Osimertinib reduces CNS recurrence in resected EGFR-mutated NSCLC

In patients with stage IB–IIIA EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC) who have undergone complete tumour resection, adjuvant osimertinib significantly reduces the risk of recurrence, including in the central nervous system (CNS), results of an exploratory analysis of the phase III ADAURA trial have shown.

In the prespecified exploratory analysis, osimertinib reduced the risk of CNS recurrence or death by 82 percent vs placebo. In the overall population of the trial, median CNS disease-free survival (DFS) was not reached in the osimertinib arm vs 48.2 months in the placebo arm (hazard ratio [HR], 0.18; 95 percent confidence interval [CI], 0.10 to 0.33; p<0.0001). CNS DFS rates were 100 percent vs 97 percent at 12 months, 98 percent vs 85 percent at 24 months, and 98 percent vs 82 percent at 36 months. [Tsuboi M, et al, ESMO 2020, abstract LBA1]

The ADAURA trial included 682 patients with completely resected EGFRm NSCLC who were randomized (1:1) to receive osimertinib (80 mg QD) or placebo for 3 years. As reported previously, DFS in patients with stage II–IIIA disease – the primary endpoint – was significantly improved with osimertinib vs placebo (24-month DFS rate, 90 percent vs 44 percent; median DFS, not reached vs 19.8 months; HR, 0.17; 99.06 percent CI, 0.11 to 0.26; p<0.001). In the overall population of patients with stage IB–IIIA disease, DFS was also significantly improved with osimertinib vs placebo (24-month DFS rate, 89 percent vs 52 percent; median DFS, not reached vs 27.5 months; HR, 0.20; 99.12 percent CI, 0.14 to 0.30; p<0.001). [N Engl J Med 2020, doi: 10.1056/NEJMoa2027071]

The current analysis of disease recurrence patterns showed that 11 percent of patients in the osimertinib arm vs 46 percent of those in the placebo arm had DFS events.

“In the osimertinib arm, the majority [62 percent] of patients with disease recurrence had local/regional recurrence only, and only 38 percent of the patients had metastatic recurrence,” reported investigator Dr Masahiro Tsuboi of National Cancer Center Hospital East, Kashiwa, Japan. “In the placebo arm, 62 percent of patients with disease recurrence had metastatic recurrence, while 39 percent had local/regional recurrence.”

The most common site of disease recurrence was the lung (6 percent in the osimertinib arm vs 18 percent in the placebo arm in the overall population), followed by lymph nodes (3 percent vs 14 percent). CNS recurrence occurred in 1 percent vs 10 percent of patients.

“The estimated probability of observing CNS recurrence [in the absence of non-CNS recurrence or death] at 18 months was <1 percent with osimertinib vs 9 percent with placebo. The cumulative incidence of CNS recurrence was consistently lower in the osimertinib vs placebo arm,” he continued.

“The CNS is a common site of distant recurrence among patients with EGFRm NSCLC treated with EGFR tyrosine kinase inhibitors,” said Tsuboi. [J Thorac Oncol 2019;14:503-512; J Clin Oncol 2015;33:4007-4014] “Our findings reinforce adjuvant osimertinib as a highly effective, practice-changing treatment for patients with stage IB–IIIA EGFRm NSCLC following complete tumour resection.”

“In patients with stage I–III NSCLC, the goal of treatment is to improve cure rates. The ADAURA trial demonstrated an impressive, but early and immature, DFS difference with osimertinib vs placebo, and superior CNS control with osimertinib. However, OS data of at least 3 years are needed because DFS improvement may not translate into better cure rates,” said invited discussant Professor John Vansteenkiste of the University Hospital KU Leuven, Belgium.

“Treatment for stage I–III NSCLC should be of good tolerability and able to control CNS disease. A substantial proportion of these patients are cured by surgery alone, while minimal residual disease [MRD] after surgery can [also] be eliminated by chemotherapy,” Vansteenkiste continued. “About half of the osimertinib-treated patients in ADAURA experienced diarrhoea, while about a quarter experienced skin problems. In view of these adverse event rates and the cost of osimertinib, MRD measurement is crucial for selecting patients for adjuvant osimertinib treatment.”