Osimertinib Achieves Extended Disease-Free Survival in EGFR-Mutant NSCLC

In patients with early-stage EGFR mutated non–small cell lung cancer (NSCLC) following complete tumor resection, treatment with osimertinib (Tagrisso) reduced the risk for central nervous system (CNS) death or progression by 82%, findings presented during the European Society of Medical Oncology (EMSO) Virtual Congress 2020 show.

Masahiro Tsuboi, MD, PhD, a principal investigator for the trial, said that, based on these data, adjuvant osimertinib would be an effective and practice-changing treatment in this setting.

Tsuboi, director of the Department of Thoracic Surgery and Oncology for Japan’s National Cancer Center Hospital East, added that treatment with osimertinib was associated with fewer locoregional and distant relapses, a lower incidence of metastatic disease among those who did have relapse, and fewer CNS recurrence events.

“It’s time to change the notion that treatment for early-stage EGFR-mutated lung cancer ends after surgery, since recurrence rates are still very high even after adjuvant chemotherapy,” Tsuboi said in a news release. “These new data showing low rates of recurrence, particularly in the brain, combined with the remarkable disease-free survival benefit, clearly demonstrate that Tagrisso provides patients with more time living cancer-free.”

In results from the ADAURA trial (NCT02511106) simultaneously published in the New England Journal of Medicine, adjuvant osimertinib demonstrated a clinically meaningful improvement in CNS disease-free survival (DFS) compared with placebo (HR, 0.18; 95% CI, 0.10-0.33; P <.0001)^.1,2

The median CNS DFS was not reached in the experimental arm compared with 48.2 months in the placebo arm.

In total, 45 patients had CNS DFS events, 6 (2%) in the osimertinib arm and 39 (11%) with placebo. Of those who had recurrence, 4 (1%) of the osimertinib arm experienced CNS recurrence versus 33 (10%) in the placebo arm.

Investigators concluded that the estimated probability of observing CNS recurrence at 18 months was less than 1% with osimertinib (95% CI, 0.2-2.5) versus 9% (95% CI, 5.9-12.5) with placebo.

Eleven percent of patients in the experimental arm had a DFS event compared with 46% in the placebo arm. Overall, 38% of patients assigned to osimertinib had metastatic recurrence compared with 61% in the placebo arm.

In the international, randomized, placebo-controlled, double-blind, phase III ADAURA trial, 682 patients with primary nonsquamous stage IB to IIIA NSCLC harboring EGFR mutations, with exon 19 deletions or L858R mutations, were assigned to 80 mg once-daily osimertinib (n = 339) or placebo (n = 343). Patients received treatment for 3 years, or until disease recurrence or discontinuation criteria were met.

The primary end point was investigator-assessed DFS in patients with stage II to IIIA disease. Secondary end points comprised DFS in the overall population; DFS at 2, 3, 4, and 5 years; overall survival (OS), safety, and quality of life.

Inclusion criteria comprised patients who had and had not previously received adjuvant chemotherapy. Patients also must have been at least 18 years old, had a World Health Organization performance status of 0 or 1, brain imaging if it was not completed in the preoperative setting, had undergone complete resection with negative margins, and had a maximum interval between surgery and randomization of either 10 weeks without adjuvant chemotherapy or 26 weeks if patients did undergo adjuvant chemotherapy.

About 10% to 15% of patients with NSCLC in the United States and Europe and 30% to 40% of patients in Asia have EGFR mutated NSCLC. These patients are particularly sensitive to treatment with EGFR-tyrosine kinase inhibitors (TKIs). Osimertinib is a third-generation, irreversible EGFR-TKI with clinical activity against CNS metastases.

In July, the FDA granted a breakthrough therapy designation to osimertinib for the adjuvant treatment of patients with stage IB, II, and IIIA EGFR-mutated NSCLC following complete resection with curative intent. Data from ADAURA presented at the 2020 ASCO Virtual Scientific Meeting demonstrated that adjuvant osimertinib induced statistically significant and clinically meaningful improvement in DFS for this population. Osimertinib reduced the risk for disease recurrence or death by 79% in (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).³

Osimertinib was associated with superior DFS rates at 1 (97% vs 69%), 2 (89% vs 53%), and 3 years (79% vs 41%). In April 2020, an Independent Data Monitoring Committee recommended that the trial be 2 years early based on the efficacy findings.

Osimertinib is approved by the FDA for the first-line treatment of patients with locally advanced or metastatic EGFR-mutant NSCLC and the treatment of locally advanced or metastatic EGFR T790M mutation–positive NSCLC.

_References

_{1. Tsuboi M. Osimertinib adjuvant therapy in patients (pts) with resected EGFR mutated (EGFRm) NSCLC (ADAURA): Central nervous system (CNS) disease recurrence. Presented at: the 2020 ESMO Virtual Congress; September 19-21, 2020. Abstract #LBA1.}

_{2. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Engl J Med. Published online September 2020. doi:10.1056/NEJMoa2027071}

_{3. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl; abstr LBA5). doi: 10.1200/JCO.2020.38.18_suppl.LBA5}