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by Dr. C.H. Weaver M.D. updated 8/2021

Data from the Phase 1 CHRYSALIS clinical trial evaluating Rybervant (amivantamab) in patients with advanced non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations were presented for the first time at the 2021 World Conference on Lung Cancer (WCLC) in Singapore. Rybervant - a bispecific antibody showed significant anti-cancer activity and durable responses with a tolerable safety profile in patients with NSCLC and EGFR exon 20 insertion mutations leading to FDA approval.1

Bispecific Antibodies

Bispecific antibody constructs represent an innovative immunotherapy approach that helps the body’s immune system target cancer cells and appears very promising for the treatment of lung and other cancers. Bispecific antibodies have two arms -one arm of the drug attaches to a specific protein on the cancer cell, and the other arm activates immune cells in the patient to kill the cancer cells.

Lung CancerConnect 490

About EGFR Exon 20 Insertion-Mutant NSCLC

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have epidermal growth factor receptor - mutated (EGFRm) NSCLC. These patients are particularly sensitive to treatment with precision cancer medicines known as EGFR-tyrosine kinase inhibitors (TKIs) which block the cell-signaling pathways that drive the growth of EGFR expressing lung cancer cells. EGFR exon 20 insertion mutations occur in 1% to 2% of NSCLC’s and patients with these mutations don't typically respond well to treatment with TKI’s available to treat the majority of EGFRm NSCLCs.5 Exon 20 mutations have a worse prognosis than other EGFRm because there are currently no FDA-approved therapies and current EGFR TKIs and chemotherapy provide limited benefit for these patients.2-5

About Rybervant (amivantamab)

Rybervant is a fully human EGFR and mesenchymal epithelial transition (MET) bispecific antibody with immune cell-directing activity. Rybervant targets the Exon 20 mutation - the third most prevalent EGFR mutation in NSCLC. By combining an EGFR-binding domain at one end with one targeting MET which is a common resistance mechanism Rybervant targets both the primary mutation and the resistance EGFR and MET mutations and amplifications at the same time.6-9

The Phase 1 CHRYSALIS clinical trial assessed the effectiveness and safety of Ryberbant in patients with NSCLC and EGFR exon 20 insertion mutations who had progressed on prior platinum-based chemotherapy.

The overall response to treatment was 40% and 4% of patients achieved a complete response. The median duration of response was 11.1 months and 63% of patients had responses of at least six months or greater duration. The most common side effects reported were rash, infusion-related and paronychia (nail damage), and itching. No treatment-related deaths were reported.

Lazertinib is a potent third-generation EGFR tyrosine kinase inhibitor (TKI) that shows a promising safety profile, including low rates of EGFR-related toxicities and is being evaluated in combination with Rybervant.

EGFR mutations leading to uncontrolled cancer cell growth and division are some of the most common mutations in NSCLC. EGFR exon 20 insertion mutations are the third most prevalent primary EGFR mutation often go undetected because of the limited use of Next Generation Sequencing (NGS) testing. Amivantamab received full FDA approval in May 2021.  It is increasingly important for patients to understand the importance of blood based NGS testing and insure it is performed at the time of their diagnosis.2

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Bispecific Antibodies in Lung Cancer

Other bispecific antibodies being developed in lung cancer include; zenocutuzumab (MCLA-128), and tarlatamab (AMG-757) - MCLA-128 in NRG1 fusion–positive tumors, and AMG 757 in small cell lung cancer.


NRG1 fusions are observed at low incidence across tumors that preserve the EGF-like domain and are potentially actionable; they are best detected through RNA-NFS. HER2-directed therapy has been found to be a suboptimal strategy but are currently under investigation.

Zenocutuzumab is being tested in patients with NRG1 fusion–positive solid tumors. In 24 evaluable patients with NSCLC, the confirmed ORR was 25%; 1 additional PR was confirmed after the cutoff date, bringing the ORR in this subset to 29% (7/24). The bispecific antibody also showed promise in other solid tumors. The ORRs for the 12 patients with PDAC and 9 patients with other NRG1 fusion–positive cancers were 42% and 22%, respectively.11

Lung Newsletter 490

Tarlatamab (AMG 757)

Tarlatamab is a bispecific T-cell engager against DLL3 that is being evaluated in small cell lung cancer (SCLC). Updated results from a multicenter clinical trial were presented at the 2021 ASCO Annual Meeting.12

Patients with SCLC had to have received at least 1 line of systemic therapy and either progressed or recurred following at least 1 platinum-based chemotherapy, as well as an ECOG performance status of 0 to 2, at least 1 measurable lesion, and adequate organ function. At a median follow-up of 11.2 months, the confirmed response rate in 64 evaluable patients with advanced disease was 20% and median DOR was 8.7 months, the median time to response was 1.8 months.


  1. Sabari, J. et al. Amivantamab, an EGFR-MET bispecific antibody, in EGFR Exon 20 insertion mutant non-small cell lung cancer.. Accessed January 2021.
  2. Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets.. Accessed January 2021.
  3. Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological and Histological Samples in Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence. Int J Clin Exp Pathol. 2013:6;2800-12.
  4. Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011:29;2121-27.
  5. Fang, Wenfeng. BMC Cancer. EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer. Accessed April 7, 2020.
  6. Grugan et al. MAbs. 2017;9(1):114-126.
  7. Moores et al. Cancer Res. 2016;76(13)(suppl 27216193):3942-3953.
  8. Yun et al. Cancer Discov. 2020;10(8):1194-1209.
  9. Vijayaraghavan et al. Mol Cancer Ther. 2020;19(10):2044-2056
  10. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed June 4, 2021.
  11. Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. J Clin Oncol. 2021;39(suppl 15):3003. doi:10.1200/JCO.2021.39.15_suppl.3003
  12. Owonikoko TK, Champiat S, Johnson ML, et al. Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immuno-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC). J Clin Oncol. 2021;39(suppl; abstr 8510). doi:10.1200/JCO.2021.39.15_suppl.8510