# Zipalertinib—A Novel Treatment Opportunity for Non-Small Cell Lung Cancers with Exon 20 Insertions and Uncommon EGFR Mutations

## TL;DR

Zipalertinib is a new drug being tested to treat non-small cell lung cancer with specific genetic mutations that are hard to treat with existing therapies.

## Contribution

Zipalertinib is a novel irreversible tyrosine kinase inhibitor with activity against uncommon EGFR mutations and exon 20 insertions in NSCLC.

## Key findings

- Zipalertinib shows significant clinical activity in NSCLC patients with exon20ins and uncommon mutations.
- It is being evaluated in combination with chemotherapy and as monotherapy in multiple clinical trials.
- The drug has demonstrated efficacy in brain metastases and is being tested in the adjuvant setting.

## Abstract

Zipalertinib is a novel oral and irreversible targeting uncommon EGFR mutations and exon 20 insertions. The drug is currently undergoing an extensive clinical study programme (REZILIENT 1–4) and results of the ongoing trials will help to better define the role of zipalertinib alone or in combination with chemotherapy for treatment of NSCLC patients.

Non-small cell lung cancer (NSCLC) represents over 80% of all lung cancer cases and still has a huge mortality worldwide. Targeting epidermal growth-factor receptor (EGFR) alterations with overall response rates of more than 80% has provided a paradigm shift in the treatment of NSCLC; however, NSCLC patients harbouring uncommon mutations and exon 20 insertions still have a dismal prognosis underscoring the urgent need to develop novel EGFR tyrosine kinase inhibitors (TKIs) with proven activity against these EGFR alterations. Zipalertinib is a newly developed oral, irreversible compound which is characterized by its unique pyrrolopyrimidine structure which discriminates this novel TKI from others. It is active against the classical mutations (i.e., del19, L858R) and some of the uncommon mutations (e.g., T790M, G719X, S768I, L861Q, but not C797S) and is predominantly active in NSCLC cells harbouring exon20ins. Zipalertinib is currently being extensively evaluated in several clinical NSCLC trials (REZILIENT 1–4) and has shown significant clinical activity in NSCLC patients with uncommon mutations, exon20ins, and in brain metastases (REZILIENT 3 trial). Moreover, zipalertinib in combination with platinum-based chemotherapy followed by zipalertinib monotherapy as first-line therapy is currently being evaluated in the pivotal, ongoing REZILIENT 3 randomized trial. In addition, the efficacy of zipalertinib is also studied in the adjuvant setting (REZILIENT 4 trial, stage IB-IIIA NSCLCs with exon20ins and uncommon mutations). The role and the integration of therapies targeting exon20ins or uncommon mutations into the first- and second-line treatment armamentarium for NSCLC patients is not yet fully established, and the therapeutic impact of monotherapies (e.g., sunvozertinib, firmonertinib) versus combinations with standard platinum-based chemotherapy (e.g., zipalertinib, amivantamab) currently still lacks robust evidence to further change the therapeutic landscape for these patients. Therefore, results from the ongoing trials are eagerly awaited and are expected to shed some light on these open questions.