Which immunotherapy is good for endometrial cancer? Jemperli treatment response rate is amazing
Post-mortem analysis data from the PHASE 1 GARNET trial announced during the 2021 ESMO Conference showed that patients with endometrial cancer with high tumor mutation load (TMB-H) had a high response rate to monotherapy PD-1 immunotherapy Jemperli (Dostarlimab), regardless of mismatch repair (MMR) or MMR.Microsatellite stability (MSI) status.
Jemperli drug Introduction
Product name: Jemperli
Drug name: Dostarlimab
Other names: TSR-042
Developer: GlaxoSmithKline (GSK)
Jemperli is a humanized anti-PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with the ligands PD-L1 and PD-L2. The drug works by targeting the cellular pathway of PD-1/PD-L1 (a protein present in human immune cells and some cancer cells). The drug has been approved as a monotherapy in the United States and the European Union for patients with dMMR recurrence or advanced endometrial cancer who use a platinum-containing regimen or progress after using a platinum-containing regimen.
Jemperli trial treatment data
Both regulatory decisions are based on data from the single-arm phase 1 GARNET trial, which evaluated the use of Jemperli monotherapy in multiple tumor types, including two groups of endometrial cancer patients. The GARNET study (NCT02715284) was conducted in multiple phases. Phase 1 served as a dose-finding phase, and Phase 2A consisted of a fixed-dose safety trial. Phase 2B of the study included an expanded cohort of patients with dMMR/MSI-H (cohort A1; n = 129) and MMRp/MSS endometrial cancer (cohort A2; n = 161). The primary endpoints of the study were ORR and time to response according to RECIST v1.1 criteria and a blinded independent central review (BICR).
To be eligible for inclusion in the A1 and A2 cohorts, patients must have experienced disease progression during or after platinum-based doublet therapy, have previously received two or fewer treatments for relapsed or advanced disease, and have measurable disease at baseline. Patients also needed to be unresponsive to anti-PD-L1 drugs. Patients could be screened based on local MMR/MSI testing results, using immunohistochemistry (IHC), polymerase chain reaction, or next-generation sequencing (NGS) performed at a locally certified laboratory. However, patient cohort allocation was based on MMR IHC results. Study participants received 500 mg of Jemperli intravenously (IV) every 3 weeks for 4 cycles, followed by 1000 mg IV every 6 weeks until disease progression.
In the post-hoc analysis, TMB status was an exploratory biomarker, determined using the Foundation One test. TMB-H status was defined as having 10 or more mutations/gigabases, and TMB-L status was defined as having fewer than 10 mutations/gigabases. As of the data cutoff date of March 1, 2020, a total of 129 patients with dMMR/MSI-H endometrial cancer and 161 patients with MMRp/MSS disease were enrolled and received Jemperli treatment. These populations constituted the safety populations for cohorts A1 and A2, respectively. The primary efficacy population included those who were followed for 24 weeks or more during the study and had at least one measurable lesion at baseline, according to BICR. In total, 105 patients with dMMR/MSI-H disease and 156 patients with MMRp/MSS disease were available for analysis.
The median age of patients was 64 years old (range 30-86). Most patients with dMMR/MSI-H status had FIGO stage I or STAGE II disease at the time of initial diagnosis (54.3%); most patients in the MMRp/MSS cohort had FIGO stage III or STAGE IV disease (62.8%). In terms of histology, most patients in the A1 cohort showed grade 1/2 endometrial cancer (67.6%), while most patients in the A2 cohort showed serous diseases (37.8%). In the A1 and A2 cohorts, most patients had received at least one previous treatment (62.9% and 46.2%, respectively), and had previously received radiation therapy (70.5% and 60.9%, respectively).
Among endometrial cancer patients with dMMR/MSI-H (n = 105), 82.9% (n = 87) had TMB-H status, 12.4% (n = 13) had TMB-L status, and 4.8% (n = 5) had indeterminate TMB status. Among patients with MMRp/MSS disease (n = 156), 90.4% (n = 141) had TMB-L status, 7.0% (n = 11) had TMB-H status, and 2.6% (n = 4) had indeterminate TMB status. The median mutation/giant number was 20.17 (range, 2.52–428.69) in patients with dMMR/MSI-H type endometrial cancer (n = 100), while it was 3.78 (range, 0–83.22) in patients with MMRp/MSS type disease (n = 152).
The overall response rate (ORR) of Jemperli was 44.9% (95% CI, 34.8%–55.3%) in patients with TMB-H status (n = 44/98) and 13.0% (95% CI, 8.1%–19.3%) in patients with TMB-L (95% CI, 8.1%–19.3%). In patients with TMB-H and deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) status (n = 39/87), the ORR was 44.8% (95% CI, 34.1%–55.9%), compared to 23.1% (95% CI, 5.0%–53.8%) in patients with dMMR/MSI-H and low TMB status (n = 3/13). In patients with TMB-H status and mismatch repair proficient (MMRp)/microsatellite stable (MSS) disease, the ORR of this drug was 45.5% (95% CI, 16.7%–76.6%), while in patients with TMB-L status and MMRp/MSS disease it was only 12.1% (95% CI, 7.2%–18.6%) (n = 17/141).
The pre-specified interim analysis cutoff date was March 1, 2020. Additional data showed significant overlap between the TMB-high and dMMR/MSI-H patient populations. The response rates to Jemperli were similar for TMB-H and dMMR/MSI-H endometrial cancer, at 44.9% and 44.8%, respectively (n = 47/105; 95% CI, 35.0%–54.8%). Furthermore, the ORR achieved with this drug in patients with MMRp disease and TMB-H status was significantly comparable to that experienced by patients with dMMR/MSI-H and TMB-H status, at 45.5% and 44.8%, respectively. Among the 11 patients with MMRp/TMB-H endometrial cancer, all had MSI and POLe test results; according to Foundation Medicine's NGS test, one patient was MSI-H, one patient had a median MSI score, and nine patients were MSS. No mutations in the POLe exonuclease domain were found in any of the 11 patients.
Reminder: PD-1 immunotherapy Jemperli can produce a high response in TMB-H endometrial cancer patients, and it is expected to become a new treatment option for these patients.
