Jemperli (dostarlimab-gxly) is an anti-programmed cell death receptor-1 (PD-1) antibody indicated for the treatment of adults with mismatch repair-deficient (dMMR) recurrent or advanced solid tumours and dMMR-recurrent or advanced endometrial cancer.
Dostarlimab was discovered by AnaptysBio, a biotechnology company based in the US, using its proprietary somatic hypermutation antibody platform.
The drug was licensed to the US-based pharmaceutical company Tesaro through an exclusive licence and collaboration agreement in March 2014. It joined the GlaxoSmithKline (GSK) portfolio in 2019 after GSK acquired Tesaro.
GSK is currently responsible for the research, development, commercialisation and manufacturing of the antibody.
AnaptysBio partnered with Sagard Healthcare Royalty Partners, a royalty investment unit of Sagard, to monetise a part of its future Jemperli royalties and milestones in October 2021.
The drug is available in 500mg/10ml (50mg/ml) dosage strength as a clear to slightly opalescent, colourless to yellow solution in a single-dose vial for intravenous infusion.
Regulatory approvals for Jemperli
Dostarlimab was granted breakthrough therapy designation by the US Food and Drug Administration (FDA) for recurrent or advanced dMMR endometrial cancer in May 2019.
In December 2019, GSK submitted a biologics licence application to the FDA for the treatment of dMMR-recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that had progressed on or after the previous treatment with a platinum-containing regimen.
The therapy received accelerated approval from the FDA for this indication in April 2021. In the same month, the therapy was approved by the European Commission, becoming the first anti-PD-1 therapy available for endometrial cancer in Europe.
The FDA also approved Roche’s VENTANA MMR RxDx Panel, a first-of-its-kind immunohistochemistry-based assay, as a companion diagnostic test to help identify endometrial cancer patients eligible for dostarlimab-gxly in the same month.
In August 2021, the FDA granted accelerated approval to Jemperli for dMMR-recurrent or advanced solid tumour patients who had progressed on or after previous therapy with no suitable alternative options.
The VENTANA MMR RxDx Panel received FDA approval to help identify dMMR solid tumour patients eligible for the therapy in August 2021.
The drug was approved in Canada for recurrent or advanced endometrial cancer in December 2021. It was conditionally approved as monotherapy for the treatment of adult patients with recurrent or advanced dMMR endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen in Australia in February 2022.
The FDA granted full approval to the drug for the treatment of adult patients with dMMR recurrent or advanced endometrial cancer in February 2023.
Causes and incidence of dMMR tumours
Mismatch repair is a normal repair mechanism of healthy cells that correct mistakes during DNA replication through enzymes. The improper functioning of enzymes leads to dMMR, which causes unrepaired errors in the DNA. The accumulation of such errors may cause cancer.
DMMR is the most common in colorectal, gastrointestinal and endometrial cancers. An estimated 14% of solid tumours diagnosed in the US are dMMR.
Jemperli’s mechanism of action
Jemperli is a humanised monoclonal antibody that binds to the PD-1 receptor present on T-cells with high affinity and prevents its interactions with PD-L1 and PD-L2 ligands, thus blocking PD-1 activity and decreasing tumour growth.
Clinical trials on Jemperli
Jemperli’s efficacy for treating dMMR solid tumours was evaluated in GARNET, a Phase I, multi-centre, non-randomised, open-label, multi-cohort clinical trial.
The FDA’s accelerated approval of the therapy was based on tumour response rate and durability of response drawn from combined data from two cohorts from the GARNET trial, namely the dMMR endometrial cancer cohort A1 and the dMMR solid-tumour cohort F.
The cohort F included 209 patients with dMMR recurrent or advanced non-endometrial cancers, with increased incidence in colorectal, small intestine and stomach cancers.
Patients were given a 500mg intravenous dose of dostarlimab every three weeks for the first four doses and a subsequent dose of 1,000mg every six weeks until the disease progressed or reached intolerable levels of toxicity.
The trial’s primary endpoint was the overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review (BICR) according to version 1.1 of the Response Evaluation Criteria in Solid Tumours (RECIST) specification.
In the trial, an ORR of 41.6% was achieved in all dMMR solid tumours, including endometrial and non-endometrial solid tumours, with a 9.1% complete response rate and 32.5% partial response rate.
In addition, the median DOR was 34.7 months, with 95.4% of the patients sustaining a response for six months or more.
An ORR of 38.7% was observed in the dMMR solid tumour non-endometrial cancer cohort, which included 106 patients.
The most common adverse reactions reported in the 267 patients evaluated for safety were fatigue, decreased muscle strength, anaemia, diarrhoea and nausea.
The FDA’s full approval for the drug was based on additional data taken from the A1 expansion cohort of the ongoing GARNET trial. In Cohort A1, 141 patients with dMMR advanced or recurrent endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen were recruited to evaluate the drug’s efficacy.
ORR and DOR were the primary endpoints of the study. The patients in the study achieved a confirmed ORR of 45.4%, with a 15.6% complete response rate and a 29.8% partial response rate. Median DOR was not reached when measured from the time of first response while median follow-up for DOR was 27.9 months.
The most common adverse reactions observed in the patients during the trial were fatigue, anaemia, rash, nausea, diarrhoea, constipation and vomiting.
Additional clinical trials on Jemperli
GSK conducted a Phase II, randomised, double-blind clinical trial named PERLA to evaluate dostarlimab with chemotherapy versus pembrolizumab plus chemotherapy in first-line patients with metastatic non-squamous non-small cell lung cancer (NSCLC).
The study enrolled 243 patients and the objective response rate was the study’s primary endpoint.
The patients treated with dostarlimab combination achieved a confirmed objective response rate of 46% compared to 37% in the pembrolizumab combination.
Another randomised, open-label trial COSTAR Lung Phase III enrolled 750 patients to study the efficacy and safety of cobolimab, a TIM-3 antagonist, plus dostarlimab plus docetaxel compared to dostarlimab plus docetaxel to docetaxel alone in patients with advanced NSCLC who have progressed on prior anti-PD-(L)1 therapy and chemotherapy. Overall survival is the primary endpoint of the study.