Osimertinib Monotherapy or Combination With Chemotherapy for Advanced NSCLC Concurrent EGFR and TP53 Mutations

Inclusion Criteria

• •1. Provision of informed consent prior to any study specific procedures;
• •2. Male or female, aged at least 18 years;
• •3. Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1;
• •4. Life expectancy of at least 3 months;
• •5. Histologically or cytologically confirmed stage IV or recurrent non-squamous non-small cell lung carcinoma with activating EGFR mutations (exon 19 deletion or exon 21 L858R point mutation) and concurrent TP53 mutations;
• •6. No prior palliative chemotherapy, or palliative biological (including targeted therapies such as EGFR and vascular epidermal growth factor (VGEF) inhibitors) or immunological therapy （Previous adjuvant chemotherapy is permitted if treatment was completed more than 6 months before day 1. Palliative radiotherapy to a metastatic site is permitted, but palliative wide field radiotherapy to the lung must be completed at least 4 weeks before day 1 with no persistence of any radiotherapy-related toxicity;
• •7. Adequate organ function, including the following:
• •* Adequate bone marrow reserve: absolute neutrophil (segmented and bands) counts (ANC) ≥ 1.5X109/L, Platelets ≥100X109/L, HGB ≥90g/L. The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted;
• •* Tumour Hepatic: total bilirubin ≤ 1.5 times the upper limit of normal (x ULN) if no liver metastases or ≤ 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases; alanine aminotransferase (ALT) \& aspartate aminotransferase (AST) ≤ 2.5 x ULN if no demonstrable liver metastases or AST\&ALT ≤ 5 x ULN in the presence of liver metastases;
• •* Serum Creatinine ≤ 1.5 times the ULN and Creatinine Clearance ≥ 50 ml/min.
• •8. Females must be using highly effective contraceptive measures, 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
• •9. Post-menopausal defined as aged 50 years or more and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
• •10. Women under 50 years old would be consider postmenopausal if they have been amenorrhoeic 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
• •* Demonstrated absence of HCV co-infection or history of HCV co-infection;
• •* Demonstrated absence of HIV infection;
• •* Negative for HBsAg and positive for hepatitis B core antibody \[anti-HBc IgG\]. In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (TBD by hepatologist) post treatment or
• •* Positive for HBsAg, but for \>6 months have had transaminases levels below ULN and HBV DNA levels below\<100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (TBD by hepatologist) post treatment.