Trastuzumab Deruxtecan in Non–Small-Cell Lung Cancer

TO THE EDITOR:

Both intravenous antibody–drug conjugates and oral tyrosine kinase inhibitors targeting receptor tyrosine-protein kinase erbB-2 (ERBB2 or HER2) are under late-stage development for lung cancers with ERBB2 mutations. Li et al. (Jan. 20 issue)¹ report the initial data from the DESTINY-Lung01 trial of trastuzumab deruxtecan, including for 9 patients with a response who had previously received an ERBB2 tyrosine kinase inhibitor. However, the specific tyrosine kinase inhibitor was not provided. The majority of clinically available ERBB2 tyrosine kinase inhibitors (afatinib, dacomitinib, lapatinib, and neratinib) do not have an effective therapeutic window against either common ERBB2 exon 20 insertion mutations or rare ERBB2 point mutations that drive lung-cancer tumorigenesis.² New ERBB2 tyrosine kinase inhibitors, such as poziotinib and mobocertinib, have shown both preclinical therapeutic windows and clinical activity (albeit limited) in ERBB2-mutated lung cancers.^2-5 We report (in a case series supported by the National Cancer Institute [R37CA218707]) consecutive cases of patients receiving poziotinib before trastuzumab deruxtecan (Fig. 1). These cases suggest that cross-resistance to ERBB2 tyrosine kinase inhibitors and antibody–drug conjugates may be uncommon owing to their disparate mechanisms of action. Additional studies characterizing mechanisms of resistance to tyrosine kinase inhibitors, antibody–drug conjugates, and appropriate sequencing or combinations of therapies in ERBB2-mutated cancers are warranted.

Figure 1. Three Patients with Lung Cancer with ERBB2 Exon 20 Mutations Who Received Trastuzumab Deruxtecan after Use of Poziotinib.

All the patients received poziotinib at varying doses as part of the ongoing ZENITH20 trial, and this portion of their cancer care has been reported previously.^3-5 Patient 1, who had lung adenocarcinoma with an ERBB2 P780_Y781insGSP mutation, had received carboplatin, pemetrexed, and pembrolizumab before the initiation of poziotinib. After a period of response to poziotinib, progression ensued. Repeat biopsy did not reveal on-target resistance mutations or alternative off-target aberrations (FoundationOne CDx). The patient received trastuzumab deruxtecan with rapid clinical and radiographic response that was maintained for 6 months before progressive disease developed. Patient 2, who had lung adenocarcinoma with an ERBB2 A775_G776insYVMA mutation, had not previously received treatment at the time of initiation of poziotinib. After a period of response, the patient had clinical and radiographic progression. Repeat biopsy did not reveal on-target resistance mutations or alternative off-target aberrations (FoundationOne CDx). The use of trastuzumab deruxtecan led to rapid clinical and radiographic improvement that is ongoing at the time of this report (>11 months). Patient 3, who had lung adenocarcinoma with an ERBB2 A775_G776insYVMA mutation, had received carboplatin, pemetrexed, and pembrolizumab, followed by trastuzumab emtansine (11 months, data not shown), followed by carboplatin and gemcitabine before the initiation of poziotinib. The best response to poziotinib was stable disease, and the best response to trastuzumab deruxtecan was stable disease for a 6-month period followed by eventual radiographic progression and death. Repeat tumor biopsy was not performed. Data on clinical, radiographic, and survival outcomes used to report these cases were obtained from an ongoing institutional review board–approved protocol at our institution.