A Phase 2 Study of Osimertinib and S-1 in Treatment Resistant EGFR Mutant NSCLC

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed EGFR mutant NSCLC.

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >20 mm with conventionaltechniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.

• Prior therapy: Patient with recurrent and/or metastatic EGFR mutant NSCLC, that hasprogressed on osimertinib as most recent line of treatment, and the primary doctorintends to continue with osimertinib treatment.

• Patients with no matched alterations (tumor or plasma) where clinical trials orapproved systemic anti-cancer therapy are available, are eligible

• Patients with matched alterations on rebiopsy (tumor or plasma) who declinedmatching clinical trials, or approved systemic anti-cancer therapy, are eligible

• Age ≥21 years.

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).

• Patients must have adequate organ and marrow function as defined below:

• absolute neutrophil count ≥1,500/mcL

• platelets ≥100,000/mcL

• total bilirubin ≤ institutional upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN

• creatinine ≤ institutional ULN OR glomerular filtration rate (GFR) ≥50mL/min/1.73 m2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trialprovided that DDI with osimertinib has been addressed.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression.

• Patients with asymptomatic new or progressive brain metastases (active brainmetastases) or leptomeningeal disease are eligible if the treating physiciandetermines that immediate CNS specific treatment is not required and is unlikely tobe required during the first cycle of therapy.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

• The effects of S-1 on the developing human fetus are unknown. For this reason andbecause cytotoxic agents are known to be teratogenic, women of childbearingpotential (WOCBP) must use appropriate method(s) of contraception. WOCBP must have anegative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalentunits of HCG) within 24 hours prior to the start of treatment. Women must not bebreastfeeding. Men who are sexually active with WOCBP must use any contraceptivemethod with a failure rate of less than 1% per year.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study or those who have notrecovered from adverse events due to agents administered more than 4 weeks earlier (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

• Patients who are receiving any other investigational agents.

• Patients are excluded if they have symptomatic brain metastases or leptomeningealmetastases.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to S-1.

• Concomitant medications: Patients should only be excluded from trial participationwhen clinically relevant known or predicted drug-drug interactions or potentialoverlapping toxicities will impact safety or efficacy. Please include scientific orclinically based rationale for exclusion.

• Patients with uncontrolled intercurrent illness including, but not limited to,ongoing or active infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, or psychiatric illness/social situations

• Pregnant women are excluded from this study because both compounds are potentiallyteratogenic.

• Subjects with concomitant second malignancies (except adequately treatednon-melanomatous skin cancers, in situ cervical cancers, localized prostate canceror in situ breast cancer) are excluded unless a complete remission was achieved atleast 3 years prior to study entry and no additional therapy is required oranticipated to be required

• Prior organ allograft or allogeneic bone marrow transplantation

• Prisoners or subjects who are involuntarily incarcerated

• Subjects who are compulsorily detained for treatment of either a psychiatric orphysical (eg, infectious disease) illness

• Inability to comply with restrictions and prohibited activities/treatments in thisstudy.