AZD3759 Elicits Responses in Untreated EGFR-Mutant NSCLC With CNS Metastases

The EGFR TKI AZD3759 elicited clinical responses and had an acceptable toxicity profile when administered at a dose of 200 mg twice daily in patients with untreated EGFR-mutant non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases, according to data from the phase 2 TRUMP (CTONG1702; NCT03574402) presented at the 2023 European Lung Cancer Conference.¹

At a median follow-up of 21.9 months, AZD3759 induced an overall response rate (ORR) of 70% (95% CI, 50.6%-85.3%) in all patients (n = 30), meeting the primary end point of the trial. All responders had confirmed partial responses to treatment. In patients who received 200 mg and 300 mg of AZD3759, the ORRs were 80% (95% CI, 51.9%-95.7%) and 60% (95% CI, 32.3%-83.7%), respectively.

“This is the first report to present phase 2 study outcomes of AZD3759 with promising efficacy and tolerable safety in the selected population with CNS metastases,” lead study author Si-Yang Maggie Liu, MD, of Guangdong Lung Cancer Institute, in Guangdong, China, and colleagues, wrote in a poster on the data.

Previously, data from the phase 3 FLAURA trial (NCT02296125) demonstrated that the EGFR TKI osimertinib (Tagrisso) had superior clinical activity over the first-generation TKIs erlotinib (Tarceva) or gefitinib (Iressa) in patients with untreated EGFR-mutated, advanced NSCLC.2 In the CFS full-analysis set,patients who received osimertinib (n = 61) experienced a median CNS progression-free survival (PFS) that was not yet reached (95% CI, 16.5-not calculable [NC]) vs 13.9 months (95% CI, 8.3-NC) with standard EGFR TKIs (n = 67). Moreover, osimertinib elicited a CNS ORR of 66% (95% CI, 62%-77%) vs 43% (95% CI, 31%-56%) with the control TKIs.

TRUMP, the prospective umbrella trial, utilized Simon’s 2-stage design to determine sample size and enrolled patients with histologically or cytologically confirmed NSCLC with brain or leptomeningeal metastases.1,3 Patients were required to have measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 to 2, and an expected survival of more than 12 weeks.³

Of the 30 patients enrolled in the study, 15 received AZD3759 at a twice-daily dose of 300 mg and 15 received it at 200 mg twice daily.1 The agent was given on days 1 to 28 of each 28-day cycle. Courses were repeated every 2 cycles until disease progression or unacceptable toxicity.³

The study’s primary end point was confirmed ORR, and key secondary end points included PFS, overall survival, disease control rate (DCR), and duration of response by RECIST v1.1 criteria. Investigators also evaluated safety and health-related quality of life. All efficacy end points were measured according to RECIST v1.1 criteria.

The median age in all enrolled patients was 58.5 years (range 35-72).¹ Regarding biological sex, 46.7% of patients were male and 53.3% were female. Moreover, 40% of patients were current or former smokers and 60.0% were never smokers. Most patients had an ECOG performance status of 1 (96.7%). In terms of baseline disease stage, 6.7% of patients had stage IVA disease and 93.3% had stage IVB disease.

At the time of diagnosis, all patients had adenocarcinoma and brain metastases. The 200-mg and 300-mg groups each had 1 patient with leptomeningeal metastasis. Regarding EGFR mutational subtypes in all patients, 60% had exon 19 deletions and 40% had exon 21 L88R mutations. Moreover, 13.3% of patients were PD-L1 positive (1%-49%) and 16.7% were PD-L1 negative (<1%).

Additional data showed that the median PFS with AZD3759 was 12.9 months in all patients. Moreover, in this group, the overall DCR was 86.7% (95% CI, 69.3%-96.2%). In the 200-mg group (n = 15), the median PFS was 15.8 months, and the DCR was 93.3% (95% CI, 68.1%-99.8%). The median PFS in the 300-mg group (n = 15) was 10.7 months, with a DCR of 80% (95% CI, 51.9%-95.7%).

Tumor or liquid biopsy was performed for 16 patients to determine the presence of acquired resistance mechanisms. Data showed that 62.5% (n = 10) of these patients developed EGFR T790M mutations. Notably, thirteen patients in the total population went on to receive second-line osimertinib.

At the time of data cutoff, which was June 30, 2022, 1 patient remained on treatment. The remaining 29 patients discontinued treatment due to disease progression (n = 25), withdrawn consent (n = 3), and toxicity (n = 1).

Regarding safety, 93.3% of all patients experienced any-grade treatment-related adverse effects. These included rash (any grade, 83.3%; grade ≥3, 50.0%), increased aspartate aminotransferase (60%; 3.3%), itch (18%; 0%), xerosis cutis (53.3%; 0%), increased blood bilirubin (33.3%; 0%), mouth ulcer (33.3%; 6.7%), cutaneous fissure (30.0%; 0%), increased alkaline phosphatase (23.3%; 0%), increased serum creatine (23.3%; 0%), and skin exfoliation (20.0%; 0%).

References

1. Liu S-YM, Zhou Q, Lu C, et al. 20P Efficacy and safety of AZD3759 in previously untreated EGFR-mutant non-small-cell lung cancer with central nervous system metastases in a multi-center, phase 2 umbrella trial (CTONG1702). J Thorac Oncol. 2023;18(4):S52. doi:10.1016/S1556-0864(23)00274-5
2. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS response to osimertinib versus standard Epidermal Growth Factor Receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. Published online August 28, 2018. doi:10.1200/JCO.2018.78.3118
3. Phase II umbrella study directed by next generation sequencing (TRUMP). ClinicalTrials.gov. Updated December 6, 2022. Accessed April 25, 2023. https://clinicaltrials.gov/ct2/show/NCT03574402