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Impact of Adjuvant Osimertinib on CNS Recurrence of NSCLC: ADAURA Trial


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Osimertinib significantly prolonged disease-free survival compared with placebo in patients with completely resected stage II to IIIA non–small cell lung cancer (NSCLC), according to the results of the large randomized phase III ADAURA trial presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020. Study results were published online to coincide with the ESMO presentation in The New England Journal of Medicine.1,2

“In ADAURA, osimertinib demonstrated a highly statistically significant and clinically meaningful improvement in disease-free survival in patients with stage IB to IIIIA EGFR-positive NSCLC. Patients treated with osimertinib had fewer local/regional and distant relapses than the placebo group, with a lower incidence of metastatic disease among those with recurrence, including fewer central nervous system recurrence events,” said lead author Masahiro Tsuboi, MD, of the National Cancer Center Hospital East, Kashiwa, Japan.

Masahiro Tsuboi, MD

Masahiro Tsuboi, MD

“Adjuvant osimertinib demonstrated a clinically meaningful improvement in central nervous system disease-free survival compared with placebo. These findings reinforce adjuvant osimertinib as a highly effective, practice-changing treatment for patients with stage IB/II/IIIA EGFR-positive NSCLC,” Dr. Tsuboi stated. However, other experts were not convinced that osimertinib should be used in all patients after complete resection (see Expert Point of View on page 13).

Approximately 30% of patients with NSCLC present with resectable disease at diagnoses; for these patients, surgery with curative intent is primary treatment. Adjuvant cisplatin-based chemotherapy is recommended for resected stage II to IIIA and select patients with stage IB disease. However, recurrence rates are high across disease stages, ranging from 45% to 76% depending on disease stage, regardless of chemotherapy use.

EGFR tyrosine kinase inhibitors (TKI) are standard of care for patients with EGFR-positive advanced NSCLC. Osimertinib is a third-generation EGFR-TKI specifically designed to inhibit resistance mutations and to cross the blood-brain barrier and reach central nervous system (CNS) metastasis.

ADAURA Details

ADAURA compared osimertinib vs placebo in patients with completely resected stage IB to IIIA EGFR mutation–positive NSCLC after receiving adjuvant chemotherapy. The trial was unblinded 2 years early due to an evident benefit in efficacy. At ESMO 2020, Dr. Tsuboi presented the results of a prespecified exploratory analysis of disease recurrence patterns in ADAURA, including in the CNS.

“CNS is a common site of recurrence in NSCLC. Osimertinib has increased exposure in the brain compared with other EGFR TKIs,” he explained.

All 682 patients enrolled in the trial had brain imaging and complete resection of the lung with negative margins. Patients were stratified by stage and race. Baseline characteristics were well balanced between the two groups. Most patients had stage II to IIIA disease (76%), and about one-quarter of those with stage IB disease (26%) received adjuvant platinum-based chemotherapy.

In the overall study results, osimertinib demonstrated a significant and clinically meaningful improvement in disease-free survival in patients included in the trial (nonsquamous EGFR-positive NSCLC). At 24 months, in stage II to IIIA disease, 90% of the adjuvant osimertinib group were alive vs 44% of the placebo group. Among all patients, including those with stage IB disease, the 24-month disease-free survival was 89% with osimertinib vs 52% with placebo.

The benefits of osimertinib in terms of disease-free survival were observed consistently across all predefined subgroups, including disease stage and use or not of adjuvant chemotherapy.

Adjuvant osimertinib demonstrated a clinically meaningful improvement in CNS disease-free survival compared with placebo, representing an 82% reduction in the risk of CNS recurrence or death (P < .0001).

Patterns of Recurrence

When the investigators looked at the patterns of disease recurrence, 11% of patients had recurrence or death in the osimertinib arm vs 46% in the placebo arm. The majority of recurrences in the osimertinib arm were locoregional, with just 38% of patients having metastatic recurrence vs 61% in the placebo arm. “CNS recurrences are associated with significant morbidity,” Dr. Tsuboi reminded listeners.

CNS recurrences were reported in 1% of osimertinib-treated patients vs 10% of those in the placebo arm. With osimertinib, recurrence was less common in other sites also, as follows: lung (6% vs 18%), lymph nodes (3% vs 14%), and bone (1% vs 8%). Overall, 45 patients had CNS disease-free survival events: 6 (2%) in the osimertinib arm and 39 (11%) in the placebo arm.

“The estimated probability of observing CNS recurrence [in the absence of non-CNS recurrence or death] at 18 months was less than 1% with osimertinib vs 9% with placebo. The cumulative incidence of CNS recurrence was consistently lower in the osimertinib arm than in the placebo arm,” Dr. Tsuboi stated. 

 

DISCLOSURE: Dr. Tsuboi has received honoraria from AstraZeneca KK, Bristol Myers Squibb Japan, Chugai Pharma, Johnson & Johnson, Medtronic Japan, MSD KK, Novartis Pharmaceuticals Japan, Ono Pharmaceutical, Taiho Pharmaceutical, and Teijin Pharma and has received institutional research funding from Boehringer Ingelheim Japan and MSD Japan.

REFERENCES

1. Tsuboi M, Wu Y, He J, et al: Osimertinib adjuvant therapy in patients with resected EGFR mutated NSCLC (ADAURA): Central nervous system disease recurrence. ESMO Virtual Congress 2020. Abstract LBA1. Presented September 19, 2020.

2.Wu YL, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. September 19, 2020 (early release online).


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Expert Point of View: Johan Vansteenkiste, MD

Formal study discussant Johan Vansteenkiste, MD, of the University Hospitals KU Leuven, Belgium, commented on the ADAURA trial findings: “This is an impressive effect on disease-free survival [with osimertinib] and a very early snapshot of overall survival.”

Dr. Vansteenkiste continued: “In the CNS ...

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