Adjuvant osimertinib extends DFS in EGFR-mutated NSCLC
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Adjuvant osimertinib significantly prolonged DFS for patients with EGFR-mutated non-small cell lung cancer, according to results of the randomized phase 3 ADAURA trial scheduled for presentation during the ASCO20 Virtual Scientific Program.
Osimertinib (Tagrisso, AstraZeneca) is the first targeted agent in a global trial to confer statistically significant and clinically meaningful DFS improvement for this patient population.
“These are extraordinary results,” Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, as well as associate cancer center director for translational research at Yale Cancer Center, said during a presentation. “Adjuvant osimertinib provides a highly effective, practice-changing treatment for [these patients].”
Approximately one-third of patients with NSCLC present with early-stage disease, defined as stage I through stage IIIA. Surgery is the primary treatment for these patients. Adjuvant chemotherapy is standard for those with stage II or stage III disease, as well as for select patients with stage IB disease.
Despite these treatments, 5-year recurrence rates range from 45% for patients with stage IB disease to 76% for those with stage III disease.
“Clearly, we need new therapies,” Herbst said.
Osimertinib — a third-generation, irreversible EGFR-directed tyrosine kinase inhibitor — is approved in the United States for first-line treatment of patients with metastatic NSCLC whose tumors harbor EGFR mutations. Prior studies showed superior efficacy with osimertinib compared with other EGFR TKIs for treatment-naive, EGFR-mutated advanced NSCLC.
The double-blind, multinational ADAURA trial evaluated the efficacy and safety of adjuvant osimertinib vs. placebo for patients with stage IB to stage IIIA EGFR-mutated NSCLC who underwent complete tumor resection and — if indicated — adjuvant chemotherapy.
The trial included 682 adults with primary nonsquamous disease. All patients had confirmed EGFR mutations and WHO performance status of 0 or 1, and all had undergone complete resection with full recovery.
Researchers randomly assigned 339 patients to osimertinib dosed at 80 mg once daily. The other 343 patients received placebo. Treatment continued for up to 3 years.
Treatment groups were balanced with regard to disease stage (stage IB, 31% each; stage II/IIIA, 69% each), sex (women, 68% for osimertinib vs. 72% for placebo), exon 19 deletion mutation (55% vs. 56%) and exon 21 L858R mutation (45% vs. 44%).
Investigators stratified their analysis by disease stage, mutation type and race (Asian vs. non-Asian).
Investigator-assessed DFS among patients with stage II or stage IIIA disease served as the primary endpoint. Secondary endpoints included DFS in the entire study population, OS and safety.
The independent data monitoring committee recommended the trial be unblinded early due to efficacy.
Herbst reported results of an unplanned interim analysis, which showed osimertinib significantly improved DFS among patients with stage II to stage IIIA disease (median, not reached vs. 20.4 months; HR = 0.17; 95% CI, 0.12-0.23).
“This was much better than expected, and it certainly is something that will help our patients,” Herbst said.
Osimertinib also conferred a statistically significant DFS benefit in the overall study population (median, not reached vs. 28.1 months; HR = 0.21; 95% CI, 0.16-0.28).
“Even when you add the patients with earlier-stage disease, you still have curves that [have clear separation],” Herbst said. “The reduction in risk for disease progression is a little bit less because you have many patients with earlier disease but, nonetheless, this is a very positive [result] that suggests the drug will be useful for these patients, as well.”
Osimertinib-treated patients were more likely than those assigned placebo to be disease free at 2 years (stage II to stage IIIA disease, 90% vs. 44%; overall population, 89% vs. 53%).
Researchers observed the DFS benefit with osimertinib in all evaluated subgroups, including those based on age, sex, smoking status, race, disease stage, type of EGFR mutation and adjuvant chemotherapy receipt.
OS data were immature, with the majority (95.7%; n = 653) of patients still alive at the time of data cutoff. Of the 29 patients who died, 20 had been assigned placebo.
Median duration of treatment exposure was 22.3 months (range, 0-43) in the osimertinib group and 18.4 months (range, 0-48) in the placebo group.
Osimertinib appeared generally well-tolerated, exhibiting a safety profile consistent with prior reports.
The most common adverse events that occurred more frequently in the osimertinib group included diarrhea (46% vs. 19%), paronychia (25% vs. 1%), dry skin (23% vs. 6%), pruritis (19% vs. 9%), cough (18% vs. 17%), stomatitis (17% vs. 4%), nasopharyngitis (15% vs. 10%), decreased appetite (13% vs. 4%) and upper respiratory infection (13% vs. 9%).
Grade 3 or grade 4 adverse events were rare in the osimertinib group. They included diarrhea (2%), stomatitis (2%), decreased appetite (1%), paronychia (1%) and upper respiratory infection (1%).
Ten patients (3%) assigned osimertinib developed interstitial lung disease, but all cases were low grade.
Herbst described the trial as “a home run” that yielded “an important advance” in the form of a targeted therapy that can significantly delay recurrence after surgery.
He closed his presentation by acknowledging his mentor, Isaiah Fidler, DVM, PhD, professor of cancer biology at The University of Texas MD Anderson Cancer Center, who died May 8.
“He taught me, and he taught all of us, that it is metastasis — the spread of tumor — that kills patients,” Herbst said. “Drugs such as this, based on biology [and] given to patients at the earliest possible time, can prevent those metastases and allow patients to live longer, with a better quality of life.” – by Mark Leiser
Reference:
Herbst RS, et al. Abstract LBA5. Scheduled for presentation at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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Charu Aggarwal, MD, MPH
This trial shows a significant improvement in DFS and offers an option to patients with surgically resected NSCLC that harbors an EGFR mutation. The benefit is seen across all stages, as well as among those with smoking history and those who received adjuvant therapy. While we await OS data, this trial will change the way we deliver adjuvant therapy for patients with EGFR mutations. We will have to come up with pathways to ensure that molecular testing is performed for all patients.
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John Heymach, MD, PhD
Almost 2 decades ago, EGFR inhibitors were shown to benefit patients with metastatic NSCLC bearing sensitizing EGFR mutations. At long last, we now know that patients with early-stage, resectable NSCLCC bearing EGFR mutations can derive substantial benefit from these drugs, as well.
The ADAURA study achieved its primary outcome, with a striking 83% reduction in the risk for recurrence (HR for DFS = 0.17; P = .0001). At 3 years, DFS rates were 80% in the osimertinib group and 28% in the placebo group. OS data are not yet mature, but a clear trend favoring osimertinib was observed. The regimen also was well-tolerated, with about 10% of patients experiencing grade 3 or higher adverse events.
The only FDA-approved adjuvant therapies for patients with resectable NSCLC are platinum-based chemotherapy regimens. They provide modest benefits — approximately a 5% to 10% improvement in DFS at 5 years — but come at the cost of significant toxicities.
Osimertinib provides a far greater clinical benefit with a manageable safety profile. Further, the use of adjuvant osimertinib will lead to greater use of genomic profiling of early-stage tumors, which undoubtedly will facilitate testing of other targeted adjuvant therapies, such as ALK inhibitors.
There remain important unanswered questions regarding the ADAURA study. The OS data are not yet mature, and it is possible that recurrence rates may increase in the osimertinib group once the drug is discontinued. Therefore, the large DFS benefits may not translate into similarly large OS benefits. It also is not known whether 3 years is the optimal duration of therapy. Nevertheless, the study is a landmark in that it marks the expansion of our use of targeted therapies from metastatic disease to the early-stage setting, so that our most effective drugs will be serving our important goal — increasing potential cures.
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Nicholas C. Rohs, MD
These are exciting results in a therapeutic space in lung cancer that has been lacking much impactful data. However, we need to take caution when considering how to apply these findings to our current practices. We have seen other studies in which a preliminary DFS benefit did not translate to longer OS. Even with the very impressive DFS (HR = 0.21) in the overall population, it is still unclear if there is a subset of patients that we are helping cure or only delaying their eventual relapse. Delay of disease relapse is not without value, but it also is not a small thing to ask a patient still recovering from a recent cancer diagnosis, chest wall surgery and — most likely — chemotherapy to take a daily pill that probably will cause some level of adverse events. Although osimertinib has significantly better tolerance than earlier-generation TKIs, we have to remember that does not mean no adverse events. There also are concerns about added financial toxicity. For now, I don’t think it would be unreasonable to consider applying these data in the right patient, but only with a fully informed discussion about the risks/benefits and uncertainty. These data will become much more informative as they mature. To see the OS impact, as well as the timing and nature of relapses, will be very interesting.
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Herbst RS, et al. Abstract LBA5. Scheduled for presentation at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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