NEW YORK – In the three years since adjuvant treatment with AstraZeneca's Tagrisso (osimertinib) first demonstrated improved disease-free survival versus placebo in EGFR-mutated non-small cell lung cancer, an unanswered question has plagued oncologists, regulators, payors, and patients alike: Would the third-generation EGFR tyrosine kinase inhibitor ultimately enable patients to live longer?
Based on data presented Sunday at the American Society of Clinical Oncology (ASCO) annual meeting, the answer is yes.
"It is hard for me to convey how important this finding is for the field of lung cancer, and how long it's taken to get here," Nathan Pennell, the codirector of the Cleveland Clinic's lung cancer program, said during a press briefing. "The unequivocal, highly clinically significant improvement in overall survival at five years now firmly put to rest the question about whether we should be using our most effective treatment in these people based upon biomarkers, and we should firmly close the door on one-size-fits-all treatment for people with non-small cell lung cancer."
Roy Herbst, chief of medical oncology at Yale Cancer Center and lead investigator of ADAURA, presented the much-anticipated overall survival data during a packed plenary session at the meeting; the data were simultaneously published in the New England Journal of Medicine. Among 682 patients with stage IB to IIIA EGFR-mutated NSCLC in the Phase III trial, there was a 51 percent lower risk of death for those on three years of Tagrisso after surgical resection compared to those on a placebo. After five years, 88 percent of patients who had received adjuvant Tagrisso were still alive versus 78 percent in the comparator arm; the median overall survival was not yet reached in either treatment arm.
"It's the first global Phase III study to demonstrate statistically significant and clinically meaningful disease-free survival and overall survival benefit with targeted therapy in this patient population, reinforcing osimertinib as a standard of care in this group," Herbst said during the press briefing. He added, however, that the treatment implications are entirely contingent on the availability of EGFR testing as early in the treatment course as possible, ideally at the point of diagnosis. "We have to screen patients or we can't use this therapy," he said. "We have to give our best treatments early, and that will prevent deaths from metastases to the central nervous system, liver, and bones."
The need to broaden lung cancer screening guidelines, which are presently based on smoking history, came up during a presentation of another study of neoadjuvant Tagrisso treatment. That small Phase II trial didn't meet its primary endpoint by failing to show a 50 percent major pathologic response rate among Tagrisso-treated patients with early-stage surgically resectable stage I to IIIA EGFR-mutated NSCLC. Misako Nagasaka, a lung cancer specialist at University of California, Irvine, pointed out in reviewing that data that EGFR mutations tend to show up in never and light smokers and are more prevalent in Asians, and cited studies suggesting it may be useful to broaden screening guidelines to include patients more likely to harbor such biomarkers.
As precision medicine options inch toward earlier and earlier treatment settings in lung cancer, it may be time to rethink screening, Nagasaka said, adding: "We've got to find, in order to treat."
In ADAURA, the overall survival benefit was seen across patient subgroups: in patients with stage IB, II, and IIIA NSCLC patients, and in in all patients regardless of whether they were among the 60 percent who received adjuvant chemotherapy in addition to Tagrisso. Among those with stage II and IIIA disease, the five-year overall survival rates were 85 and 73 percent, respectively.
Although global regulators in nearly 100 countries, including the US, China, and Japan, have already approved adjuvant Tagrisso based on the previously reported disease-free survival data, not all oncologists have felt ready to adopt the EGFR inhibitor into standard practice in the absence of overall survival data.
"Some physicians and many of my surgeon colleagues did not recommend this because they were waiting to see does this improve overall survival?" Herbst said in his briefing. Benjamin Solomon, an oncologist at the Peter MacCallum Cancer Center in Australia, echoed this sentiment during a discussion of the ADAURA data at the plenary session. "These unprecedented overall survival results for early-stage non-small cell lung cancer [patients] are practice-changing, or practice-affirming for those who have already changed practice," Solomon said. "They dispel the notion of equivalence between early treatment with osimertinib and treatment on recurrence [and] mandate EGFR testing in patients with early-stage non-small cell lung cancer."
Payors, too, had been wary when it came to reimbursing the drug without overall survival data. The drug has a high list price at around $17,000 for a 30-day supply of 40 mg Tagrisso tablets, according to publicly available information from AstraZeneca.
"This [regulatory approval] was not always accompanied by reimbursement for osimertinib in this indication," Solomon said, adding that this has been the case in Australia, though he hopes the newly reported data will change this.
While Tagrisso was generally well tolerated in ADAURA and patients had few severe side effects, the drug did cause various low-grade side effects such as fatigue, mild rashes, diarrhea, and dry mouth, which can burden patients taking it for three years. "It's important that clinicians not underestimate the impact of continued grade 1 and 2 toxicities on patients," Solomon said.
While the initial overall survival readout from ADAURA is welcome news for lung cancer patients, oncologists are looking forward to longer term data confirming a durable overall survival benefit. In the future, researchers will report data on minimal residual disease from tissue-based and circulating tumor DNA testing.
As investigators conduct additional analyses and continue to follow patients, Solomon underscored how imperative it will be to ensure patients can access and afford not only Tagrisso but also the EGFR biomarker testing necessary to determine if they qualify for treatment.
"There is a need for global advocacy for access and reimbursement for both testing and treatment to avoid worsening disparities and inequities in global access to effective, and indeed lifesaving, treatments such as this one," he said.
Julie Gralow, ASCO's chief medical officer, also emphasized this access consideration during the press briefing on Saturday, noting that one of the key goals looking ahead should be making EGFR testing and Tagrisso available in low- and middle-income countries. "That is something that we're going to have to work on because at the present time, it's only going to be accessible in the highest-income countries," she said. "We have equity issues."
AstraZeneca, meanwhile, is moving ahead with testing Tagrisso in additional treatment settings, including as pre-surgery treatment for early-stage EGFR-mutated NSCLC in its ongoing NeoADAURA trial.