PURPOSE To evaluate the safety and efficacy of zipalertinib, an irreversible epidermal growth factor receptor (EGFR) inhibitor, in pretreated patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) mutations. METHODS REZILIENT1 (ClinicalTrials.gov identifier: NCT04036682 ) is a phase I/II open-label trial enrolling patients with locally advanced or metastatic EGFR ex20ins-mutant NSCLC previously treated with platinum-based chemotherapy with/without ex20ins-targeted therapies. Asymptomatic, treated and untreated stable CNS metastases are permitted. We report data from patients treated with zipalertinib 100 mg twice daily. The primary end points are objective response rate (ORR) and duration of response (DOR) by independent central review. RESULTS At data cutoff (December 10, 2024), 244 patients had received treatment with zipalertinib 100 mg twice daily. The primary efficacy population (8 months' follow-up) comprised patients who had received prior platinum-based chemotherapy without ex20ins-targeted therapy (125 patients), with amivantamab only (30 patients), or with amivantamab and other ex20ins-targeted therapy (21 patients). The confirmed ORR was 35.2% (95% CI, 28.2 to 42.8); median DOR was 8.8 months (95% CI, 8.3 to 12.7). Among patients who received prior platinum-based chemotherapy without ex20ins-targeted therapy, amivantamab only, or amivantamab and other ex20ins-targeted therapy, the confirmed ORR was 40%, 30%, and 14.3%, and median DOR was 8.8, 14.7, and 4.2 months, respectively. Among 68 patients with CNS metastases, the ORR was 30.9%. The most common grade ≥3 treatment-related adverse events were anemia (7%), pneumonitis and rash (2.5% each), and diarrhea, ALT increased, and platelet count decreased (2% each). CONCLUSION Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in patients with EGFR ex20ins-mutant NSCLC who received prior platinum-based chemotherapy with or without amivantamab.

BACKGROUND:The efficacy of immunotherapy combined with platinum-based chemotherapy for untreated brain metastases originating from small-cell lung cancer (SCLC) has remained unclear. METHODS:This multicenter, single-arm phase II study enrolled chemotherapy-naive patients with extensive-stage SCLC who had at least one untreated brain metastasis measuring ≥5 mm. Patients received durvalumab (MEDI4736) combined with platinum-etoposide chemotherapy for four cycles, followed by durvalumab maintenance monotherapy. The primary endpoint was the intracranial response rate, assessed using the modified RECIST for brain metastases, with target lesions defined as ≥5 mm. RESULTS:A total of 42 patients from 23 institutions were enrolled. Their median age was 70.5 years (range 35-83 years), and the median size of target brain lesions was 10 mm (range 5-57 mm). The intracranial response rate (as assessed by the modified RECIST) was 66.7% (90% confidence interval 54.0% to 77.3%), meeting the study's primary endpoint. Intracranial and extracranial lesion responses were generally consistent. The median intracranial progression-free survival was 4.2 months, with a median time to local brain therapy of 10.4 months. Subsequent local brain therapy was administered to 21 patients (50.0%), including surgery in 2, whole-brain radiotherapy in 12, and stereotactic radiotherapy in 7 patients. CONCLUSIONS:Durvalumab combined with platinum-etoposide chemotherapy demonstrated promising intracranial activity in SCLC patients with untreated brain metastases. However, only a small proportion of patients achieved a sustained response, highlighting the need for regular monitoring of brain metastases.

BACKGROUND:Brigatinib is a next-generation tyrosine kinase inhibitor (TKI) targeting ALK and ROS1. The Barossa study is a multicenter, phase II basket study of brigatinib in patients with ROS1-rearranged solid tumors. ROS1 TKI-naive patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) were enrolled in cohort 1, and ROS1-rearranged NSCLC patients treated previously with crizotinib were enrolled in cohort 2. Patients with ROS1-rearranged solid tumors other than NSCLC were enrolled in cohort 3. PATIENTS AND METHODS:Eligible patients received brigatinib at the dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary endpoint was the objective response rate (RECIST 1.1) assessed by independent central review in cohorts 1 and 2. RESULTS:Between July 2019 and June 2021, 51 patients were enrolled into the study. Of the 51, 47 patients had ROS1-rearranged NSCLC; 28 and 19 of these patients were enrolled in cohort 1 and cohort 2, respectively. The remaining four patients had other ROS1-rearranged solid tumors, including rectal, brain, and pancreas tumor in one patient each, and primary unknown tumor in one patient. The confirmed objective response rate was 71.4% [95% confidence interval (CI) 51.3% to 86.8%] in cohort 1 (TKI-naive NSCLC patients) and 31.6% (95% CI 12.6% to 56.6%) in cohort 2 (NSCLC patients treated previously with crizotinib). The median progression-free survival was 12.0 months (95% CI 5.5-22.9 months) in cohort 1 and 7.3 months (95% CI 1.3-17.5 months) in cohort 2. None of the patients in cohort 3 showed any treatment response. Pneumonitis was observed in 9.8% of all the patients. CONCLUSIONS:Brigatinib was effective in TKI-naive patients with ROS1-rearranged NSCLC. The safety profile of brigatinib was consistent with that reported from previous studies.

This secondary analysis of the J-FORCE randomized clinical trial examines the effect of olanzapine plus triplet antiemetic therapy on chemotherapy-induced nausea and vomiting in patients with a malignant tumor, stratified by 6 risk factors.

Chemoimmunotherapy is the standard first-line therapy for patients with extensive stage small cell lung cancer (ES-SCLC). Although liver metastasis has been reported to be associated with poorer survival outcomes after immunotherapy in several cancer types, the association between liver metastasis and the efficacy of immunotherapy in ES-SCLC remains unclear.