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Approval to Dostarlimab-Gxly for dMMR Endometrial Cancer

The FDA approved dostarlimab-gxly for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation.


In April 2021, dostarlimab-gxly received accelerated approval for adult patients with dMMR recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen.

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Efficacy for the regular approval was evaluated in GARNET (NCT02715284), a multicenter, multicohort, open-label trial conducted in patients with advanced solid tumors. The efficacy population consisted of a cohort of 141 patients with dMMR recurrent or advanced endometrial cancer who had progressed on or after a platinum-containing regimen. Patients treated with prior PD-1/PD-LI-blocking antibodies and/or other immune checkpoint inhibitors, or who had autoimmune diseases requiring systemic immunosuppressant agents within 2 years were excluded.


The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1. Confirmed ORR was 45.4 percent (95% CI: 37.0, 54.0), with a 15.6 percent complete response rate and a 29.8 percent partial response rate. Median DOR was not reached, with 85.9 percent of patients having durations >=12 months and 54.7 percent of patients having durations >=24 months (range: 1.2+, 52.8+).


The most common adverse reactions (>=20%) were fatigue/asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting. Immune-mediated adverse reactions can occur, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and skin adverse reactions.


The recommended dostarlimab-gxly dose/schedule (doses 1-4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.


Fast Track Designation of Pan-FGFR Inhibitor for Cholangiocarcinoma

The FDA granted Fast Track designation for an investigational pan-FGFR inhibitor, KIN-3248, for the treatment of patients with unresectable, locally advanced, or metastatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other alterations, and who have received at least one prior systemic therapy.


KIN-3248 is an irreversible, small molecule pan-FGFR inhibitor designed to address primary FGFR2 and FGFR3 oncogenic alterations, including those predicted to drive acquired resistance to current FGFR-targeted therapies, such as gatekeeper, molecular brake, and activation loop mutations observed in cancers such as intrahepatic cholangiocarcinoma (ICC) and urothelial carcinoma (UC). In preclinical studies, KIN-3248 demonstrated inhibitory activity across a wide range of clinically relevant mutations that drive primary disease and acquired resistance to other FGFR inhibitors.


The KN-4802 clinical trial (NCT05242822) is an ongoing multi-center, open-label, two-part study of approximately 120 patients evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of KIN-3248 in adults with advanced tumors harboring FGFR2 and/or FGFR3 gene alterations. In dose escalation (Part A), the trial will determine the recommended dose and schedule of KIN-3248 for further evaluation in patients with FGFR2 and/or FGFR3 gene alteration-driven cancers. Dose expansion (Part B) will assess the safety and efficacy of KIN-3248 at the recommended dose and schedule in FGFR inhibitor-naive and FGFR inhibitor pretreated patients with cancers driven by FGFR2 and/or FGFR3 gene alterations, including ICC, UC, and other advanced or metastatic solid tumors in adults.


This trial is currently enrolling across multiple sites in the U.S. and Taiwan, with additional sites expected globally. Initial dose-escalation data is anticipated in the second half of 2023.


Metabolic Immune Checkpoint Inhibitor for Leukemia Relapse After Allogeneic Stem Cell Transplant

The FDA has granted Orphan Drug Designation for LR 09, a novel metabolic immune checkpoint inhibitor, for the treatment of patients with hematological malignancies who have been diagnosed with relapse after an allogeneic stem cell transplant (SCT). LR 09 is a novel, rationally designed form of ulodesine, a purine nucleoside phosphorylase (PNP) inhibitor originally developed for the treatment of autoimmune and inflammatory disorders.


The decision to develop LR 09 for the treatment of relapse after stem cell transplantation follows the achievement of complete remission in a 3-year-old patient using a pharmacologically analogous PNP inhibitor whose U.S. development was later discontinued, and the discovery that inhibition of PNP activates (instead of suppressing) the immune system.


Recent research at the University of California, Los Angeles (UCLA) has revealed a novel, groundbreaking mode of action for LR 09 as a metabolic immune checkpoint inhibitor and supports its development for the treatment of patients experiencing relapse after allogeneic SCT. The data, published in 2022 in the Journal of Clinical Investigation, has documented the immune-activating effects of LR 09 through the elevation of intracellular guanosine, TLR7 activation, and the activation and proliferation of T cells and germinal center B cells, resulting in the initiation of graft-versus-leukemia effects (2022;


With its favorable safety profile demonstrated in earlier clinical development and its improved stability and manufacturing process versus earlier PNP inhibitors, the Orphan Drug Designation for the U.S. market now adds to the promise of LR 09 as an oral immuno-oncology agent.


Rare Pediatric Disease Designation to FLAG-003 for Diffuse Intrinsic Pontine Glioma

FLAG-003, an investigational small molecule therapy for the treatment of diffuse intrinsic pontine glioma (DIPG), a rare, highly aggressive, and difficult-to-treat brain tumor found in children, has been granted Rare Pediatric Disease (RPD) designation from FDA. FLAG-003, a program for the treatment of all gliomas, is engineered to cross the blood-brain barrier and specifically target and kill cancer cells by simultaneously blocking the formation of a tumor vascular system and disrupting cancer cell replication by inhibiting tubulin. The FDA grants RPD designation to drugs intended for the prevention or treatment of rare pediatric diseases.


FLAG-003 is a novel, multi-specific, small molecule therapeutic designed to target, bind, and kill cancer cells through two well-established mechanisms of action (MoA): anti-angiogenesis and tubulin inhibition. By simultaneously constricting the tumor vascular system and inhibiting tubulin formation needed for cellular division, FLAG-003 holds the potential to kill cancer cells while leaving normal healthy cells unharmed.


Importantly, due to its remarkably low molecular weight, preclinical data have demonstrated the ability of FLAG-003 to cross the blood-brain barrier. as well as evade detection by the Pgp-efflux pump, two characteristics that make it a promising investigational product candidate for the treatment of gliomas, including glioblastoma multiforme and diffuse intrinsic pontine glioma.