1. Kumar Das, Dibash PhD

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Lung cancer is one of the leading causes of cancer mortality, accounting for almost 25 percent of all cancer deaths. Non-small cell lung cancer (NSCLC) makes up to 85 percent of all lung cancers, and epidermal growth factor receptor (EGFR) mutations are present in 15-20 percent of NSCLC patients. EGFR exon 20 insertion mutations (EGFR Ex20ins) are the third most prevalent activating EGFR mutation. EGFR Ex20ins, which account for ~4-10 percent of all EGFR mutations in NSCLC, generally do not respond to available EGFR tyrosine kinase inhibitors (TKIs) and have poor outcomes. Patients with newly diagnosed metastatic NSCLC with EGFR Ex20ins have a real-world median overall survival (OS) of 16.2 months.

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Fortunately, as a kinase which is readily druggable, EGFR continues to present itself an attractive therapeutic target for realizing the potential of targeted therapy in oncology. On May 21, the FDA granted accelerated approval to amivantamab-vmjw, the first fully human, bispecific antibody directed against EGFR and MET receptors, to address the high unmet need of the treatment of patients with genetically defined locally advanced or metastatic NSCLC and EGFR Ex20ins mutations. The FDA simultaneously approved the Guardant360 CDx liquid biopsy blood test as a as a companion diagnostic for amivantamab-vmjw.


The accelerated FDA approval of amivantamab-vmjw is based on positive results from the multicenter, multicohort, open-label Phase I CHRYSALIS trial. The study evaluated the efficacy, safety, and pharmacokinetics of amivantamab-vmjw as a monotherapy and in combinations, including the novel third-generation EGFR TKI lazertinib, in 81 patients with locally advanced or metastatic NSCLC with EGFR Ex20ins mutations whose disease had progressed on or after platinum-based chemotherapy.


In this ongoing Phase I study, patients with locally advanced or metastatic NSCLC with EGFR Ex20ins mutations received amivantamab-vmjw 1,050 mg (baseline body weight <80kg) or 1,400mg (baseline body weight >=80kg) as an intravenous infusion once weekly for 4 weeks, then administered every 2 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was disease response using overall response rate (ORR), according to RECIST v1.1.


Results demonstrated an ORR of 40 percent (95% CI, 29-51) among 81 patients that received prior platinum-based chemotherapy. Amivantamab-vmjw elicited a complete response rate of 3.7 percent and a partial response rate of 36 percent. The median duration of response was 11.1 months (95% CI, 6.9-not estimable); 63 percent of responders had a response duration of 6 months or more. The most common adverse reactions (>= 20%) reported were rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, vomiting, and laboratory abnormalities.


Oncology Times connected with Melina Elpi Marmarelis, MD, Assistant Professor of Medicine at the Hospital of the University of Pennsylvania. With her substantial expertise in NSCLC, Marmarelis provides her insights on the approval of amivantamab-vmjw and EGFR exon 20 insertion mutations.


Oncology Times: When thinking about this class of mutations, what are some of the main challenges/key resistance mechanisms of selectively targeting EGFR Ex20ins mutationsin NSCLC?


Marmarelis: "The first challenge in targeting EGFR Ex20ins mutations is that this is a heterogeneous class of alterations that cause different conformational changes in EGFR, and therefore, variable access to drug binding sites. For example, it was observed early on that some insertions, such as A763_Y764insFQEA, are sensitive to first-generation tyrosine kinase inhibitors and other alterations are not. This provides a challenge in thinking of targeting EGFR Ex20ins mutations in the same way.


Oncology Times: How does amivantamab-vmjwshift the treatment standard for patients living with NSCLC with EGFR Ex20ins mutations?


Marmarelis: "The approval of amivantamab-vmjw opens up a targeted treatment option for patients with EGFR Ex20ins mutations. Given the current approval, patients will still be treated with chemotherapy in the first-line, but at the time of disease progression will have amivantamab-vmjw available as a non-chemotherapy option."


Oncology Times: Currently, amivantamab-vmjw is to be utilized in the second-line setting after initial platinum chemotherapy. Can you envision amivantamab-vmjweventually being moved to the first-line setting and being combined with other agents?


Marmarelis: "Yes, I do think that amivantamab-vmjw will eventually be used in the first-line setting. While the overall response rate and median progression free survival (40% and 8.3 months, respectively) are lower than what we have seen for other approved first-line targeted therapies, amivantamab-vmjw still represents an effective non-chemotherapy option for patients with EGFR Ex20ins mutations.


"Since amivantamab-vmjw is a bispecific antibody and does not cross the blood-brain barrier, it does not have any intracranial activity. With brain metastases being very prevalent in patients with EGFR alterations, intracranial activity is an important attribute of any successful treatment in this space. Current clinical trials evaluating amivantamab-vmjw with the third-generation tyrosine kinase inhibitor lazertinib could address this deficiency of amivantamab-vmjw monotherapy."


Oncology Times: Are there other new investigational agent(s) targeting EGFR Ex20ins mutations in NSCLC that you are particularly excited about?


Marmarelis: "There are several oral tyrosine kinase inhibitors in development targeting EGFR Ex20ins mutations in NSCLC. Data on mobocertinib in patients with EGFR Ex20ins mutations and prior platinum chemotherapy exposure was presented at 2021 ASCO Annual Meeting (EXLAIM cohort, Abstract 9014). Efficacy data was promising and mobocertinib appears to be similarly effective regardless of the position of the EGFR exon 20 insertion (near loop vs. far loop positions). Interestingly, the central nervous system was still a very common site of disease progression suggesting that intracranial control may be a challenge for many of the drugs targeting EGFR exon 20.


Previous data presented on poziotinib has also shown efficacy in EGFR exon 20 disease with some challenges managing the side effect profile (Sig Transduct Target Ther 2019; Less is known about CLN-081, another oral EGFR TKI, but overall response rates look promising in a small cohort requiring further validation in larger studies (J Clin Oncol 2021; doi: 10.1200/JCO.2021.39.15_suppl.9077).


Dibash Kumar Das is a contributing writer.