Phase II study of osimertinib in NSCLC patients with EGFR exon 20 insertion mutatio
- Conditions
- Neoplasms
- Registration Number
- KCT0003481
- Lead Sponsor
- Seoul National University Hospital
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 15
1.Provision of informed consent prior to any study specific procedures
2.Male or female must be > 19 years of age.
3.Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy with local confirmation of the presence of the EGFR exon 20 insertion mutation
4.Disease progression while on standard chemotherapy (platinum doublet chemotherapy or single-agent chemotherapy in selected patients)
5.Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
6.Patients must have a life expectancy = 12 weeks
7.Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
•Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
•Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution
•Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
8.Male patients should be willing to use barrier contraception
9.Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
10. At least one lesion, not previously irradiated, that can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must have short axis = 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
11. Provision of archival FFPE(Formalin-fixed, paraffin-embedded) tissue (3 slices of 10µm thickness in EP tube)
12. Provision of informed consent for translational genetic research
1.Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site)
2.Previous treatment with 3rd generation EGFR-TKIs (osimertinib, olumtinib, EGF816 etc.)
3.Treatment with an investigational drug within five half-lives of the compound
4.Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inhibitors of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior) (Appendix A). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on CYP3A4.
5.Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
6.Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
7.Patients with symptomatic CNS(Central Nervous System) metastases who are neurologically unstable; however, those with asymptomatic CNS metastases who do not require steroids for at least 4 weeks prior to start of osimertinib are eligible.
8.Past medical history of ILD(Interstitial Lung Disease), drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD
9.Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
Absolute neutrophil count <1.5 x 109/L
Platelet count <100 x 109/L
Haemoglobin <90 g/L
Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) or liver metastases
Creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
10.Any of the following cardiac criteria:
Mean resting corrected QT interval (QTc using Fredericia’s formula) > 470 msec
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval
11.Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel re
Study & Design
- Study Type
- Interventional Study
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method overall response rate (ORR)
- Secondary Outcome Measures
Name Time Method safety;To evaluate progression-free survival;To evaluate overall survival