The US Food and Drug Administration (FDA) has approved a new indication for dostarlimab-gxly (Jemperli®; GSK), a programmed cell death receptor-1 (PD-1) blocking antibody, for the treatment of adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumors, as determined by the FDA-approved Ventana MMR RxDx panel test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

This indication received accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

“For patients with tumors expressing the dMMR biomarker, there continues to be a significant need for new and effective treatments. I’m excited about GSK’s second oncology FDA approval this year, and the new treatment option it provides for these patients,” noted Hal Barron, MD, Chief Scientific Officer, and President R&D, GSK.

Mismatch Repair Deficiency
In normal cells, mismatch repair (MMR) is a process that recognizes and corrects errors that are spontaneously introduced during DNA replication via enzymes. Under normal conditions, the enzymes as part of the MMR system restore DNA integrity by detecting and fixing the erroneous strands.[1] When this repair mechanism is defective, it is known as mismatch repair-deficient (dMMR). When the enzymes no longer function properly the results may lead to errors in the DNA that go unchecked. Accumulation of these errors attributes to mutations in the MMR proteins, MLH1, PMS2, MSH2, and MSH6. and may lead to cancer.[2][3]

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What is mismatch repair (MMR)? Image courtesy: ® 2019 – 2021 Roche/Ventana. Used with permission.

Multiple studies have demonstrated that MMR deficiency correlates with higher expression of PD-1 or PD-L1, possibly due to increased neoantigen expression associated with tumor mutation burden that results from replication errors. [4][5] Thus, MMR proteins may be useful as predictive biomarkers for PD-1 targeted therapy; specifically, a loss of expression of one or more MMR proteins might predict an increased likelihood of response to such therapy.[6][7][8]

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According to results from a structured literature review and meta-analysis investigating pooled prevalence estimates of dMMR across solid tumors, the prevalence of dMMR across solid tumors in the US has been estimated at 14%.[9]

Mismatch repair-deficient tumors contain abnormalities that affect the proper repair of DNA when copied in a cell.[1] In the US, the prevalence of dMMR across patients with solid tumors has been estimated at 14%.[2] Mismatch repair-deficient status is a biomarker that has been shown to predict response to immune checkpoint blockade with PD-1 therapy.[10][11] Tumors with this biomarker are most commonly found in endometrial, colorectal, and other gastrointestinal cancers, but may also be found in other solid tumors.[2][9][1]

Important new treatment option
“Dostarlimab is an important new treatment option for patients with mismatch repair-deficient recurrent or advanced solid cancers who have progressed and have no alternative options,” explained Jubilee (Robinson) Brown, Professor and Division Director of Gynecologic Oncology at Atrium Health Levine Cancer Institute, and investigator on the GARNET study.

“As we saw in the GARNET trial, of those patients who respond to treatment with dostarlimab, nearly all continued to respond for six months or longer,” Brown added.

Regulatory development
Dostarlimab was approved by the U.S. Food and Drug Administration (FDA) in April 2021 for the treatment of advanced or recurrent deficient mismatch repair endometrial cancer (dMMREC). This is the first AnaptysBio-generated antibody being developed in collaboration with GSKof eight currently under clinical development, to obtain FDA approval.

Jubilee Brown, MD, Professor and Division Director of Gynecologic Oncology at Atrium Health Levine Cancer Institute

In April 2021 the European Medicines Agency (EMA) granted conditional marketing authorization in the European Union for dostarlimab for use in women with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer who have progressed on or following prior treatment with a platinum-containing regimen, which approval makes dostarlimab the first anti-PD-1 therapy available for endometrial cancer in Europe.

This new indication follows an FDA priority review of the Biologics License Application and is based on the collective results from the dMMR endometrial cancer cohort A1 and the dMMR solid-tumor (non-endometrial cancer) cohort F of the ongoing GARNET trial. The GARNET trial is a multicentre, non-randomized, multiple parallel-cohort, open-label study. Cohort F included patients with dMMR recurrent or advanced non-endometrial cancers, with the highest prevalence in colorectal, small intestine, and stomach cancers.

The major efficacy outcomes of the GARNET trial are objective response rate (ORR) and duration of response (DoR), as assessed against RECIST v 1.1 by blinded independent central review. Results in all dMMR solid tumors, including endometrial and non-endometrial solid tumors (n=209), demonstrated an ORR of 41.6% (95% CI; 34.9-48.6) with a complete response rate of 9.1% and a partial response rate of 32.5%. The median DoR was 34.7 months (range 2.6-35.8+) with 95.4% of patients maintaining a response for six months or longer. In the dMMR solid tumor non-endometrial cancer cohort (n=106), results demonstrated an ORR of 38.7% (95% CI; 29.4-48.6).

As part of the trial, participating patients received 500 mg of dostarlimab as an intravenous infusion once every three weeks for four doses, followed by 1,000 mg once every six weeks until disease progression or unacceptable toxicity. Among the 267 patients with recurrent or advanced dMMR solid tumors who were evaluable for safety, the most commonly reported adverse reactions (≥20%) were fatigue/asthenia (42%), anemia (30%), diarrhea (25%), and nausea (22%). The most common Grade 3 or 4 adverse reactions (≥2%) were anemia, fatigue/asthenia, increased transaminases, sepsis, and acute kidney injury. Grade 3 or 4 laboratory abnormalities (≥2%) included decreased lymphocytes, decreased sodium, increased alkaline phosphatase, and decreased albumin.

In April 2021, the FDA granted accelerated approval for dostarlimab for the treatment of adult patients with dMMR recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen. This approval was based on data from cohort A1, which included 71 patients with dMMR endometrial cancer.

With the dMMR solid-tumor approval, the US prescribing information for this indication includes efficacy data for an additional 32 patients in the endometrial cancer cohort A1 (n=103). The additional results for this cohort show an ORR of 44.7% (95% CI; 34.9-54.8) with a DoR range of 2.6-35.8+ months. The results of the endometrial cancer cohort of the GARNET trial represent the largest dataset to date evaluating an anti-PD-1 as a monotherapy treatment for women with endometrial cancer.

Dostarlimab is also being developed by GSK for the treatment of other tumor types and treatment settings, including currently ongoing phase III trials in recurrent or primary advanced endometrial cancer in combination with chemotherapy standard of care (RUBY) and the phase III FIRST study of platinum-based therapy with dostarlimab and niraparib versus standard of care platinum-based therapy as first-line treatment of stage III or IV non-mucinous epithelial ovarian cancer. In addition, dostarlimab is being evaluated as monotherapy and in combination therapy across multiple tumor types and other cancers, including platinum-resistant ovarian cancer, non-small cell lung cancer, multiple myeloma, and melanoma.

Discovery and development
Dostarlimab was generated by AnaptysBio using its proprietary somatic hypermutation (SHM) antibody platform. Previously known as GSK4057190, dostarlimab was discovered by AnaptysBio, a clinical-stage antibody development company advancing therapeutic antibody product candidates focused on unmet medical needs, [12] and licensed to Tesaro, under a Collaboration and Exclusive License Agreement signed in March 2014. The collaboration has resulted in three monospecific antibody therapies that have progressed into the clinic. [Note] In 2019 Tesaro was acquired by GSK and significantly strengthening GSK’s oncology pipeline.

“We are pleased that dostarlimab has been FDA-approved for a second indication and will be available to a broader cohort of solid tumor patients,” said Hamza Suria, president, and chief executive officer of AnaptysBio, who was appointed as the company’s Chief Executive Officer in 2011 and has since led AnaptysBio’s transformation from its early platform technology focus to the development of a robust antibody product pipeline across key therapeutic areas.

“AnaptysBio’s capital-efficient business model is focused upon advancing our wholly-owned first-in-class antibodies to multiple clinical catalysts over the upcoming 18 months and is supported by milestone and royalty revenues under our GSK collaboration,” Suria concluded.

In expanding the company’s oncology pipeline and portfolio of cancer treatments, GSK is also studying dostarlimab in earlier lines of treatment for endometrial cancer and in combination with other therapeutic agents for patients with advanced/metastatic cancers beyond endometrial cancer.

Financial impact
As a result of this second FDA approval of dostarlimab in dMMR recurrent or advanced solid tumors, AnaptysBio has earned a US $20 million milestone payment, Earlier in 2021, AnaptysBio received a milestone payment of US$ 10 million from GSK for acceptance of the BLA filing with the FDA for this second indication. AnaptysBio also received US$ 20 million and US$ 10 million milestone payments in April 2021 for FDA and European Medicines Agency (EMA) approvals of dostarlimab for adult patients with a certain type of endometrial cancer, after having received a total of US$ 15 million from GSK during 2020 for the FDA’s and EMA’s acceptance of these BLA and Marketing Authorisation Application (MAA) filings for dostarlimab.

AnaptysBio further anticipates an additional US US $15 million and US$ 165 million in milestone payments upon achievement of certain dostarlimab regulatory and commercial milestones, respectively.

Finally, Royalties due to AnaptysBio for dostarlimab range from 8% to 25% of global net sales, where AnaptysBio will receive 8% of annual global net sales below $1 billion, and 12-25% of net sales above $1 billion. GSK has recently disclosed peak year annual sales estimates of UK£ 1-2 billion for dostarlimab.[13]

Note
Dostarlimab, previously known as and TSR-042 and GSK4057190, a PD-1 antagonist; Cobolimab, (GSK4069889), a TIM-3 antagonist; and GSK4074386, a LAG-3 antagonist. GSK is responsible for the ongoing research, development, commercialization, and manufacture of each of these Products under the Agreement.

Clinical trials
Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET) – NCT02715284

Highlights of Prescribing Information
Dostarlimab-gxly (Jemperli®; GSK)[Prescribing Information]

References
[1] 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.
[2] National Cancer Institute at the National Institutes of Health. Definition of mismatch repair deficiency. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mismatch-repair-deficiency. Accessed May 5, 2021.
[3] Microsatellite Instability – Defective DNA Mismatch Repair: ESMO Biomarker Factsheet. Retrieved March 30, 2021, from https://oncologypro.esmo.org/education-library/factsheets-on-biomarkers/microsatellite-instability-defective-dna-mismatch-repair. (ESMO p1 [DNA mismatch repair] lines 1-2).
[4] Yamashita H, Nakayama K, Ishikawa M, et al. Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer. Oncotarget. 2017:9(5):5652-5664.
[5] Xiao X, Dong D, He W, et al. Mismatch repair deficiency is associated with MSI phenotype, increased tumor-infiltrating lymphocytes and PD-L1 expression in immune cells in ovarian cancer. Gynecol Oncol. 2018;149(1):146-154.
[6] Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
[7] Sloan EA, Ring KL, Willis BC, et al. PD-L1 expression in mismatch repair-deficient endometrial carcinomas, including Lynch syndrome-associated and MLH1 promoterhypermethylated tumors. Am J Surg Pathol. 2017;41(3):326-333.
[8] Dudley JC, Lin MT, Le DT, et al. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22(4):813-820.1.  Lortet-Tieulent J, J Ferlay, F Bray, and A Jemal. (2018) International patterns and trends in endometrial cancer incidence, 1978-2013. J Natl Cancer Inst. 110, 354-361.
[9] 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.
[10] Le DT, et al. PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
[11] Marabelle A, et al. Efficacy of pembrolizumab in patients with non-colorectal high microsatellite instability/mismatch repair-deficient cancer: results from the Phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10.
[12] Laken H, 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.
[13] New GSK: new ambitions for patients and shareholders. June 23, 2021.[Report]

Featured image: GSK Research, Madrid, Spain. Photo courtesy: ® 2016 – 2021 GSK. used with permission.

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