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Footnotes Footnotes

ADCC = antibody-dependent cellular cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; ADCR = antibody-dependent cytokine release; ADCT = antibody-dependent cellular trogocytosis; AKT = protein kinase B; BBB = blood-brain barrier; CNS = central nervous system; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; ERK = extracellular signal-related kinase; HGF = hepatocyte growth factor; HGFR = hepatocyte growth factor receptor; MAPK = mitogen-activated protein kinase; MOA = mechanism of action; NK = natural killer; NSCLC = non-small cell lung cancer; PI3K = phosphatidylinositol 3 kinase; TKI = tyrosine kinase inhibitor.

References

  1. O’Leary C, et al. Epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Pharmaceuticals (Basel) . 2020;13(10):273.
  2. Bylicki O, et al. Targeting the MET-signaling pathway in non-small–cell lung cancer: Evidence to date. Onco Targets Ther . 2020;13:5691–5706.
  3. Brazel D and Nagasaka M. Spotlight on amivantamab (JNJ-61186372) for EGFR exon 20 insertions positive non-small cell lung cancer. Lung Cancer . 2021;12:133–138.
  4. Cho BC, et al. 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. Clin Lung Cancer . 2023;24(2):89–97.
  5. Bazhenova L, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer . 2021;162:154–161.
  6. Soria JC, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med . 2018;378(2):113–125.
  7. Riess JW, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol . 2018;13(10):1560–1568.
  8. Zubair T and Bandyopadhyay D. Small molecule EGFR inhibitors as anti-cancer agents: discovery, mechanisms of action, and opportunities. Int J Mol Sci . 2023;24(3):2651.
  9. Yun J, et al. YH25448, an irreversible EGFR-TKI with potent intracranial activity in EGFR mutant non-small cell lung cancer. Clin Cancer Res . 2019;25(8):2575–2587.
  10. Westover D, et al. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors.Ann Oncol . 2018;29(suppl_1):i10–i19.
  11. Yun HC, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci . 2008;105(6):2070–2075.
  12. Engelman JA, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science . 2007;316(5827):1039–1043.
  13. Moores SL, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. Cancer Res . 2016;76(13):3942–53.
  14. Grugan KD, et al. Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs . 2017;9(1):114–126.
  15. Vijayaraghavan S, et al. 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(10):2044–2056.
  16. FDA. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer . Last accessed December 2023.
  17. RYBREVANT® (amivantamab). US Prescribing information. Janssen Biotech, Inc. 11/2022.
  18. Zhou C, et al. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med . 2023;389(22):2039–2051.
  19. Cho BC, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Presented at the European Society for Medical Oncology Congress 2023, LBA14; October 20–24, 2023.
  20. Passaro A, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase III MARIPOSA-2 study. Ann Oncol . 2024;35(1):77–90.
  21. Leighl NB, et al. Amivantamab monotherapy and in combination with lazertinib in post-osimertinib EGFR-mutant NSCLC: Analysis from the CHRYSALIS study. Presented at the European Society for Medical Oncology Congress 2021; September 16–21, 2021.
  22. Yun J, et al. Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC. Cancer Discov . 2020;10(8):1194–1209.
  23. Ahn MJ, et al. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study. Clinical Trial Lancet Oncol . 2019;20(12):1681–1690.
  24. Cho BC, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Presented at the European Society for Medical Oncology Congress 2023, LBA14; October 20–24, 2023.

Amivantamab approval

  • Based on clinical data from the Phase 1 CHRYSALIS trial (ClinicalTrials.gov NCT02609776 ), the FDA granted accelerated approval for amivantamab in May 2021 as therapy for adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy16,17
  • Amivantamab is being evaluated in other studies, including as combination therapy, in various Phase 3 trials18–20

Why combine amivantamab and lazertinib?

  • Preclinical and early clinical studies suggest improved inhibition of tumor growth when both the extracellular and intracellular catalytic domains of the EGFR receptor are simultaneously targeted9,13,15,21–23
  • Lazertinib is a mutation selective, CNS-penetrant, third-generation EGFR TKI with intracellular activity that targets T790M and common EGFR mutations9

Key hypothesis

  • Combining amivantamab with lazertinib may be potent against acquired resistance, such as EGFR T790M-mutated tumors, while also increase blood-brain barrier (BBB) penetration and CNS activity4,9
  • Mechanistically, simultaneous treatment with amivantamab and lazertinib provides a multi-pronged approach, with two structurally distinct mechanisms of EGFR inhibition: the extracellular binding of EGFR with amivantamab and the intracellular TKI activity of lazertinib4
  • The combination of amivantamab and lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations was FDA approved based on results from the Phase 3 MARIPOSA trial (ClinicalTrials.gov NCT04487080).
The unmet need in NSCLC What is amivantamab? MOA: Ligand blocking MOA: Receptor degradation MOA: Immune cell-directed activity Conclusions
Ligand blocking Receptor degradation Immune
cell-directed activity
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Increased
dual-receptor
avidity
Enhanced
FcγR binding
Fully human
antibody
Dual-receptor
targeting
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Amivantamab approval
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Combining amivantamab and lazertinib
ADCP
ADCR
ADCC
Trogocytosis
Receptor internalization and degradation
Ligand blocking
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Simultaneous binding
of EGFR and MET
Low fucose
backbone
Amivantamab is a
bispecific antibody
Acquired
resistance
TKI therapy
Resistant EGFR
‍ gene mutations
Common EGFR
‍ gene mutations
EGFR and MET interdependence
EGFR activity in tumors
MET signaling
EGFR signaling
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Amivantamab
Mechanism of action
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Johnson &Johnson Innovative Medicine | 03/2024

Patients with EGFR -mutated NSCLC are often treated with EGFR TKIs, although some more uncommon mutations are resistant to TKI therapy.4,5

Amivantamab is a
first-in-class bispecific antibody targeting both the EGFR and MET signaling pathways by binding the extracellular regions of the respective receptors.3,4

Amivantamab reduces ligand-induced receptor activation by blocking the binding of EGF to EGFR, and HGF to MET.4,13

The binding of the Fc region of amivantamab to the Fcγ receptors on immune cells induces several effector functions through activation of the immune cells. Of these, trogocytosis is the most prominent activity.4,15

Amivantamab is a bispecific antibody that acts via three different mechanisms of action and has a design tailored around higher selectivity and specificity.3,4

The EGFR gene is a key oncogene that is mutated in different cancer types, including NSCLC, and regulates cell proliferation and survival.1

A majority of NSCLC tumors eventually acquire resistance to therapy through various mechanisms, leading to disease progression.4,10–12

Amivantamab inhibits receptor activation and downstream signaling through three separate mechanisms of action (MOA).4

Amivantamab reduces downstream signaling as a result of EGFR and MET receptor degradation following receptor internalization.4,13

Other immune cell-directed activities include cellular cytotoxicity, phagocytosis, and cytokine release.4,14