EGFR TKI combination with immunotherapy in non-small cell lung cancer

ABSTRACT

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has significantly improved clinical outcomes compared with chemotherapy in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR gene mutation.

Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy. Nivolumab combined with erlotinib was associated with 19% of grade 3 toxicities. The combination of osimertinib plus durvalumab in pretreated or chemo naïve NSCLC patients showed encouraging clinical activity, however, this combination was associated with high incidence of interstitial lung disease (38%), leading to termination of further enrollment. The combination of gefitinib plus durvalumab demonstrated encouraging activity but higher incidence of grade 3/4 liver enzyme elevation (40–70%). The treatment related Grade 3–4 adverse events were observed in 39% of patients when treated with atezolizumab plus erlotinib.

Expert opinion: Given the relatively high incidence of treatment-related toxicities associated with combination of EGFR TKI and immunotherapy, further development of this approach remains controversial. Until now, the combination of EGFR TKI and immunotherapy should be investigational.

KEYWORDS:

• EGFR mutation
• immunotherapy
• NSCLC
• EGFR TKI

Article highlights

• EGFR tyrosine kinase inhibitors (TKI) including first, second and third generation significantly improved response rate and progression free survival in non-small cell lung cancer (NSCLC) patients with EGFR mutation, however, almost all patients develop resistance.

• Immune check point inhibitors, anti-PD1 or anti-PD-L1 antibody demonstrated durable response in some proportion of NSCLC patients.

• Given that activation of oncogenic EGFR pathway upregulates PD-L1 expression in preclinical study, combination of EGFR TKI with immunotherapy is considered promising treatment approach.

• Early phase clinical study of combination of osimertinib with durvalumab was associated with unexpectedly high incidence of interstitial lung disease and gefitinib combined with durvalumab demonstrated high incidence of ALT/AST elevation. Combination of atezolizumab plus erlotinib was not associated with interstitial lung disease, however, 39% of treatment related grade 3-4 adverse events were observed.

• The use of combination approach with EGFR TKIs and immunotherapy should be considered investigational.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Additional information

Funding

This paper was not funded.