NEW YORK – Treating EGFR-mutant non-small cell lung cancer patients with AstraZeneca's Tagrisso (osimertinib) first may not make a difference in overall survival versus treating them with AstraZeneca's Iressa (gefitinib) first, then switching to Tagrisso, according to an exploratory analysis from the Phase II APPLE trial presented during the European Lung Cancer Congress Wednesday.
Although the overall survival outcomes were not significantly different according to the treatment sequencing, the analysis suggested upfront Tagrisso could reduce the risk of disease progression in the brain.
Jordi Remon Masip, an oncologist at Paris-Saclay University and the Gustave Roussy Institute in France, presented the results from the APPLE trial, in which investigators randomized patients to one of three treatment arms. Patients were eligible for enrollment in APPLE if they had confirmed EGFR-mutant stage IV NSCLC and had not received prior EGFR-directed therapy, though prior adjuvant or neoadjuvant chemo or radiation was allowed.
The trial's three randomized arms involved separate approaches to sequencing patients' targeted treatments. In arm A, patients received the third-generation EGFR TKI Tagrisso upfront. In arm B, patients received the first-generation EGFR-TKI Iressa first, then switched to Tagrisso if and when a liquid biopsy revealed EGFR T790M resistance mutations in circulating tumor DNA or radiological progression. Finally in arm C, patients received Iressa first, then switched to Tagrisso if and when their cancers showed, in this case, radiologic progression.
In the US, Tagrisso and Iressa both have US Food and Drug Administration approval as first-line treatment for metastatic NSCLC patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Tagrisso also has approval as later-line treatment for EGFR T790M mutation-positive NSCLC patients whose lung cancers progressed after treatment with an earlier EGFR TKI.
Back in September, during the European Society for Medical Oncology Congress, Remon Masip shared data from arms B and C as somewhat of a proof-of-concept analysis to show that serial, blood-based monitoring with liquid biopsy was a feasible way to monitor patients and decide if and when to switch them from an earlier generation EGFR TKI — in this case Iressa — to Tagrisso. "The APPLE trial is the first prospective trial that reported that it's completely feasible to perform liquid biopsy in the daily clinical practice for monitoring the status of EGFR T790M mutations in patients initially treated with gefitinib," Remon Masip said Wednesday, pointing out that this was a significant finding, given as 70 percent of the patients initially treated with Iressa might have a molecular progression detectable with circulating tumor DNA analysis before they have a standard radiological disease progression.
Now, with data from all three trial arms available, Remon Masip sought to compare the sequential approaches.
For the analysis presented Wednesday, Remon Masip pooled arms B and C into one group representing patients who received Iressa as frontline treatment. The analysis included 136 patients in total.
After 18 months of treatment on the study, 84.4 percent of patients in arm A — that is, those who received frontline Tagrisso — were alive, versus 82.3 percent of patients alive in arms B and C. The median overall survival time for patients in arm A was not yet reached at the time of the study cutoff, versus 42.8 months among patients in arms B and C.
"It's really important that more than 80 percent of patients were still alive regardless of the treatment strategy," Remon Masip said. "In the exploratory subgroup analysis for the overall survival, we could not define any patient characteristics that might suggest that one strategy is better over the other, even when we look at this overall survival according to specific EGFR mutation subtype and also the brain metastases status at baseline."
In terms of progression-free survival, 51.1 percent of patients in arm A were alive without any disease progression after 18 months, versus 61 percent of patients in the combined B and C arms. Importantly, Remon Masip and colleagues looked into the 68 patients from all arms of the study whose cancers had recurred with brain metastases. At 18 months on treatment, they found that 82.2 percent of patients who'd received Tagrisso upfront were alive without any brain progression, which was only true of 63.5 percent of patients on the Iressa-first treatment regimens. The median time to brain progression was 54 months for patients initially randomized to upfront Tagrisso versus 22.3 months for patients who received the sequential treatment approach. This, Remon Masip emphasized, corresponded with a 46 percent reduction in the risk of brain progression for the patients who received upfront Tagrisso.
Cost concerns, future considerations
The safety profile was more or less consistent across the different treatment sequences, Remon Masip noted in his presentation. Between the comparable overall survival outcomes and similar safety profiles, he acknowledged that the results don't fully address the question as to which approach was a better bet — the upfront Tagrisso treatment or the Iressa first, then Tagrisso at progression — for these patients. While there were fewer instances of brain metastases with Tagrisso first, the overall survival netted out to be about the same. Given this finding, Remon Masip suggested that investigators design future clinical trials with the goal of assessing stratification methods. For example, if initial treatment with Iressa does not successfully clear all of a patient's circulating tumor DNA, the patient might fall into a subpopulation that would benefit from treatment escalation. He urged investigators to validate this in future clinical trials.
During a discussion following Remon Masip's Wednesday presentation, Daniel Tan, a medical oncologist at the National Cancer Centre Singapore, brought up another important consideration: the cost difference between the two EGFR TKIs.
"Cost has to be a consideration in our practice," Tan said. The list price for a 30-day supply of 40 mg Tagrisso tablets is around $17,000, according to publicly available information, which is more than double the list price of around $8,211 for a month's supply of 250 mg Iressa tablets.
"There's an expanding molecular and therapeutic toolbox that can potentially individualize these frontline options," Tan said. "I think there needs to be continuous reassessment of risk-benefit ratios, and these need to be tailored to individual patients, but also within the constraints of each healthcare system."
As Remon Masip pointed out, there wasn't an actual cost-benefit analysis built into the APPLE trial design, but "it's something that we should obviously discuss based on how much money we can spare by starting with the sequential treatment approach in some populations."
He added as well that it might be worth asking "if the cost of the drugs should decrease or not based on the benefit in overall survival."