CHICAGO – Although 15 percent of early-stage EGFR-mutated non-small cell lung cancer patients had less residual tumor after neoadjuvant treatment with AstraZeneca's Tagrisso (osimertinib) in a Phase II trial, the benefit fell short of oncologists' expectations.
At the American Society of Clinical Oncology's annual meeting Friday, Jacqueline Aredo, an internal medicine resident at the University of California, San Francisco, presented data from the trial, which took place at UCSF, UC Davis Health, and the University of Colorado. Researchers enrolled patients with surgically resectable stage I to IIIA EGFR-mutated NSCLC. Patients received Tagrisso for up to two months before undergoing surgery to remove their tumors. The primary endpoint was major pathologic response, defined as 10 percent or less residual viable tumor following neoadjuvant treatment; researchers had powered the trial to detect a major pathologic response in half the Tagrisso-treated patients.
At the meeting, however, Aredo reported that only 4 out of 27 evaluable patients, or 15 percent, had a major pathologic response. None of the patients had a complete pathologic response, or total eradication of the residual viable tumor following neoadjuvant treatment. This Phase II study did not meet its primary endpoint, Aredo said, since it failed to show the expected 50 percent major pathologic response rate.
Currently, patients with early-stage EGFR-mutated NSCLC are given neoadjuvant chemotherapy, to which around 10 percent of patients have a major pathologic response, and among those who do, overall survival is improved by around 5 percent. Aredo and colleagues wanted to see in their study if neoadjuvant Tagrisso would boost the major pathologic response rate and bring overall survival improvements with it.
Although the trial failed to meet its primary endpoint, out of nine patients who had positive lymph nodes at the start of the study, four patients, or 44 percent, had lymph node downstaging after receiving Tagrisso. Additionally, 24 out of 27 evaluable patients, or 89 percent, went on to have surgery to remove their tumors after neoadjuvant treatment. Three patients received concurrent chemoradiotherapy, one of whom did so because of cancer progression.
Aredo pointed out that most patients received neoadjuvant treatment for a short time, around two months. "It is possible that with a longer duration of [neoadjuvant] treatment, we may have been able to induce more responses," she noted.
In reviewing this data, Misako Nagasaka, a lung cancer specialist at UC Irvine, agreed that these results won't change the standard of care "at least not yet," but it showed that neoadjuvant Tagrisso treatment was "feasible, safe, and possibly effective." Moreover, Nagasaka noted that studies like this are useful for improving understanding of the underlying tumor biology.
Aredo's team additionally conducted exploratory analyses to probe mechanisms of disease persistence that may explain the lower-than-expected major pathologic response rate. Targeted exome sequencing of patients' surgical resection samples identified a higher rate of RBM10 loss-of-function mutations in patients who didn't achieve a pathological response versus those who did. RBM10 is a tumor suppressor gene that promotes cell death, and tumor cells with mutations in RBM10 "are more likely to survive when exposed to an EGFR tyrosine kinase inhibitor," Aredo said.
Data from prior cell studies gave researchers reason to hypothesize that perhaps increased YAP expression was promoting cell survival and hindering EGFR-mutant NSCLC patients from responding to neoadjuvant treatment. In this study, IHC testing showed significantly increased YAP nuclear expression in cells of patients who had residual disease after surgery compared to cells from patients taken before they got Tagrisso.
"Now, we know that [Tagrisso] is effective in treating EGFR-mutated NSCLC," Aredo said. "Based on these analyses in our study, we suggest that RBM10 mutations as well as upregulation of the YAP pathway could be mechanisms of disease persistence." Aredo and colleagues are investigating other possible mechanisms of tumor persistence including the tumor microenvironment.
Although Aredo described this as a small pilot study, oncologists' interest in Tagrisso's potential as a neoadjuvant treatment has been piqued ever since they saw its activity in the adjuvant setting. Tagrisso created a buzz at this same meeting three years ago after researchers reported a 79 percent reduction in disease recurrence or death for patients who received the targeted drug after surgery, as compared to those in the placebo arm of the ADAURA trial. Based on this data, the US Food and Drug Administration approved the third-generation EGFR inhibitor at the end of 2020 as an adjuvant treatment option for early-stage EGFR-mutant NSCLC.
The lackluster results from the study conducted by Aredo and colleagues are not the end of the story for AstraZeneca's ambitions to move Tagrisso into even earlier treatment lines, however. Nagasaka highlighted several larger studies of neoadjuvant targeted treatment that are underway in this patient subset. One study that oncologists are eagerly awaiting a readout from next year is AstraZeneca's 300-plus patient NeoADAURA trial.
Even if some of these trials are successful in bringing a new EGFR inhibitor to market for EGFR-mutant NSCLC, patients have to be diagnosed with early-stage cancer first in order to receive them. Nagasaka noted that lung cancer screening is performed on people between 50 and 80 years old who currently smoke; have smoked a pack a day for 20 years or two packs a day for 10 years; or have quit smoking in the last 15 years. "However, most of the patients with genomic alterations, such as in EGFR, have never smoked or are light smokers," she said. "If they don't qualify for lung cancer screening, how do we find these patients in early stage?"
Nagasaka cited a recent meta-analysis of lung cancer screening studies, which showed that the relative risk of detecting the disease by low-dose CT scan was similar in Asian female never-smokers and male ever-smokers. The prospective National Lung Cancer Screening Program in Taiwan also showed the effectiveness of low-dose CT screening in a high-risk never-smoker population. Based on these data, Nagasaka proposed that as precision medicine options inch toward earlier and earlier treatment settings in lung cancer, it may be time to rethink screening. "We gotta find, in order to treat," she said.