乳腺癌 - SERENA-6和VERITAC-2数据符合预期

Issuer of report:HSBC Bank plcView HSBC Global Research at:https://www.research.hsbc.comListen to our insightsFind out moreHSBC Global Research PodcastsRajesh Kumar*Head, European Life Sciences & Healthcare ResearchHSBC Bank plcrajesh4kumar@hsbcib.com+44 20 7991 1629Morten Herholdt*Analyst, Life Sciences & Healthcare ResearchHSBC Bank plcmorten.herholdt@hsbc.com+ 44 20 7992 4082Yifeng Liu*Analyst, Life Sciences & Healthcare ResearchHSBC Bank plcyifeng.liu@hsbc.com+44 20 7 9919355Shubhangi Gupta*, Ph.D.Analyst, Life Sciences & Healthcare ResearchHSBC Securities and Capital Markets (India) PrivateLimitedshubhangi.gupta@hsbc.co.in+91 80 4555 2143Yash Singhee*AssociateBangalore* Employed by a non-US affiliate of HSBC Securities (USA) Inc, and isnot registered/ qualified pursuant to FINRA regulationsEquitiesBiopharmaGlobal ◆◆◆ Context for the dataSeventy percentof breast cancer cases are characterised as ER+/HER2-(Estrogen receptorpositive & human epidermalgrowth factor receptor 2 negative). The standard first-line therapytends to be endocrine therapy + CDK4/6 inhibitors with anAromatase Inhibitor (AIs, e.g. letrozole).Sadly, most patients develop treatment resistance,leading to disease progression. ESR1 geneticmutation (c40-50% patients) is often the source of such resistance to the first line therapy.Medical consensus on standard of care following first line is lacking, with endocrine therapyremaining as the backbone.Fulvestrant(first-in-class selective ER degrader)is deliveredintramuscularly as it ashas poor solubility.Several targeted therapeutics are available as well,but these agents are associated with burdensome adverse events.Tumours with ESR1 mutationsbecomeresistant to aromatase inhibitors. However, thesetumours are expected to remainsensitive to selective estrogen-receptor degraders (SERDs,e.g. camizestrant or fulvestrant), which degrade and antagonize ER, or PROTAC degraders(e.g.vepdegestrant).Camizestrant’s SERENA-6 dataIn patients on first-line therapy (AI+CDK4/6) who develop resistance due to ESR1m, themutation might be detectable with a circulating ctDNA assaysixmonths prior to diseaseprogression. Such detection might allow for adaptive treatment to delay clinical progression by atimely switch to a SERD. Earlier evidence from such a switch with fulvestrant (with palbociclib)was the basis for this hypothesis. SERENA-6 tested this hypothesis forcamizestrant.1.Patientswith HR+/HER2advanced breast cancer with greater thansixmonths on first-linearomatase inhibitors(anastrozole/letrozole) + CDK4/6i (abemaciclib/palbociclib/ribociclib)enrolledforctDNA testingfor ESR1m(2-3 monthswith routine imaging).Those withevidence of molecularESR1m(with or without physical evidence of mutation and drugresistance)were randomised 1:1 to switch to camizestrant (75 mg) with continued CDK4/6i(type and doseunchanged, and placebo replacing aromatase inhibitor) versuscontinuingAI + CDK4/6i + placebo for camizestrant.2.The primary endpoint was investigator-assessed PFS (per RECIST v1.1). Prespecifiedinterim analysis data cutoff was28Nov 2024. 33.After 171 PFS events,HR (hazard ratio)for PFS was 0.44 (95% CI 0.31–0.60, p<0.00001;median PFS 16.0 vs 9.2 months), withbenefit consistent across subgroups.4.12-monthPFS rate 60.7% (95% CI 51.1–69.0)for active arm (vs 33.4% (95% CI 24.9–42.2)for control).At 24 monthsthePFS rate was29.7% (95% CI 19.0–41.2)for active arm (vs5.4% (95% CI 0.7–18.2)for control).5.PFS2 hazard ratio was 0.52 (95% CI 0.33–0.81; 27% maturity).OS is immature (12%).6.Adverse events>=grade 3 were reported in 60%patientsin the camizestrantarm (45.8% inthecontrol arm). The increased risk in the camizestrantarmwasmainly dueto hematologicadverse events, but consistent with the control arm on an exposure time-adjusted basis.Treatment discontinuationratedue toAEwere 1.3% for camizestrant(1.9% for AI).Vepdegestrant’s VERITAC-2 dataThe hypothesis was that Vepdegestrant’s different mechanism (proteolysis-targeting chimera(PROTAC) ER degrader) as a different and more efficacious option in the second line setting.The clinical data supports the hypothesis, albeit scope for further expansion into otherindications seems limited.1.Vepdegestrant demonstrated statistically significantandclinically meaningful improvementinprogression free survival (PFS) (vs fulvestrant)in the ESR1m population.PFS by BICRwas significantly longer with vepdegestrant(vs fulvestrant)amongpatientswith ESR1m(174 events, HR=0.57 [95% CI 0.42–0.77]; P=0.0001); mPFS (95% CI) was 5.0months(3.7–7.4)(vsfulvestrant2.1months(1.9–3.5)).2.No statistically significant improvement in PFS was observedin the all patient population(mPFS (95% CI)was 3.7 months(3.6–5.3) vs 3.6 (2.2–3.8).3.Well tolerated with low discontinuation rates due to TEAEs (treatment-emergent adverseevents) were mostly grade½;Grade≥3 TEAEs occurred in 23.4% ofpatientsin thevepdegestrant arm (vs 17.6% fulvestrant); TEAEs led to discontinuation of vepdegestrant in2.9% ofpatients(vs 0.7% fulvest