Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutation

Phase II Study of Osimertinib in NSCLC Patients With EGFR Exon 20 Insertion Mutation

This is a single-arm, non-randomized multicentre phase 2 study in NSCLC patients with EGFR exon 20 insertion mutation, whose disease has progressed on standard chemotherapy.

EGFR exon 20 insertion-mutant NSCLCs are generally resistant to 1st-generation EGFR tyrosine kinase inhibitors (TKIs) as well as 2nd-generation EGFR TKIs (overall response rates of 0-8.7%). Osimertinib is an oral, potent, irreversible EGFR-TKI selective for sensitizing EGFR and EGFR T790M resistance mutations with a significant selectivity margin against wild-type EGFR. Osimertinib is potent with a wide therapeutic window in Ba/F3 cells with EGFR exon 20 insertion mutations. Therefore, this study will be performed to investigate the efficacy of osimertinib in NSCLC patients with EGFR exon 20 insertion mutation

Inclusion Criteria:

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 0-1.
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:
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 measurable lesion
11. Provision of archival FFPE tissue
12. Provision of informed consent for translational genetic research

Exclusion Criteria:

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 osimertinib (3rd generation EGFR TKIs such as 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 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, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD
9. Inadequate bone marrow reserve or organ function
10. QTc prolongation (mean resting corrected QTc > 470 msec)
11. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib
12. History of hypersensitivity to osimertinib (or drugs with a similar chemical structure or class to osimertinib) or any excipients of these agents
13. Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry
14. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
15. Previous allogeneic bone marrow transplant.
16. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.