2018-11-08| Trials & Approvals

Next Gen IO update – early phase clinical trials of anti-TIGIT/LAG3 antibodies

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By Ajay V. Patil

Development of immunotherapy drugs against CTLA4, PD-1 and PD-L1 followed screening, early phase investigations for some promising next generation targets. Updates from investigative studies of MK-4280 (anti-LAG3) and MK-7684 (anti-TIGIT) are scheduled to be unveiled at SITC 2018 meeting.

Next generation checkpoint therapies and early phase clinical trials in focus

CTLA4, PD1 and PD-L1 class of immunotherapies paved new therapeutic regimens for multiple cancers and they are now considered as promising therapies against several advanced stage metastatic tumors. The search for next generation candidates in this class gave rise to screening of various checkpoint proteins including; LAG-3, TIM-3, TIGIT, VISTA, OX40, ICOS, GITR, 4-1BB and CD40. Some of them are already in the early stage clinical trials. Two such important studies are being carried out (by Merck & Co.) for MK-4280 (anti-LAG3 monoclonal antibody) and MK-7684 (anti-TIGIT monoclonal antibody). Both of them are open-label, multi-arm, multicenter, dose-finding clinical trials with primary study objectives set for evaluation of safety and tolerability, pharmacokinetics, and objective response rate (ORR).

MK-4280 (anti-LAG3) early phase preliminary data

This anti-LAG-3 therapy, was evaluated both as monotherapy (n=18) and in combination with KEYTRUDA® pembrolizumab (n=15) in 33 patients with metastatic solid tumors who had failed standard treatment options. Dose range – 7, 21, 70, 210, and 700 mg for MK-4280 and pembrolizumab was used at fixed dose of 200 mg administered every three weeks for 35 cycles or until progression, intolerable toxicity, or investigator or patient decision.

In preliminary update; one partial response was observed (6%) (n=1/18) for monotherapy arm and partial responses were observed in four patients (n=4/15) (27%) of combination arm. Disease control rates; 17 percent for monotherapy and 40 percent for combination arm. Among treatment related adverse effects (TRAEs), 6 percent and 20 percent were grade 3-4 toxicities in monotherapy and combination arms respectively. Six percent of patients in the monotherapy arm and 13 percent of patients in the combination arm discontinued treatment. The most common TRAEs were fatigue and arthralgia in the monotherapy arm and fatigue, pyrexia, pruritus, and maculopapular rash in the combination therapy arm.

MK-7684 (anti-TIGIT) early phase I preliminary data

This anti-TIGIT therapy, was investigated as monotherapy (n=34) and in combination with Pembrolizumab (n=34) in advanced solid tumor bearing patients who had failed standard treatment options. MK-7684 (dose range: 2.1, 7, 21, 70, 210 and 700 mg) and pembrolizumab (200 mg fixed dose) were administered every three weeks for up to 35 cycles or until progression, intolerable toxicity, or investigator or patient decision. Thirteen patients who progressed on the monotherapy arm were crossed over to the combination arm.

In the monotherapy and combination arms, one partial response (3%) (n=1/34) and eight partial responses were observed (19%) (n=8/43), and the disease control rates were 35 percent and 47 percent, respectively. Preliminary data showed no dose limiting toxicities. In monotherapy and combination arms, 6 percent and 11 percent grade 3-4 toxicities were observed respectively. No patients discontinued because of TRAEs. The most common TRAEs were fatigue and pruritus in the monotherapy arm and pruritus in the combination arm.





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