Adding First-Line Chemo Boosts PFS in EGFR-Mutant Lung Cancer

SINGAPORE — Treatment with osimertinib (Tagrisso) plus chemotherapy reduced the risk of disease progression or death by 38% compared with osimertinib monotherapy in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), according to data from a phase III trial.

Interim results from the FLAURA2 study showed that investigator-assessed median progression-free survival (PFS) improved by 8.8 months with osimertinib plus pemetrexed and platinum chemotherapy versus the EGFR inhibitor alone (25.5 months vs 16.7 months; HR 0.62, 95% CI 0.49-0.79, P<0.0001), reported Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

One- and 2-year PFS rates were 80% and 57%, respectively, in the combination arm versus 66%% and 41% in the monotherapy arm. Results were similar on blinded independent central review.

“Based on these findings, osimertinib plus platinum-pemetrexed offers a new first-line treatment option for patients with advanced EGFR-mutant advanced lung cancer,” Jänne said during a presentation at the World Conference on Lung Cancer.

Currently, EGFR-tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced EGFR-mutant NSCLC, Jänne pointed out, with osimertinib — a third-generation TKI — the preferred first-line treatment based on the prior FLAURA trial, which demonstrated the superiority of osimertinib in PFS and overall survival (OS) compared with earlier-generation EGFR inhibitors.

“Despite osimertinib’s efficacy, most patients will, unfortunately, develop disease progression at some point during the course of their treatment,” Jänne said. However, he pointed out that even studies of first-generation EGFR-TKIs combined with chemotherapy have shown enhanced efficacy. Thus, the rationale for evaluating osimertinib and chemotherapy in this setting.

Jänne reported the PFS benefit was consistent across all predefined subsets.

Patients with central nervous system (CNS) metastases at baseline achieved a median investigator-assessed PFS of 24.9 months with the combination versus 13.8 months with osimertinib monotherapy (HR 0.47, 95% CI 0.33-0.66). In patients without CNS metastases, median PFS was 27.6 months versus 21 months (HR 0.75, 95% CI 0.55-1.03), respectively.

A PFS benefit was also seen in patients harboring common EGFR mutations. Those with an EGFR exon 19 deletion type had a median PFS of 27.9 months with the combination versus 19.4 months with monotherapy (HR 0.60, 05% CI 0.44-0.83), while those with exon 21 (L858R) mutations had a median PFS of 24.7 months and 13.9 months, respectively (HR 0.63, 95% CI 0.44-0.90).

Median OS data and time to second PFS were immature at the time of this analysis.

Discussant Yi-Long Wu, MD, of Guangdong Provincial People’s Hospital in Guangzhou, China, said that mature OS results are needed before determining whether the FLAURA2 model should become the standard of care in the first line for advanced EGFR-mutant NSCLC, and that currently it “may be” an option in that setting.

However, he added that it “should” become a first-line option for special subgroups of patients, such as those with brain metastases or exon 21 mutations.

The median duration of osimertinib exposure was 22.3 months in the combination arm and 19.3 months in the monotherapy arm. Patients in the combination arm received a median of 12 cycles of pemetrexed, while 77% of the patients completed four cycles of platinum-based chemotherapy with either cisplatin or carboplatin.

Most common adverse events (AEs) in the combination arm were related to chemotherapy, including neutropenia and thrombocytopenia, Jänne said. “There were no common grade 4 AEs in the monotherapy arm.”

“One of the questions that arises is that when you do combination therapies, are you going to increase toxicities such as interstitial lung disease, which can be seen with osimertinib?” Jänne pointed out. Here, in this trial, there was no difference in the incidence of interstitial lung disease between groups (eight cases in the combination arm and 10 in the monotherapy arm).

For the study, 557 patients were randomized 1:1 to osimertinib plus chemotherapy (osimertinib 80 mg once daily plus pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin AUC5 for four cycles) followed by maintenance osimertinib plus pemetrexed or osimertinib monotherapy until disease progression/discontinuation.

A majority of patients in the study were female, with a median age of 61-62 years. Jänne noted that about 40% of patients in each group had CNS metastases.

Ongoing analyses from the trial include CNS response and progression (per central review), patient-reported outcomes, post-progression endpoints, and circulating tumor DNA analyses, Jänne noted.

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