Advertisement

Amivantamab, an epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) bispecific antibody, designed to enable multiple mechanisms of action and broad clinical applications

Open AccessPublished:November 10, 2022DOI:https://doi.org/10.1016/j.cllc.2022.11.004

      Abstract

      Substantial therapeutic advancements have been made in identifying and treating activating mutations in advanced non-small cell lung cancer (NSCLC); however, resistance to epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) inhibitors remains common with current targeted therapies. Amivantamab, a fully human bispecific antibody targeting EGFR and MET, is approved in the United States and other countries for the treatment of patients with advanced NSCLC with EGFR exon 20 insertion mutations, for whom disease has progressed on or after platinum-based chemotherapy. Preliminary efficacy and safety have also been demonstrated in patients with common EGFR- or MET-mutated NSCLC. Amivantamab employs three distinct potential mechanisms of action (MOAs) including ligand blocking, receptor degradation, and immune cell-directing activity, such as antibody-dependent cellular cytotoxicity and trogocytosis. Notably, efficacy with amivantamab does not require all three MOAs to occur simultaneously, broadening applicability by using diverse antitumor mechanisms. This review focuses on the molecular characteristics of amivantamab and its unique MOAs leading to in vitro and in vivo efficacy and safety in preclinical and clinical studies.

      Keywords

      Introduction

      Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide.
      • Sung H
      • Ferlay J
      • Siegel RL
      • Laversanne M
      • Soerjomataram I
      • Jemal A Bray.
      Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ,
      • Thai AA
      • Solomon BJ
      • Sequist LV
      • Gainor JF
      • Heist RS.
      Lung cancer.
      The disease is typically diagnosed in advanced or late stages for which treatment options are limited, and outcomes are generally poor. NSCLC has a 5-year survival rate of 14% for stage 3A, which drops to <5% for stages 3B and 4.
      • Mazzarella L
      • Guida A
      • Curigliano G.
      Cetuximab for treating non-small cell lung cancer.
      Advancement in treatment options for this disease has accelerated in the last 10 to 20 years due to the identification of activating mutations, improved diagnostic techniques, and the development of targeted therapies. Although these advancements have improved outcomes in some subtypes of NSCLC, resistance to these treatments is common.
      This review describes the molecular characteristics, mechanisms of action (MOAs), and clinical efficacy of amivantamab, a fully human bispecific antibody targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) with enhanced crystallizable fragment (Fc):Fc receptor (FcR) binding, leading to activation of innate immune response. Amivantamab was approved by the US Food and Drug Administration (FDA) in May 2021 for the treatment of patients with advanced or metastatic NSCLC (mNSCLC) with EGFR exon 20 insertion (ex20ins) mutations, whose disease has progressed on or after platinum-based chemotherapy. The goal of this article is to summarize published data augmented with clinician hands-on experience to promote understanding of amivantamab's molecular design, MOAs, and clinical impact to address unmet needs.

      Overview and Discussion

      NSCLC is the second most commonly diagnosed malignancy and the leading cause of cancer-related mortality worldwide.
      • Sung H
      • Ferlay J
      • Siegel RL
      • Laversanne M
      • Soerjomataram I
      • Jemal A Bray.
      Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ,
      • Thai AA
      • Solomon BJ
      • Sequist LV
      • Gainor JF
      • Heist RS.
      Lung cancer.
      Among the most frequently mutated genes in NSCLC is EGFR, which globally accounts for 23% to 30% of activating mutations in NSCLC.
      • Zhang YL
      • Yuan JQ
      • Wang KF
      • Fu XH
      • Han XR
      • Threapleton D
      • Yang ZY
      • Mao C
      • Tang JL.
      The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis.
      ,
      • Sholl LM
      • Aisner DL
      • Varella-Garcia M
      • Berry LD
      • Dias-Santagata D
      • Wistuba II
      • Chen H
      • Fujimoto J
      • Kugler K
      • Franklin WA
      • Iafrate AJ
      • Ladanyi M
      • Kris MG
      • Johnson BE
      • Bunn PA
      • Minna JD
      • Kwiatkowski DJ
      • LCMC Investigators
      • et al.
      Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience.
      Oncogenic EGFR mutations increase the activity of the receptor (EGFR), resulting in elevated ligand-independent downstream signaling. Although baseline levels of EGFR signaling are essential for normal cellular activities, including DNA synthesis and cell proliferation, excess activity can result in uncontrolled growth and tumorigenesis.
      • Wee P
      • Wang Z.
      Epidermal growth factor receptor cell proliferation signaling pathways.
      The current standard of care for patients diagnosed with EGFR-mutated NSCLC varies based on the nature of the mutation. Common mutations account for up to 85% of EGFR mutations and typically include exon 19 deletions or L858R substitution in exon 21.
      • Harrison PT
      • Vyse S
      • Huang PH.
      Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer.
      Common mutations can be effectively targeted with EGFR tyrosine kinase inhibitors (TKIs), including the third-generation EGFR TKI osimertinib, which results in an objective response rate of up to 80% in first-line treatment.
      • Soria JC
      • Ohe Y
      • Vansteenkiste J
      • Reungwetwattana T
      • Chewaskulyong B
      • Lee KH
      • Dechaphunkul A
      • Imamura F
      • Nogami N
      • Kurata T
      • Okamoto I
      • Zhou C
      • Cho BC
      • Cheng Y
      • Cho EK
      • Voon PJ
      • Planchard D
      • Su WC
      • Gray JE
      • Lee SM
      • Hodge R
      • Marotti M
      • Rukazenkov Y
      • Ramalingam SS
      • Investigators FLAURA
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      The next most common type of EGFR mutations consists of EGFR ex20ins, which account for 4% to 10% of all EGFR mutations and are typically resistant to first-, second-, and third-generation EGFR TKIs. Until FDA approval of the bispecific antibody amivantamab, no targeted therapies were available for the treatment of EGFR ex20ins. Mobocertinib, an oral, irreversible TKI targeting EGFR ex20ins, was subsequently approved by the FDA for the treatment of adult patients with locally advanced or mNSCLC with EGFR ex20ins whose disease had progressed on or after platinum-based chemotherapy.
      • Zhou C
      • Ramalingam SS
      • Kim TM
      • Kim SW
      • Yang JC
      • Riely GJ
      • Mekhail T
      • Nguyen D
      • Garcia Campelo MR
      • Felip E
      • Vincent S
      • Jin S
      • Griffin C
      • Bunn V
      • Lin J
      • Lin HM
      • Mehta M
      • Jänne PA
      Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial.
      Other therapies being evaluated for the treatment of ex20ins NSCLC include osimertinib in combination with bevacizumab (ClinicalTrials.gov Identifier: NCT04974879), and poziotinib, a TKI in development for EGFR and HER2 exon 20 mutations, in combination with ramucirumab (ClinicalTrials.gov Identifier: NCT05045404). In addition, the small molecules CLN-081 (ClinicalTrials.gov Identifier NCT04036682), DZD9009 (ClinicalTrials.gov Identifier NCT03974022), and LNG-451
      • Murray B
      • Pandey A
      • Roth B
      • Saxton T
      • Estes DJ
      • Agrawal H
      • Vishwakarma S
      • Hallur G
      • Ahmad I;
      • Trivedi R
      • Jenkins H
      • Pearson PG.
      LNG-451 (BLU-451) is a potent, CNS-penetrant, wild-type EGFR sparing inhibitor of EGFR exon 20 insertion mutations.
      are being evaluated for the treatment of EGFR ex20ins.
      For all EGFR-mutated NSCLC, resistance to EGFR TKIs and chemotherapy is inevitable, leaving this large patient population with limited treatment options when progression occurs. Most resistance mechanisms to EGFR TKIs involve alterations of EGFR itself, such as upregulated expression or the acquisition of additional mutations. For example, the T790M mutation accounts for approximately half of acquired resistances to first- and second-generation EGFR TKIs.
      • Westover D
      • Zugazagoitia J
      • Cho BC
      • Lovly CM
      • Paz-Ares L.
      Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors.
      In addition to EGFR-dependent resistance mechanisms, alterations to the MET receptor are common resistance pathways. Like EGFR, baseline MET signaling promotes survival in healthy cells but can be oncogenic at abnormally high expression levels. MET-dependent resistance can manifest through point mutations or gene amplification. MET amplification is a particularly common resistance mechanism, occurring in 10% to 20% of patients treated with osimertinib.
      • Passaro A
      • Janne PA
      • Mok T
      • Peters S.
      Overcoming therapy resistance in EGFR-mutant lung cancer.
      Increased levels of hepatocyte growth factor (HGF), a MET ligand, can also induce EGFR TKI resistance through the activation of MET.
      • Yano S
      • Yamada T
      • Takeuchi S
      • Tachibana K
      • Minami Y
      • Yatabe Y
      • Mitsudomi T
      • Tanaka H
      • Kimura T
      • Kudoh S
      • Nokihara H
      • Ohe Y
      • Yokota J
      • Uramoto H
      • Yasumoto K
      • Kiura K
      • Higashiyama M
      • Oda M
      • Saito H
      • Yoshida J
      • Kondoh K
      • Noguchi M.
      Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort.
      Of note, MET amplifications and MET exon 14 skipping mutations account for 2% to 4% and 3% to 4% of primary activating mutations in mNSCLC, respectively. Tumors with MET mutations can be treated with MET TKIs or other MET-specific inhibitors but are associated with poor prognosis.
      • Chu QS.
      Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion.
      Moreover, upregulation of the EGFR pathway has been demonstrated as a mechanism of resistance to MET TKIs.
      • Migliore C
      • Morando E
      • Ghiso E
      • Anastasi S
      • Leoni VP
      • Apicella M
      • Cora' D
      • Sapino A
      • Pietrantonio F
      • De Braud F
      • Columbano A
      • Segatto O
      • Giordano S
      miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling.
      ,
      • Recondo G
      • Bahcall M
      • Sholl L
      • Leonardi G
      • Ricciuti B
      • Nguyen T
      • Venkatraman D
      • Lamberi G
      • Umeton R
      • Janne P.
      Mechanisms of resistance to MET tyrosine kinase inhibitors in patients with MET exon 14 mutant non-small cell lung cancer (meeting abstr).
      Capmatinib and tepotinib are FDA-approved MET TKIs for the treatment of patients with mNSCLC whose tumors have MET exon 14 skipping mutations; however, no targeted agents are currently approved for MET amplified cancers.
      In addition to their reciprocal resistance upon TKI treatment (MET-dependent resistance in EGFR-mutated cancers and EGFR-dependent resistance in MET-mutated cancers), EGFR and MET have been shown to dimerize to promote oncogenic signaling and remodeling of the tumor microenvironment.
      • Jo M
      • Stolz DB
      • Esplen JE
      • Dorko K
      • Michalopoulos GK
      • Strom SC.
      Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells.
      • Ortiz-Zapater E
      • Lee RW
      • Owen W
      • Weitsman G
      • Fruhwirth G
      • Dunn RG
      • Neat MJ
      • McCaughan F
      • Parker P
      • Ng T
      • Santis G.
      MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mutations and altered by MET kinase inhibition.
      • Tang Z
      • Du R
      • Jiang S
      • Wu C
      • Barkauskas DS
      • Richey J
      • Molter J
      • Lam M
      • Flask C
      • Gerson S
      • Dowlati A
      • Liu L
      • Lee Z
      • Halmos B
      • Wang Y
      • Kern JA
      • Ma PC.
      Dual MET-EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer.
      Cross-talk between EGFR and MET signaling is well documented, and these pathways can compensate for one another when signaling from either individual protein is inhibited.
      • Puri N
      • Salgia R.
      Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer.
      The interdependence between these two pathways suggests that simultaneously targeting EGFR and MET could improve clinical outcomes by concomitantly inhibiting both pathways and reducing occurrence of MET- and/or EGFR-mediated resistance. Therefore, the bispecific antibody, amivantamab, was designed to simultaneously inhibit EGFR and MET pathways.
      Amivantamab is a fully human Fc-active immunoglobulin G1 (IgG1) bispecific antibody with high affinity (KD) binding to both EGFR (1.4 nanomolar/liter) and MET (KD of 40 picomolar/liter).
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      ,
      • Haura EB
      • Cho BC
      • Lee JS
      • Han J-Y
      • Lee KH
      • Sanborn RE
      • Govindan R
      • Cho EK
      • Kim S-W
      • Reckamp KL
      • Sabari JK
      • Thayu M
      • Bae K
      • Knoblauch RE
      • Curtin J
      • Haddish-Berhane N
      • Sherman LJ
      • Lorenzi MV
      • Park K Bauml.
      JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC) (meeting abstr).
      Amivantamab targets the extracellular domains of EGFR and MET, leading to inhibition of both pathways independent of their intracellular cancer-driving or treatment-acquired mutation(s). The potential broad applicability of amivantamab can be attributed to its novel design leading to dual targeting of EGFR and MET, activation of innate immune cells through enhanced FcR binding, and improved safety profile. We review the design, MOAs, and activity of amivantamab by highlighting key published preclinical data, as well as clinical efficacy and safety.

      Design of amivantamab enables multiple MOAs

      Amivantamab architecture and engineering are depicted in Figure 1. Briefly, amivantamab was derived from two parental monoclonal antibodies (mAbs), one targeting EGFR and one targeting MET.
      • Neijssen J
      • Cardoso RMF
      • Chevalier KM
      • Wiegman L
      • Valerius T
      • Anderson GM
      • Moores SL
      • Schuurman J
      • Parren PWHI
      • Strohl WR
      • Chiu ML.
      Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET.
      The parental mAbs were combined using the Genmab DuoBody controlled antigen-binding fragment (Fab) arm exchange process,
      • Gramer MJ
      • van den Bremer ET
      • van Kampen MD
      • Kundu A
      • Kopfmann P
      • Etter E
      • Stinehelfer D
      • Long J
      • Lannom T
      • Noordergraaf EH
      • Gerritsen J
      • Labrijn AF
      • Schuurman J
      • van Berkel PH
      • Parren PW.
      Production of stable bispecific IgG1 by controlled Fab-arm exchange: scalability from bench to large-scale manufacturing by application of standard approaches.
      ,
      • Labrijn AF
      • Meesters JI
      • de Goeij BE
      • van den Bremer ET
      • Neijssen J
      • van Kampen MD
      • Strumane K
      • Verploegen S
      • Kundu A
      • Gramer MJ
      • van Berkel PH
      • van de Winkel JG
      • Schuurman J
      • Parren PW.
      Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange.
      resulting in a bispecific antibody with single arm binding sites (i.e., monovalent) to each antigen. In addition, the parental mAbs were produced in an engineered cell line incorporating low levels of fucose into the Fc region,
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      ,
      • Haura EB
      • Cho BC
      • Lee JS
      • Han J-Y
      • Lee KH
      • Sanborn RE
      • Govindan R
      • Cho EK
      • Kim S-W
      • Reckamp KL
      • Sabari JK
      • Thayu M
      • Bae K
      • Knoblauch RE
      • Curtin J
      • Haddish-Berhane N
      • Sherman LJ
      • Lorenzi MV
      • Park K Bauml.
      JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC) (meeting abstr).
      ,
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      to enhance antibody binding to FcRs on immune effector cells, thus promoting antitumor immune cell-directing activity.
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      ,
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      Figure 1
      Figure 1Engineered Fc mutations within EGFR and MET antibodies lead to bispecific amivantamab formation following controlled Fab-arm exchange process. EGFR, epidermal growth factor receptor; Fab, antigen-binding fragment; Fc, crystallizable fragment; MET, mesenchymal-epithelial transition factor.
      Preclinical studies demonstrated that amivantamab elicits its anti-tumor activity through three potential MOAs: 1) ligand blocking, 2) receptor degradation, and 3) immune cell-directing activity (Figure 2). Each of these mechanisms is described next and shown in this Video.
      Figure 2
      Figure 2Schematic of amivantamab's three MOAs - ligand blocking, receptor degradation, and activation of immune-cell-directing activity: MOA, mechanism of action.

      Ligand blocking

      The binding of amivantamab's Fab arms to each receptor prevents EGFR and MET ligands from binding to their respective receptors. In vitro studies have demonstrated that amivantamab, with single Fab binding to each receptor, inhibits ligand binding to EGFR and MET with similar potency as the parental, bivalent mAbs.
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      In a cellular context, ligand blocking by amivantamab reduces ligand-induced receptor activation, measured by inhibition of receptor phosphorylation and downstream signaling. Ligand-induced EGFR and MET phosphorylation were reduced by the binding of amivantamab in cell lines with EGFR activating (L858R) and/or acquired resistance (T790M) mutations and MET amplification.
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      This provided early evidence for potential anti-tumor activity of amivantamab in patients with EGFR mutations.
      The ligand-blocking activity of amivantamab was compared with that of the combination of monovalent EGFR and MET antibodies of equimolar concentration. These monovalent anti-EGFR and anti-MET antibodies are engineered with one arm binding to EGFR or MET and the second arm binding to an inert antigen absent on the test cell line. These studies demonstrated that amivantamab more potently blocked ligand-induced receptor phosphorylation than the combination of the monovalent anti-EGFR and anti-MET antibodies.
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Boakye K
      • Lacy ER
      • Sanders R
      • Sepulveda MA
      • Moores SL
      • Chiu ML.
      Impact of cell-surface antigen expression on target engagement and function of an epidermal growth factor receptor x c-MET bispecific antibody.
      The enhanced blocking of downstream signaling observed with amivantamab may result from the increased intrinsic propensity of amivantamab to bind both EGFR and MET targets when expressed on the same tumor cell through cross-arm binding.
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Boakye K
      • Lacy ER
      • Sanders R
      • Sepulveda MA
      • Moores SL
      • Chiu ML.
      Impact of cell-surface antigen expression on target engagement and function of an epidermal growth factor receptor x c-MET bispecific antibody.
      ,
      • Castoldi R
      • Ecker V
      • Wiehle L
      • Majety M
      • Busl-Schuller R
      • Asmussen M
      • Nopora A
      • Jucknischke U
      • Osl F
      • Kobold S
      • Scheuer W
      • Venturi M
      • Klein C
      • Niederfellner G
      • Sustmann C.
      A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity.

      Receptor degradation

      When bound to EGFR and/or MET on the tumor cell surface, amivantamab triggers receptor internalization and degradation, a process by which antibody-bound receptors are engulfed by the cell membrane, internalized, and trafficked to lysosomes, where the antibody-receptor complex is degraded.
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      In pre-clinical models, EGFR and MET protein levels were significantly reduced in tumors treated with amivantamab.
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      The interaction of amivantamab with immune cells was determined to further enhance the loss of receptors from the cell surface, both in vitro and in vivo,
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      as discussed in detail in the next section.

      Immune cell-directing activity

      The binding of the Fc region of amivantamab to immune cells induces several effector functions. This important MOA hinges on the activation of these immune cells through amivantamab-Fc binding to their Fcg receptors (FcgRs) on immune cells (Figure 2).
      • Stewart R
      • Hammond SA
      • Oberst M
      • Wilkinson RW.
      The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer.
      Immune cell-directed activities triggered by amivantamab include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cytokine release (ADCR), and antibody-dependent cellular trogocytosis (ADCT); these mechanisms are summarized briefly in Table. 1.
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      ,
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      Table 1Immune Cell-Directing Activity Triggered by Binding of the Fc Region of Amivantamab
      Effector functionAmivantamab-activated immune cell typeBrief MOA descriptionReferences
      ADCCNK cellsRelease of cytotoxic granules causes death of target cell
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      ,
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      ,
      • Grugan KD
      • Dorn K
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Laquerre S
      • Moores SL
      • Chiu ML.
      Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
      ADCP*MacrophageTarget cell is engulfed and destroyed
      • Grugan KD
      • Dorn K
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Laquerre S
      • Moores SL
      • Chiu ML.
      Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
      ADCRVarious, including macrophage and monocyteSecretion of cytokines and chemokines that can cause death of target cell or activate other immune cells
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      ADCT*Macrophage, monocyteMediates transfer of cell surface proteins from target to effector cells
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      *Most prominent immune cell-directing activities.
      ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; ADCR, antibody-dependent cytokine release; ADCT, antibody-dependent cellular trogocytosis; Fc, crystallizable fragment; MOA, mechanism of action; NK, natural killer.
      The impact of effector functions on the overall efficacy of amivantamab has been studied extensively in in vitro and in vivo models and compared with that of an EGFR- and MET-targeting bispecific Fc-silent antibody (referred to as amivantamab-Fc-silent). For example, in an EGFR- and MET-driven xenograft model, treatment with amivantamab resulted in nearly 80% tumor growth inhibition (TGI), while treatment with amivantamab-Fc-silent resulted in <10% TGI. Moreover, amivantamab-Fc-silent had reduced ability to inhibit receptor phosphorylation, demonstrating that in addition to driving efficacy, binding of amivantamab's Fc region to FcgRs on immune cells also plays an important role in receptor and signal downmodulation.
      • Grugan KD
      • Dorn K
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Laquerre S
      • Moores SL
      • Chiu ML.
      Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
      In addition, cell culture experiments comparing amivantamab and amivantamab-Fc-silent have shown that the Fc interaction of amivantamab with immune cells is essential to drive innate cell effector functions and that the low fucosylation of amivantamab enhances natural killer-mediated ADCC.
      • Grugan KD
      • Dorn K
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Laquerre S
      • Moores SL
      • Chiu ML.
      Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
      Furthermore, amivantamab induced ADCC, ADCT, and ADCR more potently than cetuximab, a bivalent (normal fucose) anti-EGFR mAb indicated for colorectal and head and neck cancers.
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      Notably, trogocytosis was recently identified as a novel Fc-mediated effector function for amivantamab. Trogocytosis, or “cellular gnawing,” is a process in which cell surface proteins from the tumor cell membrane are removed by immune effector cells, such as monocytes, macrophages, and neutrophils. Amivantamab led to monocyte- and macrophage-dependent downmodulation of EGFR and MET through trogocytosis in cell culture and xenograft mouse models.
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      It has been hypothesized that this mechanism may extend to other nearby receptors, such as other human epidermal growth factor receptor family members, which could contribute to suppression of signaling pathways that lead to resistance.
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.

      Broad spectrum of amivantamab activity

      Although the overall activity of amivantamab encompasses multiple MOAs, not all mechanisms occur concomitantly or are required for clinical activity. Amivantamab's MOAs are tumor and context dependent. For example, amivantamab can bind to either EGFR or MET alone to successfully induce Fc-independent and -dependent effector functions.
      • Grugan KD
      • Dorn K
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Laquerre S
      • Moores SL
      • Chiu ML.
      Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
      Accordingly, amivantamab treatment has demonstrated efficacy in EGFR-mutated xenograft tumor models independent of MET alteration status,
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      and in MET amplified and MET-driven cell lines independent of the EGFR alteration status.
      • Vijayaraghavan S
      • Lipfert L
      • Chevalier K
      • Bushey BS
      • Henley B
      • Lenhart R
      • Sendecki J
      • Beqiri M
      • Millar HJ
      • Packman K
      • Lorenzi MV
      • Laquerre S
      • Moores SL.
      Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
      Thus, while amivantamab binding simultaneously to EGFR and MET demonstrated synergistic antitumor efficacy, its activity extends beyond EGFR- and MET-co-mutated tumors because of the independent activity of either arm alone. The broad spectrum of amivantamab activity is particularly beneficial in light of tumor heterogeneity, including the high variability of the solid tumor microenvironment.
      • Baghban R
      • Roshangar L
      • Jahanban-Esfahlan R
      • Seidi K
      • Ebrahimi-Kalan A
      • Jaymand M
      • Kolahian S
      • Javaheri T
      • Zare P.
      Tumor microenvironment complexity and therapeutic implications at a glance.
      Due to its multiple MOAs, amivantamab treatment achieves broad spectrum tumor killing despite the molecular alterations of the tumor and its microenvironment context.

      Amivantamab precision engineering

      Amivantamab was designed to target tumors expressing and driven by EGFR and/or MET signaling. EGFR and MET were chosen as targets for the following reasons:
      • 1)
        EGFR and MET are both highly expressed on NSCLC tumors, including co-expression in 70% of tumors with EGFR mutations.
        • Charakidis M
        • Boyer M.
        Targeting MET and EGFR in NSCLC-what can we learn from the recently reported phase III trial of onartuzumab in combination with erlotinib in advanced non-small cell lung cancer?.
        ,
        • Spigel DR
        • Ervin TJ
        • Ramlau RA
        • Daniel DB
        • Goldschmidt Jr, JH
        • Blumenschein Jr, GR
        • Krzakowski MJ
        • Robinet G
        • Godbert B
        • Barlesi F
        • Govindan R
        • Patel T
        • Orlov SV
        • Wertheim MS
        • Yu W
        • Zha J
        • Yauch RL
        • Patel PH
        • Phan SC
        • Peterson AC.
        Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer.
      • 2)
        Both EGFR and MET receptors signal through the same pro-proliferation and pro-survival pathways (extracellular signal-regulated kinase and protein kinase B), thus potentially compensating for each other upon inhibition of only one of these two receptors.
        • Puri N
        • Salgia R.
        Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer.
        This interactive relationship suggests that stronger pathway inhibition is achieved by blocking both receptors simultaneously. Supportively, in an NSCLC xenograft model with EGFR mutations and MET amplification, dual inhibition of both receptors by amivantamab was more efficacious than anti-EGFR treatment alone (erlotinib).
        • Moores SL
        • Chiu ML
        • Bushey BS
        • Chevalier K
        • Luistro L
        • Dorn K
        • Brezski RJ
        • Haytko P
        • Kelly T
        • Wu SJ
        • Martin PL
        • Neijssen J
        • Parren PW
        • Schuurman J
        • Attar RM
        • Laquerre S
        • Lorenzi MV
        • Anderson GM.
        A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      • 3)
        Resistance to EGFR TKIs most commonly occurs through alterations of EGFR and/or MET, retaining treatment-resistant cancer growth dependence on this pathway.
        • Westover D
        • Zugazagoitia J
        • Cho BC
        • Lovly CM
        • Paz-Ares L.
        Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors.
        ,
        • Passaro A
        • Janne PA
        • Mok T
        • Peters S.
        Overcoming therapy resistance in EGFR-mutant lung cancer.
      Amivantamab was selected from a panel of bispecific molecules targeting EGFR and MET.
      • Neijssen J
      • Cardoso RMF
      • Chevalier KM
      • Wiegman L
      • Valerius T
      • Anderson GM
      • Moores SL
      • Schuurman J
      • Parren PWHI
      • Strohl WR
      • Chiu ML.
      Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET.
      Parental mAbs were screened for target-specific binding, ligand-blocking activity, and lack of agonistic signaling activity. Multiple bispecific molecules were generated and retested in heterodimerized format, and amivantamab was selected based on the best multi-functional features mentioned previously. In addition, to reduce binding to healthy cells with normal EGFR expression and potentially improve tolerability, bispecifics with higher affinity to MET over EGFR were favored.
      One advantage that arises from the unique binding properties of bispecific molecules is dual-receptor avidity. Here, the favored interaction between amivantamab and the tumor cell is through binding to the target with the highest affinity (eg, MET), enabling the second arm to come into closer proximity and bind to its target, albeit with weaker affinity (eg, EGFR). Amivantamab binds EGFR extracellular domain with KD) of 1.4 nanomolar/liter and MET extracellular domain with KD of 40 picomolar/liter.
      • Moores SL
      • Chiu ML
      • Bushey BS
      • Chevalier K
      • Luistro L
      • Dorn K
      • Brezski RJ
      • Haytko P
      • Kelly T
      • Wu SJ
      • Martin PL
      • Neijssen J
      • Parren PW
      • Schuurman J
      • Attar RM
      • Laquerre S
      • Lorenzi MV
      • Anderson GM.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      This dual-arm binding of amivantamab results in an increase in overall binding affinity on cells expressing both targets, in this instance predominantly cancer cells because healthy cells rarely express concomitant high levels of these two receptors.
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Boakye K
      • Lacy ER
      • Sanders R
      • Sepulveda MA
      • Moores SL
      • Chiu ML.
      Impact of cell-surface antigen expression on target engagement and function of an epidermal growth factor receptor x c-MET bispecific antibody.
      ,
      • Zheng S
      • Moores S
      • Jarantow S
      • Pardinas J
      • Chiu M
      • Zhou H
      • Wang W.
      Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody.
      Thus, this precision target binding design of amivantamab intrinsically favors cancer-specific simultaneous binding of EGFR and MET, leading to concomitant inhibition of these interacting signaling pathways.
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Boakye K
      • Lacy ER
      • Sanders R
      • Sepulveda MA
      • Moores SL
      • Chiu ML.
      Impact of cell-surface antigen expression on target engagement and function of an epidermal growth factor receptor x c-MET bispecific antibody.
      Accordingly, in vitro studies comparing amivantamab to the combination of monovalent anti-EGFR and anti-MET mAbs showed that by simultaneously engaging EGFR and MET binding on the same cell, amivantamab promoted dual-receptor avidity and enhanced inhibition of receptor phosphorylation for the lower expressed receptor on the selected cell line.
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Boakye K
      • Lacy ER
      • Sanders R
      • Sepulveda MA
      • Moores SL
      • Chiu ML.
      Impact of cell-surface antigen expression on target engagement and function of an epidermal growth factor receptor x c-MET bispecific antibody.
      ,
      • Zheng S
      • Moores S
      • Jarantow S
      • Pardinas J
      • Chiu M
      • Zhou H
      • Wang W.
      Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody.
      Because it is derived from two parental mAbs produced in engineered cell lines that incorporate low levels of fucose into proteins, amivantamab also displays low levels of fucosylation. Low fucosylation enhances binding of the Fc region of amivantamab to FcgRIIIa on immune cells, thus enhancing engagement of immune cells and driving better immune cell-directing activity (including ADCC), compared with normally fucosylated antibodies.
      • Grugan KD
      • Dorn K
      • Jarantow SW
      • Bushey BS
      • Pardinas JR
      • Laquerre S
      • Moores SL
      • Chiu ML.
      Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.

      Efficacy and safety

      Amivantamab's target selectivity and design features, as well as the compelling large body of preclinical anti-cancer activity, supported its clinical development as a first-in-class agent against EGFR-mutant NSCLC. In 2021, amivantamab was approved for the treatment of patients with advanced NSCLC with EGFR ex20ins whose disease had progressed on or after platinum-based chemotherapy. Amivantamab was the first bispecific molecule approved for the treatment of solid tumors. Prior approvals of bispecific molecules in blood cancer include two T-cell redirectors, blinatumomab and catumaxomab, the latter for which approval was later withdrawn.
      Clinical efficacy and safety data from a cohort of patients with locally advanced or mNSCLC in the CHRYSALIS study (ClinicalTrials.gov Identifier: NCT02609776) were submitted to support FDA approval of amivantamab. The efficacy population included patients with EGFR ex20ins whose disease had progressed on or after platinum-based chemotherapy.
      RYBREVANT (amivantamab-vmjw) injection [package insert]
      Of 81 patients, 3 confirmed complete responses and 29 partial responses were observed, for an overall response rate (ORR) of 40% (95% confidence interval [CI], 29-51) as assessed by blinded independent central review. The median duration of response for the 32 responders was 11.1 months (95% CI, 6.9-not reached). Antitumor responses were observed in patients across different EGFR ex20ins, regardless of the site or type of insertions.
      • Park K
      • Haura EB
      • Leighl NB
      • Mitchell P
      • Shu CA
      • Girard N
      • Viteri S
      • Han JY
      • Kim SW
      • Lee CK
      • Sabari JK
      • Spira AI
      • Yang TY
      • Kim DW
      • Lee KH
      • Sanborn RE
      • Trigo J
      • Goto K
      • Lee JS
      • Yang JC
      • Govindan R
      • Bauml JM
      • Garrido P
      • Krebs MG
      • Reckamp KL
      • Xie J
      • Curtin JC
      • Haddish-Berhane N
      • Roshak A
      • Millington D
      • Lorenzini P
      • Thayu M
      • Knoblauch RE
      • Cho BC.
      Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study.
      Safety was evaluated in 302 patients with any driver EGFR mutation who received ≥1 dose of amivantamab.
      RYBREVANT (amivantamab-vmjw) injection [package insert]
      Because amivantamab treatment leads to EGFR and MET inhibition, adverse reactions known to occur upon inhibition of these pathways were observed in ≥20% of patients, including rash, paronychia, stomatitis, and edema.
      RYBREVANT (amivantamab-vmjw) injection [package insert]
      ,
      • Park K
      • Haura EB
      • Leighl NB
      • Mitchell P
      • Shu CA
      • Girard N
      • Viteri S
      • Han JY
      • Kim SW
      • Lee CK
      • Sabari JK
      • Spira AI
      • Yang TY
      • Kim DW
      • Lee KH
      • Sanborn RE
      • Trigo J
      • Goto K
      • Lee JS
      • Yang JC
      • Govindan R
      • Bauml JM
      • Garrido P
      • Krebs MG
      • Reckamp KL
      • Xie J
      • Curtin JC
      • Haddish-Berhane N
      • Roshak A
      • Millington D
      • Lorenzini P
      • Thayu M
      • Knoblauch RE
      • Cho BC.
      Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study.
      These adverse reactions, particularly rash, were similar to those documented with cetuximab and some TKIs, including erlotinib and afatinib.
      • Guo MZ
      • Marrone KA
      • Spira A
      • Freeman K
      • Scott SC.
      Amivantamab: a potent novel EGFR/c-MET bispecific antibody therapy for EGFR-mutated non-small cell lung cancer.
      • Kainis I
      • Syrigos N
      • Kopitopoulou A
      • Gkiozos I
      • Filiou E
      • Nikolaou V
      • Papadavid E.
      Erlotinib-associated rash in advanced non-small cell lung cancer: relation to clinicopathological characteristics, treatment response, and survival.
      • Zhang Y
      • Miao S
      • Wang F
      • Fang W
      • Chen G
      • Chen X
      • Yan F
      • Huang X
      • Wu M
      • Huang Y
      • Zhang L.
      The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis.
      Considering that amivantamab is delivered by infusion, it is not surprising that one of the most common adverse events was infusion-related reactions (IRRs). IRRs encompass a range of symptoms, including chills, dyspnea, flushing, nausea, chest discomfort, and vomiting. Although IRRs occurred in 66% of the overall safety population, their overall incidence decreases in intensity and frequency upon subsequent infusions. For this reason, the initial administration of amivantamab was split over 2 days, which led to lower incidence and severity of IRRs and therefore better patient experience. Although 65% of these patients experienced IRRs on the first day of treatment, the incidence decreased to 3.4% on the second day of treatment and continued to decrease thereafter. In addition, these IRRs were generally well tolerated, with 97% being grade 1 (mild transient reaction; infusion interruption not indicated; no intervention needed) to 2 (moderate; infusion interruption indicated but responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, narcotics, IV fluids; prophylactic medications indicated for ≤24 hours]).
      US Department of Health and Human Services
      Only 1.3% of patients permanently discontinued amivantamab treatment due to IRRs.
      RYBREVANT (amivantamab-vmjw) injection [package insert]
      To mitigate IRRs, a subcutaneous (SC) formulation of amivantamab is currently being investigated. Preliminary data from PALOMA (ClinicalTrials.gov Identifier: NCT04606381) showed that SC administration was well-tolerated and reduced IRRs to 18.2% in 33 patients with advanced solid tumors.
      • Krebs MG
      • Johnson ML
      • Cho BC
      • Lee S-H
      • Kudgus-Lokken R
      • Zemlickis D
      • Mitselos A
      • Berkay E
      • Bauml JM
      • Knoblauch RE
      • Hellemans P
      • Minchom AR.
      Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: initial safety and pharmacokinetic results from the PALOMA study.
      Although amivantamab was the first bispecific antibody approved for solid tumors, it entered a market offering several existing anti-EGFR mAb therapies (Table 2). Most notably, cetuximab (Erbitux®; Eli Lilly and Company, Indianapolis, IN 46285, USA), approved for squamous cell carcinoma of the head and neck and KRAS wild-type, EGFR-expressing, metastatic colorectal cancer, has also been investigated for the treatment of NSCLC in numerous clinical trials, including two phase 2 studies (FLEX
      • Pirker R
      • Pereira JR
      • Szczesna A
      • von Pawel J
      • Krzakowski M
      • Ramlau R
      • Vynnychenko I
      • Park K
      • Yu CT
      • Ganul V
      • Roh JK
      • Bajetta E
      • O'Byrne K
      • de Marinis F
      • Eberhardt W
      • Goddemeier T
      • Emig M
      • Gatzemeier U
      • Study Team FLEX
      Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.
      and BMS 09942) in which cetuximab was combined with chemotherapy for the treatment of EGFR-mutated mNSCLC. Because clinical benefits were marginal for the level of toxicity observed, neither study led to cetuximab approval for this indication.
      • Mazzarella L
      • Guida A
      • Curigliano G.
      Cetuximab for treating non-small cell lung cancer.
      The clinical benefit of amivantamab in broader aberrant EGFR signaling settings remains to be fully evaluated. However, amivantamab's preliminary success in EGFR ex20ins, considering the history of cetuximab and other anti-EGFR agents against NSCLC, poses an interesting question about the differentiating MOA of amivantamab compared with other agents. Several features of amivantamab, discussed throughout this review, could result in improved outcomes compared with previously evaluated anti-EGFR agents. These additional features include superior tumor-specificity due to the dual targeting of EGFR and MET, enhanced inhibition of oncogenic signaling pathways due to increased dual-receptor avidity, enhanced effector functions due to the low fucose Fc region, and reduced immunogenicity due to fully human antibody construction.
      Table 2Anti-EGFR Antibodies Approved for the Treatment of Cancer
      Generic nameAmivantamab
      RYBREVANT (amivantamab-vmjw) injection [package insert]
      Necitumumab
      PORTRAZZA (necitumumab) injection [package insert]
      Panitumumab

      VECTIBIX® (panitumumab) injection for intravenous infusion [package insert]. Thousand Oaks, CA: Amgen, Inc.

      Cetuximab
      ERBITUX® (cetuximab) injection, for intravenous infusion [package insert]
      Brand nameRybrevant™Portrazza™Vectibix®Erbitux®
      OwnerJanssenEli LillyAmgenEli Lilly
      Initial US approval2021201520062004
      IndicationLocally advanced or mNSCLC with EGFR ex20ins and disease progression on or after platinum-based chemotherapyMetastatic squamous NSCLC: in combination with gemcitabine and cisplatin (first-line)Metastatic CRC with disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens (Approval is based on progression-free survival; no data demonstrated an improvement in disease-related symptoms or increased survival)• SCCHN: in combination with radiation therapy, platinum-based therapy with fluorouracil, or after progression on platinum-based therapy

      • KRAS wild-type, EGFR-expressing, metastatic CRC: in combination with FOLFIRI for first-line treatment; in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; as single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan
      Design (schematic)Fully human anti-EGFR, anti-MET bispecific IgG1Recombinant human IgG1 mAbRecombinant human IgG2 mAbRecombinant human/mouse chimeric IgG1 mAb
      MOALigand blocking, receptor degradation, ADCC, ADCP, ADCR, ADCTReceptor degradation, ADCCLigand blockingLigand blocking, ADCC
      Most common adverse events (≥30%), all gradesAmong 129 patients: rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%)Among 538 patients: hypomagnesemia (83%), hypocalcemia (45%), rash (44%), hypophosphatemia (31%)
      Adverse events occurred at rate ≥2% higher than in the gemcitabine and cisplatin alone arm.
      Among 229 patients: skin toxicity (90%), erythema (65%), hypomagnesemia (38%), dermatitis acneiform (57%), pruritus (57%)Among 1,373 patients
      Includes patients with SCCHN or CRC enrolled in clinical trials, treated at the recommended dosage for a median of 7 to 14 weeks.
      : cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, infection
      Adverse events occurring in ≥25% of patients.
      EfficacyAmong 81 patients:

      ORR: 40%;

      DOR: 11.1 months
      Among 545 patients:

      OS: 11.5 months;

      PFS: 5.7 months
      Among 231 patients:

      PFS: 96 days
      Among 211 patients with SCCHN + radiation:
      • Locoregional control: 24.4 months
      • OS: 49.0 months
      Among 222 patients with SCCHN + platinum-based therapy + fluorouracil:
      • OS: 10.1 months;
      • PFS: 5.5 months;
      • ORR: 35.6%
      Among 608 patients with CRC + FOLFIRI:
      • PFS: 8.9 months;
      • OS: 491 months;
      • ORR: 46%
      Among 387 patients with previously treated CRC:
      • OS: 6.1 months
      Among 329 patients with CRC + irinotecan
      • ORR: 23%;
      • DOR: 5.7 months
      ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; ADCR, antibody-dependent cytokine release; ADCT, antibody-dependent cellular trogocytosis; CRC, colorectal cancer; DOR, duration of response; EGFR, epidermal growth factor receptor; ex20ins, exon 20 insertion; FOLFIRI, folinic acid, fluorouracil, and irinotecan; IgG1, immunoglobulin G1; IgG2, immunoglobulin G2; IRR, infusion-related reaction; KRAS, kirsten rat sarcoma viral oncogene homolog; mAb, monoclonal antibody; MET, mesenchymal-epithelial transition factor; mNSCLC, metastatic non-small cell lung cancer; MOA, mechanism of action; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SCCHN, squamous cell carcinoma of the head and neck.
      Note: Because clinical trials are conducted under widely varying conditions, rates of response, survival, and adverse reactions observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
      a Adverse events occurred at rate ≥2% higher than in the gemcitabine and cisplatin alone arm.
      b Includes patients with SCCHN or CRC enrolled in clinical trials, treated at the recommended dosage for a median of 7 to 14 weeks.
      c Adverse events occurring in ≥25% of patients.
      With the approval of amivantamab for previously treated patients with EGFR ex20ins advanced NSCLC and the demonstration of its broad activity in preclinical studies, various clinical trials further evaluating amivantamab efficacy in different EGFR-mutant settings are ongoing. In the frontline setting, amivantamab is being evaluated in combination with carboplatin/pemetrexed versus chemotherapy alone in patients with advanced or metastatic NSCLC harboring EGFR ex20ins in the ongoing phase 3 PAPILLON study (ClinicalTrials.gov identifier: NCT04538664).

      ClinicalTrials.gov. A study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in participants with advanced or metastatic non-small cell lung cancer characterized by epidermal growth factor receptor (EGFR) exon 20 insertions (PAPILLON). Accessed October 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04538664.

      Amivantamab is also being evaluated in a regimen with lazertinib, a brain-penetrant third-generation EGFR TKI.
      • Cho BC
      • Lee KH
      • Cho EK
      • Kim D
      • Lee J
      • Han J
      • Kim S
      • Spira A
      • Haura EB
      • Sabari JK
      • Sanborn RE
      • Bauml JM
      • Gomez JE
      • Lorenzini P
      • Infante JR
      • Xie J
      • Haddish-Berhane N
      • Thayu M
      • Knoblauch RE
      • Amivantamab Park K.
      JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced EGFR-mutant NSCLC.
      In CHRYSALIS-2 (ClinicalTrials.gov identifier: NCT04077463), the combination of amivantamab and lazertinib showed activity in patients with common EGFR exon 19 deletion or L858R mutations that progressed on osimertinib and platinum-based chemotherapy, including an ORR of 33% and clinical benefit rate (CBR) of 57%.
      • Shu CA
      • Goto K
      • Ohe Y
      • Besse B
      • Lee S-H
      • Wang Y
      • Griesinger F
      • Yang J C-H
      • Felip E
      • Sanborn RE
      • Caro RB
      • Curtin JC
      • Chen J
      • Mahoney JM
      • Trani L
      • Bauml JM
      • Knoblauch RE
      • Thayu M
      • Cho BC.
      Amivantamab and lazertinib in patients with EGFR-mutant non-small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy: Updated results from CHRYSALIS-2.
      In this study, the amivantamab plus lazertinib regimen was also evaluated in combination with carboplatin/pemetrexed, resulting in an ORR of 50% and CBR of 80% for patients with advanced NSCLC who had progressed on prior TKI therapy, including those with baseline brain metastases. The safety profile was consistent with those of the individual therapies, and no new safety signals were identified.
      • Marmarelis ME
      • Lee SH
      • Spira AI
      • Ou S-HI
      • Waqar S
      • Li S
      • Thayu M
      • Knoblauch RE
      • Bauml JM
      • Cho BC.
      Amivantamab and lazertinib in combination with platinum-based chemotherapy in relapsed/refractory EGFR-mutant NSCLC (meeting abstr).
      The phase 3 MARIPOSA-2 study (ClinicalTrials.gov identifier: NCT04988295) is comparing the amivantamab/lazertinib/carboplatin/pemetrexed combination to amivantamab/carboplatin/pemetrexed or carboplatin/pemetrexed in patients with EGFR-mutated locally advanced or metastatic NSCLC after progression on prior osimertinib.

      ClinicalTrials.gov. A study of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure (MARIPOSA-2). Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04988295

      Strikingly, for a group of 20 treatment-naive patients with advanced NSCLC harboring common EGFR exon 19 deletion or L858R mutations who were treated with amivantamab plus lazertinib in CHRYSALIS (ClinicalTrials.gov identifier: NCT02609776), ORR was 100%.
      • Cho BC
      • Lee KH
      • Cho EK
      • Kim D
      • Lee J
      • Han J
      • Kim S
      • Spira A
      • Haura EB
      • Sabari JK
      • Sanborn RE
      • Bauml JM
      • Gomez JE
      • Lorenzini P
      • Infante JR
      • Xie J
      • Haddish-Berhane N
      • Thayu M
      • Knoblauch RE
      • Amivantamab Park K.
      JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced EGFR-mutant NSCLC.
      The combination of amivantamab plus lazertinib as frontline therapy is being compared to osimertinib in patients with locally advanced or metastatic exon 19 deletion or L858R NSCLC in the phase 3 MARIPOSA study (ClinicalTrials.gov identifier: NCT04487080).

      ClinicalTrials.gov. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Accessed October 31, 2022. https://clinicaltrials.gov/ct2/show/NCT04487080

      Amivantamab plus lazertinib continues to be evaluated in multiple EGFR NSCLC populations, and the safety profile is consistently similar to that of amivantamab monotherapy.
      • Cho BC
      • Lee KH
      • Cho EK
      • Kim D
      • Lee J
      • Han J
      • Kim S
      • Spira A
      • Haura EB
      • Sabari JK
      • Sanborn RE
      • Bauml JM
      • Gomez JE
      • Lorenzini P
      • Infante JR
      • Xie J
      • Haddish-Berhane N
      • Thayu M
      • Knoblauch RE
      • Amivantamab Park K.
      JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced EGFR-mutant NSCLC.
      ,
      • Shu CA
      • Goto K
      • Ohe Y
      • Besse B
      • Park K
      • Wang Y
      • Griesinger F
      • Yang JC
      • Felip E
      • Sanborn RE
      • Bernabe Caro R
      • Bauml JM
      • Chen J
      • Fennema E
      • Mahoney J
      • Trani L
      • Knoblauch RE
      • Thayu M
      • Cho BC
      Amivantamab plus lazertinib in post-osimertinib, post-platinum chemotherapy EGFR-mutant non-small cell lung cancer (NSCLC): preliminary results from CHRYSALIS-2.
      • Leighl NB
      • Shu CA
      • Minchom A
      • Felip E
      • Cousin S
      • Cho BC
      • Park K
      • Han J
      • Boyer M
      • Lee CK
      • Moreno Garcia V
      • Tomasini P
      • Viteri S
      • Xie J
      • Mertz J
      • Artis E
      • Schnepp RW
      • Knoblauch RE
      • Thayu M
      • rigo Perez JM.
      Amivantamab monotherapy and in combination with lazertinib in post osimertinib EGFR mutant NSCLC: analysis from the CHRYSALIS study.
      • Bauml J
      • Cho BC
      • Park K
      • Lee KH
      • Cho EK
      • Kim D-W
      • Kim S-W
      • Haura EB
      • Sabari JK
      • Sanborn RE
      • Nagasaka M
      • Ou S-HI
      • Minchom AR
      • Gomez JE
      • Curtin JC
      • Gao G
      • Roshak A
      • Thayu M
      • Knoblauch RE
      • Spira AI.
      Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response (meeting abstr).
      Mechanistically, simultaneous treatment with amivantamab and lazertinib capitalizes on two structurally distinct mechanisms of EGFR inhibition, including amivantamab's extracellular inhibition of EGFR and lazertinib's intracellular EGFR TKI activity. This multi-pronged inhibition of EGFR combined with previously discussed anti-cancer features of amivantamab may provide alternative treatment for this patient population. Importantly, treatment with lazertinib may bring efficacy against brain metastases, which in many instances limits the efficacy of current therapies. Interestingly, in the CHRYSALIS study, documented CNS progression was lower (7%) with amivantamab plus lazertinib treatment than that with amivantamab monotherapy (17%) treatment.
      • Leighl NB
      • Shu CA
      • Minchom A
      • Felip E
      • Cousin S
      • Cho BC
      • Park K
      • Han J
      • Boyer M
      • Lee CK
      • Moreno Garcia V
      • Tomasini P
      • Viteri S
      • Xie J
      • Mertz J
      • Artis E
      • Schnepp RW
      • Knoblauch RE
      • Thayu M
      • rigo Perez JM.
      Amivantamab monotherapy and in combination with lazertinib in post osimertinib EGFR mutant NSCLC: analysis from the CHRYSALIS study.

      Conclusions and future directions

      Despite the improved treatment success of patients with EGFR-mutated NSCLC with EGFR TKIs, most patients will experience recurrence of disease through acquired treatment resistance mutations. Many of these resistance mutations are driven by mutations in EGFR or other gene alterations, such as MET amplification or increased expression of its ligand, HGF. To address these mechanisms of resistance and potentially prevent their occurrence in the first place, a better understanding of the driver determinants of cancer and mechanisms of resistance, coupled with improved medicines with increased safety profiles to permit combination regimens in earlier stages of cancer, even pre-malignancy, will be required to prevent and cure NSCLC.
      • Emdal KB
      • Dittmann A
      • Reddy RJ
      • Lescarbeau RS
      • Moores SL
      • Laquerre S
      • White FM.
      Characterization of in vivo resistance to osimertinib and JNJ-61186372, an EGFR/met bispecific antibody, reveals unique and consensus mechanisms of resistance.
      In this article we reviewed the design, MOAs, and clinical efficacy and safety profile of amivantamab. In summary, we discussed the three distinct MOAs of amivantamab, including ligand blocking, receptor degradation, and immune cell-directing activity, such as trogocytosis, leading to clinical efficacy in NSCLC with EGFR ex20ins. Although amivantamab is currently FDA approved as monotherapy, combination therapy strategies are currently being explored for patients with either EGFR ex20ins (with chemotherapy) or common EGFR mutations (with third-generation EGFR TKI, lazertinib). Capitalizing on the enhanced immune cell-directing activity of amivantamab through its low fucosylated Fc-region, amivantamab offers the potential for effective combination with checkpoint inhibitors or other immunologic enhancing agents for the treatment of cancer.
      Although significant progress has been made in understanding the genetic landscape of NSCLC, including identification of EGFR and MET driver pathways and the advancement of medicines to treat tumors with these alterations, further research is needed to improve outcomes to address the unmet needs of patients with NSCLC.

      Author contributions

      Byoung Chul Cho: Conceptualization, Formal analysis, Investigation, Resources, Data Curation, Writing-Original Draft, Writing-Review & Editing, Visualization, Supervision; Allison Simi: Conceptualization, Investigation, Writing-Original Draft, Writing-Review & Editing, Visualization; Joshua Sabari: Conceptualization, Writing-Original Draft, Writing-Review & Editing; Smruthi Vijayaraghavan: Conceptualization, Data Curation, Visualization, Writing-Original Draft, Writing-Review & Editing; Sheri Moores: Conceptualization, Data Curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing-Review & Editing; Alexander Spira: Supervision, Writing-Review & Editing, Resources.

      Role of the Funding Source

      This study was funded by Janssen Global Services, LLC.

      CRediT authorship contribution statement

      Byoung Chul Cho: Conceptualization, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision. Allison Simi: Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Visualization. Joshua Sabari: Conceptualization, Writing – original draft, Writing – review & editing. Smruthi Vijayaraghavan: Conceptualization, Data curation, Visualization, Writing – original draft, Writing – review & editing. Sheri Moores: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing – review & editing. Alexander Spira: Supervision, Writing – review & editing, Resources.

      Conflict of interest

      Smruthi Vijayaraghavan, Sheri Moores, and Allison Simi are employees of Janssen Pharmaceuticals. Grants or contracts: Alexander Spira: LAM Therapeutics, Roche, AstraZeneca, Boehringer-Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines. Byoung Chul Cho: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GI Innovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence Corporation. Joshua Sabari: Janssen, Loxo/Eli Lilly, Mirati, Regeneron. Royalties or licenses: Byoung Chul Cho: Champions Oncology. Consulting fees: Alexander Spira: Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array BioPharma, AstraZeneca/MedImmune, Merck, Bristol-Myers Squibb, Blueprint Medicines. Byoung Chul Cho: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines. Joshua Sabari: AstraZeneca, Mirati, Navire. Payment or honoraria: Alexander Spira: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol-Myers Squibb, Bayer. Patents planned, issued, or pending: Smruthi Vijayaraghavan, Sheri Moores Participation on a Data Safety Monitoring Board or Advisory Board: Byoung Chul Cho: KANAPH Therapeutic Inc, Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Joseah BIO. Joshua Sabari: AstraZeneca, Genentech, Janssen, Pfizer, Pharma Mar, Regeneron, Sanofi Genzyme, Takeda. Leadership or fiduciary role: Byoung Chul Cho: Gencurix Inc, Interpark Bio Convergence Corporation.Stock or stock options: Alexander Spira: Eli Lilly. Byoung Chul Cho: TheraCanVac Inc, Gencruix Inc, Bridgebio Therapeutics, KANAPH Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence Corporation. Smruthi Vijayaraghavan: Johnson & Johnson. Sheri Moores: Johnson & Johnson. Other financial or non-financial interests: Byoung Chul Cho: DAAN Biotherapeutics.

      Acknowledgments

      Medical writing was provided by Ashley D. Oney, MD, and Claire E. Brady, PharmD, (Cello Health Communications/MedErgy) and funded by Janssen Global Services, LLC.

      Appendix. Supplementary materials

      References

        • Sung H
        • Ferlay J
        • Siegel RL
        • Laversanne M
        • Soerjomataram I
        • Jemal A Bray.
        Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2021; 71: 209-249https://doi.org/10.3322/caac.21660
        • Thai AA
        • Solomon BJ
        • Sequist LV
        • Gainor JF
        • Heist RS.
        Lung cancer.
        Lancet. 2021; 398: 535-554https://doi.org/10.1016/S0140-6736(21)00312-3
        • Mazzarella L
        • Guida A
        • Curigliano G.
        Cetuximab for treating non-small cell lung cancer.
        Expert Opin Biol Ther. 2018; 18: 483-493https://doi.org/10.1080/14712598.2018.1452906
        • Zhang YL
        • Yuan JQ
        • Wang KF
        • Fu XH
        • Han XR
        • Threapleton D
        • Yang ZY
        • Mao C
        • Tang JL.
        The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis.
        Oncotarget. 2016; 7: 78985-78993https://doi.org/10.18632/oncotarget.12587
        • Sholl LM
        • Aisner DL
        • Varella-Garcia M
        • Berry LD
        • Dias-Santagata D
        • Wistuba II
        • Chen H
        • Fujimoto J
        • Kugler K
        • Franklin WA
        • Iafrate AJ
        • Ladanyi M
        • Kris MG
        • Johnson BE
        • Bunn PA
        • Minna JD
        • Kwiatkowski DJ
        • LCMC Investigators
        • et al.
        Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience.
        J Thorac Oncol. 2015; 10: 768-777https://doi.org/10.1097/JTO.0000000000000516
        • Wee P
        • Wang Z.
        Epidermal growth factor receptor cell proliferation signaling pathways.
        Cancers (Basel). 2017; 9: 52https://doi.org/10.3390/cancers9050052
        • Harrison PT
        • Vyse S
        • Huang PH.
        Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer.
        Semin Cancer Biol. 2020; 61: 167-179https://doi.org/10.1016/j.semcancer.2019.09.015
        • Soria JC
        • Ohe Y
        • Vansteenkiste J
        • Reungwetwattana T
        • Chewaskulyong B
        • Lee KH
        • Dechaphunkul A
        • Imamura F
        • Nogami N
        • Kurata T
        • Okamoto I
        • Zhou C
        • Cho BC
        • Cheng Y
        • Cho EK
        • Voon PJ
        • Planchard D
        • Su WC
        • Gray JE
        • Lee SM
        • Hodge R
        • Marotti M
        • Rukazenkov Y
        • Ramalingam SS
        • Investigators FLAURA
        Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
        N Engl J Med. 2018; 378: 113-125https://doi.org/10.1056/NEJMoa1713137
        • Zhou C
        • Ramalingam SS
        • Kim TM
        • Kim SW
        • Yang JC
        • Riely GJ
        • Mekhail T
        • Nguyen D
        • Garcia Campelo MR
        • Felip E
        • Vincent S
        • Jin S
        • Griffin C
        • Bunn V
        • Lin J
        • Lin HM
        • Mehta M
        • Jänne PA
        Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial.
        JAMA Oncol. 2021; 7e214761
        • Murray B
        • Pandey A
        • Roth B
        • Saxton T
        • Estes DJ
        • Agrawal H
        • Vishwakarma S
        • Hallur G
        • Ahmad I;
        • Trivedi R
        • Jenkins H
        • Pearson PG.
        LNG-451 (BLU-451) is a potent, CNS-penetrant, wild-type EGFR sparing inhibitor of EGFR exon 20 insertion mutations.
        Poster presented at: AACR Meeting 2022, April 8-13. 2022; (New Orleans, LA, USA)
        • Westover D
        • Zugazagoitia J
        • Cho BC
        • Lovly CM
        • Paz-Ares L.
        Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors.
        Ann Oncol. 2018; 29 (suppl): i10-i19https://doi.org/10.1093/annonc/mdx703
        • Passaro A
        • Janne PA
        • Mok T
        • Peters S.
        Overcoming therapy resistance in EGFR-mutant lung cancer.
        Nat Cancer. 2021; 2: 377-391https://doi.org/10.1038/s43018-021-00195-8
        • Yano S
        • Yamada T
        • Takeuchi S
        • Tachibana K
        • Minami Y
        • Yatabe Y
        • Mitsudomi T
        • Tanaka H
        • Kimura T
        • Kudoh S
        • Nokihara H
        • Ohe Y
        • Yokota J
        • Uramoto H
        • Yasumoto K
        • Kiura K
        • Higashiyama M
        • Oda M
        • Saito H
        • Yoshida J
        • Kondoh K
        • Noguchi M.
        Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort.
        J Thorac Oncol. 2011; 6: 2011-2017https://doi.org/10.1097/JTO.0b013e31823ab0dd
        • Chu QS.
        Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion.
        Ther Adv Med Oncol. 2020; 121758835919895756https://doi.org/10.1177/1758835919895756
        • Migliore C
        • Morando E
        • Ghiso E
        • Anastasi S
        • Leoni VP
        • Apicella M
        • Cora' D
        • Sapino A
        • Pietrantonio F
        • De Braud F
        • Columbano A
        • Segatto O
        • Giordano S
        miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling.
        EMBO Mol Med. 2018; 10: e8746https://doi.org/10.15252/emmm.201708746
        • Recondo G
        • Bahcall M
        • Sholl L
        • Leonardi G
        • Ricciuti B
        • Nguyen T
        • Venkatraman D
        • Lamberi G
        • Umeton R
        • Janne P.
        Mechanisms of resistance to MET tyrosine kinase inhibitors in patients with MET exon 14 mutant non-small cell lung cancer (meeting abstr).
        J Thorac Oncol. 2019; 14: S285
        • Jo M
        • Stolz DB
        • Esplen JE
        • Dorko K
        • Michalopoulos GK
        • Strom SC.
        Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells.
        J Biol Chem. 2000; 275: 8806-8811https://doi.org/10.1074/jbc.275.12.8806
        • Ortiz-Zapater E
        • Lee RW
        • Owen W
        • Weitsman G
        • Fruhwirth G
        • Dunn RG
        • Neat MJ
        • McCaughan F
        • Parker P
        • Ng T
        • Santis G.
        MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mutations and altered by MET kinase inhibition.
        PLoS One. 2017; 12e0170798https://doi.org/10.1371/journal.pone.0170798
        • Tang Z
        • Du R
        • Jiang S
        • Wu C
        • Barkauskas DS
        • Richey J
        • Molter J
        • Lam M
        • Flask C
        • Gerson S
        • Dowlati A
        • Liu L
        • Lee Z
        • Halmos B
        • Wang Y
        • Kern JA
        • Ma PC.
        Dual MET-EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer.
        Br J Cancer. 2008; 99: 911-922https://doi.org/10.1038/sj.bjc.6604559
        • Puri N
        • Salgia R.
        Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer.
        J Carcinog. 2008; 7https://doi.org/10.4103/1477-3163.44372
        • Moores SL
        • Chiu ML
        • Bushey BS
        • Chevalier K
        • Luistro L
        • Dorn K
        • Brezski RJ
        • Haytko P
        • Kelly T
        • Wu SJ
        • Martin PL
        • Neijssen J
        • Parren PW
        • Schuurman J
        • Attar RM
        • Laquerre S
        • Lorenzi MV
        • Anderson GM.
        A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
        Cancer Res. 2016; 76: 3942-3953https://doi.org/10.1158/0008-5472.CAN-15-2833
        • Haura EB
        • Cho BC
        • Lee JS
        • Han J-Y
        • Lee KH
        • Sanborn RE
        • Govindan R
        • Cho EK
        • Kim S-W
        • Reckamp KL
        • Sabari JK
        • Thayu M
        • Bae K
        • Knoblauch RE
        • Curtin J
        • Haddish-Berhane N
        • Sherman LJ
        • Lorenzi MV
        • Park K Bauml.
        JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC) (meeting abstr).
        J Clin Oncol. 2019; 37: 9009https://doi.org/10.1200/JCO.2019.37.15_suppl.9009
        • Neijssen J
        • Cardoso RMF
        • Chevalier KM
        • Wiegman L
        • Valerius T
        • Anderson GM
        • Moores SL
        • Schuurman J
        • Parren PWHI
        • Strohl WR
        • Chiu ML.
        Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET.
        J Biol Chem. 2021; 296100641https://doi.org/10.1016/j.jbc.2021.100641
        • Gramer MJ
        • van den Bremer ET
        • van Kampen MD
        • Kundu A
        • Kopfmann P
        • Etter E
        • Stinehelfer D
        • Long J
        • Lannom T
        • Noordergraaf EH
        • Gerritsen J
        • Labrijn AF
        • Schuurman J
        • van Berkel PH
        • Parren PW.
        Production of stable bispecific IgG1 by controlled Fab-arm exchange: scalability from bench to large-scale manufacturing by application of standard approaches.
        MAbs. 2013; 5: 962-973https://doi.org/10.4161/mabs.26233
        • Labrijn AF
        • Meesters JI
        • de Goeij BE
        • van den Bremer ET
        • Neijssen J
        • van Kampen MD
        • Strumane K
        • Verploegen S
        • Kundu A
        • Gramer MJ
        • van Berkel PH
        • van de Winkel JG
        • Schuurman J
        • Parren PW.
        Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange.
        Proc Natl Acad Sci U S A. 2013; 110: 5145-5150https://doi.org/10.1073/pnas.1220145110
        • Vijayaraghavan S
        • Lipfert L
        • Chevalier K
        • Bushey BS
        • Henley B
        • Lenhart R
        • Sendecki J
        • Beqiri M
        • Millar HJ
        • Packman K
        • Lorenzi MV
        • Laquerre S
        • Moores SL.
        Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
        Mol Cancer Ther. 2020; 19: 2044-2056https://doi.org/10.1158/1535-7163.MCT-20-0071
        • Jarantow SW
        • Bushey BS
        • Pardinas JR
        • Boakye K
        • Lacy ER
        • Sanders R
        • Sepulveda MA
        • Moores SL
        • Chiu ML.
        Impact of cell-surface antigen expression on target engagement and function of an epidermal growth factor receptor x c-MET bispecific antibody.
        J Biol Chem. 2015; 290: 24689-24704https://doi.org/10.1074/jbc.M115.651653
        • Castoldi R
        • Ecker V
        • Wiehle L
        • Majety M
        • Busl-Schuller R
        • Asmussen M
        • Nopora A
        • Jucknischke U
        • Osl F
        • Kobold S
        • Scheuer W
        • Venturi M
        • Klein C
        • Niederfellner G
        • Sustmann C.
        A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity.
        Oncogene. 2013; 32: 5593-5601https://doi.org/10.1038/onc.2013.245
        • Stewart R
        • Hammond SA
        • Oberst M
        • Wilkinson RW.
        The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer.
        J Immunother Cancer. 2014; 2: 29https://doi.org/10.1186/s40425-014-0029-x
        • Grugan KD
        • Dorn K
        • Jarantow SW
        • Bushey BS
        • Pardinas JR
        • Laquerre S
        • Moores SL
        • Chiu ML.
        Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
        mAbs. 2017; 9: 114-126https://doi.org/10.1080/19420862.2016.1249079
        • Baghban R
        • Roshangar L
        • Jahanban-Esfahlan R
        • Seidi K
        • Ebrahimi-Kalan A
        • Jaymand M
        • Kolahian S
        • Javaheri T
        • Zare P.
        Tumor microenvironment complexity and therapeutic implications at a glance.
        Cell Commun Signal. 2020; 18: 59https://doi.org/10.1186/s12964-020-0530-4
        • Charakidis M
        • Boyer M.
        Targeting MET and EGFR in NSCLC-what can we learn from the recently reported phase III trial of onartuzumab in combination with erlotinib in advanced non-small cell lung cancer?.
        Transl Lung Cancer Res. 2014; 3: 395-396https://doi.org/10.3978/j.issn.2218-6751.2014.09.03
        • Spigel DR
        • Ervin TJ
        • Ramlau RA
        • Daniel DB
        • Goldschmidt Jr, JH
        • Blumenschein Jr, GR
        • Krzakowski MJ
        • Robinet G
        • Godbert B
        • Barlesi F
        • Govindan R
        • Patel T
        • Orlov SV
        • Wertheim MS
        • Yu W
        • Zha J
        • Yauch RL
        • Patel PH
        • Phan SC
        • Peterson AC.
        Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer.
        J Clin Oncol. 2013; 31: 4105-4114https://doi.org/10.1200/JCO.2012.47.4189
        • Zheng S
        • Moores S
        • Jarantow S
        • Pardinas J
        • Chiu M
        • Zhou H
        • Wang W.
        Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody.
        MAbs. 2016; 8: 551-561https://doi.org/10.1080/19420862.2015.1136762
        • RYBREVANT (amivantamab-vmjw) injection [package insert]
        Horsham, PA: Janssen Biotech. July 2021;
        • Park K
        • Haura EB
        • Leighl NB
        • Mitchell P
        • Shu CA
        • Girard N
        • Viteri S
        • Han JY
        • Kim SW
        • Lee CK
        • Sabari JK
        • Spira AI
        • Yang TY
        • Kim DW
        • Lee KH
        • Sanborn RE
        • Trigo J
        • Goto K
        • Lee JS
        • Yang JC
        • Govindan R
        • Bauml JM
        • Garrido P
        • Krebs MG
        • Reckamp KL
        • Xie J
        • Curtin JC
        • Haddish-Berhane N
        • Roshak A
        • Millington D
        • Lorenzini P
        • Thayu M
        • Knoblauch RE
        • Cho BC.
        Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study.
        J Clin Oncol. 2021; 39: 3391-3402https://doi.org/10.1200/JCO.21.00662
        • Guo MZ
        • Marrone KA
        • Spira A
        • Freeman K
        • Scott SC.
        Amivantamab: a potent novel EGFR/c-MET bispecific antibody therapy for EGFR-mutated non-small cell lung cancer.
        Oncol Haematol. 2017; 17: 42-47https://doi.org/10.17925/OHR.2021.17.1.42
        • Kainis I
        • Syrigos N
        • Kopitopoulou A
        • Gkiozos I
        • Filiou E
        • Nikolaou V
        • Papadavid E.
        Erlotinib-associated rash in advanced non-small cell lung cancer: relation to clinicopathological characteristics, treatment response, and survival.
        Oncol Res. 2018; 26: 59-69https://doi.org/10.3727/096504017X14913452320194
        • Zhang Y
        • Miao S
        • Wang F
        • Fang W
        • Chen G
        • Chen X
        • Yan F
        • Huang X
        • Wu M
        • Huang Y
        • Zhang L.
        The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis.
        J Thorac Dis. 2017; 9: 1980-1987https://doi.org/10.21037/jtd.2017.06.08
        • US Department of Health and Human Services
        Common terminology for adverse events (CTCAE) Version 5.0 2017. 2017; (Published November 27Accessed May 17, 2022)
        • Krebs MG
        • Johnson ML
        • Cho BC
        • Lee S-H
        • Kudgus-Lokken R
        • Zemlickis D
        • Mitselos A
        • Berkay E
        • Bauml JM
        • Knoblauch RE
        • Hellemans P
        • Minchom AR.
        Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: initial safety and pharmacokinetic results from the PALOMA study.
        in: Presented at AACR Annual Meeting. Abstract CT198, New Orleans, LA2022 (April 8-13)
        • Pirker R
        • Pereira JR
        • Szczesna A
        • von Pawel J
        • Krzakowski M
        • Ramlau R
        • Vynnychenko I
        • Park K
        • Yu CT
        • Ganul V
        • Roh JK
        • Bajetta E
        • O'Byrne K
        • de Marinis F
        • Eberhardt W
        • Goddemeier T
        • Emig M
        • Gatzemeier U
        • Study Team FLEX
        Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.
        Lancet. 2009; 373: 1525-1531https://doi.org/10.1016/S0140-6736(09)60569-9
      1. ClinicalTrials.gov. A study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in participants with advanced or metastatic non-small cell lung cancer characterized by epidermal growth factor receptor (EGFR) exon 20 insertions (PAPILLON). Accessed October 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04538664.

        • Cho BC
        • Lee KH
        • Cho EK
        • Kim D
        • Lee J
        • Han J
        • Kim S
        • Spira A
        • Haura EB
        • Sabari JK
        • Sanborn RE
        • Bauml JM
        • Gomez JE
        • Lorenzini P
        • Infante JR
        • Xie J
        • Haddish-Berhane N
        • Thayu M
        • Knoblauch RE
        • Amivantamab Park K.
        JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced EGFR-mutant NSCLC.
        Presented at: ESMO Congress, VirtualSeptember 20, 2020 (Abstract 12580)
        • Shu CA
        • Goto K
        • Ohe Y
        • Besse B
        • Lee S-H
        • Wang Y
        • Griesinger F
        • Yang J C-H
        • Felip E
        • Sanborn RE
        • Caro RB
        • Curtin JC
        • Chen J
        • Mahoney JM
        • Trani L
        • Bauml JM
        • Knoblauch RE
        • Thayu M
        • Cho BC.
        Amivantamab and lazertinib in patients with EGFR-mutant non-small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy: Updated results from CHRYSALIS-2.
        J Clin Oncol. 2022; 40: 9006https://doi.org/10.1200/JCO.2022.40.16_suppl.9006
        • Marmarelis ME
        • Lee SH
        • Spira AI
        • Ou S-HI
        • Waqar S
        • Li S
        • Thayu M
        • Knoblauch RE
        • Bauml JM
        • Cho BC.
        Amivantamab and lazertinib in combination with platinum-based chemotherapy in relapsed/refractory EGFR-mutant NSCLC (meeting abstr).
        J Thorac Oncol. 2022; 17: S68https://doi.org/10.1016/j.jtho.2022.07.114
      2. ClinicalTrials.gov. A study of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure (MARIPOSA-2). Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04988295

      3. ClinicalTrials.gov. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Accessed October 31, 2022. https://clinicaltrials.gov/ct2/show/NCT04487080

        • Shu CA
        • Goto K
        • Ohe Y
        • Besse B
        • Park K
        • Wang Y
        • Griesinger F
        • Yang JC
        • Felip E
        • Sanborn RE
        • Bernabe Caro R
        • Bauml JM
        • Chen J
        • Fennema E
        • Mahoney J
        • Trani L
        • Knoblauch RE
        • Thayu M
        • Cho BC
        Amivantamab plus lazertinib in post-osimertinib, post-platinum chemotherapy EGFR-mutant non-small cell lung cancer (NSCLC): preliminary results from CHRYSALIS-2.
        Presented at: ESMO Congress; September 16-21. 2021; (Virtual. Abstract 1193MO)
        • Leighl NB
        • Shu CA
        • Minchom A
        • Felip E
        • Cousin S
        • Cho BC
        • Park K
        • Han J
        • Boyer M
        • Lee CK
        • Moreno Garcia V
        • Tomasini P
        • Viteri S
        • Xie J
        • Mertz J
        • Artis E
        • Schnepp RW
        • Knoblauch RE
        • Thayu M
        • rigo Perez JM.
        Amivantamab monotherapy and in combination with lazertinib in post osimertinib EGFR mutant NSCLC: analysis from the CHRYSALIS study.
        Oral presentation at: ESMO Congress; September 16-21. 2021; (Virtual. Abstract 1192MO)
        • Bauml J
        • Cho BC
        • Park K
        • Lee KH
        • Cho EK
        • Kim D-W
        • Kim S-W
        • Haura EB
        • Sabari JK
        • Sanborn RE
        • Nagasaka M
        • Ou S-HI
        • Minchom AR
        • Gomez JE
        • Curtin JC
        • Gao G
        • Roshak A
        • Thayu M
        • Knoblauch RE
        • Spira AI.
        Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response (meeting abstr).
        J Clin Oncol. 2021; 39: 9006https://doi.org/10.1200/JCO.2021.39.15_suppl.9006
        • PORTRAZZA (necitumumab) injection [package insert]
        Indianapolis, IN: Eli Lilly and Company. November 2015;
      4. VECTIBIX® (panitumumab) injection for intravenous infusion [package insert]. Thousand Oaks, CA: Amgen, Inc.

        • ERBITUX® (cetuximab) injection, for intravenous infusion [package insert]
        Branchburg, NJ: ImClone LLC. 2016;
        • Emdal KB
        • Dittmann A
        • Reddy RJ
        • Lescarbeau RS
        • Moores SL
        • Laquerre S
        • White FM.
        Characterization of in vivo resistance to osimertinib and JNJ-61186372, an EGFR/met bispecific antibody, reveals unique and consensus mechanisms of resistance.
        Mol Cancer Ther. 2017; 16: 2572-2585https://doi.org/10.1158/1535-7163.MCT-17-0413