Upfront osimertinib matches sequential treatment for prolonging survival in EGFR-mutant NSCLC

Patients with nonsmall cell lung cancer (NSCLC) harbouring EGFR mutation appear to experience similar survival outcomes with either frontline osimertinib therapy or sequential treatment approach of gefitinib followed by osimertinib, although upfront osimertinib leads to a significant reduction in the risk of brain progression, as shown in the results of the APPLE trial presented at ELCC 2023.

The median overall survival (OS) was not reached with upfront osimertinib as opposed to 42.8 months with sequential treatment (hazard ratio [HR], 1.01, 90 percent confidence interval [CI], 0.61–1.68). More than 80 percent of patients in both treatment arms remained alive at 18 months (84.4 percent and 82.3 percent, respectively), reported lead researcher Dr Jordi Remon from Gustave Roussy in Villejuif, France. [ELCC 2023, abstract 1O]

Meanwhile, the median progression-free survival (PFS) was 19.50 months with upfront osimertinib vs 21.39 months with sequential treatment (HR, 0.87, 90 percent CI, 0.60–1.26). The 18-month PFS rates in the respective treatment arms were 51 percent and 61 percent.

“In all arms, 68 brain progression events were observed,” Remon said, noting that more patients in the upfront osimertinib remained free of brain progression at 18 months (82.2 percent and 63.5 percent).

Median time to brain progression was 34.3 months (95 percent confidence interval [CI], 26.9–NR) with upfront osimertinib and 22.3 months (95 percent CI, 18.6–22.3) with sequential treatment. The corresponding hazard ratio was 0.54 (90 percent CI, 0.34–0.86).

“It’s true that when we started osimertinib, there was a significant reduction in the risk of brain progression. However, we obtained a very comparable OS between upfront osimertinib and sequential treatment approach,” Remon pointed out.

APPLE was a three-arm phase II noncomparative trial exploring the effect of sequential treatment approach of gefitinib followed by osimertinib as opposed to frontline osimertinib. A total of 156 patients were randomly assigned to one of the following treatment arms: arm A (osimertinib until RECIST progression; n=53), arm B (gefitinib until the emergence of circulating tumour DNA EGFR T790M mutation or RECIST progression; n=52), and arm C (gefitinib until RECIST progression; n=51). Following progression, patients in the arms B and C were then switch to osimertinib.

Of the patients, 136 were included in the per-protocol population, and data from arms B and C were pooled in the analysis. Most patients were women (arms A and B/C: 56.6 percent and 69.9 percent, respectively) and had EGFR Del19 (66 percent and 64 percent). Baseline brain metastases rates were 19 percent and 29.1 percent, respectively. Among patients in arms B/C, 70 percent received osimertinib at disease progression.

Liquid biopsy useful

Another important finding that Remon highlighted was that performing liquid biopsies in daily clinical practice is feasible for monitoring the status of T790M mutation in patients initially treated with gefitinib.

Earlier, Remon and colleagues presented their preliminary data, which showed that 17 percent of patients who were initially treated with gefitinib had a molecular progression before a RECIST progression. This led to an earlier switch to osimertinib, which yielded an 18-month PFS of 87 percent. [ESMO 2022, abstract LBA51]

The lack of clearance of the circulating tumour DNA on EGFR TKI may identify a subpopulation of patients with a poor prognosis who could obtain benefit from escalating treatment strategies, Remon said.