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Capmatinib plus nazartinib in patients with EGFR-mutated non-small cell lung cancer
Enriqueta Felip1, Giulio Metro2, Ross A Soo3
1Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), UVic-UCC, IOB-Quiron, Barcelona, Spain.
Purpose:
This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC).
Methods:
In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients.
Results:
The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %).
Conclusion:
Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable.
Clinical Trial Registration:
ClinicalTrials.gov NCT02335944.
Insights
This study found that combining capmatinib and nazartinib demonstrated antitumor activity in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) resistant to EGFR-TKIs. The combination therapy showed an acceptable safety profile.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Non-small cell lung cancer (NSCLC) with EGFR mutations presents a significant therapeutic challenge, particularly upon resistance to standard EGFR-tyrosine kinase inhibitors (TKIs).
- Investigating novel combination therapies is crucial for overcoming acquired resistance mechanisms and improving patient outcomes in advanced NSCLC.
Purpose of the Study:
- To evaluate the efficacy and safety of combining capmatinib with nazartinib in patients with advanced EGFR-mutated NSCLC.
- To determine the recommended phase 2 dose (RP2D) for this combination therapy.
- To explore the impact of mutation status (T790M, MET) and prior treatment lines on treatment response.
Main Methods:
- A phase 1b/2 open-label trial enrolled patients with advanced EGFR-mutated NSCLC.
- Phase 1b established the maximum tolerated dose (MTD) and RP2D of escalating capmatinib doses combined with nazartinib.
- Phase 2 enrolled patients into distinct groups based on mutation status, prior treatments, and food intake, assessing overall response rate (ORR) and safety.
Main Results:
- The RP2D was determined to be capmatinib 400 mg twice daily plus nazartinib 100 mg once daily.
- In phase 2, ORRs varied across groups, with the highest observed in treatment-naïve EGFR-mutated NSCLC (61.7%).
- Treatment-related adverse events included peripheral edema (54.9%), nausea (41.7%), and diarrhea (34.0%), with an overall acceptable safety profile.
Conclusions:
- Capmatinib plus nazartinib demonstrates significant antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC.
- The combination therapy is a potential treatment option for specific NSCLC patient populations.
- Further investigation into the role of MET and T790M status in treatment response is warranted.
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