Summit：我们认为中国仅有的HARMONi-6试验结果对全球III期试验无参考意义，HARMONi-3的总生存期预计无统计学意义

+1917 344 8613jeffrey.walch@bernsteinsg.comYiZhao +1 917 344 8324yi.zhao@bernsteinsg.com SMMT Summit: We see no read-through from China-only HARMONi-6to the global Ph3. Non-statistically significant OS expected forHARMONi-3 by Rebecca Liang) China-only HARMONi-6 (OSIA HR=0.66) offer limited or no read-through to expectations for SMMT's global HARMONi-3Ph3.The patient population forChina-only HARMONi-6 deviates signficantly from both historical global PD-1+VEGF Ph3trials and the expected population for SMMT's HARMONi-3. In particular, we note key trialdesigndifferencesandpatientselectionmethodologiesthatcouldfavorAkeso'sChina-only HARMONi-6 (exclusion of patients>75years old; only 3.8%female)vs HARMONi-3(no upper-bound age exclusion; historical ~33% female for global PD-1+VEGFPh3s) andcontribute to our negative outlookfor SMMT's global ivonescimab Ph3 trials in NSCLC. The differential efficacyfor ivonescimab is demonstratedby the recent negative PFS interimanalysis for SMMT's global HARMONi-3 (equates to HR >0.67-0.71 via our outside-inanalysis).This result was signifciantly less favorable than the positive PFS analysis forAkeso's China-only HARMONi-6 (reported HR=O.60O).Akeso's HARMONi-6OS interimresult (HR= O.66) passed the critical value threshold. However, it continued the pattern ofdurability degradation for anti-VEGF mAb from PFS to OS: in this case degrading from HR=O.60 to 0.66.We expectthecontinued durability degradation from PFSto OSto occur inHARMONi-3resulting in ivonescimab's failure topass (our outside-in calculated)critical valueFthreshold for OS IA (HR CV= 0.71-0.75 in 2H'26) and OS FA (HR CV= 0.81 in 2H'27). Thus,we reiterateourbasecaseprojectionof non-statisticallysignificantoverall survival read-outsforHARMONi-3/-7inNSCLC. InvestmentImplications We rate SMMTUnderperform withPT $7.70(-56%) based on our DCFvaluation. 1.We reiterate ourbase case projectionfor HARMONi-3:Overall survival trendwitha non-statisticallysignificant hazardratio 2.We sharpenouranswers forHARMONi-3 and HARMONi-7's risk-adjusted revenueprojections:Increase PTSand decrease market share to accountfor the potential of a positivetrial with low-clinical significance NON-STATISTICALLYSIGNIFICANTHAZARDRATIO HR= 0.60 in China-only HARMONi-6WehypothesizethatthepotentialbiologicalrationaleandexplanationfordifferentialperformancebetweenglobalvsChina onlytrials for ivonescimab is due to the projected differences in the ITT patient populations (e.g.,age, sex) Exhibit 1. Ivonescimabis not unique to see differential results between experiments (e.g., clinical trials). Efficacy results for the same drug in the samesetting can be different even when repeat trials are conducted in the same regions. However,given differences in inclusion/O.60)to continue through the OS analyses. OURHYPOTHESIS:IVONESCIMAB'SDIFFERENTIALPERFORMANCEISDUETOSIGNIFICANTLYDIFFERENTPATIENTSELECTIONMETHODOLOGIESFORHARMONI-3VSHARMONI-6 China-only HARMONi-6 excluded patients >75 years old, which deviates from historical global PD-1+VEGF trialsand SMMT's global HARMONi-3 Ph3 Akeso's China-only HARMONi-6's excluded patients>75 years old Exhibit 1.HARMONi-3,as well as other prior global anti-PD-1 + anti-VEGF Ph3 trials, do not contain this age cap restriction within their inclusion/exclusion criteria Exhibit 2. The resultsfor HARMONi-3 have yet to be disclosed, therefore limiting our outside-in analysis to be only hypothesis generating. However,historical results of anti-PD-1 + anti-VEGF Ph3 trials in NSCLC have demonstrated decreased efficacy (increased HR)forpatients with advanced age (e.g., either >65 or >75 years old) vs the general ITT population Exhibit 2. In addition, reducedeffiacy for addition of anti-VEGF for advanced age patients was also evident in HARMONi-6's OS IA: ITT HR= 0.66, vs Age 65+HR=0.93. All three trials (LEAP-006, LEAP-007 and IMPower150) did not feature an age cap within their inclusion/exclusion criteria.IMPower150 presented efficacydata forthe>75 yearold patientpopulation.However,bothLEAP-006 andLEAP-007presented overall survival data for patients >65 years old.The IMPower150 data set for patients >75 year old (N=56)demonstrated greater efficacy degradation (HR= 1.39) vs ITT (HR= 1.01) compared to the LEAP-006 and LEAP-007 subgroupdata for patients 65+ years old. The biological rationalefor historical decreased efficacy of anti-VEGF in patients with advanced age maybe explained by theolder vs patients younger than 70 years old (Selle et al, International Journal of Gynecological Cancer & Volume 28, Number 4,May 2018). significantly from ~33% in historical global PD-1+VEGF trialsAkeso's China-only HARMONi-6's effectively excluded female patients from the ITT population: only 3.8% of patients in the ivonescimab arm were female.This leads to signficant challenges in applying HARMONi-6's results to the broaderglobal patientpopulation. As a reference point, historical global PD-1+VEGF Ph3 trials in NSCLC (LEAP-007, LEAP-006, IM