Amivantamab-Vmjw: A Novel Treatment for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutation after Progression on Platinum-Based Chemotherapy

Abstract

Objective:
This study is a comprehensive review of the clinical pharmacology, pharmacokinetics, efficacy, safety, and clinical applicability of amivantamab-vmjw for metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutation.

Data synthesis:
The literature search to identify clinical trials returned only the CHRYSALIS phase 1 study. In a phase I trial, amivantamab-vmjw was associated with an overall response rate (ORR) of 40% (95% CI, 29-51) in the EGFR exon20ins NSCLC patient population (n = 81) after platinum-based chemotherapy. There were 3 complete responses (CRs) and 29 partial responses (PRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9-not reached; NR). The median progression-free survival (PFS) was 8.3 months (95% CI, 6.5-10.9), and overall survival (OS) was 22.8 months (95% CI, 14.6-NR).

Application to clinical practice:
This review summarizes the pharmacology, clinical evidence, and use of amivantamab-vmjw for patients with locally advanced or metastatic NSCLC with EGFR exon20ins mutation.

Conclusion:
The FDA approval of amivantamab-vmjw, the first bispecific antibody to target the exon20ins mutation, represents an important advancement in the treatment of patients with NSCLC with limited effective treatment options. The initial findings of the CHRYSALIS trial demonstrate an overall tumor response benefit with an acceptable safety profile.

Full text

Citation: Shah, V.; McNatty, A.;
Simpson, L.; Ofori, H.; Raheem, F.
Amivantamab-Vmjw: A Novel
Treatment for Patients with NSCLC
Harboring EGFR Exon 20 Insertion
Mutation after Progression on
Platinum-Based Chemotherapy.
Biomedicines 2023,11, 950.
https://doi.org/10.3390/
biomedicines11030950
Academic Editor: Bruno
Kaufmann Robbs
Received: 26 February 2023
Revised: 11 March 2023
Accepted: 15 March 2023
Published: 20 March 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
biomedicines
Review
Amivantamab-Vmjw: A Novel Treatment for Patients with
NSCLC Harboring EGFR Exon 20 Insertion Mutation after
Progression on Platinum-Based Chemotherapy
Vishal Shah 1,* , Andrea McNatty 2, Lacey Simpson 1, Henry Ofori 1and Farah Raheem 1
1Department of Pharmacy, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, USA
2Seagen, Bothell, WA 85054, USA
*Correspondence: shah.vishal@mayo.edu
Abstract:
Objective: This study is a comprehensive review of the clinical pharmacology, pharmacoki-
netics, efficacy, safety, and clinical applicability of amivantamab-vmjw for metastatic non-small cell
lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mu-
tation. Data Synthesis: The literature search to identify clinical trials returned only the CHRYSALIS
phase 1 study. In a phase I trial, amivantamab-vmjw was associated with an overall response rate
(ORR) of 40% (95% CI, 29–51) in the EGFR exon20ins NSCLC patient population (n = 81) after
platinum-based chemotherapy. There were 3 complete responses (CRs) and 29 partial responses
(PRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9—not reached; NR).
The median progression-free survival (PFS) was 8.3 months (95% CI, 6.5–10.9), and overall survival
(OS) was 22.8 months (95% CI, 14.6—NR). Application to Clinical Practice: This review summa-
rizes the pharmacology, clinical evidence, and use of amivantamab-vmjw for patients with locally
advanced or metastatic NSCLC with EGFR exon20ins mutation. Conclusion: The FDA approval
of amivantamab-vmjw, the first bispecific antibody to target the exon20ins mutation, represents an
important advancement in the treatment of patients with NSCLC with limited effective treatment
options. The initial findings of the CHRYSALIS trial demonstrate an overall tumor response benefit
with an acceptable safety profile.
Keywords: amivantamab-vmjw; lung cancer; EGFR; exon 20; NSCLC
1. Introduction
Lung cancer is one of the most common types of cancer among both males and fe-
males, accounting for 25% of all cancer-related deaths [
1
–
3
]. NSCLC accounts for 85% of all
diagnosed types of lung cancer [
1
,
4
]. NSCLC is biologically and molecularly diverse, and
targeted therapies against oncogenic driver mutations have become pivotal in improving
survival outcomes [
1
,
5
]. Due to the heterogeneous nature of NSCLC, over 600 EGFR muta-
tion variants have been described [
6
]. Driver mutations within the EGFR exons
18–21 occur
in up to 40% of NSCLC cases [
6
,
7
]. Point mutations in exons 18, 19, and 21 represent
85% of EGFR mutation-positive NSCLC cases and have been shown to be responsive to
targeted treatment using EGFR-specific tyrosine kinase inhibitors (TKIs) [
8
,
9
]. The next
most frequently occurring EGFR mutation is exon20ins, accounting for approximately 12%
of cases.
EGFR exon20ins mutations are defined by in-frame insertions and duplications near
the EGFR kinase domain. EGFR exon20ins mutations contain a modified active site that
hinders the binding of currently approved EGFR TKI molecules, resulting in low response
rates of <9%. [
8
,
9
] Due to this low response rate, the median OS in NSCLC with EGFR
exon20ins mutations is only 16 months [
10
–
14
]. The absence of tumor response to standard
EGFR TKIs and suboptimal efficacy of chemotherapy highlight the cruciality of identifying
targeted therapy with activity against EGFR exon20ins mutations in NSCLC.
Biomedicines 2023,11, 950. https://doi.org/10.3390/biomedicines11030950 https://www.mdpi.com/journal/biomedicines

Biomedicines 2023,11, 950 2 of 11
Amivantamab-vmjw presents a novel mechanism as a bispecific EGFR and mes-
enchymal epithelial transition (MET) receptor antibody with accelerated FDA approval
in May 2021 for patients with metastatic NSCLC with EGFR exon20ins mutations who
have progressed after platinum-based chemotherapy [
15
]. The accelerated approval was
based on the positive results of overall response rate as well as the duration of response
demonstrated by an open-label, phase I clinical trial [
8
]. In this article, we describe the
pharmacology, clinical efficacy, and safety of amivantamab-vmjw for treatment of EGFR
exon20ins mutation-positive NSCLC.
2. Pharmacology
Acquired resistance to standard of care treatments can develop in NSCLC due to
mutations in EGFR and activation of the MET pathway. EGFR and MET pathways are
required for tumor cell proliferation and growth. The mutations in the EGFR protein
activate a chain of events that constitutes subsequent growth and survival signaling in
cancer cells [
7
,
9
]. EGFR mutations develop in up to 85% of patients with NSCLC [
8
].
Driver mutations in the exons of the EGFR tyrosine kinase domain have been evolving
targets for NSCLC therapies. First-, second-, and third-generation EGFR TKIs have been
established as standard of care treatment for NSCLC with EGFR mutations except for
exon20ins mutations. EGFR exon20ins mutation is a distinct subtype of EGFR oncogenic
mutations that has been shown to be unresponsive to third-generation EGFR TKIs [
8
,
9
].
The use of EGFR TKIs can also induce MET receptor amplification, which bypasses the
EGFR pathway, causing signaling downstream to promote cancer cell proliferation and
resistance to standard of care treatments [16].
Amivantamab-vmjw demonstrates a novel mechanism of action as a fully humanized
immunoglobulin G1-based bispecific antibody that targets the domains of EGFR and MET.
In vivo
and
in vitro
studies of amivantamab-vmjw demonstrated a dose-dependent induc-
tion of EGFR and MET downregulation, antiproliferative effect, and antibody-dependent
cellular cytotoxicity [
15
]. Antitumor effects were shown with both Fc receptor-independent
and -dependent mechanisms. Fc-independent functions block EGFR and MET signal-
ing via ligand binding and receptor inactivation. Amivantamab-vmjw binding to the
exon20ins-mutated EGFR tyrosine kinase receptor results in degradation of EGFR and
MET receptors [
7
,
9
,
17
]. The Fc-dependent mechanism of action plays in important role in
amivantamab-vmjw pharmacological activity through antibody-dependent cellular cyto-
toxicity by activation of natural killer cells, macrophages, and monocytes. A subsequent
cytokine and chemokine release is triggered along with downmodulation of EGFR and
MET receptors through trogocytosis with Fc interaction [7].
Amivantamab-vmjw is a bispecific monoclonal antibody produced from two different
bivalent parental antibodies. The EGFR arm is a derivative of zalutumumab, which has a
conformational epitope of EGFR domain III, but is different from epitopes of cetuximab
and panitumumab. The epitope on the MET-binding arm blocks the HGF ligand but is
dissimilar from onartuzumab [
18
]. Amivantamab-vmjw binds to extracellular domains of
EGFR and MET receptors with a dissociation constant of 1.43 and 0.04 nM, respectively [
19
].
3. Pharmacokinetics and Pharmacodynamics
The phase 2 clinical trial recommended dose of amivantamab-vmjw was selected
based on serum EGFR and MET target saturation in addition to the determined preclinical
concentration of 168 ug/mL [
8
]. Saturation of EGFR and MET circulating targets was
achieved with doses above 700 mg. Dosing was determined by weight utilizing population
kinetics to minimize pharmacokinetic variability, leading to recommendations of 1400 mg
with weight
≥
80 kg and 1050 mg for <80 kg. The volume of distribution and clearance
of amivantamab-vmjw increased due to body weight escalation, which is attributed to
the two-tiered weight-based dosing. Exposure was similar when comparing the 1050 mg
dose at <80 kg and 1400 mg for those who weighed
≥
80 kg. Pharmacokinetic results of
amivantamab-vmjw showed no clinically significant differences regarding age sex, race,

Biomedicines 2023,11, 950 3 of 11
creatinine clearance (CrCl)
≥
29 mL/min, or mild hepatic impairment. Amivantamab-
vmjw was not investigated in CrCl < 29 mL/min or in moderate (bilirubin 1.5 to 3 times
upper limit normal (ULN)) or severe (total bilirubin > 3 times ULN) hepatic impairment.
Mean linear clearance was determined to be 0.36 L/d and have a terminal half-life of
11.3 (+/−4.53) days [8,15].
4. Clinical Trial Efficacy
The safety and efficacy of amivantamab-vmjw was evaluated in the CHRYSALIS trial,
a phase I, open-label, multicenter, dose escalation and dose expansion study that included
patients with advanced NSCLC with EGFR exon20ins mutation. Patients included were
adults
≥
18 years, had metastatic or unresectable NSCLC, ECOG status of
≤
1, and had
progressed on standard of care therapy. Patients with untreated or active brain metastasis
were not included in the trial. Previously treated and asymptomatic brain metastases
were allowed. Patients in the dose expansion phase had documented EGFR mutations or
MET mutations and quantified disease defined by RECIST 1.1 criteria. Tissue or central
next-generation sequencing (NGS) circulating tumor DNA (ctDNA) testing was utilized to
detect EGFR exon20ins mutations.
The dose escalation phase was a 3 + 3 design that assessed amivantamab-vmjw
dosing weekly for the first 28 days followed by biweekly dosing. Patients were divided
into six different dose cohorts for dose escalation. The analysis presented here includes
patients with NSCLC EGFR exon20ins mutations (cohort D). The main objective of the dose
escalation phase was to determine the maximum tolerated dose for the phase II portion of
the study. For phase II, dose expansion, six cohorts were identified based on EGFR and MET
mutations or amplifications and previous therapy status. The primary objective for the
phase II portion of the study was ORR. Secondary endpoints included DOR; clinical benefit
rate (CBR), defined as PR or CR or stable disease for
≥
11 weeks; PFS; and OS. Treatment
with amivantamab-vmjw extended until disease progression, unacceptable toxicity, or
withdrawal of consent.
From May 2016 to June 2020, 362 patients were enrolled in the study. Patients com-
prised in the safety population included those with EGFR exon20ins mutations that pro-
gressed on platinum-based therapy and were treated at the phase II dose (n = 114).
A total
of 258 patients were given a dosage of 1050 mg for patients weighing < 80 kg and 1400 mg
for patients
≥
80 kg given once weekly for the first four weeks, then biweekly starting at
week five. The efficacy population consisted of the first 81 patients with EGFR exon20ins
mutations that had received previous platinum-based chemotherapy and had
≥
3 disease
assessments at data cutoff. Data were assessed through 8 October 2020 for this popula-
tion. The median age of the efficacy population was 62 years (42–84 years), and 59% were
women, 49% were of Asian descent, 53% were nonsmokers, and 95% had adenocarcinoma.
The median number of previous lines of therapy was two (range 1–7). All patients had
previously received platinum-based chemotherapy, 25% received prior EGFR TKIs, and
46% had received prior immuno-oncology therapies. Approximately 22% of patients had
treated brain lesions at enrollment.
At median follow up of 9.7 months, the ORR was 40% (95% CI, 29–51) with 3 confirmed
CR and 29 PR outcomes, as evaluated by a blinded independent central review. The
investigator-assessed ORR was 36% (95% CI, 25–47). The median DOR was 11.1 months
(95% CI, 6.9-NR). CBR was observed in 74% of patients (95% CI, 63–83). Median PFS was
8.3 months (95% CI, 6.5–10.9). Median OS was 22.8 months (95% CI, 14.6-NR). The overall
survival endpoint is currently immature. Efficacy endpoints are summarized in Table 1[
8
].

Biomedicines 2023,11, 950 4 of 11
Table 1.
Efficacy Outcomes of Amivantamab-vmjw for NSCLC Harboring EGFR Exon20ins
Mutations [8].
Response CR No.
(%)
PR No.
(%)
SD No.
(%)
PD No.
(%)
ORR %
(95% CI)
NE No.
(%)
mPFS
(95% CI)
mOS
(95% CI)
Efficacy
population (n = 81)
3 (4) 29 (36) 39 (48) 8 (10) 40 (29–51) 2 (2) 8.3 mo
(6.5–10.9)
22.8 mo
(14.6-NR)
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, overall response
rate; NE, not evaluable; mPFS, median progression-free survival; mo. Months; mOS, median overall survival; NR,
not reached; NSCLC, non-small cell lung cancer.
5. Safety
The National Cancer Institute Common Terminology Criteria for Adverse Events
(CTCAE), version 4.03 was applied for grading AEs. The most frequent AEs observed in the
CHRYSALIS trial were rash (84%), infusion-related reactions (IRR (64%)), paronychia (50%),
musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%),
stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). Rash including
acneiform dermatitis, paronychia, stomatitis, and diarrhea are associated with on-target
anti-EGFR TKIs activity, while peripheral edema is associated with on-target anti-MET
activity. Grade
≥
3 AEs were reported in 16% of patients including rash (4%), IRRs (3%),
and neutropenia (3%). All grade interstitial lung disease and pneumonitis occurred in 4%
of patients [8,15]. The types and rates of AEs are summarized in Table 2.
Table 2. Reported Adverse Events with Amivantamab-vmjw in CHRYSALIS [8].
Common AE Safety Population (n = 114) No. (%) Patients Treated with the Phase II Dose
(n = 258) No. (%)
Total Grade 1 Grade 2 Grade ≥3 Total Grade 1 Grade 2 Grade ≥3
Rash 98 (86) 43 (38) 51 (45) 4 (4) 202 (78) 101 (39) 94 (36) 7 (3)
Infusion-related
reactions 75 (66) 9 (8) 63 (55) 3 (3) 167 (65) 21 (8) 140 (54) 6 (2)
Paronychia 51 (45) 28 (25) 22 (19) 1 (1) 104 (40) 50 (19) 51 (20) 3 (1)
Constipation 27 (24) 18 (16) 9 (8) 0 58 (23) 36 (14) 22 (9) 0
Dyspnea 22 (19) 12 (11) 8 (7) 2 (2) 52 (20) 28 (11) 13 (5) 11 (4)
Nausea 22 (19) 17 (15) 5 (4) 0 (55) 21 40 (16) 14 (5) 1 (0.4)
Vomiting 12 (11) 10 (9) 2 (2) 0 29 (11) 22 (9) 6 (2) 1 (0.4)
Fatigue 21 (18) 15 (13) 4 (4) 2 (2) 47 (18) 29 (11) 16 (6) 2 (1)
Stomatitis 24 (21) 11 (10) 13 (11) 0 50 (19) 33 (13) 17 (7) 0
Cough 16 (14) 11 (10) 5 (4) 0 40 (16) 25 (10) 15 (6) 0
Myalgia 14 (12) 12 (11) 2 (2) 0 28 (11) 23 (9) 5 (2) 0
Dose reduction due to AEs occurred in 13% of patients of which rash was the most
frequent cause (10%). Adverse events causing permanent discontinuation of treatment
occurred in
≥
11% of patients and included pneumonia, IRRs, pneumonitis/interstitial lung
disease, pleural effusion, and rash [8,15].
Overall, 66% of patients treated with amivantamab-vmjw resulted in IRRs, causing in-
fusion interruptions in 59% of patients. IRRs developed almost exclusively on
cycle 1 day 1
(65%) or day 2 (3.4%). IRRs rarely developed during subsequent cycles (1.1%). Of the
reported IRRs, 97% of them were grade 1–2, 2.2% were grade 3, and 0.4% were
grade 4
.
There were no predisposing factors identified. To mitigate the development of IRRs, the
first dose was split over two days (cycle 1 day 1 and 2). Prophylactic premedications were
required (Table 3). The median time for onset was 1 h (range, 0.1 to 18 h) after the start of the
infusion. Dose modifications due to IRRs occurred in 62% of patients, and
1.3% terminated
treatment due to IRRs. Signs and symptoms of IRR are listed in Table 2.

Biomedicines 2023,11, 950 5 of 11
Table 3. Prophylactic Premedications for Infusion-Related Reactions and Antiemetics [8].
Required Premedications
Medication Dose and Route of
Administration
Dosing Window Prior to
Drug Administration Cycle/Day
Glucocorticoid aDexamethasone 10 mg IV or
Methylprednisolone 40 mg IV 45 to 60 min Cycle 1 day 1 and cycle 1
day 2 only
Antihistamine bDiphenhydramine 25–50 mg IV, 15 to 30 min
PO, 30 to 60 min All cycles
Antipyretic bAcetaminophen 650–1000 mg IV, 15 to 30 min
PO, 30 to 60 min All cycles
Optional Premedications
Glucocorticoid aDexamethasone 10 mg or
Methylprednisolone 40 mg
IV, 45 to 60 min
PO, 60 to 90 min Cycle 1 day 8 and beyond
H2 receptor antagonist Famotidine 20 mg IV 15 to 30 min Any cycle
Antiemetics Ondansetron 8 mg PO or 16 mg IV 15 to 30 min Any cycle
PO, oral; IV, intravenous.
a
beginning with cycle 1 day 8, optional pre-dose steroids were administered if clinically
indicated for patients who experienced an infusion-related reaction on cycle 1 day 1 or cycle 1 day 2.
b
Required
at all doses.
If patients experienced infusion reactions during subsequent cycles, infusion was
interrupted until symptom resolution and resumed at 50% of the previous infusion rate [
8
].
Management of IRRs included infusion interruptions, reducing the rate of administration,
and administration of supportive care, including antihistamines, antipyretics, glucocorti-
coids, epinephrine, and meperidine, which is shown in Table 3[8].
EGFR inhibitors have been shown to cause skin-related toxicities [
17
,
20
]. Prevention of
the EGFR inhibitor induced rash-related AEs during the CHRYSALIS trial, which included
using broad-spectrum sunscreen and alcohol-free emollients and limiting exposure to
sunlight [
8
]. Management of EGFR inhibitor-induced rash consisted of antihistamines,
corticosteroids, topical antibiotics (clindamycin), systemic antibiotics (doxycycline 100 mg
BID or minocycline 100 mg BID), antiseptic soaks, and local corticosteroids [8].
6. Dosing and Administration
The suggested dosing for amivantamab-vmjw is based on the patient’s baseline body
weight. Subsequent body weight changes do not require further dose adjustments. For
patients weighing < 80 kg, the recommended dose is 1050 mg (3 vials) [
15
]. For patients
weighing
≥
80 kg, the recommended dose is 1400 mg (4 vials) [
15
]. For the first 4 weeks,
amivantamab-vmjw is administered weekly. Starting at week 5, amivantamab-vmjw is ad-
ministered every 2 weeks (Table 4). Administration of an antihistamine (diphenhydramine
25 to 50 mg) and antipyretic (acetaminophen 650 to 1000 mg) is required prior to all doses
of amivantamab-vmjw. A glucocorticoid (dexamethasone 10 mg or methylprednisolone
40 mg
) administration is mandatory prior to cycle 1, days 1 and 2 of amivantamab-vmjw
infusion (Table 3) [
15
]. Dose modifications for toxicity are outlined in Table 5, and modifica-
tion guidance for adverse reactions is found in Table 6.
Table 4. Amivantamab-vmjw Dose Based on Body Weight and Dosing Schedule [15].
Baseline Body Weight (kg) Dose (mg) Number of 350 mg/7 mL Vials
<80 kg 1050 mg 3
≥80 kg 1400 mg 4
Dosing Schedule
Cycle 1–4 Week 1 aSplit infusion on C1D1 and C1D2
Weeks 2–4 Infusion on Day 1
Cycles 5+ Every 2 weeks starting at week 5
aC1D1: Cycle 1 Day 1; C1D2: Cycle 1 Day 2.

Biomedicines 2023,11, 950 6 of 11
Table 5. Amivantamab-vmjw Dose Reduction Levels for Adverse Reactions [15].
Body Weight at Baseline Dose Level Dose
Less than 80 kg 0 1050 mg
−1 700 mg
−2 350 mg
Greater than or equal to 80 kg
−3
0
−1
−2
−3
Discontinue
1400 mg
1050 mg
700 mg
Discontinue
Table 6. Amivantamab-vmjw Dose Modifications for Adverse Reactions [15].
Toxicity Severity
(CTCAE Grade *) Dose Modification
Dermatologic
2
•Supportive care treatment
•Reassess after 2 weeks
•Dose reduction if rash does not improve
3
•Hold amivantamab
•Supportive care management
•Resume with dose reduction ≤Grade 2
•Discontinue if no improvement within 2 weeks
4•Permanently discontinue
Severe blistering, bullous,
exfoliation of skin
(including TENS)
•Permanently discontinue
Infusion related
reactions
1 or 2
•Stop infusion and monitor for symptom resolution
•Supportive care management
•Resume at 50% initial infusion rate
•Escalate infusion rate after 30 min if no additional symptoms occur
•Corticosteroid premedication for subsequent infusions a
3
•Stop infusion and monitor for symptom resolution
•Supportive care management
•Resume at 50% initial infusion rate
•Escalate infusion rate after 30 min if no additional symptoms occur
•Corticosteroid premedication for subsequent infusions a
•Permanently discontinue with recurrent Grade 3
4•Permanently discontinue
Interstitial lung dis-
ease/Pneumonitis Any •Hold dose if suspected
•Permanently discontinue if confirmed
Other 3
•Hold dose until recover ≤Grade 1 or baseline
•Resume same dose if recovery within 1 week
•Resume with dose reduction if recovery within 1–4 weeks
•Permanently discontinue if no recovery in 4 weeks
4
•Hold dose until recover ≤Grade 1 or baseline
•Resume with dose reduction if recovery within 4 weeks
•Permanently discontinue if no recovery in 4 weeks
•Permanently discontinue with recurrent Grade 4
TENS: toxic epidermal necrolysis. * NCI Common Terminology Criteria for Adverse Events (CTCAE) severity
Grade 1–5 scale.
a
Dexamethasone 10 mg IV or methylprednisolone 40 mg IV 45–60 min prior to amivantamab
administration.
Amivantamb-vmjw is administered as an intravenous infusion using an in-line low
protein-binding polyethersulfone 0.2-micron filter. To minimize infusion reactions, the first
dose is split over day 1 and day 2. Additionally, the administration tubing set is primed
with 15–25 mL of diluent (dextrose or saline) to slow initial exposure to amivantamab-vmjw.

Biomedicines 2023,11, 950 7 of 11
Another strategy to minimize the risk for IRRs is withdrawing and discarding 10 mL of
blood prior to flushing the catheter with dextrose or saline at the end of drug administration
to avoid rapid infusion of residual amivantamab-vmjw. Additionally, do not flush when
infusion must be interrupted for toxicity [21].
While there are no data evaluating amivantamab-vmjw administration vis a peripheral
versus central line, it is suggested to infuse amivantamab-vmjw via a peripheral line in
weeks 1 and 2 when IRRs are most frequent. Administration via a peripheral line allows for
slower infusion, thus reducing the risk for IRRs. A central line can be utilized following the
first two weeks of therapy. It is also recommended to consider dose preparation as close
to administration time as possible to allow for potential extended infusion times if IRRs
occur [
22
]. Recommended administration rates vary based on dose and treatment cycles
and are summarized in Table 7.
Table 7. Infusion Rates of Amivantamab-vmjw Administration [15].
1050 mg Dose (for <80 Kg)
Week Dose (Prepared in 250 mL Bag) Initial Infusion Rate Subsequent Infusion Rate
1 (split dose)
Day 1 350 mg 50 mL/h 75 mL/h
Day 2 700 mg 50 mL/hr 75 mL/h
2 1050 mg 85 mL/h
3+ 1050 mg 125 mL/h
1400 mg Dose (for ≥80 Kg)
Week Dose (prepared in 250 mL bag) Initial Infusion Rate Subsequent Infusion Rate
1 (split dose)
Day 1 350 mg 50 mL/h 75 mL/h
Day 2 1050 mg 35 mL/h 50 mL/h
2 1400 mg 65 mL/h
3+ 1400 mg 125 mL/h
7. Cost
Amivantamab-vmjw is available as a single-dose 350 mg/7 mL (50 mg/mL) vial. The
average wholesale price for each vial is around USD 3296 [
23
]. For patients weighing less
than 80 kg, the dose is three vials, and the cost is approximately USD 9888. For patients
weighing more than or equal to 80 kg, the dose is four vials, the cost is approximately
USD 13,184
. The CHRYSALIS study patients were treated for the median duration of
5.6 months
, which amounts to approximately USD 138,432 to USD 184,576 for six treatment
cycles. Center for Medicare and Medicaid Services (CMS) has established a new HCPCS
level II code J9061 in 2 mg increments for billing purposes.
8. Application to Clinical Practice
Patients with EGFR exon20ins mutations in NSCLC represent 10–12% of all EGFR
mutations. Prognosis is usually poor, and effective treatment options have been very limited.
Efficacy with EGFR TKIs, such as erlotinib or osimertinib, are limited by low-binding
affinity at the tyrosine kinase domain of Exon 20. Upfront platinum-based chemotherapy
is offset by a median OS of 12.5 months in the relapsed or refractory setting, making
amivantamab-vmjw an attractive choice for second- or third-line therapy [24].
Recently, an oral EGFR exon20ins mutation-directed TKI, mobocertinib, was approved
by the FDA for treatment of advanced NSCLC. The ORR in 114 patients with NSCLC har-
boring EGFR exon20ins mutations who had made progress on platinum-based chemother-
apy was 28% (95% CI, 20–37) [
25
]. Approximately 46% of patients exhibited treatment-
related AEs of grade
≥
3. Diarrhea and rash were the most frequently reported AEs, at
90% (21% grade ≥3) and 45%, respectively [25].
Amivantamab-vmjw presents a manageable safety and toxicity profile with IRRs being
the most common adverse effect. IRRs can be mitigated with splitting of the dose over

Biomedicines 2023,11, 950 8 of 11
two days
during week 1 and administration of antihistamines, antipyretics, and glucocorti-
coids prior to infusion. IRRs were managed by infusion interruption and reduction of the
infusion rate. The incidence of IRRs decreases dramatically from day 1 to day 2 and in subse-
quent weeks with reported rates of 65% on week 1 day 1, 3.4% on day 2, 0.4% on week 2, and
1.1% for all ensuing infusions. Administration of pre-infusion glucocorticoids is required
on week 1
days 1 and 2
but optional in subsequent cycles. Continuation of pre-infusion
antihistamines and antipyretics is recommended for all cycles. Practical recommenda-
tions include administering amivantamab-vmjw through a peripheral line on
days 1 and 2
,
scheduling infusion appointments early in the morning, preparing amivantamab-vmjw
close to the scheduled administration appointment to allow for extended infusion time
during appropriate working hours of the infusion center, and having cardiopulmonary
resuscitation equipment and medication needed to treat infusion reactions readily available.
Dermatologic reactions were commonly seen in CHRYSALIS trial with 86% of pa-
tients experiencing rash of any grade, including dermatitis acneiform, which is one of
the most common on-target dermatological AEs associated with EGFR inhibitors. The
median time for the onset of rash was 14 days (range, 1 to 276 days). Topical steroids
and/or topical antibiotics and oral antibiotics are typically recommended for EGFR in-
hibitors’ mediated rash. Other interventions include applications of topical emollients
and broad-spectrum UVA/UVB sun lotion during treatment and for 2 months following
discontinuation of treatment.
Amivantamab-vmjw was FDA approved based on early efficacy data that led to a
Breakthrough Therapy designation. This was based on the investigator-assessed ORR
of 41%, median DOR of 7 months, and CBR of 72%. This efficacy analysis is based on a
small sample size of 81 patients [
8
]. Furthermore, patients with active or untreated brain
metastases were excluded, and the benefit of amivantamab-vmjw is unknown in this patient
population, which is a key limitation of this therapy. Efficacy analysis is ongoing for patients
with EGFR exon20ins mutations in other disease states besides NSCLC, in patients who
have not been previously treated with platinum-based chemotherapy, and in combination
with other therapies. The National Comprehensive Cancer Network (NCCN) guidelines
suggest (category 2A) either amivantamab-vmjw or mobocertinib for subsequent therapy
for patients with exon20ins mutations who have progressed during or after initial systemic
treatment including chemotherapy with or without immunotherapy [
26
]. Comparison
of mobocertinib and amivantamab-vmjw is outlined in Table 8. After progression on
amivantamab-vmjw or mobocertinib, the recommendation is to switch to the exon20ins
mutation-targeted treatment that was not previously given. Ongoing clinical trials targeting
exon20ins mutations are included in Table 9.
Table 8.
FDA-Approved Treatments for Locally Advanced or Metastatic NSCLC with EGFR
Exon20ins Mutations in the Recurrent Setting [8].
CHRYSALIS (Amivantamab-Vmjw) (n = 81) Study 101 (Mobocertinib) (n = 114)
ORR 40% (95% CI, 29–51%): 3.7% CR; 36% PR 28% (95% CI, 20–37) all PR
DOR 11.1 mo (95% CI 6.9, NE) 17.5 mo (95% CI, 7.4–20.3; n = 32/114)
DOR ≥6 mos 63% 59%
mOS 22.8 mo 24 mo
mPFS 8.3 mo 7.3 mo
ORR, overall response rate; CR, complete response; DOR, duration of response; mOS, median overall survival;
mPFS, median progression-free survival; NSCLC, non-small cell lung cancer; PR, partial response.

Biomedicines 2023,11, 950 9 of 11
Table 9. Ongoing Clinical Trials of Exon20ins Mutation-Targeted Therapy in NSCLC [27–33].
Trial aInvestigational Intervention(s) Phase Allocation/Design NSCLC Condition
PAPILLON
(NCT04538664)
Amivantamab-vmjw and
carboplatin-pemetrexed compared with
carboplatin-pemetrexed
3Randomized,
open-label EGFR exon20ins mutation
MARIPOSA-2
(NCT04988295)
Amivantamab-vmjw and lazertinib in
combination with platinum-based
chemotherapy compared with
platinum-based chemotherapy alone
3Randomized,
open-label
EGFR-mutated Osimertinib
failure
EXCLAIM
(NCT04129502)
TAK-788 (mobocertinib) compared with
platinum-based chemotherapy 3Randomized,
open-label
EGFR Exon 20 insertion
mutation
CLN-081
(NCT04036682) CLN-081 1/2a N/A, open-label EGFR Exon 20 insertion
mutation
Poziotinib
(NCT03066206) Poziotinib 2 N/A, open-label
Mutant advanced solid tumors
EGFR or HER2
ZENITH20
(NCT03318939) Poziotinib 2 N/A, open-label EGFR or HER2 Exon
20 insertion mutation
FAVOUR
(NCT04858958) Furmonertinib mesilate 1b Randomized,
open-label
EGFR Exon 20 insertion
mutation
aClinicaltrials.gov identifier.
9. Conclusions
The FDA approval of amivantamab-vmjw, the first bispecific antibody to target EGRF
exon20ins, represents an important development in the treatment of patients with advanced
or metastatic NSCLC who have previously had limited effective treatment options. The
early findings of the CHRYSALIS trial not only show a benefit in overall response rate, but
also a relatively tolerable safety and toxicity profile. In addition, the efficacy results show
durable responses in patients who do benefit from this therapy. CHRYSALIS is an ongoing
study that is evaluating the effectiveness and safety of amivantamab-vmjw as monotherapy
and in combination with other therapies in NSCLC and other solid malignancies harboring
EGFR exon20ins mutations. Long-term follow up is necessary to confirm efficacy and safety
in the study population and in real-world patients.
Author Contributions:
Conceptualization and methodology, V.S., A.M. and F.R.; writing-original
draft preparation, all authors; writing-review and editing, all authors. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
König, D.; Savic Prince, S.; Rothschild, S.I. Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on
treatment of the most important actionable oncogenic driver alterations. Cancers 2021,13, 804. [CrossRef] [PubMed]
2.
Centers for Disease Control and Prevention. An Update on Cancer Deaths in the United States. Available online: https://www.cdc.
gov/cancer/dcpc/research/update-on-cancer-deaths/ (accessed on 8 February 2022).
3.
American Lung Association. Lung Cancer Fact Sheet. Available online: https://www.lung.org/lung-health-diseases/lung-
disease-lookup/lung-cancer/resource-library/lung-cancer-fact-sheet (accessed on 8 February 2022).
4.
Melosky, B.; Wheatley-Price, P.; Juergens, R.A.; Sacher, A.; Leighl, N.B.; Tsao, M.-S.; Cheema, P.; Snow, S.; Liu, G.; Card, P.B.;
et al. The rapidly evolving landscape of novel targeted therapies in advanced non-small cell lung cancer. Lung Cancer
2021
,160,
136–151. [CrossRef] [PubMed]
5.
Meador, C.B.; Sequist, L.V.; Piotrowska, Z. Targeting EGFR Exon 20 insertions in non-small cell lung cancer: Recent advances and
clinical updates. Cancer Discov. 2021,11, 2145–2157. [CrossRef] [PubMed]

Biomedicines 2023,11, 950 10 of 11
6.
Passaro, A.; Mok, T.; Peters, S.; Popat, S.; Ahn, M.J.; de Marinis, F. Recent advances on the role of EGFR tyrosine kinase inhibitors
in the management of NSCLC with uncommon, non exon 20 insertions, EGFR Mutations. J. Thorac. Oncol.
2021
,16, 764–773.
[CrossRef] [PubMed]
7.
Vijayaraghavan, S.; Lipfert, L.; Chevalier, K.; Bushey, B.S.; Henley, B.; Lenhart, R.; Sendecki, J.; Beqiri, M.; Millar, H.J.;
Packman, K.; et al.
Amivantamab-vmjw (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor down-
modulation and antitumor activity by monocyte/macrophage trogocytosis. Mol. Cancer Ther.
2020
,19, 2044–2056. [CrossRef]
[PubMed]
8.
Park, K.; Haura, E.B.; Leighl, N.B.; Mitchell, P.; Shu, C.A.; Girard, N.; Viteri, S.; Han, J.-Y.; Kim, S.-W.; Lee, C.K.; et al. Amivantamab-
vmjw 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, 3391–3402. [CrossRef] [PubMed]
9.
Yun, J.; Lee, S.H.; Kim, S.Y.; Jeong, S.Y.; Kim, J.H.; Pyo, K.H.; Park, C.W.; Heo, S.G.; Yun, M.R.; Lim, S.; et al. Antitumor activity
of amivantamab-vmjw (JNJ-61186372), an EGFR-MET bispecific antibody, in diverse models of EGFR exon 20 insertion-driven
NSCLC. Cancer Discov. 2020,10, 1194–1209. [CrossRef] [PubMed]
10.
Ramalingam, S.S.; Vansteenkiste, J.; Planchard, D.; Cho, B.C.; Gray, J.E.; Ohe, Y.; Zhou, C.; Reungwetwattana, T.; Cheng, Y.;
Chewaskulyong, B.; et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N. Engl. J. Med.
2020,382, 41–50. [CrossRef]
11.
Beau-Faller, M.; Prim, N.; Ruppert, A.M.; Nanni-Metéllus, I.; Lacave, R.; Lacroix, L.; Escande, F.; Lizard, S.; Pretet, J.-L.;
Rouquette, I.; et al.
Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre
observational study by the French ERMETIC-IFCT network. Ann. Oncol. 2014,25, 126–131. [CrossRef] [PubMed]
12.
Naidoo, J.; Sima, C.S.; Rodriguez, K.; Busby, N.; Nafa, K.; Ladanyi, M.; Riely, G.J.; Kris, M.G.; Arcila, M.E.; Yu, H.A. Epidermal
growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib. Cancer
2015,121, 3212–3220. [CrossRef] [PubMed]
13.
Yasuda, H.; Park, E.; Yun, C.H.; Sng, N.J.; Lucena-Araujo, A.R.; Yeo, W.-L.; Huberman, M.S.; Cohen, D.W.; Nakayama,
S.;
Ishioka, K.; et al.
Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon
20 insertion
mutations in lung cancer. Sci. Transl. Med.
2013
,5, 216ra177, Erratum in Sci. Transl. Med.
2014
,6, 225er1. [CrossRef]
[PubMed]
14.
Lee, C.K.; Davies, L.; Wu, Y.L.; Mitsudomi, T.; Inoue, A.; Rosell, R.; Zhou, C.; Nakagawa, K.; Thongprasert, S.; Fukuoka, M.; et al.
Gefitinib or Erlotinib vs Chemotherapy for EGFR Mutation-Positive Lung Cancer: Individual Patient Data Meta-Analysis of
Overall Survival. J. Natl. Cancer Inst. 2017,109, djw279. [CrossRef] [PubMed]
15. Horsham, P.A. Amivantamab-Vmjw (Rybrevant) [Package Insert]; Janssen Biotech: Horsham Township, PA, USA, 2021.
16.
Zhang, Z.; Yang, S.; Wang, Q. Impact of MET alterations on targeted therapy with EGFR-tyrosine kinase inhibitors for EGFR-
mutant lung cancer. Biomark. Res. 2019,7, 27. [CrossRef] [PubMed]
17. Kozuki, T. Skin problems and EGFR-tyrosine kinase inhibitor. Jpn. J. Clin. Oncol. 2016,46, 291–298. [CrossRef] [PubMed]
18.
Neijssen, J.; Cardoso, R.M.F.; Chevalier, K.M.; Wiegman, L.; Valerius, T.; Anderson, G.M.; Moores, S.L.; Schuurman, J.;
Parren, P.W.
;
Strohl, W.R.; et al. Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET. J. Biol. Chem.
2021
,
296, 100641. [CrossRef] [PubMed]
19.
Moores, S.L.; Chiu, M.L.; Bushey, B.S.; Chevalier, K.; Luistro, L.; Dorn, K.; Brezski, R.J.; Haytko, P.; Kelly, T.; Wu, S.-J.; et al.
A Novel
Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res.
2016,76, 3942–3953. [CrossRef] [PubMed]
20.
Giovannini, M.; Gregorc, V.; Belli, C.; Roca, E.; Lazzari, C.; Viganò, M.G.; Serafico, A.; Villa, E. Clinical Significance of Skin Toxicity
due to EGFR-Targeted Therapies. J. Oncol. 2009,2009, 849051. [CrossRef] [PubMed]
21.
Data on File. Investigational Product Preparation Instruction for Intravenous Administration of JNJ-61186372 (Amivantamab) for Global
Sites; TV-TEC-168067; Janssen Research & Development, LLC.: Raritan, NJ, USA, 2021.
22.
Park, K.; Sabari, J.; Haura, E.B.; Shu, A.; Spira, R.; Salgia, K.L.; Reckamp, R.E.; Sanborn, R.; Govindan, J.M.; Bauml, J.C.; et al.
Management of Infusion-Related Reactions (IRRs) in Patients Receiving Amivantamab. In Proceedings of the European Society
for Medical Oncology (ESMO) Virtual Congress 2021, Webcast Online, 16–21 September 2021.
23.
Drugs.com. Rybrevant Prices, Coupons and Patient Assistance Programs. Available online: https://www.drugs.com/price-
guide/rybrevant (accessed on 29 January 2022).
24.
Dersarkissian, M.; Bhak, R.; Lin, H.; Li, S.; Cheng, M.; Lax, A.; Huang, H.; Duh, M.; Ou, S. P2.01-103 Real-world treatment
patterns and survival in non-small cell lung cancer patients with EGFR exon 20 insertion mutations. J. Thorac. Oncol.
2019
,
14, S681. [CrossRef]
25.
Zhou, C.; Ramalingam, S.S.; Kim, T.M.; Kim, S.W.; Yang, J.C.-H.; Riely, G.J.; Mekhail, T.; Nguyen, D.; Campelo, M.R.G.;
Felip, E.; et al.
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
,7, e214761.
[CrossRef] [PubMed]
26.
National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 3.2022). Available online: https://www.nccn.
org/professionals/physician_gls/pdf/nscl.pdf (accessed on 11 July 2022).

Biomedicines 2023,11, 950 11 of 11
27.
Janssen Research & Development. 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). ClinicalTrials.gov Identifier: NCT04538664. Updated
21 June 2022. Available online: https://www.clinicaltrials.gov/ct2/show/record/NCT04538664 (accessed on 29 June 2021).
28.
Janssen Research & Development, LLC. 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). ClinicalTri-
als.gov Identifier: NCT04988295. Updated 21 June 2022. Available online: https://www.clinicaltrials.gov/ct2/show/record/
NCT04988295 (accessed on 29 June 2021).
29.
Takeda. TAK-788 as First-Line Treatment Versus Platinum-Based Chemotherapy for Non-Small Cell Lung Cancer (NSCLC)
with EGFR Exon 20 Insertion Mutations. ClinicalTrials.gov Identifier: NCT04129502. Updated 21 June 2022. Available online:
https://www.clinicaltrials.gov/ct2/show/record/NCT04129502 (accessed on 29 June 2021).
30.
Cullinan Pearl. A Phase 1/2a, Open-Label, Multi-Center Trial to Assess Safety, Tolerability, Pharmacokinetics, Pharmacody-
namics, and Efficacy of CLN-081 in Patients with Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations.
ClinicalTrials.gov Identifier: NCT04036682. Updated 21 June 2022. Available online: https://www.clinicaltrials.gov/ct2/show/
record/NCT04036682 (accessed on 29 June 2021).
31.
M.D. Anderson Cancer Center. Poziotinib in EGFR Exon 20 Mutant Advanced NSCLC. ClinicalTrials.gov Identifier:
NCT03066206. Updated 21 June 2022. Available online: https://www.clinicaltrials.gov/ct2/show/record/NCT03066206
(accessed on 29 June 2021).
32.
Spectrum Pharmaceuticals, Inc. Phase 2 Study of Poziotinib in Patients With NSCLC Having EGFR or HER2 Exon 20 Insertion
Mutation. ClinicalTrials.gov Identifier: NCT03318939. Updated 21 June 2022. Available online: https://www.clinicaltrials.gov/
ct2/show/record/NCT03318939 (accessed on 29 June 2021).
33.
Allist Pharmaceuticals, Inc. Study of FURMONERTINIB in Patients with NSCLC Having Exon 20 Insertion Mutation (FAVOUR).
ClinicalTrials.gov Identifier: NCT04858958. Updated 21 June 2022. Available online: https://www.clinicaltrials.gov/ct2/show/
record/NCT04858958 (accessed on 29 June 2021).
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