Osimertinib plus chemo bumps up PFS in advanced EGFR-mutated NSCLC

In the first-line treatment of patients with advanced nonsmall cell lung cancer (NSCLC) harbouring EGFR mutation, the combination of osimertinib plus pemetrexed and platinum-based chemotherapy outperformed osimertinib alone in terms of extending progression-free survival (PFS), according to the interim results of the phase III FLAURA2 trial presented at WCLC 2023.

Median PFS increased by about 8.8 months per investigator (25.5 vs 16.7 months) and by about 9.5 months per blinded independent central review (BICR; 29.4 vs 19.9 months). Osimertinib plus pemetrexed and platinum-based chemotherapy lowered the risk of progression or death by 38 percent compared with osimertinib alone (investigator-assessed: hazard ratio [HR], 0.62, 95 percent confidence interval [CI], 0.49–0.79; p<0.0001; 51 percent maturity; BICR-assessed: HR, 0.62, 95 percent CI, 0.48–0.80; p<0.0002; 43 percent maturity). [Janne P A, et al, WCLC 2023]

PFS rates in the combination vs the monotherapy arm at the 1- and 2-year mark were 80 percent vs 66 percent and 57 percent vs 41 percent per investigator, respectively, and 80 percent vs 67 percent and 62 percent vs 47 percent per BICR, respectively.

Of note, the PFS benefit with osimertinib plus pemetrexed and platinum-based chemotherapy was consistent across all predefined subgroups. For example, investigator-assessed median PFS was prolonged by 11.1 months (HR, 0.47) in the subgroup of patients with central nervous system (CNS) metastases and by 6.6 months (HR, 0.75) in the subgroup of those without CNS metastases. Likewise, median PFS was longer by 8.5 months (HR, 0.60) in the subgroup of patients with EGFR exon 19 deletion type and by 10.8 months (HR, 0.63) in the subgroup with exon 21 (L858R) mutations.

“Second PFS and OS data were immature at this interim analysis,” with a maturity of 34 percent and 27 percent, respectively, said principal study investigator Prof Pasi Janne from Dana-Farber Cancer Institute in Boston, Massachusetts, US.

Safety

In FLAURA2, 557 patients were randomly assigned to receive osimertinib plus pemetrexed and platinum-based chemotherapy (n=279) or osimertinib monotherapy (n=278).

Baseline characteristics were generally balanced between the combination and monotherapy arms, including age (median 61 vs 62 years), sex (62 percent vs 61 percent women), race (64 percent vs 63 percent Asian), EGFR mutation type (61 percent vs 60 percent with exon 19 deletion; 38 percent with L858R in both treatment arms), and the presence of CNS metastases (42 percent vs 40 percent).

The median total duration of osimertinib exposure was 22.3 months in the combination arm and 19.3 months in the monotherapy arm. The combination arm received a median of 12 cycles of pemetrexed, and 211 patients (76 percent) completed four cycles of platinum-based chemotherapy.

Adverse events (AEs) possibly causally related to treatment occurred in 97 percent of patients in the combination arm and in 88 percent of those in the monotherapy arm, of whom 19 percent and 5 percent had serious AEs. AEs led to death in five and one patients in the combination and monotherapy arms, respectively.

“The safety profiles were as expected for each treatment and were manageable with standard medical practice,” Janne said.

Most AEs observed in the combination arm were related to chemotherapy, including anaemia, diarrhoea, and nausea, among others, he added. Meanwhile, there were no common grade 4 AEs in the monotherapy arm.

Janne pointed out that when considering combination therapies, the question of whether toxicities such as interstitial lung disease—which can be seen with osimertinib—are going to increase often comes up. But safety data from FLAURA2 showed no difference in the incidence of interstitial lung disease between the combination and monotherapy arms (eight vs 10 cases, respectively).