靶向HER3在EGFR TKI抗性EGFR突变的非小细胞肺癌（NSCLC）中的作用

By Domenique Catalano April 2025 Targeting HER3 in EGFR TKI-resistant EGFR-mutatedNon-Small Cell Lung Cancer (NSCLC) The unmet need in EGFR-mutated NSCLCprogressing on osimertinib and platinum-based chemotherapy To date, multiple ADC and bsAb HER3-targetedtherapies are in clinical development, and asof December 2024, the US FDA approved itsfirst HER3-targeted antibody, zenocutuzumab(marketed as Bizengri, HER2/HER3 bsAb),for adults with NSCLC or pancreatic ductaladenocarcinoma (PDAC) harboring an NRG1gene fusion with disease progression on or afterprior systemic therapy.2This approval marks asignificant advancement for HER3 as a targetand bsAbs as a drug class, making this the 14thbsAb approved by the FDA. As a handful ofcompanies make brisk progression in this field,zenocutuzumab’s approval paves the way formore HER3-targeted therapies to support theevolving landscape for HER3 treatments. Effective treatment options are lacking forEGFR-mutated NSCLC patients who haveprogressed on standard-of-care, first-lineosimertinib (marketed as Tagrisso, third-generation EGFR tyrosine kinase inhibitor) andplatinum-based chemotherapy. The ability ofHER3 to heterodimerize with multiple partners,such as EGFR, HER, MET and PI3K, makesthis target a key player in acquired resistanceagainst targeted therapies.1 In NSCLC, HER3 overexpression is knownto enhance tumor proliferation, impactingresistance to EGFR tyrosine kinase inhibitors(TKIs).1Though its weak intracellular tyrosinekinase activity makes HER3 a challenging targetfor drug development, recent technologicaladvancements like antibody-drug conjugates(ADCs) and bispecific antibodies (bsAbs)have improved HER3’s targetability andpharmacological potential. Hence, targetingHER3 may be a valuable tool in this unmetNSCLC patient population. This analysis dives into the emerging HER3-targeted drugs and studies for EGFR-mutatedNSCLC patients who have progressed on priortreatment with osimertinib/EGFR TKIs andplatinum-based chemotherapies. Targeting HER3 in EGFR TKI-resistant EGFR-mutatedNon-Small Cell Lung Cancer (NSCLC) Prevalence of NSCLC and EGFR mutationsin NSCLC According to the World Health Organization(WHO), lung cancer is the leading cause ofglobal cancer incidence and cancer-relateddeaths worldwide, accounting for the highestmortality rates in men and women.3As depictedin Citeline’s Datamonitor Healthcare NSCLCEpidemiology Report, 508,039 newly diagnosedNSCLC cases were estimated across the US,Japan, France, Germany, Italy, Spain, and theUK in 2024, with 183,096 of those cases in theUS. By 2042, Citeline forecasts the number ofNSCLC diagnosed incident cases will increase by 33% to 244,253 new cases in the US aloneand by 22% to 618,618 across the seven majormarkets, including the US, Japan and 5EU.Despite rapid advancements, many NSCLCpatients face poor prognoses, mainly due tolack of effective treatment options for certaingenetic mutations or resistance to availabletherapies. The lack of effective therapies in thesecond-line NSCLC space is a huge unmet need,as evidenced by the growing number of NSCLCtrials across all lines of therapy in the last 10years, as shown in Figure 1. Targeting HER3 in EGFR TKI-resistant EGFR-mutatedNon-Small Cell Lung Cancer (NSCLC) Figure 2 shows that EGFR mutations are themost prevalent oncogenic driver mutation inNSCLC patients, where 14% to 38% of NSCLCpatients are diagnosed with EGFR mutations.4EGFR mutations are more prevalent in Asianand Caucasian populations, with EGFR exon 19 deletions or exon 21 L858R point mutationscomprising approximately 90% of all EGFRmutations.4EGFR’s prevalence defines it asa significant driver gene in this type of lungcancer. Targeting HER3 in EGFR TKI-resistant EGFR-mutatedNon-Small Cell Lung Cancer (NSCLC) Current standard-of-carein EGFR-mutated NSCLC EGFR TKIs altered the treatment landscapefor advanced EGFR-mutated NSCLC patients.While first- or second-generation EGFR TKIslike afatinib (Gilotrif), erlotinib (Tarceva), andgefitinib (Iressa) are approved as first-linetherapy and have been clinically shown toimprove median progression-free survival,many patients develop resistance. The twomost common resistance mutations are EGFRexon 20 insertion and p.T790M mutations.Third-generation EGFR TKIs were developed totackle this resistance and have been approvedworldwide. Due to its superior efficacy as demonstrated inthe Phase III FLAURA trial, osimertinib remainsthe standard-of-care as the preferred treatmentfor NSCLC patients whose tumors harboractivating EGFR mutations (exon 19 deletionor L858R point mutation). However, resistantmechanisms to osimertinib are quite diverse.Disease progression following treatment withthird-generation EGFR TKIs remains inevitable,and managing resistance is a struggle. Whileamivantamab plus chemotherapy is a category1 recommended treatment in NSCLC patientswith EGFR exon 19 deletions or exon 21 L858Rmutations who experienced disease progressionafter treatment with