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Immune Cell Dynamics in EGFR-Mutated NSCLC Treated With Afatinib and Pembrolizumab: Results From a Phase IB Study
Jonathan W Riess1, Matthew S Lara1, Miguel Lopez de Rodas2
1University of California Davis Comprehensive Cancer Center, Sacramento, California.
Introduction:
EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC.
Methods:
Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood.
Results:
A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment.
Conclusions:
Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.
Insights
This study found that combining afatinib with pembrolizumab in EGFR-mutated NSCLC showed modest activity and immune changes, with some patients experiencing partial responses or stable disease. The combination was generally well-tolerated, with immune-related adverse events observed.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- EGFR-mutated NSCLC shows limited response to PD-1/PD-L1 inhibitors.
- Combination therapy may overcome resistance to single-agent immunotherapy.
Purpose of the Study:
- Evaluate the safety and immunomodulatory effects of afatinib plus pembrolizumab in EGFR-mutant NSCLC.
- Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).
Main Methods:
- Phase 1/2 trial enrolling patients with advanced EGFR-mutant NSCLC progressing on prior EGFR TKIs.
- Dose escalation and expansion phases to determine MTD/RP2D.
- Assessed safety, tolerability, and immunomodulatory effects via cytokine and immune cell subset analysis.
Main Results:
- MTD established at afatinib 40 mg daily and pembrolizumab 200 mg every 21 days.
- No dose-limiting toxicities observed; 36% experienced immune-related adverse events (irAEs).
- Modest activity observed: 2 partial responses, 7 stable disease among 10 assessable patients. Increased NK and NKT cells, decreased exhausted CD8+ T-cells.
Conclusions:
- Afatinib and pembrolizumab demonstrate modest activity and are associated with irAEs in EGFR-mutant NSCLC post-TKI progression.
- Pro-inflammatory immune cell changes correlate with antitumor activity and irAEs.
- Combination therapy warrants further investigation in this patient population.
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