Phase III Study Comparing Osimertinib Monotherapy to Combination Therapy With Osimertinib,Carboplatin and Pemetrexed for Untreated Patients With Advanced Non-squamous Non-Small Cell Lung Cancer With Concurrent EGFR and TP53 Mutations

This is a phase III clinical trial aimed to compare the efficacy and safety of Osimertinib monotherapy and combination of Osimertinib, pemetrexed and carboplatin in untreated patients with advanced non-small cell lung cancer with concurrent EGFR and TP53 mutation.

This is a multicenter, randomized, open label, phase III study comparing the progression free survival, overall survival, response rate, toxicity, quality of life between Osimertinib monotherapy and combination of osimertinib, pemetrexed, carboplatin in first-line treatment of advanced non-small cell lung cancer patients with concurrent EGFR and TP53 mutation. Besides, the association between other genetic mutations and efficacy will also be analyzed as exploratory endpoint. Eligible patients will be randomized to receive either osimertinib or osimertinib combined with pemetrexed and carboplatin in a 1:1 ratio.

Eligibility Criteria:
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; Hepatic: bilirubin ≤ 1.5 times the upper limit of normal (xULN), alanine aminotransferase (ALT) \& aspartate aminotransferase (AST) ≤ 3.0 times the ULN if no demonstrable liver metastases (AST, ALT ≤ 5 XULN is acceptable if liver has tumor involvement); Serum Creatinine ≤ 1.5 times the ULN and Creatitne Clearance ≥ 50 ml/min;
8. At least one measurable lesion (according to RECIST1.1). Baseline measurable lesions were defined as: non-lymph node lesions with longest diameter ≥ 10 mm or lymph node lesions with short diameter ≥ 15 mm measured by CT or MRI. No previous regional treatment such as radiotherapy should be performed to treat Measurable lesions. Tumor tissue previous received radiotherapy should not be biopsied during the screening period. If there is only one measurable lesion, biopsy of this lesion if permitted but the baseline imaging examination of this lesion must be performed at least 14 days after the biopsy.

Exclusion Criteria:

1. Known severe hypersensitivity to Osimertinib, carboplatin, pemetrexed or any of the excipients of the above-mentioned product. Known severe hypersensitivity to pre-medications required for treatment with carboplatin / pemetrexed doublet chemotherapy;
2. History or presence of any other malignancy with the exception of cancer in situ which has undergone radical resection and has not relapsed within 5 years (eg. basal cell carcinoma or cervical cancer);
3. Past medical history of interstitial lung disease, drug induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease;
4. Any unresolved chronic toxicity ≥ CTCAE grade 2 from previous anticancer therapy;
5. As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease);
6. Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study;
7. Pregnancy or breast feeding;
8. Use of unapproved drugs or research drugs within 30 days before the start of the study;
9. Symptomatic brain metastases.