QVQLVESGGG VVQPGRSLRL SCAASGFTFS TYGMHWVRQA PGKGLEWVAV IWDDGSYKYY
GDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDG ITMVRGVMKD YFDYWGQGTL
VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KRVEPKSCDK THTCPPCPAP
ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR
EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP
PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFLLYSKLTV
DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK
QVQLVQSGAE VKKPGASVKV SCETSGYTFT SYGISWVRQA PGHGLEWMGW ISAYNGYTNY
AQKLQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDL RGTNYFDYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
AIQLTQSPSS LSASVGDRVT ITCRASQDIS SALVWYQQKP GKAPKLLIYD ASSLESGVPS
RFSGSESGTD FTLTISSLQP EDFATYYCQQ FNSYPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
DIQMTQSPSS VSASVGDRVT ITCRASQGIS NWLAWFQHKP GKAPKLLIYA ASSLLSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ ANSFPITFGQ GTRLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: A22-A96, A152-A208, A228-C214, A234-B228, A237-B231, A269-A329, A375-A433, B22-B96, B146-B202, B222-D214, B263-B323, B369-B427, C23-C88, C134-C194, D23-D88, D134-D194)
FDA APPR 2021/5/21 Rybrevant
- JNJ 61186372
|Non-small cell lung cancer (EGFR exon 20 insertion)|
FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer
On May 21, 2021, the Food and Drug Administration granted accelerated approval to amivantamab-vmjw (Rybrevant, Janssen Biotech, Inc.), a bispecific antibody directed against epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.
FDA also approved the Guardant360® CDx (Guardant Health, Inc.) as a companion diagnostic for amivantamab-vmjw.
Approval was based on CHRYSALIS, a multicenter, non-randomized, open label, multicohort clinical trial (NCT02609776) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 81 patients with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients received amivantamab-vmjw once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.
The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review (BICR) and response duration. The ORR was 40% (95% CI: 29%, 51%) with a median response duration of 11.1 months (95% CI: 6.9, not evaluable).
The most common adverse reactions (≥ 20%) were rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting.
The recommended dose of amivantamab-vmjw is 1050 mg for patients with baseline body weight < 80 kg, and 1400 mg for those with body weight ≥ 80 kg, administered weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Brazilian Health Regulatory Agency (ANVISA) and United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 2 months ahead of the FDA goal date.
This product was granted breakthrough therapy designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
The most common side effects include rash, infusion-related reactions, skin infections around the fingernails or toenails, muscle and joint pain, shortness of breath, nausea, fatigue, swelling in the lower legs or hands or face, sores in the mouth, cough, constipation, vomiting and changes in certain blood tests.
Amivantamab is a bispecific epidermal growth factor (EGF) receptor-directed and mesenchymal–epithelial transition (MET) receptor-directed antibody. It is the first treatment for adults with non-small cell lung cancer whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations.
Amivantamab, also known as JNJ-61186372, is an anti-EGFR-MET bispecific antibody, derived from Chinese hamster ovary cells, approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.1,9 Patients with NSCLC often develop resistance to drugs that target EGFR and MET individually, so amivantamab was developed to attack both targets, reducing the chance of resistance developing.1,2 Amivantamab was found to be more effective than the EGFR inhibitor erlotinib or the MET inhibitor crizotinib in vivo.1,3 Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors, and were generally treated with platinum-based therapy.5
Amivantamab was granted FDA approval on 21 May 2021.9
Amivantamab is indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.
The U.S. Food and Drug Administration (FDA) approved amivantamab based on CHRYSALIS, a multicenter, non-randomized, open label, multicohort clinical trial (NCT02609776) which included participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. Efficacy was evaluated in 81 participants with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy.
The FDA collaborated on the review of amivantamab with the Brazilian Health Regulatory Agency (ANVISA) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.
Society and culture
Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET
Preparation of BsAb panel
The generation of parental antibodies followed expression and purification protocols as described (30
). The MET parental mAbs had the F405L mutation and the EGFR parental mAbs had the K409R mutation. The IgG1 b12 arm served as isotype control and null arm to preserve the BsAb architecture. The low fucose parental mAbs were generated using proprietary cell lines. The quality of the BsAb were confirmed as being monodisperse and monomeric via size exclusion chromatography and being pure via SDS-PAGE.
Flow cytometric binding assay
Binding to cells expressing EGFR and MET (A549 [ATCC CCL-185], NCI-H1975 [ATCC, CRL-5908], and NCI-H441 [ATCC HTB-174] cells) was evaluated using flow cytometry (fluorescence-activated cell sorting [FACS]). All BsAbs and controls were diluted in FACS buffer (PBS supplemented with 1% bovine serum albumin and 0.2% sodium azide). After 1 h incubation, unbound antibodies were removed by a FACS buffer wash. The cells were then incubated with goat anti-human IgG-PE (Jackson) for FACS detection (BD FACS Canto). The mean fluorescence intensity of the cells in the live gate was plotted against antibody concentration, and the EC50 was determined by nonlinear regression fitting. Anti-EGFR zalutumumab and anti-MET 5D5 (onartuzumab) were positive controls and anti-CD20 7D8 (Genmab) was the negative control.
MET phosphorylation assay
A549 cells were incubated with 30 μg/ml of test antibody for 15 min and tested for MET phosphorylation using rabbit anti-phospho MET (Tyr1234–1235) (Cell Signaling 3129) and total MET protein using mouse anti-human MET antibody (Cell Signaling 3127). A score of 1 to 4 was given, where 1 = no visible band, 2 = slightly visible band, 3 = phosphorylation comparable with weak agonist (MET B IgG1), and 4 = phosphorylation level similar to positive controls (MET A and MET 5D5 IgG1 mAbs).
Test molecules were added to H1975, KP4 (Riken Cell bank, RCB1005), or NCI-H441 cells plated at 5000 or 10,000 (KP4) cells/well in 96-well plates. After 6 (KP4) or 7 (H1975 and NCI-H441) days of incubation at 37 °C and 5% CO2, the number of viable cells was determined using an AlamarBlue assay (Biosource DAL1100). A615 values were measured and plotted in a bar diagram.
EGFR phosphorylation assay
Approximately 106 A549 or SNU-5 cells/well were grown overnight in six-well plates and incubated for 15 min with 30 μg/ml of antibody in the absence or presence of 40 ng/ml EGF. After cell lysis, Western blots determined EGFR phosphorylation status with phospho-EGFR (Tyr1068) antibody (Cell Signaling 2234) and total EGFR protein using an anti-EGFR antibody (Cell Signaling 2232).
Expression and purification of proteins for crystallization
Human MET Sema-PSI region (residues 39–564) containing a C-terminal 8xHis tag was expressed in Tni PRO insect cells infected with recombinant baculovirus. The culture was harvested 72 h post infection, and the MET Sema-PSI protein was purified by affinity and size exclusion chromatography. Briefly, MET was captured with a Ni-NTA resin (Novagen) equilibrated in TBS, 10 mM imidazole, pH 7.4 and eluted from the column with 250 mM imidazole, TBS, pH 7.4. Fractions containing MET were identified by SDS-PAGE and loaded into a Superdex 200 column (GE Healthcare) equilibrated in 20 mM Tris, 50 mM NaCl, pH 7. The final protein concentration was determined by absorbance at 280 nm.The anti-MET Fab of amivantamab was transiently expressed in Expi293F cells. Briefly, the cells were cotransfected with separate plasmids encoding the Fab heavy and light chains at 3:1 (light:heavy chain) molar ratio following transfection kit instructions (Life Technologies). The culture was harvested 5 days post transfection, and the Fab was purified by affinity and cation exchange chromatography. Briefly, the Fab was captured with a HiTrap resin (GE Healthcare) equilibrated in PBS pH 7.2 and eluted from the column with a gradient of 30 to 300 mM imidazole in PBS pH 7.2. The eluate was buffer exchanged into 25 mM NaCl, 20 mM MES pH 6.0, bound to a Source 15S column (GE Healthcare), and eluted with a NaCl gradient in 20 mM MES pH 6.0.
Crystallization and structure determination
The amivantamab anti-MET Fab–MET Sema-PSI complex was prepared by overnight mixing of MET and Fab at a molar ratio of 1:1.3 (excess Fab) at 4 °C, while buffer exchanging to 20 mM Hepes pH 7.0. The complex was captured with a monoS 5/50 column (GE Healthcare) equilibrated in 20 mM Hepes pH 7.0 and eluted from the column with a gradient of NaCl. The complex was concentrated to 4.8 mg/ml.Crystallization trials for the Fab–MET complex were carried out with a Mosquito LCP robot (TTP LabTech) for the setup of sitting drops on 96-well plates (Corning 3550) and a Rock Imager 54 (Formulatrix) for plate storage at 20 °C and automated imaging of drops. Small crystals were initially obtained from 2 M NH4(SO4)2, 0.1 M MES pH 6.5, and they were used as seeds in next rounds of optimization. Crystals suitable for X-ray diffraction were obtained from 2.5 M sodium formate, 5% PEG 400 Da, 0.1 M Tris pH 8.5 after multiple rounds of seeding. The crystals were soaked for a few seconds in a cryoprotectant solution containing mother liquor supplemented with 20% glycerol and then flash frozen in liquid nitrogen. X-ray diffraction data were collected with a Pilatus 6M detector on beamline 17-ID at the Advanced Photon Source (Argonne National Laboratory), and the diffraction data were processed with the program HKL2000. The crystal structure of the Fab–MET complex was solved by molecular replacement with PHASER using previously solved MET Sema-PSI (PDB code 1SHY) and anti-HER3 Fab RG7116 (PDB code 4LEO) structures as search models. The structure was refined with PHENIX, and model adjustments were performed using COOT. His tags (at C-terminal of heavy chain and PSI), Fab interchain disulfide bond, heavy chain residues 133 to 139, Sema residues 303 to 309, 407, and glycan linked to N399 are disordered and not included in the structure. The Fab was numbered sequentially and Sema-PSI numbering starts at the N terminus of the signal peptide.
Epitope and paratope residues were assigned within a 4-Å contact distance cutoff using the CCP4 program CONTACT. The epitope area was calculated with the CCP4 program AREA. The buried surface area of binding residues was calculated with the program MOE (47
). Structural overlays of equivalent Cα atoms in the Sema domain (residues 40–515; PDB codes 1SHY, 4K3J, 2UZX, and 2UZY) were performed with COOT. Molecular graphics were generated with PyMol (PyMOL Molecular Graphics System, Version 1.4.1, Schrödinger, LLC) and MOE. The atomic coordinates and structure factors for the amivantamab anti-MET Fab–MET Sema-PSI complex were deposited in the RCSB PDB (accession code 6WVZ).
HCC827-HGF xenograft model
Female SCID Beige mice CB17.B6-Prkdcscid Lystbg/Crl (Charles River) bearing established subcutaneous HCC827-HGF tumors were randomized 13 days post inoculation (day 1). Individual tumor volumes ranged from 144 to 221 mm3; mean tumor volume ranged from 180 to 184 mm3. PBS and amivantamab (10 mg/kg) were dosed i.p. biweekly for 3 weeks. Crizotinib (30 mg/kg), erlotinib (25 mg/kg), crizotinib (30 mg/kg) and erlotinib (25 mg/kg), and vehicle controls (0.5% carboxymethyl cellulose in sterile water and 1% carboxymethyl cellulose in 0.1% Tween 80) were dosed daily p.o. for 3 weeks. Subcutaneous tumors were measured twice weekly as the mean tumor volume (mm3 ± standard error of the mean [SEM]). To calculate the percent tumor growth inhibition (%TGI) for group A versus group B, the tumor volumes were log transformed, where A = treated and B = control. The difference between these transformed values was taken at day 1 versus the designated day. Means were taken and converted by anti-log to numerical scale. Percentage TGIs were then calculated as (1 − A/B) × 100%. In vivo experiment was reviewed and approved by the Charles River Laboratories Institutional Animal Care and Use Committee and was done in accordance with the Guide for Care and Use of Laboratory Animals.
- ^ Jump up to:a b “Rybrevant- amivantamab injection”. DailyMed. Janssen Pharmaceutical Companies. Retrieved 25 May 2021.
- ^ Jump up to:a b c d e f “FDA Approves First Targeted Therapy for Subset of Non-Small Cell Lung Cancer”. U.S. Food and Drug Administration (FDA) (Press release). 21 May 2021. Retrieved 21 May 2021. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c d e f g h i j “FDA grants accelerated approval to amivantamab-vmjw for mNSCLC”. U.S. Food and Drug Administration (FDA). 21 May 2021. Retrieved 21 May 2021. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b “Rybrevant (amivantamab-vmjw) Receives FDA Approval as the First Targeted Treatment for Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations” (Press release). Janssen Pharmaceutical Companies. 21 May 2021. Retrieved 21 May 2021 – via PR Newswire.
- ^ Jump up to:a b “Genmab Announces that Janssen has been Granted U.S. FDA” (Press release). Genmab A/S. 21 May 2021. Retrieved 21 May 2021 – via GlobeNewswire.
- ^ “Amivantamab”. SPS – Specialist Pharmacy Service. 25 February 2021. Retrieved 23 May 2021.
- ^ “Janssen Submits European Marketing Authorisation Application for Amivantamab for the Treatment of Patients with Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations” (Press release). Janssen Pharmaceutical Companies. 28 December 2020. Retrieved 23 May 2021 – via Business Wire.
- ^ World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83” (PDF). WHO Drug Information. 34 (1).
- ^ Kaplon H, Reichert JM (2021). “Antibodies to watch in 2021”. mAbs. 13 (1): 1860476. doi:10.1080/19420862.2020.1860476. PMC 7833761. PMID 33459118.
- ^ “Updated Amivantamab and Lazertinib Combination Data Demonstrate Durable Responses and Clinical Activity for Osimertinib-Relapsed Patients with EGFR-Mutated Non-Small Cell Lung Cancer” (Press release). Janssen Pharmaceutical Companies. 20 May 2021. Retrieved 23 May 2021 – via Business Wire.
- Neijssen J, Cardoso RM, Chevalier KM, Wiegman L, Valerius T, Anderson GM, et al. (April 2021). “Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET”. J Biol Chem. 296: 100641. doi:10.1016/j.jbc.2021.100641. PMC 8113745. PMID 33839159.
- Yun J, Lee SH, Kim SY, Jeong SY, Kim JH, Pyo KH, et al. (August 2020). “Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC”. Cancer Discov. 10 (8): 1194–1209. doi:10.1158/2159-8290.CD-20-0116. PMID 32414908.
- “Amivantamab”. Drug Information Portal. U.S. National Library of Medicine.
- Clinical trial number NCT02609776 for “Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS)” at ClinicalTrials.gov
|Target||Epidermal growth factor receptor (EGFR) and Mesenchymal–epithelial transition (MET)|
|Other names||JNJ-61186372, amivantamab-vmjw|
|License data||US DailyMed: Amivantamab|
|Legal status||US: ℞-only |
|Chemical and physical data|
|Molar mass||145902.15 g·mol−1|
|NAME||DOSAGE||STRENGTH||ROUTE||LABELLER||MARKETING START||MARKETING END|
|Rybrevant||Injection||350 mg/1||Intravenous||Janssen Biotech, Inc.||2021-05-21||Not applicable|
/////////Amivantamab, FDA 2021, APPROVALS 2021, PEPTIDE, Rybrevant, アミバンタマブ (遺伝子組換え), CNTO-4424, JNJ 61186372, JNJ-611, JNJ-61186372, breakthrough therapy designation, Janssen Biotech
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