Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study

Abstract

Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.

Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.

Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.

Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

Trial registration: ClinicalTrials.gov NCT02609776.

Conflict of interest statement

Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, LOXO, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, JNJ, Eisai, Puma BiotechnologySpeakers' Bureau: Boehringer IngelheimResearch Funding: AstraZeneca, MSD Oncology Eric B. HauraConsulting or Advisory Role: Janssen Oncology, Revolution Medicines, Ellipses Pharma, Janssen Research & Development, AmgenResearch Funding: Janssen, Novartis, Revolution Medicines, AstraZeneca, Incyte, Genentech, Spectrum PharmaceuticalsPatents, Royalties, Other Intellectual Property: Protein-Protein Interactions as Biomarkers Patent Natasha LeighlHonoraria: Boehringer IngelheimConsulting or Advisory Role: XcoveryResearch Funding: Novartis, Roche Canada, Guardant Health, MSD, EMD Serono, LillyTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb, Nektar, GlaxoSmithKline, Roche, AstraZeneca Paul MitchellHonoraria: MSD, AstraZeneca, RocheConsulting or Advisory Role: Roche, Specialised Therapeutics, PUMA Biotechnology, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Amgen Catherine A. ShuConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Genentech/RocheResearch Funding: Celgene, Genentech/Roche, Janssen, MedImmuneTravel, Accommodations, Expenses: Genentech/Roche Nicolas GirardEmployment: AstraZenecaConsulting or Advisory Role: Roche, Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Bristol Myers Squibb, MSD, Takeda, GlaxoSmithKline, AbbVie, Pharmamar, Janssen, SanofiResearch Funding: Roche, AstraZeneca, Boehringer IngelheimTravel, Accommodations, Expenses: Roche, AstraZeneca, Bristol Myers Squibb, MSD Oncology Santiago ViteriConsulting or Advisory Role: Roche, Bristol Myers Squibb, Janssen, Takeda, Reddy Pharma Iberia, Merck KGaASpeakers' Bureau: Bristol Myers Squibb, RocheTravel, Accommodations, Expenses: Roche, MSD, Merck KGaA Ji-Youn HanHonoraria: Roche, AstraZeneca, Bristol Myers Squibb, TakedaConsulting or Advisory Role: MSD Oncology, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Takeda, PfizerResearch Funding: Roche, Pfizer, Ono Pharmaceutical, Takeda Chee Khoon LeeHonoraria: AstraZeneca, Pfizer, Amgen, Takeda, Yuhan, Boehringer IngelheimConsulting or Advisory Role: Novartis, Boehringer Ingelheim, Takeda, AstraZeneca, Yuhan, AmgenResearch Funding: AstraZeneca, Roche, Merck KGaA Joshua K. SabariConsulting or Advisory Role: AstraZeneca, Janssen Oncology, Navire, Pfizer, Regeneron, Medscape, Takeda Alexander I. SpiraStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers SquibbResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, LAM Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Loxo, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Dong-Wan KimResearch Funding: Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim, Amgen, Daiichi Sankyo, Chong Kun Dang Pharmaceutical, BridgeBio Pharma, GlaxoSmithKlineTravel, Accommodations, Expenses: Daiichi Sankyo, Amgen Ki Hyeong LeeConsulting or Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Lilly Rachel E. SanbornHonoraria: AstraZeneca, AmgenConsulting or Advisory Role: Genentech/Roche, AstraZeneca, EMD Serono, Blueprint Medicines, Daiichi Sankyo/Lilly, Janssen Oncology, MacrogenicsResearch Funding: Bristol Myers Squibb, MedImmune, Merck, AstraZenecaTravel, Accommodations, Expenses: AstraZeneca José TrigoConsulting or Advisory Role: Takeda, Boehringer Ingelheim, Bristol Myers Squibb, Merck SeronoSpeakers' Bureau: MSD Oncology, AstraZeneca, Merck Serono, RocheTravel, Accommodations, Expenses: MSD Oncology, Bristol Myers Squibb, AstraZeneca Koichi GotoHonoraria: Guardant Health, Janssen, Daiichi Sankyo Co Ltd, Amgen, Eisai, Kyowa Kirin Co Ltd, Bristol Myers Squibb, AstraZeneca Japan, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Lilly Japan, Boehringer Ingelheim, Life Technologies, MSD K.K, Nippon Kayaku, Takeda, OtsukaConsulting or Advisory Role: OtsukaResearch Funding: Medical & Biological Laboratories Co Ltd, Kyowa Kirin Co Ltd, Amgen Astellas BioPharma, Kissei Pharmaceutical, Merck, Merus, NEC Corporation, Spectrum Pharmaceuticals, Shanghai HaiHe Pharmaceutical, MSD K.K, AstraZeneca Japan, Taiho Pharmaceutical, Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon Pharma Co Ltd, Takeda, Astellas Pharma, Eisai, Lilly Japan, Pfizer, Bristol Myers Squibb, Ignyta, Life Technologies, Janssen, Xcoo, Loxo, Sysmex, Amgen James Chih-Hsin YangHonoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Lilly, PfizerConsulting or Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Lilly, MSD Oncology, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda Oncology, Amgen, Incyte, Merck Serono, Jenssen, GSK, Takeda, Daiichi Sankyo, NovartisTravel, Accommodations, Expenses: Pfizer Ramaswamy GovindanHonoraria: Genentech/AbbVie, AbbVie, Geneplus-Beijing InstituteConsulting or Advisory Role: Genentech/Roche, AbbVie, AstraZeneca/MedImmune, Pfizer, Bristol Myers Squibb, Nektar, Jounce Therapeutics, F. Hoffmann La Roche AG, Janssen, Amgen, Achilles Therapeutics Joshua M. BaumlConsulting or Advisory Role: Bristol Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron, Inivata, Novartis, Foundation MedicineResearch Funding: Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen, Pfizer, Mirati Therapeutics Pilar GarridoConsulting or Advisory Role: Roche Pharma AG, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Takeda, Lilly, Pfizer, Novartis/Pfizer, Boehringer Ingelheim, AbbVie, Amgen, Bayer, Gebro Pharma, Nordic Group, Boehringer Ingelheim, Janssen Biotech, Janssen Oncology, GlaxoSmithKlineSpeakers' Bureau: Roche Pharma AG, Takeda, AstraZeneca, MSD Oncology, BMS, Pfizer, Novartis, Boehringer Ingelheim, Nordic Group, Janssen, Boehringer Ingelheim, Janssen OncologyTravel, Accommodations, Expenses: AstraZeneca, Roche, Bristol Myers SquibbOther Relationship: Janssen Oncology, Novartis Matthew G. KrebsHonoraria: RocheConsulting or Advisory Role: Roche, Achilles Therapeutics, Janssen, Seattle Genetics, OM Pharma, BayerSpeakers' Bureau: Roche, JanssenResearch Funding: RocheTravel, Accommodations, Expenses: AstraZeneca, BerGenBio, Immutep Karen L. ReckampConsulting or Advisory Role: Amgen, Tesaro, Boehringer Ingelheim, Takeda, AstraZeneca, Seattle Genetics, Calithera Biosciences, Genentech, Blueprint Medicines, Daiichi Sankyo/Lilly, EMD Serono, Janssen Oncology, Lilly, Merck KGaAResearch Funding: Bristol Myers Squibb, Pfizer, ARIAD, Xcovery, Adaptimmune, Genentech/Roche, Boehringer Ingelheim, AbbVie, ACEA Biosciences, Loxo, GlaxoSmithKline, Guardant Health, Janssen Oncology, Seattle Genetics, Zeno Pharmaceuticals, Calithera Biosciences, Elevation Oncology, Daiichi Sankyo/Astra Zeneca John XieEmployment: JNJStock and Other Ownership Interests: JNJ Joshua C. CurtinEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson/Janssen Nahor Haddish-BerhaneEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Amy RoshakEmployment: Janssen Pharmaceutical Company of Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Dawn MillingtonEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson/JanssenTravel, Accommodations, Expenses: Janssen Research & Development Patricia LorenziniEmployment: Janssen Pharmaceuticals of Johnson & Johnson Meena ThayuEmployment: Janssen OncologyStock and Other Ownership Interests: Johnson & Johnson/JanssenOther Relationship: Janssen Oncology Roland E. KnoblauchEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & JohnsonTravel, Accommodations, Expenses: Johnson & Johnson Byoung Chul ChoLeadership: Gencurix Inc, Interpark Bio Convergence CorpStock and Other Ownership Interests: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, KANAPH Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence CorpConsulting or Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Yuhan, Pfizer, Janssen, Takeda, MSD, Ono Pharmaceutical, Eli Lilly, Medpacto, Blueprint Medicines, KANAPH Therapeutic Inc, Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec IncResearch Funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence CorpPatents, Royalties, Other Intellectual Property: Champions OncologyOther Relationship: DAAN BiotherapeuticsNo other potential conflicts of interest were reported.

Figures

FIG 1.

CHRYSALIS study design and patient disposition for amivantamab monotherapy. The CHRYSALIS study consisted of a dose-escalation and dose-expansion phase. (A) Patients with advanced NSCLC were enrolled in dose-escalation cohorts and patients were assigned to dose-expansion cohorts on the basis of EGFR and MET mutation status and previous therapy. (B) Patients were allocated to six different dose cohorts in the dose-escalation portion of the study. The safety population included all patients with EGFR Exon20ins NSCLC who had progressed on previous platinum-based chemotherapy and were treated at the RP2D (n = 114) by the data cutoff of June 8, 2020. At this clinical cutoff, the first 81 patients (four from dose escalation cohort, four from cohort A, and 73 from cohort D) met the criteria of having at least three scheduled disease assessments or discontinued, had disease progression, or died and were defined as the pivotal efficacy population. 3GTKI, third-generation tyrosine kinase inhibitor; amp, amplification; C, cycle; EGFR, epidermal growth factor receptor; Exon20ins, exon 20 insertion; NSCLC, non–small-cell lung cancer; RP2D, recommended phase II dose; SOC, standard of care; TKI, tyrosine kinase inhibitor.

FIG 2.

Tumor response over time and ORR by subgroups. (A) Spider plot of percent change from baseline in sum of target lesion diameters over time in the efficacy population (n = 81) as assessed by BICR. aOne patient discontinued before any disease assessment and is not included in the plot. Dotted lines at 20% and –30% indicate thresholds for PD and PR, respectively, as per RECIST, v1.1. (B) Results of prespecified (age, sex, race, baseline ECOG PS, history of smoking, and previous immunotherapy) and post hoc (history of brain metastases, previous lines of therapy, and previous EGFR TKI) subgroup analysis of ORR in the efficacy population on the basis of BICR. bDoes not include nine patients with race not reported and multiple race. BICR, blinded independent central review; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; SoD, sum of lesion diameters; TKI, tyrosine kinase inhibitor; UNK, unknown.

FIG 3.

Tumor reduction and responses in the efficacy population. (A) Waterfall plot displaying best percent change from baseline in sum of target lesion diameters by location of EGFR Exon20ins (determined by Guardant360 testing) for patients in the efficacy population (n = 81) as assessed by BICR. aOne patient discontinued before any disease assessment and is not included in the plot. Dotted lines at 20% and –30% indicate thresholds for progressive disease and partial response, respectively, as per RECIST, v1.1. (B) Insertion regions of EGFR Exon20ins identified in the efficacy population and ORR as assessed by BICR for each key region of exon 20 (blue, red, and teal boxes). Site of EGFR Exon20in could not be identified by ctDNA analysis for 18 patients (dark orange). BICR, blinded independent central review; CBR, clinical benefit rate; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; Exon20ins, exon 20 insertion; ORR, overall response rate; SoD, sum of lesion diameters.