The introduction of tyrosine kinase inhibitor therapy earlier in the treatment timeline for patients with EGFR-mutant non–small cell lung cancer holds the promise of improving overall survival for this patient population.
Frances A. Shepherd, MD
The introduction of tyrosine kinase inhibitor (TKI) therapy earlier in the treatment timeline for patients with EGFR-mutant non–small cell lung cancer (NSCLC) holds the promise of improving overall survival (OS) for this patient population, according to Frances A. Shepherd, MD.
EGFR TKIs have delivered improvements in progression-free survival (PFS) over chemotherapy as first-line therapy for patients with the mutation in clinical trials in advanced and metastatic disease settings but investigators have been looking for ways to boost OS results, Shepherd said during a presentation at the virtual 21st Annual International Lung Cancer Congress®.1
Now, the recently reported findings from the phase 3 ADAURA trial (NCT02511106) demonstrate a role for osimertinib (Tagrisso), a third-generation EGFR TKI, as adjuvant therapy in patients with early-stage disease, Shepherd noted.2
“We’ve gone from nihilism to hope in the last 15 years,” said Shepherd, a 2016 Giants of Cancer Care® award winner who is the Scott Taylor Chair in Lung Cancer Research at Princess Margaret Cancer Centre in Toronto, Canada. “[I’m hoping] that finally we will be able to introduce EGFR TKI therapy at a time when we can change the cure rate and not just the PFS.”
Shepherd, who also is a professor at the University of Toronto, said EGFR TKIs are “never curative in advanced EGFR-mutant NSCLC.” She said several studies that tested the first-generation EGFR TKIs erlotinib (Tarceva) or gefitinib (Iressa) in the adjuvant setting demonstrated an HR benefit for disease-free survival (DFS) versus placebo or chemotherapy but not an OS benefit.
At the same time, she noted, adjuvant chemotherapy for patients with EGFR-mutant NSCLC resulted in improvements in DFS (HR, 0.58) and OS (HR, 0.44) in the JBR.10 trial (NCT00002583).1 In that study, patients with completely resected stage II or stage IIIA NSCLC were randomized to receive cisplatin plus vinorelbine or observation.3
“Do not forget there is an enormous survival benefit from chemotherapy because these patients respond so well,” Shepherd said.
In ADAURA, investigators randomized 682 patients to receive either osimertinib at 80 mg once daily or placebo, with treatment continuing for 3 years until disease recurrence, completion, or discontinuation criteria are met. The study population consisted of patients with completely resected stage IB, II, or IIIA NSCLC with or without adjuvant chemotherapy after surgery.
In patients with stage II to IIIA disease, osimertinib therapy reduced the risk of disease recurrence or death by 83% (HR, 0.17; 95% CI, 0.12-0.23; P <.0001). The median DFS in months was not reached with osimertinib (95% CI, 38.8-not calculable[NC]) compared win 20.4 months (95% CI, 16.6-24.5). In the overall trial population, a key secondary end point, osimertinib demonstrated a reduction in the risk of disease recurrence or death of 79% (HR, 0.21; 95%, CI 0.16-0.28; P <.0001). The median DFS was not reached with osimertinib (95% CI, NC-NC). versus 28.1 months with placebo (95% CI, 0.16-0.28).2
The 2-year DFS rates with osimertinib were 87% for patients with stage IB disease, 91% for stage II, and 88% for stage IIIA compared with 73%, 56%, and 32%, respectively, for placebo.
The ADAURA study was unblinded early upon recommendation of an independent monitoring committee. At the time of the unblinding, the study had completed enrollment and all patients had been followed up for at least 1 year. Shepherd said the panel looked at “these enormous differences in disease-free survival. “We never saw anything like this with chemotherapy,” she said.
Shepherd said there was no subset that did not derive benefit from adjuvant osimertinib. OS findings were immature at data cut off (3% maturity for osimertinib, 7% for placebo). Median OS was not reached with either osimertinib or placebo, but the trend showed a benefit with osimertinib (HR, 0.40; 95% CI, 0.18-0.90).2 “They gave us an early snapshot of overall survival,” Shepherd said, adding that “it is too early to tell” but the osimertinib curve appears to be on top.
Osimertinib is very well tolerated, Shepherd said. “There were very few grade 3 or 4 toxicities. The pneumonitis that we fear from early reports from Asia was minimal and the same in both arms, and the QTC prolongation was seen in 22 patients and 4 in the placebo group. Those important toxicities were present but not at an unexpected level or a level that would cause us to worry in the curative situation.”
The ADAURA study is continuing to assess OS as a secondary endpoint. Moving forward, Shepherd said, investigators would need to evaluate more data including patterns of recurrence, particularly for central nervous system relapse. “We know that osimertinib has great CNS penetration,” Shepherd said.
Osimertinib initially was approved by the FDA in November 2015 for treating patients with metastatic NSCLC whose tumors harbor the EGFR T790M resistance mutation and who have progressed on or after EGFR TKI therapy. The drug was approved in the first-line setting for patients with metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations after demonstrating significantly improved PFS and overall response rates over gefitinib or erlotinib therapy in the FLAURA trial (NCT02296125).4