressed on T-cells inhibits T-cell proliferation. Moreover, the PD-1 pathway signaling can reduce the ability of T-cells to detect and eliminate cancer cells; blocking this pathway can therefore inhibit this activity.8

Dostarlimab is a humanized monoclonal antibody of the immunoglobulin G4 isotype that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby enhancing the antitumor immune response. In preclinical studies, inhibition of PD-1 activity resulted in decreased endometrial tumor growth.8

Dosing and Administration

Dostarlimab is available as a 500-mg/10-mL (50-mg/mL) solution in a single-dose vial.8 The recommended dosing of dostarlimab for dose 1 through 4 is 500 mg every 3 weeks; all subsequent dosing, beginning 3 weeks after dose 4, is 1000 mg every 6 weeks. Dostarlimab is administered as an intravenous infusion over 30 minutes.8

Pivotal Clinical Trial: GARNET

The efficacy of dostarlimab was evaluated in the GARNET study, a multicenter, multicohort, open-label phase 1 clinical trial that included patients with advanced endometrial cancer (median age, 64 years; performance status 0 or 1).4,8

The study included 71 patients with recurrent or advanced dMMR endometrial cancer whose disease had progressed during or after a platinum-containing chemotherapy regimen. The interim efficacy analysis included these 71 patients.4

Upon study entry, 66% of the patients had stage IV disease, based on the International Federation of Gynecology and Obstetrics staging. Most (70%) of the patients had endometrioid carcinoma type 1, 6% had serous carcinoma, and 2.8% had mixed and undifferentiated carcinoma.4,8

All enrolled patients received dostarlimab 500 mg intravenously every 3 weeks for 4 doses, followed by 1000 mg intravenously every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity. All patients in the study received previous anticancer treatment; 90% had previous surgery and 79% received previous radiotherapy to remove the tumor. Approximately 40% of patients had received ≥2 lines of previous anticancer treatment.4,8

Overall, 30 (42.3%) of the patients who received dostarlimab achieved an overall response (ie, complete or partial response). The median duration of response was not reached at the time of the analysis, with a median follow-up of 11.2 months. Furthermore, 93.3% of the patients sustained their response to dostarlimab therapy for ≥6 months (Table).4,8

Table

The disease control rate was 57.7%, and the median progression-free survival was 8.1 months.4

Adverse Reactions

The most common (≥20%) adverse reactions reported with dostarlimab were fatigue/asthenia (48%), nausea (30%), diarrhea (26%), anemia (24%), and constipation (20%).8

The most common (≥20%) all-grade laboratory abnormalities were lymphopenia (37%), leukopenia (21%), hypoalbuminemia (30%), increased alkaline phosphatase (25%), increased creatinine (27%), and hyponatremia (26%).8

Serious adverse events occurred in 34% of patients who received dostarlimab and included sepsis (2.9%), acute kidney injury (2.9%), urinary tract infection (2.9%), abdominal pain (2.9%), and pyrexia (2.9%).

Adverse reactions led to permanent discontinuation of dostarlimab in 5 (4.8%) patients.8

Dostarlimab has no contraindications.8

Warnings and Precautions

Immune-mediated adverse reactions, which can be severe or fatal, can occur in any organ system or tissue at any time after starting treatment with a PD-1/PD-L1 inhibitor, including dostarlimab. Patients should be monitored for signs and symptoms of such adverse reactions. Clinical chemistries, including liver and thyroid function, should be tested at baseline and periodically during dostarlimab treatment. Depending on the severity of the reaction, it may be necessary to withhold or permanently discontinue dostarlimab and administer corticosteroids.8

Severe or life-threatening infusion-related reactions have been reported with PD-1/PD-L1 inhibitors, including dostarlimab. Patients should be monitored for signs and symptoms of infusion-related reactions. Depending on the severity of the reaction, it may be necessary to interrupt, slow the rate of infusion, or permanently discontinue dostarlimab.8

Fatal and other serious complications can occur in patients who undergo allogeneic hematopoietic stem-cell transplant before or after receiving a PD-1/PD-L1 inhibitor. Patients should be followed closely for transplant-related complications.8

Based on its mechanism of action, dostarlimab can cause fetal harm in a pregnant woman. Females of reproductive potential should be tested for pregnancy status before initiating dostarlimab therapy and be advised to use effective contraception during treatment and for 4 months after the last dose of dostarlimab.8

Use in Specific Populations

Data are not available on the use of dostarlimab in pregnant women, on the presence of dostarlimab in human milk, or on its effects on the breastfed child or on milk production. Given the potential for serious adverse events in a breastfed infant, women should be advised not to breastfeed during treatment with and for 4 months after the last dose of dostarlimab.8

No overall differences in the safety or efficacy of dostarlimab were observed between patients aged 65 years or older and those younger than 65 years.8

Conclusion

Dostarlimab, a PD-1 inhibitor, targets and inhibits the PD-1/PD-L1 cellular pathway, thereby enhancing the body’s anticancer immune response. The treatment options for patients with recurrent or advanced endometrial cancer are limited. The approval of dostarlimab provides the first immunotherapy option for women with recurrent or advanced dMMR endometrial cancer whose disease progresses during or after platinum-based chemotherapy.

In the pivotal GARNET study, 42.3% of patients with recurrent or advanced dMMR endometrial cancer who received dostarlimab had a response to treatment, and 12.7% of them achieved a complete response; the vast majority (93.3%) of patients sustained their response to therapy for ≥6 months.

References

  1. American Cancer Society. What is endometrial cancer? Updated March 27, 2019. www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html. Accessed June 8, 2021.
  2. National Cancer Institute. Endometrial cancer treatment (PDQ)–health professional version. Updated April 9, 2021. www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq. Accessed June 10, 2021.
  3. National Cancer Institute SEER Program. Cancer stat facts: uterine cancer. https://seer.cancer.gov/statfacts/html/corp.html. Accessed June 10, 2021.
  4. Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti–programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial. JAMA Oncol. 2020;6:1766-1772.
  5. US Food and Drug Administration. FDA approves immunotherapy for endometrial cancer with specific biomarker: approval is for recurrent or advanced mismatch repair deficient (dMMR) endometrial cancer. April 22, 2021. www.fda.gov/news-events/press-announcements/fda-approves-immunotherapy-endometrial-cancer-specific-biomarker. Accessed June 7, 2021.
  6. Backes FJ, Haag J, Cosgrove CM, et al. Mismatch repair deficiency identifies patients with high-intermediate–risk (HIR) endometrioid endometrial cancer at the highest risk of recurrence: a prognostic biomarker. Cancer. 2019;125:398-405.
  7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Uterine Neoplasms. Version 3.2021. June 3, 2021. www.nccn.org/login?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed June 14, 2021.
  8. Jemperli (dostarlimab-gxly) injection, for intravenous use [prescribing information]. GlaxoSmithKline; April 2021. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Jemperli/pdf/JEMPERLI-PI-MG.PDF. Accessed June 14, 2021.
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