Targeting EGFR Exon 20 Insertion Mutation in Non–small cell Lung Cancer: Amivantamab and Mobocertinib

Abstract

Objective

To evaluate clinical data regarding the use of amivantamab and mobocertinib for epidermal growth factor receptor (EGFR) exon 20 insertion mutation non–small cell lung cancer (NSCLC) and assess their potential impact on the care of patients.

Data Sources

A comprehensive literature search of PubMed and Clinicaltrials.gov was conducted using the terms amivantamab, Rybrevant, JNJ-61186372, mobocertinib, Exkivity, TAK-788.

Study Selection and Data Extraction

Relevant English-language clinical trials were evaluated.

Data Synthesis

Amivantamab and mobocertinib were Food and Drug Administration (FDA) approved based on phases 1 and 2 studies. Amivantamab demonstrated an overall response rate (ORR) of 40% and median progression-free survival (PFS) of 8.3 months. Patients commonly experienced rash (86%), paronychia (45%), and stomatitis (21%). Mobocertinib demonstrated an ORR of 28% and median PFS of 7.3 months in phase 1/2 study. Patients frequently experienced diarrhea (91%), rash (45%), and paronychia (38%). Cardiac monitoring is recommended with mobocertinib due to risk of QTc prolongation and cardiac failure.

Relevance to Patient Care

For NSCLC patients who possess an EGFR exon 20 insertion mutation, amivantamab and mobocertinib are indicated as second-line therapy. Ongoing studies are evaluating these therapies as first-line monotherapy and as part of combination regimens in multiple cancer types. Dosage forms, drug interactions, and patient comorbidities should be considered when deciding which of the 2 agents may be most appropriate.

Conclusion

Amivantamab and mobocertinib target an uncommon NSCLC mutation that has historically marked a poor prognosis because of innate resistance to previously approved EGFR tyrosine kinase inhibitors. Promising results from early phase trials supported accelerated FDA approval.

Keywords

amivantamab mobocertinib exon 20 insertion NSCLC

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References

Siegel

Miller

Fuchs

Jemal

Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654.

Baraibar

Mezquita

Gil-Bazo

Planchard

Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC. Crit Rev Oncol Hematol. 2020;148:102906. doi:10.1016/j.critrevonc.2020.102906.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: non-small cell lung cancer. Version 1.2022. Accessed February 27, 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

Herbst

Morgensztern

Boshoff

The biology and management of non-small cell lung cancer. Nature. 2018;553:446-454. doi:10.1038/nature25183.

Lamberti

Andrini

Sisi

, et al. Beyond EGFR, ALK, and ROS1: current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma. Crit Rev Oncol Hematol. 2020;156:103119. doi:10.1016/j.critrevonc.2020.103119.

Vyse

Huang

PH.

Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther. 2019;4:5. doi:10.1038/s41392-019-0038-9.

Remon

Hendriks

LEL

Cardona

Besse

EGFR exon 20 insertions in advanced non-small cell lung cancer: a new history begins. Cancer Treat Rev. 2020;90:102105. doi:10.1016/j.ctrv.2020.102105.

Soria

Ohe

Vansteenkiste

, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113-125. doi:10.1056/NEJMoa1713137.

Rybrevant (amivantamab-vmjw) [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761210s000lbl.pdf.

10.

Exkivity (mobocertinib) [package insert]. Lexington, MA: Takeda Pharmaceuticals, Inc.; 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf.

11.

Park

Haura

Leighl

, et al. Amivantamab 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(30):3391-3402. doi:10.1200/JCO.21.00662.

12.

Zhou

Ramalingam

Kim

, 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(12):e214761. doi:10.1001/jamaoncol.2021.4761.

13.

Vijayaraghavan

Lipfert

Chevalier

, et al. Amivantamab (JNJ-61186372), an Fc enhanced EGFR/cMet bispecific antibody, induces receptor downmodulation and antitumor activity by monocyte/macrophage trogocytosis. Mol Cancer Ther. 2020;19(10):2044-2056. doi:10.1158/1535-7163.MCT-20-0071.

14.

Gonzalvez

Vincent

Baker

, et al. Mobocertinib (TAK-788): a targeted inhibitor of EGFR exon 20 insertion mutants in non–small cell lung cancer. Cancer Discov. 2021;11(7):1672-1687. doi:10.1158/2159-8290.CD-20-1683.

15.

Smith

Goto

, et al. Trastuzumab deruxtecan in HER2-mutated non-small-cell lung cancer. N Engl J Med. 2022;386:241-251. doi:10.1056/NEJMoa2112431.

16.

Riely

Neal

Camidge

, et al. Activity and safety of mobocertinib (TAK-788) in previously treated non–small cell lung cancer with EGFR exon 20 insertion mutations from a phase I/II trial. Cancer Discov. 2021;11(7):1688-1699. doi:10.1158/2159-8290.CD-20-1598.

17.

Takeda

Okamoto

Nakagawa

Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88(1):74-79. doi:10.1016/j.lungcan.2015.01.026.

18.

Rao

Reeves

Chugh

, et al. Clinical approach to cardiovascular toxicity of oral antineoplastic agents: JACC state-of-the-art review. J Am Coll Cardiol. 2021;77(21):2693-2716. doi:10.1016/j.jacc.2021.04.009.

19.

Shah

Aredo

Padda

, et al. EGFR exon 20 insertion NSCLC and response to platinum-based chemotherapy. Clin Lung Cancer. 2022;23(2):e148-e153. doi:10.1016/j.cllc.2021.07.001.

20.

Janssen Pharmaceutical K.K. A Phase 2, Open-Label Study of Amivantamab in Subjects With Previously Treated Advanced or Metastatic Gastric or Esophageal Cancer. clinicaltrials.gov; 2022. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04945733.

21.

Wise-Draper

Phase II Study to Evaluate Amivantamab in Recurrent and Metastatic Adenoid Cystic Carcinoma. clinicaltrials.gov; 2021. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT05074940.

22.

Memorial Sloan Kettering Cancer Center. A Phase 2 Single-Arm Study of Amivantamab (JNJ-61186372) and Lazertinib in Metastatic EGFR-Mutant Lung Cancer With Progressive or New CNS Metastases on Previous Treatment. clinicaltrials.gov; 2022. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04965090.

23.

Janssen Research & Development, LLC. A Randomized, Open-Label Phase 3 Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Patients With EGFR Exon 20ins Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer. clinicaltrials.gov; 2021. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04538664.

24.

Janssen Research & Development, LLC. A Phase 3, Randomized Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib Versus Lazertinib as First-Line Treatment in Patients With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer. clinicaltrials.gov; 2022. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04487080.

25.

Takeda. A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-788 in Japanese Non-Small Cell Lung Cancer Patients. clinicaltrials.gov; 2021. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT03807778.

26.

Millennium Pharmaceuticals, Inc. A Randomized Phase 3 Multicenter Open-Label Study to Compare the Efficacy of TAK-788 as First-Line Treatment Versus Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations. clinicaltrials.gov; 2022. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04129502.

27.

Millennium Pharmaceuticals, Inc. A Phase 1 Pharmacokinetic Study of Oral Mobocertinib in Subjects With Severe Renal Impairment and Normal Renal Function. clinicaltrials.gov; 2021. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04056455.

28.

Millennium Pharmaceuticals, Inc. Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in Subjects With Moderate or Severe Hepatic Impairment and Normal Hepatic Function. clinicaltrials.gov; 2021. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04056468.

29.

Nagasaka

Balmanoukian

Madison

Zhang

Klempner

SI.

Amivantamab (JNJ-61186372) induces clinical, biochemical, molecular, and radiographic response in a treatment-refractory NSCLC patient harboring amplified triple EGFR mutations (L858R/T790M/G796S) in cis. Lung Cancer. 2022;164:52-55. doi:10.1016/j.lungcan.2021.12.022.