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Pharmacology: Pharmacodynamics: Mechanism of action: Dostarlimab is a humanised mAb of the IgG4 isotype that binds to PD-1 receptors and blocks the interactions of binding with its ligands PD-L1 and PD-L2. The inhibition of PD-1 pathway-mediated immune response results in reactivation of T-cell function such as proliferation, cytokine production, and cytotoxic activity. Dostarlimab potentiates T-cell responses, including anti-tumour immuno responses through blockade of PD-1 binding to PD-L1 and PD-L2. In syngeneic mouse tumour models, blocking PD-1 activity resulted in decreased tumour growth.
Clinical efficacy and safety: RUBY: Randomised controlled study of combination therapy in treatment of adult patients with primary advanced or recurrent EC: The efficacy and safety of dostarlimab in combination with carboplatin-paclitaxel were investigated in a multicentre, randomised, double blinded, placebo-controlled Phase 3 study conducted in patients with primary advanced or recurrent EC.
Patients were randomised (1:1) to receive dostarlimab 500 mg plus carboplatin AUC 5 mg/mL/min and paclitaxel 175 mg/m2 every 3 weeks for 6 cycles followed by dostarlimab 1000 mg every 6 weeks (n = 245) or placebo plus carboplatin AUC 5 mg/mL/min and paclitaxel 175 mg/m2 every 3 weeks for 6 cycles followed by placebo every 6 weeks (n = 249). Randomisation was stratified by MMR/MSI status, prior external pelvic radiotherapy, and disease status (recurrent, primary Stage III, or primary Stage IV).
The key eligibility criteria for the study were International Federation of Gynaecology and Obstetrics (FIGO) primary Stage III or Stage IV disease, including Stage IIIA to IIIC1 disease with presence of evaluable or measurable disease per RECIST v.1.1, Stage IIIC1 patients with carcinosarcoma, clear cell, serous, or mixed histology (containing ≥10% carcinosarcoma, clear cell, or serous histology) regardless of presence of evaluable or measurable disease on imaging, Stage IIIC2 or Stage IV disease regardless of presence of evaluable or measurable disease. The study also included patients with first recurrent EC with a low potential for cure by radiation therapy or surgery alone or in combination, including patients who had first recurrent disease and were naïve to systemic anticancer therapy or who had received prior neo-adjuvant/adjuvant systemic anticancer therapy and had a recurrence or progressive disease ≥6 months after completing treatment (first recurrence). Treatment continued for up to 3 years or until unacceptable toxicity, disease progression or investigator decision. Treatment could continue beyond 3 years or beyond disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed every 6 weeks through week 25, every 9 weeks through week 52 and every 12 weeks thereafter.
The primary efficacy outcome measures were progression-free survival (PFS) assessed by the investigator according to RECIST v1.1 in subjects with dMMR/MSI-H primary advanced or recurrent EC and in all subjects (overall population) with primary advanced or recurrent EC, and overall survival (OS) in all subjects (overall population) with primary advanced or recurrent EC. Secondary endpoints included objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central radiologists' (BICR) review and investigator assessment according to RECIST v1.1, and PFS2, defined as the time from treatment randomisation to the date of assessment of progression on the first subsequent anticancer therapy following study treatment or death by any cause, whichever was earlier.
A total of 118 patients with dMMR/MSI-H EC were evaluated for efficacy in the RUBY study. Baseline demographics and characteristics of the overall study population were: median age 64 years (49% age 65 years or older); 85% White, 9% Black, 2% Asian; and Eastern Cooperative Oncology Group (ECOG) performance score (PS) 0 (57%) or 1 (43%); and primary stage III 20%; primary stage IV 30%; recurrent EC 50%.
The identification of dMMR/MSI-H tumour status was prospectively determined based on local testing assays (IHC, PCR or NGS), or central testing (IHC) when no local result was available.
Efficacy results are shown in Table 1 and Figures 1, 2 and 3. The overall median treatment duration in weeks was 38 (range 2 to 193). Dostarlimab plus carboplatin-paclitaxel demonstrated statistically significant improvements in PFS in both the dMMR/MSI-H and overall populations and OS in the overall population versus placebo plus carboplatin-paclitaxel. (See Table 1.)
Click on icon to see table/diagram/imagePre-specified exploratory analyses of PFS and OS were performed in patients with MMRp/MSS EC (n = 376). The PFS HR was 0.76 (95% CI: 0.59, 0.98) with a median PFS of 9.9 months for dostarlimab plus carboplatin-paclitaxel (n = 192) versus 7.9 months for placebo plus carboplatin-paclitaxel (n = 184) (cut-off date 28 Sept 2022). The OS HR was 0.79 (95% CI: 0.60, 1.04) with a median OS of 34 months for dostarlimab plus carboplatin-paclitaxel versus 27 months for placebo plus carboplatin-paclitaxel (cut-off date 22 Sept 2023). (See Figures 1, 2 and 3.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageGARNET: patients with recurrent or advanced dMMR/MSI-H EC who have progressed on or after treatment with a platinum-containing regimen: The efficacy and safety of JEMPERLI monotherapy were investigated in the GARNET study, a multicentre, uncontrolled, multiple parallel cohort, open-label study. The GARNET study included expansion cohorts in subjects with recurrent or advanced solid tumours who have limited available treatment options. Cohort A1 enrolled patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) EC who have progressed on or after a platinum-containing regimen.
Patients received 500 mg dostarlimab every 3 weeks for 4 cycles followed by 1000 mg dostarlimab every 6 weeks. Treatment continued until unacceptable toxicity or disease progression for up to two years.
The major efficacy outcome measures were ORR and DOR as assessed by BICR review according to response evaluation criteria in solid tumours (RECIST) v1.1. The efficacy population was defined as patients who had measurable disease by BICR at baseline and had minimum of 24 weeks follow-up or had less than 24 weeks of follow-up and discontinued due to adverse events or disease progression.
A total of 143 patients with dMMR/MSI-H EC were evaluated for efficacy in the GARNET study. Among these 143 patients, the baseline characteristics were: median age of 65 years (52% aged 65 years or older); 77% White, 3.5% Asian, 2.8% Black; and ECOG PS 0 (39%) or 1 (61%). At the time of diagnosis, 21% of the patients with dMMR/MSI-H EC were FIGO Stage IV. At study entry (the most recent FIGO stage), 67% of the patients were FIGO Stage IV. The median number of prior lines of therapy was one: 63% of patients had one prior line, 37% had two or more prior lines. Forty-nine patients (34%) received treatment only in the neoadjuvant or adjuvant setting before participating in the study.
The identification of dMMR/MSI-H tumour status was prospectively determined based on local testing. Local diagnostic assays (IHC, PCR or NGS) available at the sites were used for the detection of the dMMR/MSI-H expression in tumour material. Most of the sites used IHC as it was the most common assay available.
Table 2 includes the efficacy data for the 143 patients. The overall median treatment duration in weeks was 34 (range 2 to 220). Twenty four percent of subjects who received any amount of dostarlimab received treatment ˃ 102 weeks (2 years). (See Table 2.)
Click on icon to see table/diagram/imageEfficacy and PD-L1 status: Clinical activity was observed regardless of tumour PD-L1 combined positive score (CPS) by IHC. The relationship between PD-L1 status and efficacy was analysed post-hoc in patients with available tissue samples (N = 81) among the efficacy population from Cohort A1 of the GARNET study using a data cut-off date of 01 March 2020. Among 23 patients with PD-L1 CPS <1%, ORR was 30.4% (7/23, 95% CI 13.2, 52.9) and among 58 patients with PD-L1 CPS ≥1%, ORR was 55.2% (32/58, 95% CI 41.5, 68.3).
Elderly patients: Of the 108 patients treated with dostarlimab in the GARNET study efficacy population, 50.0% were older than 65 years.
Consistent results were observed in the elderly population, where the ORR by BICR (95% CI) was 42.6% (29.2%, 56.8%) in patients ≥65 years.
Of the 53 patients treated with dostarlimab in combination with platinum-containing chemotherapy in the RUBY study efficacy population, 43.4% were older than 65 years.
Consistent results were observed in the elderly population, where an improvement in PFS by investigator according to RECIST v1.1 was demonstrated in patients ≥65 years randomised to dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel, HR of 0.25 (95% CI 0.11, 0.56).
Paediatric population: The licensing authority has deferred the obligation to submit the results of studies with dostarlimab in all subsets of the paediatric population in the treatment of all conditions included in the category of malignant neoplasms, except haematopoietic and lymphoid tissue (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: The pharmacokinetics (PK) of dostarlimab were assessed as a monotherapy and when administered in combination with chemotherapy.
Dostarlimab monotherapy or in combination with chemotherapy was characterised using population PK analysis from 869 patients with various solid tumours, including 546 patients with EC. When dosed at the recommended therapeutic dose for monotherapy (500 mg administered intravenously every 3 weeks for 4 doses, followed by 1,000 mg every 6 weeks), or at the recommended therapeutic dose for combination with chemotherapy (500 mg administered intravenously every 3 weeks for 6 doses, followed by 1000 mg every 6 weeks), dostarlimab shows an approximate two-fold accumulation (Cmin), consistent with the terminal half-life (t1/2). The exposure of dostarlimab as monotherapy and/or in combination with chemotherapy was similar.
Absorption: Dostarlimab is administered via the intravenous route and therefore estimates of absorption are not applicable.
Distribution: The mean volume of distribution of dostarlimab at steady state is approximately 5.8 L (CV% of 14.9%).
Biotransformation: Dostarlimab is a therapeutic mAb IgG4 that is expected to be catabolised into small peptides, amino acids, and small carbohydrates by lysosome through fluid-phase or receptor-mediated endocytosis. The degradation products are eliminated by renal excretion or returned to the nutrient pool without biological effects.
Elimination: The mean clearance is 0.007 L/h (CV% of 30.2%) at steady state. The t1/2 at steady state is 23.2 days (CV% of 20.8%).
Dostarlimab clearance was estimated to be 7.8% lower when dostarlimab was given in combination with chemotherapy. There was no meaningful impact on dostarlimab exposure.
Linearity/non-linearity: Exposure (both maximum concentration [Cmax] and the area under the concentration-time curve, [AUC0-tau] and [AUC0-inf]) was approximately dose proportional.
Pharmacokinetic/pharmacodynamic relationship: Based on exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety when doubling the exposure of dostarlimab. Full receptor occupancy as measured by both the direct PD-1 binding and interleukin 2 (IL-2) production functional assay was maintained throughout the dosing interval at the recommended therapeutic dosing regimen.
Special populations: A population PK analysis of the patient data indicates that there are no clinically important effects of age (range: 24 to 86 years), gender or race, ethnicity, or tumour type on the clearance of dostarlimab.
Renal impairment: Renal impairment was evaluated based on the estimated creatinine clearance [CLCR mL/min] (normal: CLCR ≥90 mL/min, n = 305; mild: CLCR = 60-89 mL/min, n = 397; moderate: CLCR = 30-59 mL/min, n = 164; severe: CLCR = 15-29 mL/min, n = 3 and ESRD: CLCR <15 mL/min, n = 1). The effect of renal impairment on the clearance of dostarlimab was evaluated by population pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of dostarlimab were found between patients with mild or moderate renal impairment and patients with normal renal function. There are limited data in patients with severe renal impairment.
Hepatic impairment: Hepatic impairment was evaluated as defined using the US National Cancer Institute criteria of hepatic dysfunction by total bilirubin and AST (Normal: total bilirubin (TB) & AST < = upper limit of normal (ULN), n = 772; mild: TB > ULN to 1.5 ULN or AST > ULN, n = 92; and moderate: TB > 1.5-3 ULN, any AST, n = 5). The effect of hepatic impairment on the clearance of dostarlimab was evaluated by population pharmacokinetic analyses in patients with mild hepatic impairment compared to patients with normal hepatic function. No clinically important differences in the clearance of dostarlimab were found between patients with mild hepatic impairment and normal hepatic function. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment.
Toxicology: Preclinical safety data: Nonclinical data reveal no special hazard for humans based on repeat-dose toxicity studies of duration up to 3 months in the cynomolgus monkey. No studies have been performed to assess the potential of dostarlimab for carcinogenicity or genotoxicity. Animal reproduction and development toxicity studies have not been conducted with dostarlimab. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss. These results indicate a potential risk that administration of dostarlimab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.
No notable effects on the male and female reproductive organs were observed in monkeys in the 1-month and 3-month repeat-dose toxicology studies; however, these results may not be representative at all of the potential clinical risk because of the immaturity of the reproductive system of animals used in the studies. Therefore, fertility toxicity remains unknown.
