Physician’s Weekly interviews principle investigator, Roy S. Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology) and Professor of Pharmacology; Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital; Associate Cancer Center Director for Translational Research, Yale Cancer Center
gkkAdjuvant osimertinib demonstrated a statistically significant and clinically meaningful reduction for the risk for central nervous system (CNS) recurrence among patients with resected stage IB–IIIA EGFR-mutated non-small-cell lung cancer (NSCLC), in the phase III ADAURA trial exploratory analysis presented at the ESMO Virtual Congress 2020 held 19-21 September, 2020, by Masahiro Tsuboi (National Cancer Center Hospital East, Japan) .
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, with demonstrated efficacy as a frontline agent for metastatic NSCLC with confirmed EGFR-mutation, which was published in the New England Journal of Medicine . The phase III ADAURA clinical trial attempted to assess whether this agent is also effective in earlier stages of metastatic disease characterized by EGFR mutation, namely as an adjuvant therapy after complete surgical resection of stage IB, II, or IIIA disease. The exploratory analysis of data from the ADAURA trial, presented at the ESMO Virtual Congress 2020, expanded on the primary analysis presented at ASCO 2020 which showed that adjuvant osimertinib reduced the risk for recurrence or death by 79% versus placebo.
Briefly, oral osimertinib (80 mg, once daily) was compared with placebo for a treatment duration of up to 3 years or until disease recurrence; median duration of exposure was 22.3 months (range 0-43). The primary endpoint was disease-free survival (DFS), and the key secondary endpoint was overall survival (OS). The study was unblinded early under the recommendation from an Independent Data Monitoring Committee due to efficacy. At the time of the unblinding, randomized patients (n=682) had been followed up for at least 1 year. For the primary endpoint in stage II-III patients, the DFS curves separated early on and showed an 83% reduced risk of disease recurrence for the osimertinib arm (HR 0.17; 95% CI 0.12-0.23; P<0.0001). Adding in the early-stage IB patients to the overall population did not change this trend (HR 0.21; 95% CI 0.16-0.28; P<0.0001), indicating that osimertinib benefits early-stage patients as well. Osimertinib was well tolerated. Osimertinib versus placebo DFS rates at 2 years were 89% vs 53%, respectively.
The presentation at ESMO specifically addressed whether CNS metastases, which are associated with significant morbidity, could be deterred by osimertinib. In the ADAURA cohort, the most common site for disease recurrence was the lung, occurring at rates of 6% and 18% in the osimertinib and placebo groups, respectively. The researchers reported that with a median follow-up of 22 months, the CNS recurrence rate was 1% among the patients who received osimertinib and 10% among those who received placebo. Osimertinib generated a 82% reduction in the risk for CNS recurrence, which Prof. Tsuboi commented, was “clinically meaningful” and “highly statistically significant”.
While the median CNS DFS was not reached for the patients in the osimertinib arm, it was 48.2 months in the placebo arm. The conditional probability of CNS recurrence at 18 months was less than 1% in the osimertinib arm as compared with 9% in the placebo arm. The main conclusion of this analysis was that osimertinib shows a significant benefit in preventing brain metastases in early stage NSCLC.
Physician’s Weekly asked ADAURA senior investigator Prof. Roy Herbst for some additional information:
Could you comment on the impact of this analysis?
“These are exciting results that could be life-changing for many patients. Waiting for the overall survival data from ADAURA will take a few more years, and until we know those data we will be dealing with recurrences. Most of those will be in the lung, but all oncologists and their patients dread a CNS metastasis,” says Dr. Herbst. “Osimertinib provides such a high magnitude of disease-free survival benefit in this arena, I think it will change practice. In the past, we haven’t had much success fighting recurrence in the liver, lung and brain of NSCLC in patients with EGFR mutations. These study results will hopefully be practice-changing and have a huge impact on patient care. Treating earlier will save some of these patients from brain metastases.”
Dr. Herbst says that these updated results from the ADAURA trial once again demonstrated a statistically significant and clinically meaningful improvement in disease-free survival in the adjuvant treatment of patients with early-stage EGFR mutations for NSCLC. “It’s so critical to provide patients with this type of lung cancer a new treatment option.”
What still needs to be done?
“Results in general from ADAURA have been some of the most impressive that we’ve ever seen in an adjuvant setting; these CNS recurrence results are truly exciting. We can’t wait to look at what happens in the liver and lung recurrences next. Also, the science end of the trial has a lot to tell us, while we continue to keep the trial and gather more data,” says Dr. Herbst. To expand this knowledge base, the LAURA trial will look at osimertinib after chemoradiation in the locally advanced unresectable stage IIIA-3B setting, explains Dr. Herbst, and the FLAURA2 trial will combine with chemotherapy in the metastatic setting. Furthermore, there will be the neo-ADAURA trial, which is going to look at osimertinib in patients before any therapy or surgery, providing solid data on response rates as opposed to progression, or disease-free-survival, because the tumor is initially intact.
“One can actually imagine a trial where you cut out the whole tumor to determine whether it might be resistant to a given agent, so you can know what to do next. You might even think about combining it with chemotherapy in some instances,” says Dr. Herbst. For the time being, we can be satisfied that the ADAURA trial results give another 30% of lung cancer patients, albeit only 10-15% of those in the US but 2-3 times that number in Asia, another sliver of a win. A good number of patients, in fact 5-10%, now have the ability to get a targeted agent to prevent reoccurrence.”
- Tsuboi M, et al. Abstract LBA1. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
- Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113‐125.