Adjuvant osimertinib demonstrated a statistically significant and clinically meaningful benefit for patients with stage IB, II, or IIIA EGFR-mutant non-small cell lung cancer (NSCLC) with complete tumor resection in the phase 3 ADAURA trial, presented by Prof. Roy Herbst (Yale Cancer Center, USA) .
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, with demonstrated efficacy as a frontline agent for metastatic NSCLC with confirmed EGFR-mutation . The phase 3 ADAURA clinical trial attempted to assess whether this agent is also effective in earlier stages of the metastatic disease characterized by EGFR mutation, namely as adjuvant therapy after complete surgical resection of stage IB, II, or IIIA disease.
Oral osimertinib (80 mg, once daily) was compared with placebo for a treatment duration of up to 3 years or until disease recurrence. The primary endpoint was disease-free survival (DFS), and the key secondary endpoint was overall survival (OS). Other secondary endpoints include DFS at 2, 3, and 5 years; patient health-related quality of life and symptoms; and plasma concentrations.
The study was unblinded (a.k.a. open-label) early under the recommendation from an Independent Data Monitoring Committee due to efficacy, as indicated by Prof. Herbst, who further described the unplanned interim analysis. At the time of the unblinding, all patients had been enrolled and randomized (n=682) and all patients had been followed up for at least 1 year. For the primary endpoint in stage II-III patients, the DFS curves separated early on and showed an 83% reduced risk of disease recurrence for the osimertinib arm (HR 0.17; 95% CI 0.12-0.23; P<0.0001). Adding in the early-stage IB patients to the overall population did not change this trend (HR 0.21; 95% CI 0.16-0.28; P<0.0001), indicating that osimertinib benefits early-stage patients as well. DFS across all subgroups in the overall population (i.e. age, gender, smoking status, Asian vs non-Asian, EGFR mutation, and adjuvant chemotherapy) favored osimertinib.
The median duration of exposure was 22.3 months (range 0-43) for the osimertinib arm and 18.4 months (range 0-48) for the placebo arm. Osimertinib was well tolerated with a safety profile consistent with its known safety profile (diarrhea, paronychia, dry skin, and pruritus being the most common). There were no adverse events leading to death in the osimertinib arm. The rate of grade 3-4 adverse events was low. Interstitial lung disease was reported in 10 (3%) patients in the osimertinib arm and in 0 patients in the placebo group; cardiac QTc interval prolongation was reported in 22 patients (7%) in the osimertinib arm and 4 patients (1%) in the placebo arm.
In conclusion, adjuvant osimertinib is the first targeted agent in a global randomized trial to show a significant and clinically meaningful improvement in DFS in patients with stage IB/II/IIIA EGFR-mutant NSCLC. Overall, there was a 79% reduction in the risk of disease recurrence or death with osimertinib. Osimertinib versus placebo DFS rates at 2 years were 89% vs 53%, respectively. Consistent improvement was observed in DFS regardless of prior adjuvant chemotherapy. The safety profile was beneficial. In short, adjuvant osimertinib provides a highly effective, practice-changing treatment for patients with stage IB/II/IIIA EGFRm NSCLC after complete tumor resection.
1. Herbst RS et al. Phase III study assessing the efficacy of adjuvant use of targeted agent osimertinib in patients with localized non-small-cell lung cancer and EGFR mutation after complete tumor resection and adjuvant chemotherapy. ASCO Virtual Meeting, 29-31 May 2020, Abstract LBA5.
2. Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113‐125.