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Adjuvant osimertinib improves DFS in early-stage EGFR-positive NSCLC

Dr. Roy Herbst
Yale School of Medicine and Yale Cancer Center, New Haven
Connecticut, US
Dr. David Spigel
Sarah Cannon Research Institute, Nashville
Tennessee, US
09 Jul 2020
The third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) osimertinib is a standard of care in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC). Results of the ADAURA study, presented at the American Society of Clinical Oncology 2020 Virtual Scientific Programme (ASCO 2020), support earlier use of osimertinib in the adjuvant setting, with superior disease-free survival (DFS) in patients who underwent complete resection of stage IB/II/IIIA EGFR-positive NSCLC. 

“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, 3435 percent and 3435 percent, respectively). A total of 5556 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)

406mo03

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)

406mo04

“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)

406mo05

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 EGFRT790M 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.”

 


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Most Read Articles
Prof Winnie Yeo, 2 days ago
Despite the availability of antiemetics, a substantial proportion of patients receiving chemotherapy experience chemotherapy-induced nausea and vomiting (CINV), significantly impacting treatment compliance and quality of life (QoL). At the 24th Annual Scientific Symposium of the Hong Kong Cancer Institute, Professor Winnie Yeo of the Department of Clinical Oncology, Chinese University of Hong Kong, presented results of a local study showing superior efficacy of the fixed-dose netupitant/palonosetron (NEPA) combination regimen vs aprepitant-based regimen in controlling CINV in breast cancer patients receiving highly emetogenic anthracycline-cyclophosphamide (AC) chemotherapy.
Christina Lau, 14 Jul 2020

Flat-dose nivolumab, administered as a 30-minute infusion, is well tolerated and active in Asian patients with previously treated advanced non-small-cell lung cancer (NSCLC), according to results of the phase IIIb CheckMate 870 study.

Natalia Reoutova, 17 Jul 2020

At a median follow-up of 22.9 months, atezolizumab plus carboplatin and etoposide (CP/ET), given as a first-line treatment, continued to demonstrate an improvement in overall survival (OS) vs placebo plus CP/ET in patients with extensive-stage small-cell lung cancer (ES-SCLC), according to updated results of the IMpower133 trial presented at the American Association for cancer Research (AACR) 2020 Virtual Annual Meeting II.

Dr. Herman Sung-Yu Liu, 2 days ago
Although first- and second-generation tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL), resistance or intolerance to these agents has limited their effectiveness, particularly in patients who harbour the BCR-ABLT315I mutation. In an interview with MIMS Oncology, Dr Herman Sung-Yu Liu, Specialist in Haematology & Haematological Oncology in private practice in Hong Kong, discussed the management of CML and Ph+ ALL using the third-generation TKI, ponatinib, the only agent in its class with activity against the T315I mutation.