For patients with resected stage II to stage III NSCLC and select stage IB patients, adjuvant chemotherapy is standard of care, but recurrence rates are high. ADAURA is a phase 3, double-blind, randomized study of the efficacy and safety of osimertinib versus placebo in patients with stage IB to stage IIIA EGFR-mutated NSCLC after complete tumor resection and adjuvant chemotherapy, when indicated. An independent data monitoring committee recommended that the trial be unblinded early due to efficacy.
To be eligible for participation in the study, patients had to be ≥18 years (≥20 years in Japan and Taiwan); have a performance status of 0 or 1; primary nonsquamous stage IB, II, or IIIA NSCLC; confirmed EGFR mutation (either ex19del or L858R); and complete resection of primary NSCLC with full recovery from surgery. Patients could receive postoperative chemotherapy. Participants were randomized 1:1 to oral once-daily osimertinib 80 mg or placebo and received treatment for up to 3 years. Patients were stratified by disease stage (IB, II, IIIA), mutation type (ex19del, L858R), and race (Asian, non-Asian). Investigator-determined disease-free survival (DFS) in stage II to IIIA patients was the primary end point of the study. Overall survival (OS) and safety were secondary end points.
Researchers randomized 682 patients to treatment: 339 to osimertinib and 343 to placebo. Baseline characteristics were balanced between arms: female 68%/72%; stage IB 31%/31% (osimertinib/placebo); stage II/IIIA 69%/69%; ex19del 55%/56%; and L858R 45%/44%.
The DFS hazard ratio (HR) was 0.17 (95% confidence interval [CI], 0.12-0.23; P <.0001) in stage II and stage IIA patients. The 2-year DFS rate was 90% in the osimertinib arm compared with 44% in the placebo arm. The DFS HR was 0.21 (95% CI, 0.16-0.28; P <.0001) in the overall population. OS data were immature at the time of data cutoff. The safety profile of osimertinib was consistent with prior reports.
Adjuvant osimertinib is the first targeted agent evaluated in a global trial that shows a statistically significant and clinically meaningful improvement in DFS in patients with stage IB, stage II, and stage IIIA EGFR-mutated NSCLC after complete tumor resection and adjuvant chemotherapy (when indicated).
CheckMate-568 Evaluated Nivolumab plus Ipilimumab with Chemotherapy in Metastatic NSCLC
In Part 1 of the phase 2 CheckMate-568 study, the combination of nivolumab and ipilimumab was shown to be active and tolerable in patients with advanced non–small-cell lung cancer (NSCLC). Part 2 of CheckMate-568 investigated whether adding chemotherapy to this combination can further improve initial disease control.
Adult patients with untreated stage IV NSCLC received nivolumab (NIVO; 360 mg every 3 weeks) and ipilimumab (IPI; 1 mg/kg every 6 weeks) combined with 2 cycles of histology-based platinum-doublet chemotherapy. Patients then received treatment for up to 2 years with NIVO plus IPI (without chemotherapy) until disease progression or unacceptable toxicity.
Dose-limiting toxicity (DLT) within the first 9 weeks, safety, and tolerability were the primary end points of this study. Treatment was deemed safe if ≤25% of at least 22 evaluable patients had a DLT, which included uncontrolled grade 3 non-skin treatment-related adverse events (TRAEs), grade 4 TRAEs, grade 2 treatment-related pneumonitis not resolved within 14 days, and treatment-related hepatic function abnormalities.
Thirty-six patients received treatment, with 97% completing 2 cycles of chemotherapy combined with NIVO plus IPI. Three patients stopped receiving IPI while continuing treatment with NIVO. After minimum follow-up of 26 months, only 1 (3%) patient experienced a DLT (transient, asymptomatic grade 3 AST and ALT elevation) within the first 9 weeks.
Grade 3/4 TRAEs occurred in 75% of patients; 25% of patients experienced a TRAE (including colitis, encephalopathy, pneumonitis, and arthralgia) that led to discontinuation. These TRAEs occurred outside of the 9-week window for DLT assessment.
The most common TRAEs (defined as adverse events of potential immunologic causes) were skin-related and occurred in 50% of patients (any grade). Endocrine (3 patients, 8%), skin-related, gastrointestinal, and pulmonary (each in 2 patients, 6%) were the most common grade 3/4 select TRAEs. No treatment-related deaths occurred.
Adding 2 cycles of platinum-doublet chemotherapy to NIVO plus IPI showed promising clinical activity, with a disease control rate of 89% and an overall response rate of 47%. Median progression-free survival was 10.8 months, and median overall survival was 19.4 months. Thirteen of 36 patients were alive after a minimum follow-up of 26 months.
These results suggest that, in patients with untreated advanced NSCLC, addition of 2 cycles of platinum-doublet chemotherapy to NIVO plus IPI is effective and tolerable with no unexpected safety signals.
Gainor JF, Schneider JG, Gutierrez M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) with two cycles of chemotherapy (chemo) in first-line metastatic non-small cell lung cancer (NSCLC): CheckMate 568 Part 2. J Clin Oncol. 2020;38:suppl (abstract 9560).
Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38:suppl (abstract LBA5).