Rybrevant (Amivantamab) Treatment of EGFR Positive Non-Small Cell Lung Cancer

A new under‑the‑skin version of Rybrevant offers a faster, more convenient way for people with EGFR‑mutated lung cancer to receive targeted treatment, potentially shortening clinic time while maintaining effective cancer control.

Charles H. Weaver, MD
6–8 minutes
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Data from ongoing clinical trials evaluating Rybrevant (amivantamab) in patients with advanced non-small cell lung cancer (NSCLC) and epidermal growth factor receptor mutations (EGFRm) continue to suggest a significant level of anti-cancer activity, expanding its role in the management of EGFRm NSCLC.1,15,16

EGFR mutations lead to uncontrolled cancer cell growth and are the most common mutations in NSCLC. EGFR mutations often go undetected because of the limited use of Next Generation Sequencing (NGS) testing. It is increasingly important for patients to understand the importance of blood based NGS testing and ensure it is performed at the time of their diagnosis.2

The standard of care for EGFRm NSCLC has been Tagrisso for several years but new drug combinations and treatments have recently become available. Rybrevant, a bispecific antibody received full FDA approval in May 2021 and the combination of Rybrevant and Lazcluze has now been reported to improve survival duration when compared to treatment with Tagrisso.19

Bispecific Antibodies

Bispecific antibody constructs represent an innovative immunotherapy approach that helps the body’s immune system target cancer cells and are changing 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.

About Rybrevant (amivantamab)

Rybrevant is a fully human EGFR and mesenchymal epithelial transition (MET) bispecific antibody with immune cell-directing activity. Rybrevant 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, Rybrevant targets both the primary mutation and the resistant EGFR and MET mutations and amplifications at the same time.6-9

The FDA recently approved a new under-the-skin (subcutaneous) version of Rybrevant, given together with a helper medicine called hyaluronidase, for adults with EGFR‑mutated advanced non–small cell lung cancer across all of the same situations where IV Rybrevant is already used. Instead of needing long IV infusions, this new shot can be given in just a few minutes, often with fewer infusion‑related reactions, while providing similar drug levels and cancer control to the IV form when used with lazertinib in clinical trials. For many patients, this may mean shorter clinic visits, a more comfortable treatment experience, and an additional option to discuss with their care team when planning EGFR‑targeted therapy.

MARIPOSA Clinical Trial

The MARIPOSA clinical trial enrolled 1074 previously untreated patients with newly diagnosed locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitutions and compared treatment of Rybrevant combined with Lazcluze (lazertinib) to Tagrisso, the current standard of care.16,17,18 Lazcluze is a potent third-generation EGFR tyrosine kinase inhibitor (TKI) being evaluated in combination with Rybervant.

The FDA approved Rybrevant in combination with Lazcluze for the first-line treatment of adult patients with EGFR exon 19 deletions or exon 21 L858R substitution mutations based on data from the phase 3 MARIPOSA trial which demonstrated that Rybrevant combined with Lazcluze reduced the risk of cancer progression or death by 30% compared with Tagrisso alone. Patients treated with the combination experienced a median progression-free survival of 23.7 months compared with 16.6 months for those treated with Tagrisso.2 The median duration of response was 25.8 months vs 16.8 months with the combination.2

Significant side effects however were common with the Rybervant/Lazcluze combination and included rash, nail toxicity, infusion-related reactions, musculoskeletal pain, edema, mouth sores, venous thromboembolism, numbness, fatigue, diarrhea, constipation, decreased appetite, itching, nausea, and eyed toxicity.3  In addition, venous thromboembolic events (blood clots) were observed with Rybrevant combined with Lazcluze, and the FDA recommended the use of prophylactic anticoagulation for the first 4 months of therapy.

What Does This Mean for Patients?

Patients with EGFRm NSCLC now have several treatment options. They can elect to receive treatment with the historical standard of care Tagrisso which is orally administered and well tolerated or one of two new combination regimens; Rybrevant-Lazcluze or Tagrisso + Chemotherapy (FLAURA2 Regimen).

Both combination regimens have more side effects and inconvenience than treatment with Tagrisso alone. Many patients at lower risk of cancer recurrence can be treated with Tagrisso and have chemotherapy added should their cancer progress. For patients at higher risk of cancer recurrence the benefit of initial treatment with a combination regimen should be discussed with the treating oncologist. The main side effect from FLAURA2 is chemotherapy induced low blood counts. The Rybrevant-Lazcluze combination is more inconvenient requiring two days of IV infusion and is associated with infusion reactions, and more skin rash and nail changes than Tagrisso and is requires prophylactic treatment to reduce the risk of blood clots.

Exon 20 Insertion Mutations

In July 2023 results of the Papillon clinical trial confirmed that the addition of Rybrevant to carboplatin and pemetrexed chemotherapy improves the duration of cancer free survival compared to treatment with carboplatin and pemetrexed alone in newly diagnosed advanced or metastatic EGFR exon 20 insertion–mutated NSCLC.14

The Phase 1 CHRYSALIS clinical trial assessed the effectiveness and safety of Rybrebant 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 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.

References

  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. https://bit.ly/3fCjEyT
  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
  13. Krebs M, Spira AI, Cho BC, et al. Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: Updated results from the CHRYSALIS study. J Clin Oncol. 2022;40(suppl 16):9008. doi:10.1200/JCO.2022.40.16_suppl.9008
  14. 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. Updated June 29, 2023. Accessed July 17, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04538664
  15. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). ClinicalTrials.gov. Updated September 13, 2023. Accessed September 28, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04487080
  16. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) approved in the U.S. as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer. News release. Johnson & Johnson. August 20, 2024. Accessed August 20, 2024. https://www.investor.jnj.com/news/news-details/2024/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-approved-in-the-U.S.-as-a-first-line-chemotherapy-free-treatment-for-patients-with-EGFR-mutated-advanced-lung-cancer/default.aspx
  17. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. Published online June 26, 2024. doi:10.1056/NEJMoa2403614
  18. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. August 19, 2024. Accessed August 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer
  19. Rybrevant (amivantamab-vmjw) plus lazcluze (lazertinib) show statistically significant and clinically meaningful improvement in overall survival versus osimertinib. News release. Johnson & Johnson. January 7, 2024. Accessed January 7, 2025. https://www.investor.jnj.com/news/news-details/2025/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-show-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-versus-osimertinib/default.aspx
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