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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
Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro Sinchon-dong, Seodaemun-gu, Seoul, South Korea
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 3 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 3 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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
The interdependence between these 2 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).
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 2 parental monoclonal antibodies (mAbs), 1 targeting EGFR and 1 targeting MET.
Production of stable bispecific IgG1 by controlled Fab-arm exchange: scalability from bench to large-scale manufacturing by application of standard approaches.
resulting in a bispecific antibody with single arm binding sites (ie, 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,
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
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 3 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 the MOA Video, available in the Supplementary Materials.
Figure 2Schematic of amivantamab's 3 MOAs - ligand blocking, receptor degradation, and activation of immune-cell-directing activity: ADCC = antibody-dependent cellular cytotoxicity; EGF = epidermal growth factor; HGF = hepatocyte growth factor; MOA = mechanism of action; NK = natural killer.
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.
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.
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 1 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.
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.
A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity.
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.
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
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,
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
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 Fcγ receptors (FcγRs) on immune cells (Figure 2).
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
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 FcγRs on immune cells also plays an important role in receptor and signal downmodulation.
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.
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.
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.
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 EGFR family members, which could contribute to suppression of signaling pathways that lead to resistance.
Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis.
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.
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.
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.
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?.
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 1 of these 2 receptors.
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).
Resistance to EGFR TKIs most commonly occurs through alterations of EGFR and/or MET, retaining treatment-resistant cancer growth dependence on this pathway.
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.
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 2 receptors.
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.
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.
Because it is derived from 2 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.
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 2 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.
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.
Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study.
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.
Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study.
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 [eg, antihistamines, non-steroidal anti-inflammatory drugs, narcotics, intravenous fluids; prophylactic medications indicated for ≤24 hours]).
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, et al. Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: initial safety and pharmacokinetic results from the PALOMA study. Presented at: AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT198.
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 kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type, EGFR-expressing, metastatic colorectal cancer, has also been investigated for the treatment of NSCLC in numerous clinical trials, including 2 phase 2 studies (FLEX
) 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.
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
Locally advanced or mNSCLC with EGFR ex20ins and disease progression on or after platinum-based chemotherapy
Metastatic 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
Among 545 patients: OS: 11.5 months PFS: 5.7 months
Among 231 patients: PFS: 96
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 eventss
•
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.
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.
Cho BC, Lee KH, Cho EK, et al. 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; September 9-13, 2022; Paris, France. Abstract 12580.
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%.
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.
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, et al. 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; September 9-13, 2022; Paris, France. Abstract 12580.
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, et al. 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; September 9-13, 2022; Paris, France. Abstract 12580.
Shu CA, Goto K, Ohe Y, et al. 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, et al. Amivantamab monotherapy and in combination with lazertinib in post osimertinib EGFR mutant NSCLC: analysis from the CHRYSALIS study. Presented at: ESMO Congress; September 16-21, 2021; Virtual. Abstract 1192MO.
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.
Mechanistically, simultaneous treatment with amivantamab and lazertinib capitalizes on 2 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 centralnervous system progression was lower (7%) with amivantamab plus lazertinib treatment than that with amivantamab monotherapy (17%) treatment.
Leighl NB, Shu CA, Minchom A, et al. Amivantamab monotherapy and in combination with lazertinib in post osimertinib EGFR mutant NSCLC: analysis from the CHRYSALIS study. Presented at: ESMO Congress; September 16-21, 2021; Virtual. Abstract 1192MO.
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.
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, clinical efficacy, and safety profile of amivantamab. In summary, we discussed the 3 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.
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.
This study was funded by Janssen Global Services, LLC.
Disclosures
Allison Simi,mruthi Vijayaraghavan, and Sheri Moores 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 Corp. 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 Corp. Smruthi Vijayaraghavan: Johnson & Johnson. Sheri Moores: Johnson & Johnson. Other financial or non-financial interests: Byoung Chul Cho: DAAN Biotherapeutics.
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Characterization of in vivo resistance to osimertinib and JNJ-61186372, an EGFR/met bispecific antibody, reveals unique and consensus mechanisms of resistance.
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