The 2024 European Society for Medical Oncology (ESMO) Annual Meeting was held from September 13 to 17 in Barcelona, Spain, where several significant advances in lung cancer research were presented. Dr. Antonio Passaro from the European Institute of Oncology Division of Thoracic Oncology in Milan, Italy, shared insights on the safety and antitumor activity of Zipalertinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations. Oncology Frontier had the opportunity to interview Professor Passaro on-site, where he discussed the latest advances in EGFR-targeted therapies.

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Oncology Frontier: At ESMO 2024, Zipalertinib’s safety and antitumor activity in NSCLC patients with EGFR exon 20 insertion mutations who were previously treated with Amivantamab were presented. What are your thoughts on the safety and efficacy of Zipalertinib in this patient population? (Abstract 1254MO)

Dr. Antonio Passaro: Yesterday, I had the privilege of presenting the latest data from Cohort C of the phase IIb REZILIENT1 study, which evaluates the novel TKI Zipalertinib targeting EGFR exon 20 insertion mutations. In this study, we assessed Zipalertinib’s efficacy and safety in patients who had previously been treated with Amivantamab and other targeted therapies. A total of 45 patients who had already undergone standard Amivantamab treatment were enrolled, 17 of whom had also received other TKIs targeting exon 20 insertion mutations, such as Mobocertinib, Poziotinib, or BLU-451.

The primary endpoint of this study was the objective response rate (ORR), and the results were very impressive: the ORR was 40% in evaluable patients (n=30). Among those who had previously been treated with Amivantamab and other TKIs, follow-up results showed an increase in ORR. The disease control rate (DCR) across all patients in the trial was approximately 90%, confirming the potential of TKIs in patients whose disease had progressed following Amivantamab treatment.

In terms of safety, Zipalertinib demonstrated a favorable safety profile, with only mild toxicities observed, including rash, paronychia, and anemia. The rate of treatment discontinuation or dose reduction due to toxicity was very low.

As for secondary endpoints, progression-free survival (PFS) was 9.7 months, which is particularly impressive considering the stage of treatment, disease status, and prior therapy exposure. Currently, Zipalertinib is being evaluated in a phase III trial in combination with chemotherapy as a first-line treatment. Other TKIs are also undergoing phase III trials, which could further expand treatment options for NSCLC patients with exon 20 insertion mutations.

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Oncology Frontier: Could you share your thoughts on the unmet needs in EGFR-mutant NSCLC, and how emerging EGFR-targeted therapies are shaping the future of treatment for EGFR-mutant lung cancer?**

Dr. Antonio Passaro: Currently, the main unmet needs lie in the treatment landscape for EGFR and HER2 mutations, which, while similar, are not identical. For EGFR-mutant patients, the results from the FLAURA2 (Osimertinib + Chemotherapy) and MARIPOSA (Amivantamab + Lazertinib) studies have confirmed that these combinations could serve as new standards of care in the first-line treatment of EGFR-mutant NSCLC. However, managing resistance remains a major challenge. The MARIPOSA-2 combination of chemotherapy plus Amivantamab has emerged as a new standard of care, but we still need to gain a deeper understanding of the biological mechanisms driving resistance in EGFR mutations.

During this meeting, Professor Benjamin Besse presented data on the resistance mechanisms associated with the combination of Amivantamab and Lazertinib from the MARIPOSA study (Abstract LBA55). There were many differences compared to the FLAURA2 study. The combination of Amivantamab and Lazertinib demonstrated a significantly lower incidence of EGFR and MET resistance compared to Osimertinib monotherapy, as well as a reduced incidence of TP53 resistance mutations and RB1 loss of function. During ESMO 2024, several poster presentations highlighted the potential of other strategies for EGFR-mutant patients, including ongoing research into CAR-T therapies and antibody-drug conjugates (ADCs). However, we still need more robust data to confirm the efficacy of these new treatments.

For HER2-mutant patients, the only approved drug globally is Trastuzumab Deruxtecan, but there is a lack of first-line treatment data for NSCLC patients. At ESMO 2024, we presented a new phase III trial, SOHO-02, which investigates the first-line use of the TKI BAY 2927088 in locally advanced or metastatic NSCLC with HER2 activating mutations (Abstract 1395TiP), comparing it to the current standard of care (platinum-based chemotherapy/pemetrexed/pembrolizumab). This trial is currently recruiting patients worldwide, offering a promising new opportunity for those with HER2-activating mutations.