“Around 30 percent of patients with NSCLC present with resectable disease at diagnosis,” said ADAURA’s investigator, Dr Roy Herbst of the Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, US. [Chest 2003;123:2096-2103; Ann Oncol 2010;21(Suppl 7):vii196-vii198; Arch Pathol Lab Med 2013;137:1191-1198] “Recurrence or death following surgery and adjuvant chemotherapy remains high across disease stages in early-stage NSCLC, suggesting a need to improve treatment outcomes in these patients.” [J Clin Oncol 2008;26:3552-3559]

“The promising efficacy and safety profile of osimertinib in advanced EGFR-positive NSCLC suggests that it may also be effective in early-stage EGFR-positive NSCLC,” he continued. [N Engl J Med 2018;378:113-125]

ADAURA: Osimertinib for postresection NSCLC

The randomized, phase III, double-blind ADAURA study evaluated osimertinib (80 mg QD) vs placebo, given for a planned duration of 3 years, in 682 patients with completely resected stage IB/II/IIIA NSCLC with confirmed EGFR mutations (ie, exon 19 deletion or L858R mutation). The primary endpoint was DFS by investigator assessment in stage II/IIIA patients, with a hazard ratio (HR) of 0.70 indicating superiority. Secondary endpoints included DFS in the overall population, DFS rates at 2, 3, 4 and 5 years, overall survival (OS), and safety. [Herbst R, et al, ASCO 2020, abstract LBA5]

The proportions of patients with stage IB, II or IIIA disease were well balanced (31 percent, 34–35 percent and 34–35 percent, respectively). A total of 55–56 percent of patients had received adjuvant chemotherapy before study enrolment; 64 percent of the patients were Asian.

Superior efficacy leading to early unblinding

“The study was unblinded early due to superior efficacy observed with osimertinib,” noted Herbst. “Enrolment had been completed at the time of unblinding. All patients were followed up for at least 1 year.”

Investigator-assessed DFS in patients with stage II/IIIA disease was longer with osimertinib vs placebo, with a high statistical significance (median, not reached [NR] vs 20.4 months; HR, 0.17; 95 percent confidence interval [CI], 0.12 to 0.23; p<0.0001). “An early separation of DFS curves was noted. DFS rates were 97 percent with osimertinib vs 61 percent with placebo at 1 year, 90 percent vs 44 percent at 2 years, and 80 percent vs 28 percent at 3 years,” reported Herbst. (Figure 1)

Likewise, DFS in the overall population (ie, patients with stage IB/II/IIIA disease) was significantly longer with osimertinib vs placebo (median, NR vs 28.1 months; HR, 0.21; 95 percent CI, 0.16 to 0.28; p<0.0001).

“The DFS benefits were observed in all analyzed subgroups, including disease stage, EGFR mutations, and patients who had or had not received adjuvant chemotherapy,” Herbst pointed out. (Figure 2)

“In the osimertinib arm, 2-year DFS rates were consistent across stages IB, II and IIIA disease,” Herbst noted. At 2 years, DFS rates were 87 percent vs 73 percent (HR, 0.50; 95 percent CI, 0.25 to 0.96) in patients with stage IB disease, 91 percent vs 56 percent (HR, 0.17; 95 percent CI, 0.08 to 0.31) in those with stage II disease, and 88 percent vs 32 percent (HR, 0.12; 95 percent CI, 0.07 to 0.20) in those with stage IIIA disease. The DFS curves also separated early when patients with stage II or stage IIIA disease were analyzed separately. (Figure 3)

An early snapshot of OS in patients with stage II/IIIA disease showed a favourable trend for osimertinib (2-year OS rate, 100 percent vs 93 percent for placebo; median OS, not reached vs not reached; HR, 0.40; 95 percent CI, 0.18 to 0.90).

Osimertinib was well tolerated, with a safety profile consistent with that established in previous studies such as FLAURA and AURA3. [N Engl J Med 2018;378:113-125; N Engl J Med 2017;376:629-640] The most common adverse events (AEs) in the osimertinib arm included diarrhoea (46 percent), paronychia (25 percent) and dry skin (23 percent). Grade ≥3 AEs occurred in 20 percent of patients receiving osimertinib vs 14 percent of patients receiving placebo. Three percent of patients in the osimertinib arm had grade 1/2 interstitial lung disease. QTc prolongation was reported in 7 percent of patients in the osimertinib arm vs 1 percent in the placebo arm.

Conclusion

“Osimertinib is the first EGFR-TKI in a global trial to show a significant and clinically meaningful DFS improvement in the adjuvant setting in patients with stage IB/II/IIIA EGFR-positive NSCLC after complete tumour resection,” concluded Herbst. “Osimertinib will provide a highly effective, practice-changing adjuvant treatment for these patients.”

Targeting EGFR mutations in early-stage NSCLC

“Osimertinib was approved by US FDA for treatment of EGFR^T790M mutation-positive NSCLC after EGFR-TKI failure in 2017, and for first-line treatment of EGFR-positive advanced NSCLC in 2018, after showing positive results vs standard of care in the AURA3 and FLAURA studies, respectively,” noted discussant Dr David Spigel of Sarah Cannon Research Institute, Nashville, Tennessee, US. [N Engl J Med 2017;376:629-640; https://www.fda.gov/drugs/resources-information-approved-drugs/osimertinib-tagrisso; N Engl J Med 2018;378:113-125; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-first-line-treatment-metastatic-nsclc-most-common-egfr-mutations] “ADAURA is a well-designed study that demonstrated substantial DFS benefits of osimertinib across subsets of patients after complete resection of early-stage EGFR-positive NSCLC.”

“In ADAURA, DFS with osimertinib vs placebo was impressive in patients with stage II/IIIA disease, with a HR of 0.17. The HR remained high at 0.21 when patients with stage IB disease were included in the secondary analysis,” he continued. “The study also showed a consistent benefit with osimertinib regardless of disease stage. Notably, the impact appeared to be greater in stage IIIA vs stage IB disease, but the DFS HR was impressive at 0.50 even in those with stage IB disease.”

“Osimertinib was well tolerated in ADAURA, with very few severe AEs. However, low-grade diarrhoea and low-grade paronychia/dry skin occurred in about half and about a quarter of the patients, respectively. These have to be taken into consideration when prescribing a 3-year-long therapy,” Spigel pointed out.

Remaining question and way forward

“A previous phase III study evaluating adjuvant use of the EGFR-TKI erlotinib, given for 2 years, in patients with completely resected stage II/IIIA EGFR-positive NSCLC showed a DFS advantage favouring erlotinib vs chemotherapy [HR, 0.60; 95 percent CI, 0.42 to 0.87; p=0.0054]. However, the benefits were not sustained after 2 years of erlotinib treatment, raising the question of whether adjuvant EGFR-targeted therapy cures or simply defers disease that cannot be eradicated,” Spigel highlighted. [Lancet Oncol 2018;19:139-148] “Due to early unblinding of the ADAURA study, this question remains unanswered.”

“Given the impressive and substantial DFS improvements with adjuvant osimertinib in ADAURA, it should be considered as the new standard of care after complete resection of early-stage EGFR-positive NSCLC,” Spigel concluded. “All NSCLC patients, regardless of disease stage, should now be tested for EGFR sensitizing mutations.”