Jemperli (dostarlimab-gxly)

P1, N=18, Active, not recruiting, University of Washington | Recruiting --> Active, not recruiting

P2, N=62, Completed, GlaxoSmithKline

First-line durvalumab plus chemotherapy with olaparib, and dostarlimab plus chemotherapy, were more beneficial for survival in the pMMR/MSS and dMMR/MSI-H populations, respectively. Only pembrolizumab plus chemotherapy versus chemotherapy was cost-effective for patients with dMMR/MSI-H endometrial cancer in the USA.

P2, N=0, Withdrawn, AGO Research GmbH | N=100 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=0, Withdrawn, Vall d'Hebron Institute of Oncology | N=15 --> 0 | Not yet recruiting --> Withdrawn

Agents such as pembrolizumab and dostarlimab, particularly in combination with carboplatin and paclitaxel, have improved progression-free and overall survival rates for patients with MMR-deficient tumors. This review highlights the need for personalized, evidence-based approaches to gynecologic cancer screening and prevention in LS, emphasizing the importance of integrating genetic testing, patient education, and novel therapeutic options. Future research should focus on refining screening protocols and expanding non-invasive preventive strategies to improve outcomes for this high-risk population.

P4, N=100, Not yet recruiting, GlaxoSmithKline

AZUR-1 will evaluate the efficacy of dostarlimab immunotherapy in dMMR/MSI-H RC. Utilizing novel aspects including long follow-up of all patients and standardization of clinical response assessment, this study will provide international multicentric data to evaluate tumor response in an immunotherapy setting and new evidence on long-term outcomes.

Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for NTRK fusions; selpercatinib for RET fusions; dabrafenib and trametinib combination for BRAF V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden ≥10 mutations/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue-agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease.

P2, N=35, Recruiting, Hopital Foch | Not yet recruiting --> Recruiting

P2, N=23, Recruiting, GlaxoSmithKline | Trial primary completion date: Dec 2028 --> Oct 2027

P1, N=107, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | N=244 --> 107 | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Sep 2025 --> Dec 2025

P1/2, N=45, Not yet recruiting, iOnctura

P2, N=120, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting | Trial primary completion date: Sep 2028 --> Jul 2026

P1/2, N=95, Recruiting, GlaxoSmithKline | Trial completion date: Nov 2030 --> Jan 2032 | Trial primary completion date: Aug 2028 --> Oct 2029

P3, N=68, Recruiting, Centre Hospitalier Universitaire Dijon | Not yet recruiting --> Recruiting | Trial completion date: Dec 2030 --> Sep 2030 | Trial primary completion date: Dec 2030 --> Sep 2030

P2, N=10, Not yet recruiting, Universitaire Ziekenhuizen KU Leuven

P1/2, N=40, Not yet recruiting, GlaxoSmithKline | Trial completion date: Jul 2027 --> Jun 2028 | Initiation date: Aug 2024 --> Feb 2025 | Trial primary completion date: Jan 2027 --> Dec 2027

Accruals are expected to be completed by 2027, with the presentation of results by 2029. NCT06278857.

P2, N=0, Withdrawn, Ibrahim Halil Sahin | N=20 --> 0 | Trial completion date: Oct 2027 --> Jan 2028 | Initiation date: Oct 2024 --> Jan 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Oct 2026 --> Jan 2027

Dostarlimab plus CP is cost-effective as a treatment for the dMMR/MSI-H and overall populations of US patients with pA/rEC.

P2, N=22, Active, not recruiting, Mayo Clinic | Trial completion date: Sep 2024 --> Jun 2025

P3, N=68, Not yet recruiting, Centre Hospitalier Universitaire Dijon

P2, N=209, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Phase classification: P1/2 --> P2 | N=464 --> 209 | Trial primary completion date: Feb 2026 --> Feb 2029

P2, N=35, Not yet recruiting, Hopital Foch

P1/2, N=95, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting | Initiation date: Sep 2024 --> Dec 2024

P2; Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Sep 2024

A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.

They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms...For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.

This review analyzes the current landscape of existing randomized clinical trials, highlighting the efficacy of immune checkpoint inhibitors (ICIs) like pembrolizumab, avelumab, and dostarlimab. These findings underscore the importance of tailoring treatments based on the molecular characteristics of each tumor and paving the way for future advancements in the field of gynecologic oncology. Despite promising results, this article acknowledges the necessity of further research to refine patient selection criteria and explore combination strategies that can overcome resistance mechanisms.

Key to immunotherapy efficacy in EC is the tumor's mismatch repair status, with MMR-deficient tumors demonstrating a higher tumor mutational burden and increased PD-L1 expression, making them more susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab, durvalumab, and dostarlimab. To overcome resistance in cold tumors, novel therapies, including Chimeric Antigen Receptor (CAR) T cells and tumor-infiltrating lymphocytes are being explored, offering targeted immune-based strategies to enhance treatment efficacy. This review discusses the current understanding of immunotherapy in EC, emphasizing the prognostic and therapeutic implications of MMR status, TME composition, and emerging cell-based therapies.

P2, N=176, Completed, GlaxoSmithKline | Recruiting --> Completed | Trial completion date: Jul 2025 --> May 2024 | Trial primary completion date: Jul 2025 --> May 2024

P2, N=10, Recruiting, Queensland Centre for Gynaecological Cancer | Not yet recruiting --> Recruiting

P1/2, N=37, Recruiting, University of Alabama at Birmingham | Trial primary completion date: Dec 2024 --> Apr 2025

P2, N=25, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2026 --> Nov 2027 | Trial primary completion date: Oct 2025 --> Nov 2026

P3, N=785, Active, not recruiting, Tesaro, Inc. | Trial primary completion date: Sep 2022 --> Nov 2026

P1/2, N=38, Suspended, Joseph Caster, Ph.D., M.D. | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=42, Active, not recruiting, University of Hawaii | Trial primary completion date: Oct 2024 --> Oct 2025

Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

All primary and secondary efficacy assessments demonstrate the consistent benefit of dostarlimab plus carboplatin-paclitaxel. The improvements seen in survival and the manageable safety profile support the favorable benefit-risk profile for dostarlimab plus carboplatin-paclitaxel in patients with dMMR/MSI-H primary advanced or recurrent EC.

P1, N=141, Recruiting, GlaxoSmithKline | Trial completion date: Oct 2026 --> Sep 2028 | Trial primary completion date: Oct 2026 --> Sep 2028