Combination of Immune Checkpoint Therapy with EGFR-TKI Targeted Therapy

EGFR and Inhibitor

Epidermal growth factor receptor (EGFR) belongs to a 4-member family of receptor tyrosine kinases. EGFR has an extracellular ligand-binding domain, a transmembrane anchoring region, and an intracellular tyrosine kinase. This protein is found at abnormally high levels in cancer cells, and EGFR activation appears to be important in tumor growth and progression. Some types of cancers show mutations in their EGFRs.

The two-primary means of inhibiting the EGFR pathway are monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs). Both EGFR-TKIs and anti-EGFR mAbs may provide a predominantly cytostatic effect.

1. TKIs: EGFR-TKIs exert their effects intracellularly. They bind competitively to the adenosine triphosphate pocket of EGFR, inhibiting EGFR autophosphorylation and downstream signal transduction.
2. mAbs: mAbs bind to the extracellular component of the EGFR and prevent EGF from binding to its own receptor, preventing receptor subunit dimerization, EGFR autophosphorylation, and signal transduction.

Fig.1 Tumor microenvironment of EGFR-mutant NSCLC. (Jin, 2020)

Rationale of Combined Therapy

EGFR-TKI can produce a rapid immune response in advanced EGFR mutant non-small cell lung cancer (NSCLC). But the modest response duration is a major problem. On the other hand, immune checkpoint inhibitors (ICI) can induce durable anti-tumor activities but usually with low response rates. Thus, combining these two types of drugs may be a promising therapeutic option to overcome each other's limitations.

Immune Checkpoint Therapy with EGFR-TKI Targeted Therapy

Currently, EGFR-TKIs remains the first-line choice for the treatment of EGFR mutants. The activation of EGFR pathway is potentially associated with tumor PD-L1 status based on a series of preclinical evidence that activating EGFR mutation can up-regulate PD-L1 expression in NSCLC, suggesting the potentially higher sensitivity of EGFR-mutant patients to anti-PD-1 therapy. Researches on novel therapeutic approaches combining EGFR TKIs and ICIs have been conducted to improve the survival outcome of patients with EGFR mutant NSCLC.

In a phase I trial, the anti-PD-L1 mAb/EGFR-TKI combination therapy exhibited a manageable safety profile and a promising objective response in TKI naive NSCLC patients. Similar results could also be observed with the combination of another anti-PD-L1 mAb/EGFR TKI. For patients that have previously been treated with EGFR-TKIs and later developed drug resistance, anti-PD-1 mAb/EGFR-TKI combination can lead to an ORR of 15% and a 24-week PFS rate of 47%. In fact, such strategies are limited due to the overlapping toxicities when used in combination.

Fig.2 PD-1/PD-L1 immune checkpoint in NSCLC. (Hsu, 2019)

TKI remains the preferred first-line therapy for EGFR-mutant diseases. Different assays are required to determine the mechanisms underlying the response of EGFR-TKI to ICIs. Individualized and precise strategies are also in need to modify or reverse resistance and render the lesions sensitive to ICIs. Creative Biolabs provides combination therapy development services by utilizing EGFR-TKI targeted therapy and specific immune checkpoint therapy. We also offer a comprehensive set of immune checkpoint services for worldwide clients. Please feel free to contact us for more details.

References

1. Jin, R.; et al. Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: From bed to bench. Therapeutic advances in medical oncology. 2020, 12: 1758835920930333.
2. Hsu, P. C.; et al. Epidermal growth factor receptor (EGFR) pathway, yes-associated protein (YAP) and the regulation of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). International journal of molecular sciences. 2019, 20(15): 3821.

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