Phase 2 Study of D-0316 in Patients with Advanced NSCLC and EGFR T790M Mutation

D-0316, a third-generation EGFR tyrosine kinase inhibitor (TKI), has antitumor activity and acceptable toxicity in patients with EGFR T790M–positive non–small-cell lung cancer (NSCLC) who progressed after EGFR-TKI treatment.

Although they may have an initial response to treatment with an EGFR tyrosine kinase inhibitor (TKI), most patients develop resistance. The EGFR T790M mutation is detectable in approximately 50% of patients treated with first- and second-generation EGFR TKIs. D-0316 is a third-generation EGFR TKI that is selective for both EGFR TKI sensitizing and T790M resistance mutations in patients with non–small-cell lung cancer (NSCLC). At the American Association of Cancer Research Annual Meeting 2021, researchers reported results from a single-arm phase 2 study of D-0316 in NSCLC patients with EGFR T790M who progressed on previous treatment with first-line EGFR TKIs.1

In this phase 2, open-label, single-arm study, eligible patients had confirmed locally advanced or metastatic NSCLC with disease progression after first-line EGFR TKI and with a T790M mutation. Patients were initially treated with oral D-0316 50 mg. However, upon considering the benefits and risks, the dose of D-0316 was modified to 100 mg once daily with a 21-day lead-in at 75 mg once daily. The primary end point was objective response rate (ORR) based on independent review committee (IRC) according to RECIST version 1.1.1

As of October 31, 2019, 176 patients were enrolled in the 50-mg phase of the D-0316 trial. In this phase, 90 patients experienced a partial response, achieving an ORR of 51% (95% confidence interval [CI], 43.5-58.7). Disease progression or death occurred in 60 (34%) patients and the median progression-free survival (PFS) was 8.4 months (95% CI, 8.0-not evaluable).1

Between September 12, 2019, and July 29, 2020, another 689 patients were screened and 290 patients were enrolled in China. Their median age was 62 years. Patients received 100 mg D-0316 with a 21-day lead-in at 75 mg. At data cutoff (October 18, 2020), the median duration of follow-up was 5.5 months. A total of 188 of the 290 patients achieved confirmed partial responses by IRC, such that the ORR was 64.8% (95% CI, 59.0-70.3). The disease control rate was 95.2% (95% CI, 92.0-97.3). ORR was consistent across most subgroups. Among 34 patients with brain metastases at baseline, 18 patients achieved confirmed partial responses, such that the intracranial ORR was 53% (95% CI, 35.1-70.2). At the data cutoff, PFS, duration of response, and overall survival data were premature.1

The most common treatment-related adverse events (TRAEs) were thrombocytopenia (57%), headache (28%), leukopenia (23%), anemia (22%), and rash (21%). The most common grade ≥3 TRAE was thrombocytopenia (12%). One death was attributed to TRAE, specifically interstitial lung disease. Six cases of interstitial lung disease (2.1%) were observed during the study.1

Researchers concluded that D-0316 demonstrated antitumor activity and an acceptable toxicity profile in patients with EGFR T790M–positive NSCLC who have progressed after EGFR-TKI treatment.1

1. Lu S, Zhang Y, Zhang G, et al. D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study (NCT03861156). Presented at: American Association of Cancer Research Annual Meeting 2021; April 10-15, 2021. Abstract CT170.