Dostarlimab
Dostarlimab, marketed under the brand name Jemperli, is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively binds to the programmed death-1 (PD-1) receptor on T cells, blocking its interaction with ligands PD-L1 and PD-L2 to reinvigorate anti-tumor immune responses.[1] Developed as an immune checkpoint inhibitor, it is administered intravenously and primarily targets cancers with high immunogenicity, such as those exhibiting microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) phenotypes.[2] The U.S. Food and Drug Administration (FDA) granted accelerated approval to dostarlimab in April 2021 for adult patients with dMMR recurrent or advanced endometrial cancer who have progressed on or following prior platinum-containing therapy.[3] This was converted to full approval in February 2023 based on confirmed objective response rates from the GARNET trial, demonstrating durable responses in this patient population.[4] In July 2023, the FDA approved its use in combination with carboplatin and paclitaxel followed by single-agent dostarlimab for primary advanced or recurrent endometrial cancer, regardless of mismatch repair status, supported by improved progression-free survival in the RUBY trial; this indication expanded to all such patients in August 2024.[5][6] A defining clinical achievement emerged from a phase II trial at Memorial Sloan Kettering Cancer Center, where dostarlimab monotherapy yielded a 100% clinical complete response rate among 42 patients with locally advanced dMMR rectal cancer after six months of treatment, eliminating the need for chemoradiotherapy or surgery in responders with sustained responses observed up to four years.[7][8] These results, while preliminary due to the small cohort and ongoing need for mature overall survival data, highlight dostarlimab's potential in neoadjuvant settings for hypermutated tumors, prompting FDA breakthrough therapy designation for this indication in December 2024.[9] Common adverse events include fatigue, anemia, and immune-related toxicities such as hypothyroidism, consistent with PD-1 inhibitors, though severe events occur in a minority of cases.[10]Medical Indications
Endometrial Cancer
Dostarlimab-gxly (Jemperli) received accelerated approval from the U.S. Food and Drug Administration (FDA) on April 22, 2021, for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that progressed on or following prior platinum-containing therapy, based on objective response rates from the GARNET trial.[11] This was converted to regular approval on February 9, 2023, supported by continued response durability and confirmed clinical benefit in the same population.[4] In the GARNET phase 1 trial, single-agent dostarlimab demonstrated an objective response rate (ORR) of 41.6% in 153 patients with dMMR endometrial cancer, with 9.8% complete responses and median duration of response not reached after a median follow-up of 11.2 months; progression-free survival (PFS) at 6 months was 58.2%.[12] In contrast, the ORR was 15.6% in proficient mismatch repair (pMMR) endometrial cancer patients, indicating substantially lower antitumor activity in this subgroup.[13] Responses in dMMR cases were durable, with 95.4% ongoing at 6 months and 57.1% at 12 months, supporting its use as monotherapy in platinum-refractory settings.[14] The RUBY phase 3 trial evaluated dostarlimab plus carboplatin and paclitaxel followed by single-agent dostarlimab versus placebo plus chemotherapy in 494 patients with primary advanced or first recurrent endometrial cancer.[6] The combination significantly improved median PFS to 10.6 months versus 5.5 months in the control arm (hazard ratio [HR] 0.64; 95% CI, 0.51-0.80; p<0.0001), with greater benefit in dMMR patients (HR 0.28; 95% CI, 0.16-0.50).[15] Interim overall survival (OS) data showed a 36.1% reduction in death risk overall (HR 0.64; 95% CI, 0.48-0.85; p=0.002), maturing to 33% with trends favoring the dostarlimab arm across molecular subgroups.[16] FDA approval for this regimen in primary advanced or recurrent disease occurred on July 31, 2023, initially without MMR restriction, and was expanded on August 1, 2024, to all adult patients regardless of MMR status, reflecting the overall PFS and OS benefits despite attenuated efficacy in pMMR cohorts.[5][6]Mismatch Repair Deficient Solid Tumors
Dostarlimab received accelerated FDA approval on August 17, 2021, as monotherapy for adult patients with mismatch repair deficient (dMMR) recurrent or advanced solid tumors that have progressed following prior treatment, when no satisfactory alternative options exist, as confirmed by an FDA-approved companion diagnostic test.[17] This broad tumor-agnostic indication targets the approximately 2% to 3% of solid tumors characterized by dMMR status, which impairs DNA repair and often correlates with high microsatellite instability (MSI-H), rendering tumors responsive to PD-1 inhibition.[18] Approval was based on objective response rates (ORR) from the GARNET trial (NCT02715284), a multicenter phase 1/2 study, with confirmatory trials required to verify clinical benefit.[19] In GARNET cohort A1, comprising 153 patients with dMMR/MSI-H advanced solid tumors after prior systemic therapy, dostarlimab (500 mg IV every 3 weeks for 4 cycles, then 1000 mg every 6 weeks) yielded a confirmed ORR of 41.6% (95% CI: 34.9%-48.6%), including 10.1% complete responses and 31.5% partial responses, per RECIST v1.1 criteria assessed by blinded independent central review.[17][20] Responses were durable, with 95.7% ongoing at 6 months and 75.5% at 12 months among responders; median duration of response was not reached after a median follow-up of 20.7 months, and median progression-free survival was 6.3 months.[19] Efficacy extended across 16 tumor types, including endometrial (ORR 43.7%), colorectal (38.6%), gastric/GEJ (50.0%), and cervical cancers, with no significant differences by prior line of therapy or PD-L1 status.[21] As of 2025, the solid tumor indication remains accelerated, distinct from the 2023 regular approval limited to dMMR endometrial cancer, reflecting ongoing need for randomized data in non-endometrial dMMR contexts.[4] Emerging neoadjuvant data from investigator-initiated trials suggest high pathological complete response rates (up to 82% across dMMR solid tumors), potentially sparing surgery in locally advanced cases, though these remain off-label and investigational pending prospective validation.[18] Patient selection relies on validated dMMR testing via immunohistochemistry or PCR for MSI, emphasizing the role of biomarker-driven therapy in this heterogeneous population.[22]Colorectal and Rectal Cancers
Dostarlimab, a PD-1 inhibitor, has demonstrated efficacy in mismatch repair-deficient (dMMR) colorectal cancers as part of its broader accelerated approval for dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment, with the U.S. Food and Drug Administration granting this indication on August 17, 2021, based on data from the phase 1 GARNET trial showing an objective response rate (ORR) of 41.6% across dMMR tumor types.[3] In the GARNET trial's dMMR cohort (n=153 evaluable patients, including colorectal cases), the ORR was 41.6% (95% CI: 34.0-49.5), with 9.2% complete responses and a median duration of response not reached at 19.1 months' median follow-up; subgroup analysis for dMMR colorectal cancer specifically reported responses, though dMMR status limits applicability to approximately 5% of colorectal cancers.[19] These results reflect dostarlimab's role in unleashing T-cell responses against tumors with high microsatellite instability (MSI-H) or dMMR, a mechanism particularly effective in hypermutated colorectal tumors refractory to standard chemotherapy.[19] In locally advanced rectal cancer, a subset of colorectal malignancies, dostarlimab monotherapy has yielded unprecedented clinical complete response (cCR) rates in dMMR/MSI-H cases. A single-arm phase 2 trial (NCT02975785) at Memorial Sloan Kettering Cancer Center enrolled 42 patients with stage II/III dMMR locally advanced rectal adenocarcinoma, treating them with intravenous dostarlimab (500 mg every 3 weeks for 6 months); as of June 2024, all 42 achieved cCR by MRI, endoscopy, and digital rectal exam, with no disease progression, avoidance of chemoradiotherapy or surgery, and sustained responses beyond 12 months in initial completers.[8] Initial interim results from 12 patients, reported in 2022, similarly showed 100% cCR with no grade 3 or higher adverse events leading to discontinuation, highlighting potential organ preservation but limited by the small, non-randomized design and absence of long-term survival data.[7] The U.S. FDA granted breakthrough therapy designation for dostarlimab in untreated locally advanced dMMR/MSI-H rectal cancer on December 16, 2024, based on these findings, though full approval for neoadjuvant use awaits confirmatory trials like AZUR-2 (phase 3, perioperative dostarlimab vs. standard care).[23] Broader neoadjuvant applications across dMMR early-stage tumors, including non-rectal colorectal, were explored in an expanded cohort update presented in April 2025, where 6 months of dostarlimab in 103 patients (stage II-III) achieved 100% cCR in rectal cases (n= unspecified subset) but 63% in non-rectal dMMR cancers, with 92% 2-year relapse-free survival and low circulating tumor DNA levels predicting durable responses; these data support immunotherapy as a potential surgery-sparing option but underscore variability by tumor site and the need for randomized evidence.[24] Limitations include the rarity of dMMR in colorectal cancer (confining benefits to a minority), potential immune-related toxicities (e.g., colitis in up to 10-15% of PD-1 inhibitor trials), and lack of head-to-head comparisons with other immunotherapies like pembrolizumab, which showed similar ORRs in dMMR colorectal cohorts (e.g., 40% in KEYNOTE-177).[19] Ongoing studies, such as NCT05723562, aim to validate nonoperative management by comparing dostarlimab to standard trimodality therapy.[25]Adverse Effects
Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions with dostarlimab, a PD-1 inhibitor, arise from dysregulated immune activation against non-tumor tissues, potentially involving any organ system and manifesting at any time during or after treatment; these events can be severe, require intervention, or prove fatal.[26] In integrated safety analyses across trials such as GARNET (n=605 for single-agent use), immune-mediated reactions occurred in approximately 20-34% of patients, with grade ≥3 events in 4-11%; endocrinopathies like hypothyroidism were most frequent, while pneumonitis, colitis, and hepatitis were less common but carried higher risks of discontinuation or corticosteroid use.[26][27]| Adverse Reaction | All Grades (%) Single-Agent (n=605) | Grade ≥3 (%) Single-Agent | All Grades (%) Combination (n=241) | Grade ≥3 (%) Combination |
|---|---|---|---|---|
| Hypothyroidism | 8 | 0 | 12 | 0 |
| Hyperthyroidism | 2.3 | 0.2 | 3.3 | 0.4 |
| Adrenal Insufficiency | 1.2 | 0.7 | Not specified | Not specified |
| Pneumonitis | 2.3 | 1.0 | Included in overall | Included in overall |
| Colitis | 1.3 | 0.7 | Included in overall | Included in overall |
| Hepatitis | 0.5 | 0.5 | Included in overall | Included in overall |
Common Non-Immune Side Effects
In clinical trials evaluating dostarlimab as monotherapy, the most frequently reported non-immune-mediated adverse reactions (occurring in ≥20% of patients) included fatigue or asthenia (49% in dMMR endometrial cancer cohort; 42% in dMMR solid tumors cohort), anemia (35%; 30%), nausea (32%; 22%), diarrhea (29%; 25%), constipation (23%), and vomiting (23%).[26] These effects were generally mild to moderate, with grade 3 or 4 severity observed in a minority of cases, such as anemia (18% grade ≥3 in endometrial cancer) and fatigue/asthenia (3-4%).[26]| Adverse Reaction | Incidence (dMMR Endometrial Cancer, n=150) | Grade ≥3 (%) | Incidence (dMMR Solid Tumors, n=267) | Grade ≥3 (%) |
|---|---|---|---|---|
| Fatigue/Asthenia | 49% | 3.3 | 42% | 3.4 |
| Anemia | 35% | 18 | 30% | 11 |
| Nausea | 32% | 0.7 | 22% | 0.4 |
| Diarrhea | 29% | 2.7 | 25% | 1.5 |
| Constipation | 23% | 0.7 | - | - |
| Vomiting | 23% | 0.7 | - | - |