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Accelerated approval of enfortumab vedotin-ejfv + pembrolizumab for locally advanced or metastatic urothelial carcinoma

The FDA granted accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

  
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Efficacy was evaluated in EV-103/KEYNOTE-869 (NCT03288545), a multi-cohort (dose-escalation cohort, Cohort A, Cohort K) study. The dose-escalation cohort and Cohort A were single-arm cohorts treating patients with enfortumab vedotin-ejfv plus pembrolizumab, while patients on Cohort K were randomized to either the combination or to enfortumab vedotin-ejfv alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. A total of 121 patients received enfortumab vedotin-ejfv plus pembrolizumab.

 

The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68 percent (95% CI: 59, 76), including 12 percent with complete responses. The median DoR for the dose-escalation cohort + Cohort A was 22 months (range: 1+ to 46+) and for Cohort K was not reached (range: 1 to 24+).

 

The most common adverse reactions (>20%), including laboratory abnormalities, were increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, increased potassium, increased calcium, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.

 

The recommended enfortumab vedotin-ejfv dose when given with pembrolizumab is 1.25 mg/kg (up to a maximum of 125 mg for patients >=100 kg) administered as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. The recommended pembrolizumab dose, administered after enfortumab vedotin on the same day, is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

 

Fast Track Designation for SynKIR-110 to Treat Mesothelioma

Investigational new drug, SynKIR-110, received Fast Track designation from the FDA for the treatment of patients with mesothelioma. This designation is designed to facilitate the development and expedite the review of drugs intended to treat serious or life-threatening conditions and address unmet medical needs, thus enabling drugs to reach patients sooner.

 

SynKIR-110 is an investigational new drug for the treatment of mesothelin-expressing mesothelioma, cholangiocarcinoma, and ovarian cancer. Researchers are conducting a Phase I multicenter clinical trial in these tumor types to evaluate the safety, feasibility, and anti-tumor activity of SynKIR-110 (NCT05568680). They are also developing innovative treatments for patients with serious and life-threatening conditions using its novel KIR-CAR platform.

 

The KIR-CAR platform is a dual-chain CAR T-cell therapy and has been shown in preclinical animal models to be capable of maintaining antitumor T-cell activity even in challenging solid tumor environments. DAP12 acting as a novel costimulatory molecule for T cells aids additional T cell-stimulating pathways, further sustaining chimeric receptor expression and improving KIR-CAR T-cell persistence. This continued T-cell function and persistence can lead to ongoing regression of solid tumors in preclinical models, including those refractory to traditional CAR T-cell therapies. Furthermore, the KIR-CAR platform can be combined with many additional emerging technologies, such as in vivo gene engineering, advanced cell manufacturing and reprogramming, combinational therapies, and even allogeneic cellular therapies to provide the next-generation multimodal targeted immunotherapy for patients in need.