Afatinib Outperforms First-Generation EGFR-TKIs in NSCLC With Uncommon EGFR Mutations

The study offers guidance to clinicians treating the roughly 10% of patients with rare EGFR mutations.

Patients with non–small cell lung cancer (NSCLC) who have uncommon EGFR mutations appear to have better outcomes with the second-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) Gilotrif (afatinib) compared with earlier versions of EGFR-TKIs, a new study suggests.

The study is important because it delves into outcomes for a small subset of patients that has not been thoroughly studied, the authors noted in Thoracic Cancer.

Most patients with NSCLC who have EGFR mutations have exon 19 deletion or mutation of the exon 21 L858R. However, about 10% of patients have other mutations, such as T790M and exon 20 insertions.

Although early trials of EGFR-TKIs included patients with both common and uncommon EGFR mutations, more recent studies have only enrolled patients with common mutations, explained the authors of the new report. They noted that T790M and exon 20 insertions are believed to be resistant to EGFR-TKIs, although the third-generation TKI Tagrisso (osimertinib) is thought to be effective in patients with the T790M mutation. The only FDA-approved EGFR-TKI to treat NSCLC cases with uncommon, nonresistant mutations is afatinib, they said.

In the new report, the investigators wanted to see how first- and second-generation EGFR-TKIs performed as first-line therapy in a real-world setting when it came to treating people with NSCLC with uncommon mutations. They used data from 4 hospitals in Taiwan for 2011 to 2018, identifying 230 treatment-naive patients who had uncommon EGFR mutations who were treated with EGFR-TKIs. Forty-four patients had T790M mutations, and they were excluded from the analysis.

Of the remaining patients, 62 received afatinib as first-line therapy and 124 received a first-generation EGFR-TKI, either Iressa (gefitinib) or Tarceva (erlotinib). The investigators found that patients who received afatinib had superior progression-free survival (PFS; median of 6.4 vs 5.9 months; P = .022) and overall survival (OS; median of 13.4 vs 13.0 months; P = .008).

“Both gefitinib/erlotinib and afatinib were active against major uncommon mutations and compound mutations, and afatinib showed numerically longer PFS and OS than gefitinib/erlotinib,” the study authors wrote. “Although most EGFR-TKIs were not effective for exon 20 insertions, some patients benefited from treatment with afatinib.”

The authors found that among patients receiving afatinib, there was a higher overall response rate in patients with major uncommon mutations—although this did not translate into a higher disease control rate. They further found that performance status, metastasis of the liver and pleura, and dose reduction were all associated with PFS.

They said previous studies had only identified brain metastasis as a specific risk factor for patients with uncommon mutations.

“By contrast, the current study identified metastases to the liver and pleura as independent predictors of PFS,” they wrote.

The investigators cautioned that their study was retrospective and that some patients were lost to follow-up. They added that 2 therapies—Exkivity (mobocertinib) and Rybrevant (amivantamab)—have recently been developed to treat patients with exon 20 mutations, and those appear to be superior to afatinib in such patients.

“However, afatinib may represent one possible option for treatment in patients with exon 20 insertions, particularly if specific inhibitors are unavailable in daily practice,” they said.


Chang JW, Huang CY, Fang YF, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer harboring uncommon EGFR mutations: Real-world data from Taiwan. Thorac Cancer. Published online November 24, 2022. doi:10.1111/1759-7714.14537

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