Citi’s Take – The incremental nature of data from novel IO combinations isintensifying the interest in biomarkers and personalized immuno-oncology. Wecontinue to believe that BMY has included TMB (baseline tumor mutational load)within the primary endpoint of their 1st line NSCLC trial CHECKMATE-227 (Alert:BMY: CHECKMATE-227 Odds Maybe Just Got a Whole Lot Better. Reiterate BUY).    The elucidation of PDx resistance mechanism is forcing clinical pipelines to largelypivot away from inhibitory checkpoints towards the mutation-neoantigen-IFNgammaaxis (vaccines, oncolytic viruses, STING, TLR and RIG-I) and synthetic T cellactivation (bispecifics and cell therapy). We prefer Buy-rated AZN and Bayer amongthe EU majors. We prefer Buy-rated BMY, LLY and MRK in the US.    Baseline mutational load clearly on the minds of FDA – We were struck by theFDA session on biomarker use in the clinical setting. Following September’s FDAindustry meeting, the agency is committed to “pre-competitive” initiatives, toharmonize the TMB diagnostic and cut-off points upfront to avoid the confusionexperience from PD-L1 IHC experience. We anticipate that similar to CML, liquidassays will inform therapeutic management of many solid tumors within the next 5years.    BMY establishing Foundation One as validated TMB diagnostic–BMYpresented details from a bridging analysis to show calibration of Foundation OneF1) to whole exome sequencing (WES). The analysis concluded high concordancebetween F1 and WES, and supports harmonization of data across platform. Thelower cost and tissue requirements for Foundation One reduce practical barriers toadoption, however the current 12 day turnaround time remain problematic forclinicians.    Early winners and losers – We were struck by recent publications highlighting40% prevalence of HLA LOH as a PDx resistance mechanism in NSCLC. We wereintrigued by claims that RIG-1 (Merck licensed Rigontec) activation could restoreHLA expression and overcome resistance. On the clinical side, we found themonotherapy efficacy from Corvus’s A2A receptor inhibitor CPI-444 andcombination data from ARMO’s AM0010 (IL10) and Nektar’s NKTR-214 (IL2agonist) notable. BMY/ Five Prime’s CSF1R combo in heavily pre-treatedpancreatic cohort (MSS) showing limited but deep and durable responses in aknown very poor responders to PDx monotherapy. On the disappointing sideMerck’s KGaA’s PD-L1/ TGF-beta fell short of initial hopes given limited responses.    However, similar to Roche’s TCB CEA, the spider plots are more encouraging. Fulldetails of individual sessions are available on request.

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