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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
A phase II study of osimertinib in patients with NSCLC harboring EGFR exon 20 insertion: A multicenter trial of the
Yu Jung Kim1, Soyeon Kim2, Tae Min Kim3
1Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Background:
Epidermal growth factor receptor (EGFR) exon 20 insertions account for up to 10% of all EGFR mutations. Clinical outcomes in patients receiving approved EGFR exon 20 insertion-specific inhibitors have been variable. Although osimertinib has demonstrated antitumor activity in clinical trials, its clinical efficacy and translational potential remain to be determined in non-small cell lung carcinoma (NSCLC) with EGFR exon 20 insertion.
Methods:
In this multicenter phase II study, patients with advanced NSCLC harboring EGFR exon 20 insertions for whom the standard chemotherapy failed received 80 mg osimertinib once daily. The primary endpoint was the investigator-assessed objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety profile.
Results:
Among 15 patients enrolled at stage 1, the best response was most commonly disease stabilization (73.3 %), which did not meet the stage 1 threshold (objective response ≥ 2/15). As of data cutoff, two patients remained on the treatment. The median PFS and OS were 3.8 (95 % confidence interval [CI] = 1.7-5.5) months and 6.5 (95 % CI = 3.9-not reached) months, respectively. Adverse events (≥grade 3) were anemia, hypercalcemia, and pneumonia (13.3 % each), and asthenia, femur fracture, increased alkaline phosphate, hyperkalemia, bone pain, and azotemia (6.7 % each). Pre-existing EGFR C797S mutation detected in plasma limited the efficacy of osimertinib.
Conclusion:
Osimertinib at 80 mg once daily had limited efficacy and mostly showed disease stabilization with an acceptable safety profile in advanced NSCLC harboring EGFR exon 20 insertions.
Clinicaltrials:
govIdentifier: NCT03414814.
Insights
Osimertinib showed limited efficacy in advanced non-small cell lung cancer with EGFR exon 20 insertions, primarily causing disease stabilization. The safety profile was acceptable, but pre-existing mutations impacted outcomes.
Area of Science:
- Oncology
- Medical Genetics
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) exon 20 insertions represent a significant subset of EGFR mutations in non-small cell lung cancer (NSCLC).
- Current approved therapies for EGFR exon 20 insertion mutations show variable clinical efficacy.
- Osimertinib's efficacy in this specific NSCLC population requires further investigation.
Purpose of the Study:
- To evaluate the clinical efficacy and safety of osimertinib in patients with advanced NSCLC harboring EGFR exon 20 insertions.
- To determine the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with osimertinib treatment.
- To assess the translational potential and identify factors limiting osimertinib's effectiveness.
Main Methods:
- A multicenter phase II clinical study (NCT03414814) was conducted.
- Patients with advanced NSCLC and EGFR exon 20 insertions, refractory to standard chemotherapy, received 80 mg of osimertinib daily.
- Primary endpoint was investigator-assessed ORR; secondary endpoints included PFS, OS, and safety.
Main Results:
- Disease stabilization was the most common response (73.3%) in 15 patients, falling short of the primary endpoint threshold.
- Median PFS was 3.8 months and median OS was 6.5 months.
- Grade ≥3 adverse events included anemia, hypercalcemia, and pneumonia (13.3% each). Pre-existing EGFR C797S mutations were associated with limited efficacy.
Conclusions:
- Osimertinib (80 mg daily) demonstrated limited efficacy in advanced NSCLC with EGFR exon 20 insertions, primarily achieving disease stabilization.
- The drug exhibited an acceptable safety profile in this patient cohort.
- Pre-existing EGFR C797S mutations may limit osimertinib's therapeutic benefit.
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