NEW YORK – Results from the Phase III randomized ADAURA trial demonstrated a compelling disease-free survival benefit from the adjuvant use of osimertinib (AstraZeneca's Tagrisso) in patients with stage IB-IIIA non-small cell lung cancer after complete tumor resection, according to data announced as part of the American Society of Clinical Oncology's virtual annual meeting.
The ADAURA trial, for which the estimated primary completion date was February 2022, was unblinded early at the recommendation of an independent data monitoring committee that determined the EGFR-targeting tyrosine kinase inhibitor demonstrated "overwhelming efficacy" in lung cancer patients.
"If I was on that committee, I would have done the same thing," Roy Herbst, chief of medical oncology at the Yale Cancer Center and the ADAURA trial's lead researcher, said during a press conference to discuss the data earlier this week. "These are extraordinary results."
All patients with stage IB-IIIA non-small cell lung cancer treated with 80 mg of osimertinib once a day on the ADAURA trial experienced a 79 percent reduction in disease recurrence or death compared to a control arm of patients who received a placebo. After two years of the adjuvant treatment, disease-free survival rates with osimertinib versus placebo were 89 percent and 53 percent, respectively. The results were even more significant in the initial analysis restricted to patients with stage II and above, with osimertinib reducing the risk of disease recurrence by 83 percent.
The improvement in disease-free survival with osimertinib was seen across all subgroups of patients, regardless of sex, age, smoking status, race, stage of cancer, specific type of EGFR mutation (Ex19del or L858R), and whether the patient received adjuvant chemotherapy before treatment with osimertinib.
"This was much better than expected," Herbst said in an interview reflecting on the study results. "I would say it's a home run with disease-free survival." Herbst did acknowledge that overall survival results are not yet available and will take time to mature.
Evolution of TKIs in lung cancer
Osimertinib is a third-generation EGFR-targeting TKI that has already secured US Food and Drug Administration (FDA) approval as first-line treatment in the metastatic setting for patients with EGFR-positive NSCLC and as a second-line treatment for patients with EGFR T790M mutation-positive NSCLC who develop resistance to other available EGFR TKIs. In the first-line setting, osimertinib has already demonstrated progression-free survival and overall survival improvements over earlier-generation EGFR-targeting TKI inhibitors, such as gefitinib (AstraZeneca's Iressa) and erlotinib (Genentech and Astellas Oncology's Tarceva).
What makes the ADAURA trial potentially paradigm-shifting, Herbst said, is that it shows that osimertinib demonstrated a disease-free survival benefit as an adjuvant treatment for EGFR-mutated NSCLC, whereas earlier-generation drugs in this class, including gefitinib and erlotinib, have failed to show any benefit in disease-free survival in the setting of a randomized clinical trial. "There is no standard of care" for the adjuvant treatment of EGFR-mutated NSCLC, Herbst said. "Other drugs in this class, such as erlotinib and gefitinib, have been tried and then failed."
Indeed, a final analysis of the ADJUVANT CTONG1104 trial comparing gefitinib to chemotherapy in the adjuvant setting initially showed a disease-free survival benefit, but then, according to new data also presented during this year's ASCO virtual meeting, showed that the earlier-generation TKI inhibitor did not likewise improve overall survival. Herbst clarified that ADJUVANT CTONG1104 differed from ADAURA in that it compared gefitinib to chemotherapy whereas ADAURA pitted osimertinib against a placebo. But the failure of prolonged disease-free survival to translate into overall survival down the line is important to take into account when assessing a drug's benefit based on disease-free survival.
Ultimately, it will take an overall survival readout to definitively prove that osimertinib's benefit will be sustained years from now. The overall survival analysis is not yet mature.
Additionally, Herbst pointed out previous research demonstrating osimertinib's activity against central nervous system metastases. There are no definitive data on osimertinib's effect on the brain in the adjuvant context from the ADAURA trial at this time, though future results will shed light on the question of central nervous system activity.
Placebo comparator and addition of adjuvant chemo
With the number of EGFR-targeting TKIs on the market for the treatment of NSCLC, the choice to use a placebo as a comparator to evaluate osimertinib's efficacy, as opposed to any of the other targeted agents, may seem initially puzzling. However, the fact that none of these earlier agents have demonstrated survival benefits in the adjuvant setting made them unsuitable as standard-of-care comparators in the study. Placebo, Herbst said, was therefore an appropriate control for the ADAURA trial.
He noted that after surgical resection of their lung tumor, two thirds of patients get chemotherapy, but there isn't much else to offer. "The only therapy is that you come and see someone like me [an oncologist] every three months and get a scan and be nervous that the cancer will come back," Herbst said. "That's why placebo was used as a control."
Adjuvant chemotherapy, such as cisplatin, Herbst acknowledged, are sometimes, though not always, administered in the adjuvant setting for patients with NSCLC. But, even then disease recurrence rates remain high. Among patients with stage IB NSCLC treated with cisplatin, roughly 45 percent experience recurrence after five years, and in patients with stage II and III, these rates jump to 62 percent and 76 percent respectively. "Clearly, we need new therapies," he said.
Importantly, 378 out of 682 patients enrolled in the ADAURA trial did receive adjuvant chemotherapy following their surgical resections. Patients with and without this chemotherapy treatment were eligible for osimertinib. The disease-free survival benefit slightly favored the chemotherapy-treated group, but benefit was seen in the non-chemo group as well.
Toxicities and future considerations
Throughout the ADAURA trial, osimertinib was well-tolerated and demonstrated a safety profile that was consistent with prior studies of the agent. There were no adverse events leading to death among patients receiving osimertinib, and only seven percent of patients had to discontinue osimertinib. Grade three or higher adverse events were rare in the osimertinib arm, and the most common adverse events seen across all grades were diarrhea or various skin or nail reactions.
Of course, physical toxicities are not the only relevant considerations with new, often steeply-priced targeted agents such as osimertinib; there is ongoing concern among oncologists about using pricey drugs that have yet to show overall survival benefit. Down the line, financial toxicities will need to be taken into account as well as overall survival data from the ADAURA trial to allow for a more complete assessment of value and cost.
As a final note, Herbst gave a nod to the importance of these positive disease-free survival data with adjuvant osimertinib in light of the COVID-19 pandemic, a time in which many patients are afraid to come into hospitals and treatment centers due to potential exposure to the virus.
"[Osimertinib] is an oral agent, not a chemotherapy," he said, pointing out that patients treated with chemotherapy have been shown to be more vulnerable in the face of the respiratory virus. With osimertinib, he said, "maybe we won't even need to give chemotherapy someday… we'll just give the oral agent. That's a huge benefit for patients."