Advancements in Fourth-Generation EGFR Targeted Drugs: 17 Investigational Drugs Overcoming Lung Cancer Resistance

I. Epidemiology of Lung Cancer and Current Status of EGFR Targeted Therapy

Lung cancer, as the leading cause of cancer-related mortality globally, ranks second in incidence among all cancers. Pathologically, non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, with epidermal growth factor receptor (EGFR) gene mutations being the most common driver mutation type. This discovery has opened new avenues for precision treatment of lung cancer.

In the Chinese NSCLC patient population, significant epidemiological characteristics are observed regarding sensitive EGFR mutations. Statistical data indicate that the overall mutation rate is about 30%, while this figure can rise to 40% within the adenocarcinoma subtype. Notably, among non-smoking lung adenocarcinoma patients, the mutation rate reaches as high as 50%. Even in squamous cell carcinoma patients—traditionally thought to have a lower EGFR mutation rate—approximately 10% exhibit detectable mutations in advanced cases. Additionally, a mutation rate of around 15%-20% is also seen in composite small cell lung cancer (c-SCLC).

II. Mutation Spectrum and Existing Treatment Bottlenecks for EGFR

Activating mutations of the EGFR gene primarily concentrate on exons 18-21 within its receptor tyrosine kinase (RTK) domain. In terms of mutation types, deletions at exon 19 (19del) and point mutations at exon 21 L858R constitute two common forms that together account for about 90% of all detected EGFR mutations; less common variants include insertions at exon 20 (20ins), G719X, S768I, and L861Q.

Currently available targeted therapies against EGFR mutations mainly fall into two categories: monoclonal antibodies and tyrosine kinase inhibitors (EGFR-TKIs). In clinical practice, due to their ease of administration and significant efficacy, TKI drugs have become mainstays in NSCLC targeted therapy. From first-generation to third-generation TKIs such as gefitinib, erlotinib, afatinib, and osimertinib have been successively introduced into clinical use significantly improving prognosis for patients positive for EGFR mutations.

However，as clinical applications deepen，the issue surrounding resistance to targeted drugs has become increasingly prominent。Approximately half to sixty percent（50%-60%）of first-generation TKI resistant patients develop secondary T790M mutations，而a considerable proportion treated with third-generation drug osimertinib subsequently produce triple C797S or other related alterations。这些不断演变的耐药机制推动着第四代EGFRTKI的研发进程。

III.Review on Development Status Of Fourth Generation EGFRTKIs

At present there are a total number seventeen fourth generation EGFRTKIs under different stages development worldwide ，some candidate drugs already entered clinical trials .These medications mainly overcome resistance through several mechanisms : specifically targeting C797S mutants , adopting allosteric inhibition strategies , developing bispecific antibodies etc .Below we will detail these investigational drugs’ features progress . 3.1 BBT-176：Triple Mutant Specific Inhibitor Developed by Bridge Biotherapeutics Company ,BBT -176 targets Del19/T790M/C797S & L858R/T790M/C797S triple mutant fourth generation target drug .Preclinical studies show that this medication not only exhibits strong anti-tumor activity but also demonstrates excellent blood-brain barrier penetration ability suppressing brain metastatic lesions effectively.Currently it’s undergoing phase I/II trial(NCT04820023 ) assessing safety tolerance preliminary efficacy advanced NSCLC patients . 3.2 BLU -945 & BLU -701：Complementary Combination from Blueprint Medicines ** nBLU -945 developed by Blueprint Medicines company stands out among fastest progressing fourth generation EGFRTKIs designed specifically targeting either19del or L858R/T790M/C797Striple mutants preclinical research indicates its inhibitory potency against triplet mutated tumor cells exceeds existing agents by1000 –2000 times.In phase I/II Symphony study involving thirty-three subjects diagnosed with EGFRT-mutated NSCLC one achieved partial remission alongside circulating tumor DNA(ctDNA ) tests revealing marked reduction T790MandC797Smutation load.As complementary agent ,BLU -701 displays superior activity towards single double mutantEGRFs exhibiting weaker response towards BLU –945 notably showcasing exceptional central nervous system permeability offering novel therapeutic optionsforbrain metastasispatients Currently it remains phase I trial stage(NCT05153408 ). n3..BPI361175：Breakthroughs from Domestic Innovative Drug **Developed independently by Betta Pharmaceuticals,BPI361175 primarily targets late-stageNSCLCpati ents harboringEGFRC79SMutationsandotherrelatedalterations.Preclinical evidence suggests this compound effectively inhibits proliferation C797Stumorcells demonstrating favorable antitumor effects across various models featuring diverseEGF Rmutationsrepresentative domestic innovative pharmaceutical companies signifying breakthroughs our country’sdevelopment field.Fourth Generation EGF RT K Is **4..Progress Innovations Mechanism Medications Allosteric inhibitors series JBJ–04–125–02&JBJ–09–063Inallostericinhibitorsresearchfield J BJ−04−125−02 optimized based early compoundEAI045highlyefficient lowtoxicitysmallmolecule.Besides original prototypedrug breakthrough lies solving requirement co-administration cetuximab allowing monotherapy feasibility.Preclinically studied combined usagewithosimertinibtogether yield strongeranti-tumor synergistic effect.JBJ −09 −063further optimization shows better suppression properties compared previous compounds exhibiting significantly enhanced inhibiting capabilitiesagainstL858R /T790MandL858R /T790 M/C7mutants whoseactivity completely unaffectedbyC79Smutationsprovidingnewtreatmentoptionsresistantpatients. n4..Bispecific Antibody ：JNJ61186372Innovative StrategyCo-developed Janssen GenmabJN JN61186372(JNJ372 )isbispecif ic antibody simultaneously targeting bothEG FRc-METThisinnovative design enables overcoming MET amplification induced resistance issues.Phase I clinical investigation(NCT02609776 ) enrolled108 previously treatedadvancedNSCLCEG F Rmutationpositive participants showingoverallresponse ratesup30 %effective across various subtypesbasedonthese findings FDA granted Breakthrough Therapy Designation March2020 treatingmetastaticNSCLCPatientsExon20InsertionMutations ### V Overview OtherInvestigationalDrugsBesides aforementioned keydrugsseveraladditionalfourthgenerationE GF RT K Isundergoingdifferentdevelopmentphases including Roche affiliated Sino foreign pharmaceutical CH7233163 employingnon-covalentbinding mechanism unaffectedbyC79 Smutations Chengdu Diaoj iuhong DAJH1050766 capable simultaneouslytargetingbothEF GRALKdoublemutantsFirst three共 U31402 anHER3-targettingantibodyconjugate(ADC ),demonstrates effectivenessagainstmultiplemechanismsresistance.Noteworthy domestic enterprises actively engage intheir ownFourth Generation EgfrTKIdevelopmentApartfromprevious mentionedBPI361175 Zhiqiang Tianqing’sTQB3804 QiluPharmaceuticalQLH11811 Suzhou JunjingBiotechnologyWJ13404alsoexhibit promisingpreclinicaldata somehaveenteredtrial phases marking rapid improvementChina'sinnovation capacitydrugsResearchDevelopment ### VI Future Prospects ChallengesThe ongoing development process forthgenerationEgfrTKIsoffers renewed hopeovercomingtheresistancetargettherapyBased currentprogress varyingstrategies tailored respondingdifferentresistance mechanismsare required For instance addressingC79Smutation necessitates creation more specific covalentnon-covalentinhibitors whilst bypass activation dual-targetmedicationsmay prove advantageous complexhistologicaltransformations requirecombinedtherapeuticapproaches.Although prospects appear bright investigationalmedicationsstill face numerouschallenges includingblood-brainbarrierpenetrationability off-targettoxicity optimizingcombinationregimensFurther research necessary accumulationmoreclini caltrialdatatheseforthgenerationegfrtkisexpectedbecomeavailablewithinnextthreefiveyears providinglungcancerpatientsmoreprecise durabletreatmentchoices.