Amivantamab Provides New Treatment Approach in EGFR Exon 20+ NSCLC

CASE

• A 64-year-old Asian woman presented with persistent dry cough and mild progressive dyspnea over the last month. During this time, she had an unintentional weight loss of 8 lbs.
• Medical History: Hypertension and hypercholesterolemia​
• Smoking History: Never smoker​
• Physical Exam: Right lower lobe auscultation reveals decreased breath sounds​
• ECOG performance status: 1​
• CT chest scan: 3.5 cm mass in right lower lobe, small right pleural effusion with nodularity; mediastinal lymphadenopathy
• PET/CT scan: multiple bone metastases, including vertebrae and left scapula​.
• Brain MRI was negative for brain metastases.
• Mediastinal node endobronchial ultrasound: Non—small cell lung cancer (NSCLC) TTF1 positive adenocarcinoma; stage IVB​
• Negative PD-L1 expression
• Results of next-generation sequencing (NGS) pending
• The patient was started on chemotherapy doublet (cisplatin and pemetrexed)​.
• Tissue NGS showed EGFR exon 20 insertion mutation (V769_D770insASV)​.
• Four months after initiation of chemotherapy with initial partial response, the patient reported worsening back pain and shortness of breath​.
• CT scan showed disease progression​.
• Repeat brain MRI showed no metastases.

Targeted Oncology: What are patient outcomes for those with an EGFR exon 20 mutation in their disease compared with classic EGFR mutations?

MARTIN F. DIETRICH, MD, PHD​: [Looking at a] a descriptive comparison of patients with EGFR exon 20 mutation vs all other EGFR mutations from real world evidence, we see that the chance of survival with the classic mutations is better [with a median overall survival of 25.5 months (range, 24.5-27.1) vs 16.2 months (range, 11.0-19.4)].¹ The question is, is it better because the mutation is more aggressive in the disease biology and our drugs are more aggressive for [patients with an] EGFR exon 20 mutation in their disease? Is it not measuring up to the standard third generation of EGFR tyrosine kinase inhibitors [TKIs]? This is an answer we don't have.

Martin F. Dietrich, MD, PhD​

Assistant Professor of Internal Medicine

University of Central Florida in Orlando​

Orlando, FL​

So, it's clear that prognostically we're looking at a worse off subgroup of patients with lung cancer. Those patients don't have many options other than chemotherapy, while the role of immunotherapies is still up in the decision-making stage, but I would say that this is an opportunity to acknowledge how important EGFR detection is, so patients can get treated upfront.

What is the mechanism of action for amivantamab-vmjw (Rybrevant) when used to treat patients with NSCLC?

Amivantamab is our first bispecific antibody in solid tumor oncology, and unlike most of the bispecifics we're using in hematology, this is not just a connector of the immune system to a respective target; it's an inhibitor of 2 of the most important signaling targets.² EGFR and MET interplay in NSCLC and are important molecules in tumor propagation, and there are 2 mechanisms of inhibition. So, we've had EGFR antibodies for a long time...with limited success and they are not used much anymore.

The idea now is to enhance it not only through a signaling blockade, which certainly happens through receptor degradation, but also to have amivantamab serve as a connector to the immune system. Antibody-dependent cytotoxicity is activated both through natural killer cell and CD8-positive interpretation, and then a larger thrombocytosis in the macrophage system [happens] in this situation as well. So, this is a bispecific antibody that also has a bi-therapeutic approach for treatment of patients with NSCLC.

How does amivantamab compare with mobocertinib (Exkivity) in this space?

Both mobocertinib and amivantamab carry similar labels.^3,4 The FDA acknowledges that the role of immunotherapy is not clear, and basically only requires a platinum-based chemotherapy in the first-line setting. I don't think anybody takes away the immunotherapy option in the first-line setting, and there's an argument to be made for both sides, but I think those data are still open [to discuss]. We have to do a platinum-based therapy first, and then we have 2 options for the small mutational space of patients with EGFR exon 20 in their disease, either mobocertinib as a daily pill vs amivantamab as a weekly and then biweekly infusion. Mobocertinib, based on its structure, is going to be limited to EGFR exon 20. Amivantamab, with the mechanism of action not being specific to the type of EGFR alteration, as well as the inclusion of MET, has more versatility with regards to what can be can be done.

^References

^{1. Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer. 2021;162:154-161. doi:10.1016/j.lungcan.2021.10.020}

^{2. Vyse S, Huang PH. Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer. Expert Rev Anticancer Ther. 2022;22(1):3-16. doi:10.1080/14737140.2022.2016397}

^{3. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed, November 13, 2023. https://tinyurl.com/bdhvt6ve}

^{4. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. FDA. September 16, 2021. Accessed, November 13, 2023. https://tinyurl.com/mry3b98h}