Almonertinib Induces Response in EGFR T790M-Positive NSCLC With CNS Metastases

Clinical benefit was observed with almonertinib (HS-10296) as treatment of patients with EGFR T790M-mutant non–small cell lung cancer (NSCLC) who progressed on previous EGFR tyrosine kinase inhibitors (TKIs), according to findings from the phase III APOLLO study presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting.

The study results also indicated clinical efficacy against central nervous system (CNS) metastases in a cohort of patients. The agent also displayed an overall favorable safety profile.

APOLLO enrolled 244 Asian patients in 36 different sites in China (n = 189) and Taiwan (n = 55). Patients were divided into two sets to be evaluated for efficacy. The full analysis set (FAS) included patients who received at least one dose of almonertinib and had a baseline RECIST assessment and the CNS responses set (CNS RS) consisted of patients with 1 or more intracranial mesuarable lesion(s) on their baseline scan per Independent Central Review (ICR).

The objective response rate (ORR) was 68.9% (95% CI, 63-75) in the FAS versus 60.9% (95% CI, 39-80) in the CNS RS. Overall, 168 patients achieved a partial response (PR; 68.9%) and 60 had stable disease (SD; 24.6%). Twelve patients had progressive disease (PD; 4.9%). In the CNS RS, 1 patient achieved a complete response (4.3%), 12 had a PR (56.5%), 7 had SD (30.4%), and 2 had PD (8.7%).

The disease control rate (DCR) was 93.4% (95% CI, 90-96) in the FAS and 91.3% (95% CI, 12-99) in the CNS RS. The median progression-free survival (PFS) in the FAS versus the CNS RS was 12.3 months (95% CI, 9.6-13.8) and 10.8 months (95% CI, 5.5-12.6). There were 117 PFS events overall versus 11 in the CNS RS. The median duration of response (DOR) was 12.4 months (95% CI, 11.3-not calculable) in the overall population versus 11.3 months in the CNS RS.

In terms of safety, 229 patients (93.9%) experienced an adverse event (AE) in the overall population and 19 in the CNS RS (82.6%). Drug-related AEs were observed in 185 patients (75.8%) overall and 16 (69.6%) in the CNS RS. Severe AEs of grade 3 or greater occurred in 77 patients (31.6%) overall versus 8 (34.8%) in the CNS RS, and drug-related severe AEs of grade 3 or greater occurred in 38 patients (15.6%) versus 4 (17.4%), respectively.

Serious AEs (20.1%), drug-related serious AEs (5.3%), and AEs leading to dose interruption (11.9%), reduction (2.0%), or discontinuation (2.5%) were low in the overall patient population. There were 3 serious AEs (13.0%) in the CNS RS, and 3 (13.0%) had an AE leading to a dose interruption. No drug-related serious AEs or AEs leading to dose reduction or discontinuation.

Treatment was overall well-tolerated, according to the study investigators. The most common AEs of any grade were blood creatine phosphokinase increase (19.6%), rash (12.7%), aspartate aminotransferase increase (12.3%), alanine aminotransferase increase (11.4%), white blood cell count decrease (10.7%), pruritis (10.7%), anemia (9%), diarrhea (7.4%), leukopenia (7%), proteinuria (7%), platelet count decrease (6.5%), and neutrophil count decrease (6.1%).

The most common grade 3 or greater AE overall was blood creatine phosphokinase increase, which occurred in 17 patients (6.9%). Others of grade 3 or greater in severity included alanine aminotransferase increase (1.2%), platelet count decrease (0.8%), neutrophil count decrease (0.8%), and aspartate aminotransferase increase, anemia, diarrhea, leukopenia, and proteinuria (0.4% each).

Patients in the study received oral almonertinib at 110 mg once daily and were assessed by RECIST v1.1 every 6 weeks. The median age of patients was 61 years (range, 27 – 87), but the median age among patients in the CNS RS (n = 23) was 67 (range, 43 – 86). The majority of patients in the study were female (58.2%), but 60.9% were male in the CNS set. The majority of patients (62.7%) did not have CNS metastases at study entry in the overall population, while 95.7% of patients in the CNS response set did. Baseline data assessment identified 4 patients with an Ex19del or L858R mutation, 1 with a G719X combined with S7681, and 3 patients without a common sensitizing EGFR mutation.

Overall, patients had either an ECOG performance status of 0 (34.8%) or 1 (65.2%), and 73% of patients were never smokers. In terms of EGFR 7790M mutational status, 63.5% of patients had an Ex19del mutation, 34.9% had L858R mutation, and 1.6% had other. Approximately 23.4% of patients had more than 1 line of prior anti-cancer therapy, while 76.6% had only 1 line.

In the CNS RS, 78.3% of patients had an ECOG performance status of 1, and 21.7% had a 0. The majority of patients were never smokers (65.2%), and 65.2% had received only 1 line of prior therapy versus 34.8% who had more than 1 line. Approximately 47.8% had an EGFR T790M mutation with Ex19Del versus 52.2% with L858R. Most patients did not receive previous brain radiation (73.9%).

The randomized, controlled, double-blinded study remains ongoing, comparing almonertinib with gefitinib (Iressa) in the frontline setting as treatment of patients with advanced NSCLC with EGFR sensitizing mutations. Enrollment has been completed. The primary end point in the overall analysis is ORR, and secondary end points include DCR, PFS, DOR, OS, and safety. In the CNS analysis, investigators aim to analyze ORR, DCR, PFS, DOR, OS, and safety as well.

To be eligible for the study, patients had to have locally advanced or metastatic NSCLC with an EGFR T790M mutation and disease progression following prior EGFR TKI therapy. Patients with asymptomatic CNS metastases were also allowed on trial.

_Reference

_{Lu S, Wang Q, Zhang G, et al. Almonertinib (HS-10296) for central nervous system metastases in pretreated EGFR T790M locally advanced or metastatic non-small cell lung cancer data from APOLLO study. Presented at: 2020 AACR Annual Meeting; April 27-28, 2020. Abstract CT190. https://bit.ly/2WtFECz.}