Which first-line treatment provides the best survival for patients with EGFR-mutated NSCLC?

According to the results of a systematic review and network meta-analysis, osimertinib and gefitinib plus pemetrexed-based chemotherapy appear to be the best first-line treatments, as shown by their most favourable progression-free (PFS) and overall survival (OS), for patients with advanced epidermal growth factor receptor (EGFR)-mutated nonsmall cell lung cancer (NSCLC).

“Osimertinib and gefitinib plus pemetrexed based chemotherapy were consistent in providing the best PFS and OS for advanced EGFR-mutated patients” and were “preferentially recommended” to those with “exon 19 deletion or Leu858Arg mutations, respectively,” the researchers said.

This study accessed PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and several international conference databases from inception to 20 May 2019 for published and unpublished trials comparing two or more treatment in the first-line setting for patients with advanced EGFR-mutated NSCLC. Studies that met the eligibility criteria reported at least one of the following clinical outcome measures: PFS, OS, objective response rate and adverse events (AEs) of grade ≥3.

Eighteen trials were included in the meta-analysis, which involved 4,628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed-based chemotherapy, and gefitinib plus pemetrexed). [BMJ 2019;367:l5460]

Consistent with gefitinib plus pemetrexed-based chemotherapy (hazard ratio [HR], 0.95, 95 percent CI, 0.72–1.24), osimertinib correlated with the best PFS, with significant differences from other treatments: dacomitinib (HR, 0.74, 0.55–1.00), afatinib (HR, 0.52, 0.40–0.68), erlotinib (HR, 0.48, 0.40–0.57), gefitinib (HR, 0.44, 0.37–0.52), icotinib (HR, 0.39, 0.24–0.62), pemetrexed-based chemotherapy (HR, 0.24, 0.17–0.33), pemetrexed-free chemotherapy (HR, 0.16, 0.13–0.20), afatinib plus cetuximab (HR, 0.44, 0.28–0.71) and gefitinib plus pemetrexed (HR, 0.65, 0.46–0.92).

Osimertinib and gefitinib plus pemetrexed-based chemotherapy consistently delivered the most favourable OS benefit (HR, 0.94, 0.66–1.35).

On the other hand, more toxicity was observed with combination treatments, particularly erlotinib plus bevacizumab, which caused the most AEs of grade ≥3. Individual EGFR-TKIs demonstrated various toxicity spectrums.

“We also found EGFR-TKIs, especially icotinib, were associated with less toxicity, although toxicity risk generally rose when they were combined with other treatments,” the researchers said. “These findings could complement current standard of care and enhance future trial design for advanced EGFR-mutated NSCLC.”

Moreover, this finding was supported by those from previous studies, which characterized icotinib with favourable safety. This was deemed to be driven by its broad therapeutic window and high selectivity towards the target EGFR, according to the researchers. [Lung Cancer 2014;86:207-212; Lancet Oncol 2013;14:953-961; Lung Cancer 2012;76:177-182]

In subgroup analyses by the two most common EGFR mutation types, osimertinib appeared to provide the best PFS in patients with the exon 19 deletion, while gefitinib plus pemetrexed-based chemotherapy correlated with the most favourable PFS in those with the Leu858Arg mutation.

“[T]his review provides clinicians a reference source to evaluate strengths and weaknesses for practice choice among multiple promising options,” the researchers said. “Complementing recent guidelines, these findings can help answer questions of whether combination treatments had a role in the standard care of patients with advanced EGFR-mutated NSCLC, and which treatments might be most suitable for patients with the two most common mutations.”