Jemperli (dostarlimab-gxly)

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

P2, N=340, Recruiting, GlaxoSmithKline | Trial completion date: Jan 2028 --> Oct 2028 | Trial primary completion date: Jan 2025 --> Oct 2025

P2, N=62, Recruiting, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Recruiting | N=31 --> 62 | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Feb 2025 --> Feb 2026

P1, N=18, Recruiting, University of Washington | Trial primary completion date: Sep 2024 --> Dec 2025

P2, N=23, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting

P1/2, N=4, Terminated, GlaxoSmithKline

P3, N=758, Active, not recruiting, GlaxoSmithKline | Phase classification: P2/3 --> P3 | Trial primary completion date: Oct 2024 --> Apr 2025

P2, N=42, Active, not recruiting, University of Hawaii | Recruiting --> Active, not recruiting | Trial completion date: Oct 2025 --> Oct 2027

P2, N=23, Not yet recruiting, GlaxoSmithKline

P1, N=141, Recruiting, GlaxoSmithKline | Suspended --> Recruiting | Trial completion date: Apr 2029 --> May 2030 | Trial primary completion date: Sep 2028 --> Oct 2029

Patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer receiving dostarlimab+carboplatin-paclitaxel demonstrated improvements in several QoL domains over patients receiving placebo+carboplatin-paclitaxel. The observed improvements in progression free survival and overall survival while improving or maintaining QoL further supports dostarlimab+carboplatin-paclitaxel as a standard of care in this setting.

P2, N=154, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting

Clinical inputs were sourced from primary clinical trials for each respective treatment (ie, dostarlimab + CP, CP, pembrolizumab, pembrolizumab plus lenvatinib, bevacizumab + CP, and pembrolizumab + CP). Introducing dostarlimab + CP as a first-line treatment for patients with pA/rEC results in minimal budget impact PMPM from a US third-party payers' perspective. Together with the efficacy and safety results from RUBY, these results support the use of dostarlimab + CP as a treatment option.

P2, N=120, Not yet recruiting, GlaxoSmithKline

P1, N=10, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting | N=18 --> 10 | Trial completion date: Jul 2026 --> Dec 2025 | Trial primary completion date: Sep 2025 --> Mar 2024

P1, N=20, Recruiting, Imperial College London | Trial completion date: Sep 2025 --> Apr 2026 | Trial primary completion date: May 2024 --> Apr 2026

P2, N=125, Active, not recruiting, Tesaro, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P2 | Trial completion date: Mar 2026 --> Apr 2027 | Trial primary completion date: Aug 2024 --> Aug 2025

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

P2, N=360, Recruiting, GlaxoSmithKline | Trial completion date: Aug 2027 --> May 2027 | Trial primary completion date: Sep 2025 --> May 2027

P2, N=23, Active, not recruiting, Trisha Wise-Draper | Trial completion date: Jun 2027 --> Jun 2025

P1, N=97, Active, not recruiting, GlaxoSmithKline | Trial primary completion date: Mar 2025 --> Apr 2024

Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017...Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting...Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab...CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia...This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.

For advanced cervical cancer, approved ICIs as second-line treatment include cemiplimab, nivolumab, and pembrolizumab as single agents. In the first-line treatment setting, options include pembrolizumab alone or in combination with bevacizumab, as well as atezolizumab combined with a backbone platinum-based chemotherapy plus bevacizumab...For endometrial cancer, pembrolizumab monotherapy, pembrolizumab in combination with lenvatinib, and dostarlimab are currently approved as second-line treatment options...Although the inclusion of these agents in clinical practice has led to improved overall response rates and survival outcomes, many patients still lack benefits, possibly due to multiple intrinsic and adaptive resistance mechanisms to immunotherapy. This review aims to highlight the rationale for utilizing ICIs and their current role, while also delineating the proposed mechanisms of resistance to ICIs in cervical and endometrial cancer.

P1/2, N=131, Not yet recruiting, GlaxoSmithKline

P2, N=120, Recruiting, UNICANCER | Not yet recruiting --> Recruiting

P1/2, N=38, Suspended, Joseph Caster, Ph.D., M.D. | Recruiting --> Suspended

At this IA, belrestotug + dostarlimab demonstrated clinically meaningful anti-tumor activity at each dose and a manageable safety profile, supporting further evaluation in pts with previously untreated, unresectable LA/M PD-L1 high NSCLC. 1. Reck M, et al.