Adjuvant therapy with osimertinib significantly reduces CNS disease recurrence in patients with resected EGFR-mutated NSCLC

In order to get a better understanding of the influence of osimertinib on central nervous system (CNS) disease recurrence in patients with resected EGFR-mutated non-small cell lung cancer, Tsuboi et al. presented an exploratory analysis of recurrence patterns and CNS disease-free survival of the ADAURA trial. In this trial, adjuvant osimertinib was found to be associated with a 82% reduction in the risk of CNS disease recurrence or death. Moreover, CNS disease recurrence was less likely with osimertinib compared with placebo, with a conditional probability of less than 1% at 18 months with osimertinib.

Introduction

In non-small cell lung cancer (NSCLC), central nervous system (CNS) relapses are common and associated with a poor prognosis. Therefore, the impact of a specific treatment on the different sites of recurrence, including the CNS, is a key consideration in the resected EGFR-mutated NSCLC setting.  Osimertinib is a third-generation EGFR-TKI that demonstrated a highly statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs. placebo (HR [99.12% CI]: 0.20 [0.14-0.30], p<0.0001) in resected stage IB–IIIA EGFR-mutated NSCLC. At ESMO 2020, an exploratory analysis of recurrence patterns and CNS DFS of this trial was presented. In ADAURA, 682 patients with completely resected stage IB–IIIA EGFR-mutated NSCLC, with or without adjuvant chemotherapy, were randomly assigned (1:1) to receive osimertinib 80 mg once-daily or placebo until disease recurrence, treatment discontinuation, or a maximum of 3 years. An MRI or CT scan of the brain was mandated at baseline either before surgery or upon enrolment but was not required in absence of symptoms. Baseline patient characteristics were well balanced between both treatment arms.

Results

Overall, patients treated with osimertinib experienced fewer recurrence events than patients in the placebo arm (11% vs. 46%). Interestingly, most recurrences in patients enrolled to osimertinib arm were locoregional, with only 38% of patients having a metastatic recurrence (vs. 61% in the placebo arm). The most common sites of disease recurrence in both treatment arms were the lung, lymph nodes and the CNS. After a median follow-up of 22 months, a total of 45 patients suffered a CNS DFS event (defined as CNS disease recurrence or death without any CNS disease recurrence): 6 in the osimertinib arm and 39 in the placebo arm. The median CNS DFS was not reached with osimertinib, while this was reported at 48.2 months in the placebo arm (HR [95%CI]: 0.18 [0.10- 0.33], p<0.0001). At 24 months, the probability of being CNS disease-free was 98% for patients treated with osimertinib, as compared to 85% for patients treated with placebo.  Importantly, it should be taken into account that these data have a maturity of only 7%. The estimated probability of observing CNS recurrence (in the absence of non-CNS recurrence or death) at 18 months was below 1% for patients treated with osimertinib as compared to 9% for patients in the placebo arm. Finally, the cumulative incidence of CNS recurrence was consistently lower in the osimertinib arm than in the placebo arm.

Conclusions

In ADAURA, adjuvant osimertinib demonstrated a highly statistically significant and clinically meaningful improvement in DFS in patients with stage IB-IIIA EGFR-mutated NSCLC. Patients who received osimertinib experienced fewer locoregional and distant relapses than those who received placebo. Adjuvant osimertinib demonstrated an 82% reduction in the risk of CNS disease recurrence or death. CNS disease recurrence was less likely with osimertinib compared with placebo, with a conditional probability of less than 1% at 18 months of osimertinib. The reduced risk of local and distant recurrence with adjuvant osimertinib and the observed improvement in CNS DFS further reinforces adjuvant osimertinib as a highly effective, potentially practice-changing treatment option for patients with stage IB-IIIA EGFR-mutated NSCLC following complete tumour resection.

Reference

Tsuboi M, Wu Y, He J, et al. Osimertinib adjuvant therapy in patients (pts) with resected EGFR mutated (EGFRm) NSCLC (ADAURA): Central nervous system (CNS) disease recurrence. Presented at ESMO 2020; Abstract LBA1.