Dostarlimab: From preclinical investigation to drug approval and future directions

Figures & data

Table 1. Summary of patient characteristics and key outcomes of trials with anti-PD-1/PD-L1 monoclonal antibodies in mismatch-repair deficient (dMMR) endometrial cancer (EC).

	KEYNOTE-158^Citation15, Citation16	NCT02912572^Citation17	PHAEDRA^Citation18	GARNET^Citation19–22
Study drug	Pembrolizumab	Avelumab	Durvalumab	Dostarlimab
Target antigen	PD-1	PD-L1	PD-L1	PD-1
Trial design	Phase II non-randomized	Phase II non-randomized	Phase II non-randomized	Phase I
Median follow-up time, months	42.6	18.6	19	27.6
dMMR EC patients, n	79	15	36	143
Number of previous lines allowed	>1	>1	0–3	1–2
Treatment-naïve patients, n (%)	0	0	21 (60)	0
ORR, n (%; 95%CI) CR, n(%) PR, n(%)	38 (48; 37–60)•  11 (14)•  27 (34)	4 (26.7; 7.8–55.1)•  1 (6.7)•  3 (20)	17 (47; 32–63)*•  6 (17)•  11 (31)	65 (45.5; 37.1–54) 23 (16.1) 42 (29.4)
PFS, months (95% CI)	13.1 (4.3–34.4)	4.4 (1.7 – NR)	8.3 (2.4 – NR)*	6.0 (4.1–18.0)
OS, months (95% CI)	NR (27.2 – NR)	NR	NR*	NR (25.7 – NR)
TRAE all grades, % (Grade 3 or higher, %)	76 (12)	71 (19.4)	93 (36)	63.6 (13.2)

Abbreviations: CI, confidence interval; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TRAE, treatment-related adverse events.

*Assessed by iRECIST.

Table 2. Key ongoing phase III and randomized phase II clinical trials of dostarlimab as a monotherapy or in combination with other agents in solid tumors.

NCT Number, Name (if available)	Phase	Target condition(s)	Study arm(s)	Primary endpoint(s)
NCT05201547, DOMENICA	III	Stage IV treatment-naïve dMMR EC	Dostarlimab vs SoC ChT	PFS
NCT04679064, NITCHE/MITO-33	III	Recurrent/advanced EC	Dostarlimab vs SoC ChT	OS
NCT04655946, COSTAR Lung	III	Stage IV NSCLC progressed after anti-PD(L)1 therapy and chemotherapy	ChT vs ChT + Dostarlimab ± Cobolimab	OS
NCT03602859, ENGOT-Ov44/FIRST	III	Stage III-IV treatment-naïve OC	SoC ± Dostarlimab followed by maintenance with Niraparib ± Dostarlimab	PFS in PD-L1+ pts, PFS in ITT
NCT03981796, RUBY	III	Recurrent/advanced EC	SoC ± dostarlimab followed by maintenance with placebo vs dostarlimab ± niraparib	PFS, OS
NCT04139902, NEO-MEL-T	II-R	Stage III-IV unresected melanoma	Dostarlimab ± Cobolimab	MPR
NCT03833479, ATOMICC	II-R	High risk LACC	Dostarlimab vs observation	PFS

Abbreviations: ChT, chemotherapy; dMMR, mismatch-repair deficient; EC, endometrial cancer; II-R, phase II randomized; ITT, intention-to-treat population; LACC, locally advanced cervical cancer; MPR, major pathological response; OC, ovarian cancer; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; SoC, standard of care.

Table 3. Summary of clinical outcomes in patients treated with dostarlimab monotherapy in the clinical trials published so far.

Condition^(reference)	N	ORR (95% CI)	DCR (95% CI)	DOR, months (range)	mPFS (95%CI), months	mOS (95%CI), months
dMMR Endometrial Cancer^Citation22	143	45.5% (37.1–54.0%)	60.1% (51.6–68.2%)	NR (1.18+ to 47.21+)	6.0 (4.1–18.0)	NR (25.7–NR)
pMMR Endometrial Cancer^Citation22	156	15.4% (10.1–22.0%)	34.0% (26.6–42.0%)	19.4 (2.8–47.18+)	2.7 (2.6–2.8)	16.9 (13.0–21.8)
Locally advanced Rectal Cancer^Citation29	12	100% (74–100%)	100% (74–100%)	NA	NA	NA
Non-Small Cell Lung Cancer^Citation31	67	26.9% * (16.8–39.1%)	62.7% * (50.0–74.2%)	11.6 * (2.8–19.4+)	7.0 (4.3–9.5)	18.8 (11.4–20.3)
dMMR Non-EC Solid Tumors^Citation32	106	38.7% (29.4–48.6%)	NA	NR	NA	NA

Abbreviations: DCR, disease control rate; dMMR, mismatch-repair deficient; DOR, duration of response; EC, endometrial cancer; OS, overall survival; NA, not assessed; NR, not reached; pMMR, mismatch-repair proficient; PFS, progression-free survival.

*Assessed per iRECIST.

Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. JCO. 2020 Jan 1;38(1):1–10. doi:10.1200/JCO.19.02105.

 PubMed Web of Science ®Google Scholar

O’malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, Miller WH, Safra T, Italiano A, Mileshkin L, et al. Pembrolizumab in patients with microsatellite instability–High advanced endometrial cancer: results from the KEYNOTE-158 study. JCO. 2022 Mar 1;40(7):752–61. doi:10.1200/JCO.21.01874.

 PubMed Web of Science ®Google Scholar

Konstantinopoulos PA, Luo W, Liu JF, Gulhan DC, Krasner C, Ishizuka JJ, Gockley AA, Buss M, Growdon WB, Crowe H, et al. Phase II Study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer. JCO. 2019 Oct 20;37(30):2786–94. doi:10.1200/JCO.19.01021.

 PubMed Web of Science ®Google Scholar

Antill Y, Kok PS, Robledo K, Yip S, Cummins M, Smith D, Spurdle A, Barnes E, Lee YC, Friedlander M, et al. Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial. J Immunother Cancer. 2021 Jun;9(6):e002255. doi:10.1136/jitc-2020-002255.

 PubMed Web of Science ®Google Scholar

Oaknin A, Pothuri B, Gilbert L, Sabatier R, Ghamande S, Gravina A, Calvo E, Banerjee S, Miller R, Pikiel J, et al. Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): the GARNET study. JCO. 2022 Jun 1;40(16_suppl):5509. doi:10.1200/JCO.2022.40.16_suppl.5509.

 Web of Science ®Google Scholar

Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, El Dika IH, Segal N, Shcherba M, Sugarman R, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med. 2022 Jun 23;386(25):2363–76. doi:10.1056/NEJMoa2201445.

 PubMed Web of Science ®Google Scholar

Moreno V, Roda D, Pikiel J, Trigo J, Bosch-Barrera J, Drew Y, Kristeleit R, Hiret S, Bajor DL, Cruz P, et al. Safety and efficacy of dostarlimab in patients with recurrent/advanced non–small cell lung cancer: results from cohort E of the phase I GARNET trial. Clin Lung Cancer. 2022 May;23(7):e415–27. S1525730422001152. doi:10.1016/j.cllc.2022.05.013.

 PubMed Web of Science ®Google Scholar

Andre T, Berton D, Curigliano G, Ellard S, Trigo Pérez JM, Arkenau HT, Abdeddaim C, Moreno V, Guo W, Im E, et al. Safety and efficacy of anti–pd-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: results from GARNET study. JCO. 2021 Jan 20;39(3_suppl):9. doi:10.1200/JCO.2021.39.3_suppl.9.

 Web of Science ®Google Scholar