Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide [
1,
2]. Increased access to DNA sequencing for targetable mutations and rapid advancements in targeted therapeutic options have improved outcomes in many subtypes of NSCLC [
3‐
5]. Drugs targeting molecular oncogenic drivers have improved efficacy and tolerability of treatment for NSCLC patients.
EGFR is a transmembrane cell surface receptor with downstream effects that regulate cell proliferation and apoptosis [
6]. In normal cells,
EGFR signaling is responsible for DNA synthesis and cellular proliferation, however, surplus activity results in uncontrolled cellular growth and tumorigenesis [
7].
EGFR mutations generally favor the active state leading to pro-survival and antiapoptotic signals, even without the presence of a ligand [
8,
9].
EGFR is an attractive target for therapeutic development as
EGFR-mutated tumors become dependent on the
EGFR pathway and its downstream effects for survival [
6].
EGFR-mutated NSCLC is found on sequencing of 20% of Caucasians, up to 50% of Asian patients [
4,
10]. and globally,
EGFR mutations account for 23–30% of NSCLC activating mutations [
11,
12].
Classic
EGFR mutations (exon 19 deletions or exon 21 L858R substitutions) represent 85% of
EGFR mutations [
13].
EGFR exon20ins (exon20ins) consist of either point mutations or insertions of 3–21 base pairs [
14]. and are present in 4-to-12% of
EGFR-mutated NSCLC [
15]. NSCLC driven by
EGFR exon20ins portends a worse prognosis and shorter overall survival than classic sensitizing
EGFR mutations such as exon 19 deletions and exon 21 L858R point mutations [
16,
17]. Because of its structure, the active conformation with the C-helix in an inward position, forming a rigid and inflexible structure that locks the
EGFR molecules in active conformation without ligand binding [12 Yasuda],
EGFR exon20ins are classically resistant to first-, second-, and third-generation
EGFR tyrosine kinase inhibitors (TKIs) and prior to approval of amivantamab in 2021, there were no Federal Drug Administration (FDA) approved targeted therapeutic options. In May 2021, the FDA granted accelerated approval to amivantamab (Rybrevant) in adult NSCLC patients with locally advanced or metastatic
EGFR exon20ins-positive disease following platinum-based chemotherapy.
Mesenchymal-epithelial transition (
MET) is a tyrosine kinase receptor for the ligand hepatocyte growth factor (HGR) and is frequently expressed by epithelial cells of solid organs. Dysregulation of the
MET pathway results in proliferation, survival, invasion, and metastasis of tumor cells.
MET activation is both a primary oncogenic driver mutation and could be a secondary mechanism of drug resistance, making the
MET pathway an attractive therapeutic target [
18,
19].
MET aberrations can occur as overexpression, amplification or mutations.
MET is overexpressed in 20%, [
20] amplified in 1–5%, [
21] and exon 14 skipping mutations (
METex14) occur in 3–4% of NSCLC tumors [
22‐
24].
MET rearrangements have been detected in several cancer types including NSCLC and glioblastomas [
25,
26]. In chromosomal translocations, the fusion typically includes a dimerization domain resulting in constitutive activation. Although the TPR-MET fusion was first identified, [
27] a
ST7-MET fusion was reported as an acquired resistance mechansim to the third-generation TKI lorlatinib in a NSCLC patient with dual
ALK-MET aberrations [
28]. Within NSCLC tumors,
METex14 skipping mutations are most frequent in sarcomatoid carcinoma (4.9–31%), adenosquamous carcinoma (5%), adenocarcinoma (3%), and squamous cell carcinoma (2%) [
29‐
33] and are more common in patients over 70 years old, women, and never-smokers.
MET aberrations are associated with poor prognosis [
34‐
36].
MET exon 14 skipping mutations occur at high allele frequency and can co-occur with
TP53,
MDM2,
CDK4, and
HMGA2 co-amplifications while
MET-amplified patients have co-occurring
NRAS and
KRAS mutations [
37]. Conversely, one study of 30 patients with
METex14 aberrations found no overlap with mutations in
KRAS, EGFR, ERBB2, ALK, ROS1, or RET [
29].
METex14 skipping mutations are associated with worse overall survival [
38].
MET amplification has been shown to bypass
EGFR signaling pathways and confer resistance to osimertinib [
39,
40].
MET amplification was found in 15% of samples at disease progression on osimertinib [
41].
MET amplification has been described in cases of rapid and prolonged response to crizotinib [
42].
MET-mutated tumors are also associated with a worse prognosis [
43]. Additional
MET aberrations included impaired
MET receptor degradation,
MET fusion, and
MET overexpression.
Upregulation of the
EGFR signaling pathway has been shown as a mechanism of resistance to
MET TKIs [
44,
45].
MET amplification is associated with resistance in 50–60% of first- and second-generation
EGFR TKIs [
46‐
48] and 15–19% of third-generation
EGFR TKIs [
41,
49].
EGFR and
MET are co-expressed in 70% of
EGFR mutations [
50,
51]. In contrast, normal cells almost never concomitantly express both receptors [
52,
53]. Interactions between
EGFR and
MET signaling pathways is well documented in the literature and are involved in both oncogenic signaling as well as tumor microenvironment remodeling [
54‐
56]. Both
EGFR and
MET signal through the same pathways, possibly explaining frequent resistance upon inhibition of only one of these receptors [
57]. The interplay between these pathways suggests that simultaneously inhibiting both oncogenes may reduce resistance to
MET- or
EGFR-targeted agents.
The first
MET inhibitor, crizotinib, was approved in 2011 for
ALK-rearranged NSCLC and since that time,
MET-targeted drugs including capmatinib and tepotinib have been approved for NSCLC harboring
MET exon 14 skipping mutations. Capmatinib is a type 1b
MET inhibitor with a mechanism similar to that of crizotinib. The phase II GEOMETRY study, reported an objective response rate (ORR) of 41% (95% CI 29–53) in pretreated patients with
MET exon 14 skipping mutations and 68% (95% CI 48–84) in treatment naïve patients [
58]. The duration of response (DOR) was 9.7 months and 12.6 months, respectively. Among patients with
MET amplification and a gene copy number of 10 or higher, OR was seen in 29% (95% CI, 19 to 41) of pretreated patients and in 40% (95% CI, 16 to 68) of treatment naïve patients. [
51]. Tepotinib is a TKI that selectively binds
MET to promote tumor cell death and in the phase II VISION trial, tepotinib had an ORR 46% (95% CI 36–57) with median DOR 11.1 months (95% CI 7.2-NR) [
59].
In this review, we discuss the unique structure, pharmacodynamics, and pharmacokinetics of amivantamab as well as its indication towards EGFR exon20ins and beyond, focusing on dual inhibition of EGFR and MET, which could be employed for the treatment of MET-altered tumors as well as those with sensitizing EGFR mutations who have progressed on EGFR TKIs.
Structural characteristics and mechanism of action of amivantamab
Amivantamab (JNJ-61,186,372, Rybrevant, Janssen Biotech, Inc) is a fully human Fc-active immunoglobulin G1 (IgG1) bispecific antibody against both epidermal growth factor (
EGF) and
MET receptors. Amivantamab consists of two arms; one binds the extracellular domain of
EGFR to block binding between the receptor and its ligand EGF while the other arm blocks
HGF ligand from binding to the
MET receptor. Amivantamab induces degradation of both receptors in vivo, broadening its mechanism of action to include ligand-independent driven disease [
15,
60]. This results in stopping downstream signaling of pro-growth and pro-survival proteins. Amivantamab simultaneously inhibit
EGFR as well as one of the more common mechanisms of resistance to
EGFR targeting therapy through the
MET pathway. This combined inhibition has the potential to enhance depth and duration of response for patients with these mutations.
In addition to the direct inhibitory effects as a bispecific antibody, amivantamab also appears to work with the human immune system. Indeed, amivantamab has a low fructose backbone to enhance binding to FcYRIIIa/CD16a [
61]. The FcYRIIIa/CD16a receptor on NK cells, monocytes, and macrophages triggers antibody-dependent cell-mediated cytotoxicity (ADCC) of NSCLC cells. This unique structural design permits amivantamab to eliminate antigen-expressing tumor cells through ADCC, induce trogocytosis as well as antibody dependent cellular phagocytosis and antibody dependent cytokine release. This activity results in receptor-antibody complex endocytosis and removal via lysosomal trafficking [
61].
Preclinical studies
Preclinical studies have confirmed the unique characteristics of amivantamab. The low fructose backbone of amivantamab appears to enhance ADCC through stronger binding to the F-c domain [
63]. Indeed, studies in mice confirmed that tumors treated with amivantamab had lower
EGFR and
MET receptor expression as a result of receptor internalization and trogocytosis [
60].
Preclinical studies of Ba/F3 cell lines containing
EGFR exon20ins have found that amivantamab decreased EGF and
MET receptor expression [
15]. All five exon20ins studied (V769_D770insASV, D770delinsGY, H773_V774insH, Y764_V765insHH, and D770_N771ins- SVD) demonstrated a dose-dependent decrease in viability. The proposed mechanism of action is inhibition of cell proliferation through decreased pERK, pAkt, and p-S6 [
15]. Additionally, amivantamab induced apoptosis via upregulating proapoptotic proteins including
BCL2-interacting mediator of cell death (BIM) and cleaved caspase-3.
HCC827 is a lung adenocarcinoma cell line with an acquired E746_A750 deletion in the
EGFR tyrosine kinase exon 19 domain. Data from HCC827 cell lines have found superior antitumor activity of amivantamab compared to TKI erlotinib and the
MET inhibitor crizotinib. By day 34, tumor growth was inhibited 99.8% (p < 0.05) with a durable response 8 weeks after amivantamab discontinuation [
64]. In experiments with xenograft models amivantamab was more efficacious than either cetuximab or poziotinib [
15].
Additionally, amivantamab has preclinical data from resistant cell lines. Within cell lines of
EGFR activating mutations (i.e. L858R), with
EGFR resistance mutations (i.e. T790M)or
MET amplification, amivantamab blocked ligand from binding its receptor [
65]. This showed the antitumor activity of amivantamab even in tumors with mechanisms of resistance to
EGFR targeted therapy as well as the historically difficult to target
MET amplification. Further, amivantamab results in decreased cell surface
EGFR and
MET receptors both in vitro and in vivo [
60]. Importantly, amivantamab remains effective when bound to either
EGFR or
MET receptors alone [
60,
63].
Discussion/future directions
Traditional
EGFR targeted therapies such as gefitinib, erlotinib and osimertinib which are effective against those with
EGFR sensitizing mutations, were not as effective against
EGFR exon20ins-mutated NSCLC, leaving an unmet need for a significant percentage of lung adenocarcinoma patients with
EGFR mutations. Approximately 90% of exon20ins mutations occur after the C-helix of the tyrosine kinase domain, wedging the C-helix in front of the drug binding pocket resulting in active kinase formation making it difficult for drug binding [
9,
80]. This may explain resistance to first generation TKIs [
81]. Second generation TKIs in exon20ins are limited by significant toxicity at plasma concentrations below the efficacy threshold required to inhibit signaling pathways [
14]. The third generation
EGFR TKI, osimertinib, was ineffective in
EGFR exon20ins with a low overall response rate of 5% [
81,
82]. Patients with newly diagnosed
EGFR exon20ins-driven NSCLC have a median OS of 16.2 months (95% CI: 11.0-19.4) [
83] compared to a median OS of 38.6 months in those with exon 19 deletions and 21 mutations based on the FLAURA study of front-line osimertinib [
84].
Promising results from the phase I CHRYSALIS trial led to the FDA accelerated approval of amivantamab in those with
EGFR exon20ins post platinum-based therapy. Amivantamab is the first FDA-approved bispecific molecule for treatment of solid malignancies. The investigators found an ORR of 40% with a median PFS of 8.3 months. These findings are clinically meaningful considering that relapsed metastatic or unresectable NSCLC has a 5-year survival rate of less than 10% [
62]. While mobocertinib also received FDA accelerated approval for the same indication with potentially similar efficacy profile, [
85] as the confirmatory phase 3 EXCLAIM-2 study did not meet its primary endpoint, Takeda has announced its voluntary withdrawal.
Further enhancing the efficacy with combination therapy with chemotherapy may be attractive to patients especially those with an initially high tumor burden. The ongoing phase III PAPILLON trial (NCT04538664) is studying the efficacy and safety of carboplatin-pemetrexed chemotherapy with or without amivantamab in the first-line treatment setting of metastatic NSCLC with
EGFR exon20ins. This design is particularly favorable, as the standard of care first line treatment is platinum doublet, ensuring patients a “no-risk” approach, while the addition of amivantamab from first line may have a chance to induce even better efficacy results. The primary outcome of interest is PFS at 18 months with secondary outcomes including ORR, DOR, and tolerability (Table
2). Additional evidence is needed for patients with baseline brain metastases using combinations of amivantamab with chemotherapy, targeted agents, and radiation along with careful evaluation of the associated toxicity profiles.
Table 2
Ongoing Trials of Amivantamab
NCT04538664 PAPILLON | amivantamab + carboplatin + pemetrexed vs. carboplatin + pemetrexed | NSCLC | N = 300 | 3 | PFS | Recruiting |
NCT04487080 MARIPOSA | amivantamab + lazertinib vs. osimertinib vs. lazertinib | NSCLC | N = 1074 | 3 | PFS | Active, not recruiting |
NCT04988295 MARIPOSA-2 | amivantamab + lazertinib + platinum chemotherapy | NSCLC | N = 600 | 3 | PFS | Recruiting |
NCT05388669 PALOMA-3 | amivantamab + lazertinib | NSCLC | N = 640 | 3 | Serum concentration | Recruiting |
NCT04965090 | amivantamab + Lazertinib | NSCLC | N = 40 | 2 | CNS ORR | Recruiting |
NCT05074940 | amivantamab | Adenoid cystic carcinoma | N = 18 | 2 | ORR | Recruiting |
NCT05299125 | amivantamab, lazertinib, carboplatin, pemetrexed | NSCLC | N = 49 | 2 | PFS, OS | Not yet recruiting |
NCT05117931 | amivantamab | Esophagogastric cancer | N = 25 | 2 | ORR | Recruiting |
NCT04945733 | amivantamab | Gastric or esophageal cancer | N-79 | 2 | ORR | Recruiting |
NCT05498428 PALOMA-2 | amivantamab | Solid tumors | N = 260 | 2 | ORR, adverse events | Not yet recruiting |
NCT05488314 | amivantamab + capmatinib | NSCLC | N = 147 | 1/2 | Dose limiting toxicity, ORR | Not yet recruiting |
NCT05379595 | amivantamab | Colorectal cancer | N = 225 | 1b/2 | ORR, dose limiting toxicity | Recruiting |
NCT04077463 CHRYSALIS-2 | lazertinib +/- amivantamab | NSCLC | N = 460 | 1/1b | Dose limiting toxicity, ORR | Recruiting |
NCT04085315 | amivantamab + osimertinib | NSCLC | N = 38 | 1/1b | Safety and tolerability | Recruiting |
NCT05395052 | FT536 + amivantamab and other monoclonal antibodies | Solid tumors | N = 322 | 1 | Recommended dose, adverse events | Recruiting |
NCT02609776 CHRYSALIS | amivantamab | NSCLC | N = 780 | 1 | ORR, DOR, dose limiting toxicity | Recruiting |
NCT04606381 PALOMA | amivantamab | Solid tumors | N = 196 | 1 | Serum concentration, dose limiting toxicity | Recruiting |
Amivantamb, given its broad-spectrum coverage against EGFR and the fact that it is a bispecific against MET, which alterations are known to be part of the mechanism of resistance against osimertinib, is also being evaluated in the first line setting for those with EGFR exon 19 deletions and L858R mutations as well as post progression on osimertinib.
Of 20 treatment-naïve patients with classical
EGFR mutations treated with amivantamab plus lazertinib in the CHRYSALIS (NCT02609776) study, the ORR was 100% [
86]. In the post osimertinib setting, preliminary data of CHRYSALIS-2 showed promising results with ORR 36%, clinical benefit rate of 58% including one complete response. Although the median DOR was not reached, 39% of participants had a durable response at a median follow-up of 8.3 months [
79]. Sub-analysis of the heavily-pretreated population found ORR 29% with clinical benefit rate 55% and median DOR 8.6 months. Also, among eight patients with baseline brain lesions, antitumor activity was reported.
Currently, the CHRYSALIS-2 trial (NCT04077463) is studying amivantamab and lazertinib in
EGFR-NSCLC (Table
2). While the phase III MARIPOSA study (NCT04487080) is investigating the safety and efficacy of amivantamab in combination with lazertinib versus lazertinib alone or lazertinib alone in NSCLC patients with classic
EGFR mutations in the front line setting, MARIPOSA-2 study (NCT04988295) is evaluating three arms (lazertinib + amivantamab + carboplatin + pemetrexed, carboplatin + pemetrexed, amivantamab + carboplatin + pemetrexed) post progression on lazertinib in those with the classic
EGFR mutations. The primary outcome of interest is PFS with secondary endpoints of ORR, OS, DOR, intracranial PFS among others.
The safety profile of amivantamab combined with lazertinib is similar to that of amivantamab monotherapy [
86]. Most common adverse events include rash (78%), infusion-related reactions (61%), paronychia (42%), stomatitis (31%), and pruritis (24%). Grade 3 or higher adverse events were reported in 7% of participants. Similar rates of infusion-related reaction (65%), paronychia (49%), rash (41%), and stomatitis (39%) were seen in CHRYSALIS-2 [
79]. This combination has the benefit of amivantamab’s activity against extracellular
EGFR with lazertinib’s intracellular
EGFR TKI efficacy. Lazertinib also crosses the blood-brain barrier, making this combination favorable for NSCLC patients with brain metastases who have limited effective treatment options. Within the CHRYSALIS cohort, only 7% of patients on combination therapy had documented central nervous system progression compared to 17% with amivantamab monotherapy [
87]. Additional ongoing trials with amivantamab are listed in Table
2.
Currently there are no FDA approved targeted agents for
MET amplified cancers. Although new therapeutics targeting
MET include capmatinib and tepotinib for
MET exon 14 skipping mutations have become available, additional treatment options are needed. Amivantamab has shown early promising data in
MET exon 14 skipping mutations with ORR 33% in all patients and 57% in treatment-naïve patients [
72]. The median PFS was 6.7 months and was generally well tolerated.
While amivantamab is an excellent agent towards EGFR exon20ins and beyond, we must be cognizant of the adverse event profile and the inconvenience to patients. To circumvent the infusion time (and potentially infusion related reactions), multiple studies are looking at utilizing the subcutaneous version of amivantamab in NSCLC and solid tumors (PALOMA: NCT04606381, PALOMA2 NCT05498428 and PALOMA3 NCT05388669). Preliminary results look promising with a remarkably lower rate of infusion-related reactions.
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