Efficacy Study of Osimertinib in Treatment-naïve Patients With EGFR Mutant NSCLC According to TP53 Mutational Status.

Efficacy Study of Osimertinib in Treatment-naïve Patients With EGFR Mutant NSCLC According to TP53 Mutational Status.

This is a prospective, biomarker-driven, open-label, clinical trial of osimertinib in treatment- naïve patients with EGFR mutant NSCLC, to evaluate the efficacy of osimertinib according to the TP53 mutational status.

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures.

• Patients (male/female) must be > 18 years of age.

• Locally advanced or metastatic EGFR mutant NSCLC, not amenable to curative surgery or radiotherapy with confirmation of the presence of EGFR exon 19 deletion or exon 21 p.L858R.

• Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow central analysis.

• Patients must be treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with osimertinib. Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy) if at least 6 months has elapsed between the end of chemotherapy and enrolment.

• World Health Organization (WHO) performance status 0-2.

• Patients must have a life expectancy ≥ 12 weeks.

• Females should be using adequate contraceptive measures, should not be breastfeeding 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:

  1. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
  2. 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.
  3. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

• Male patients should be willing to use barrier contraception.

• 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.

• 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.

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site).

• Previous treatment with osimertinib or other drugs targeting EGFR.

• Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater.

• Patients currently receiving (or unable to adequately stop use prior to receiving the first dose of study treatment) medications or herbal supplements included in Annex 6 (Guidance Regarding Potential Interactions with Concomitant Medications).

• Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

• 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.

• Patients with spinal cord compression, symptomatic and unstable brain metastases except for those patients who have completed definitive therapy, and have had a stable neurological status for at least 2 weeks after completion of definitive therapy. Patients may be on corticosteroids to control brain metastases if they have been on a stable dose for 2 weeks (14 days) prior to the start of study treatment and are clinically asymptomatic.

• Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD.

• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

  1. Absolute neutrophil count <1.5 x 109/L.
  2. Platelet count <100 x 109/L.
  3. Haemoglobin <90 g/L.
  4. 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.
  5. Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases.
  6. Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.
  7. 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.

• Any of the following cardiac criteria:

  1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec.
  2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, and second degree heart block).
  3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including serum/plasma potassium < LLN, serum/plasma magnesium < LLN, and serum/plasma calcium <LLN), 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

• 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.

• Active second malignancy; i.e., patient known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment. Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enrol in the trial provided all chemotherapy was completed > 6 months prior and/or bone marrow transplant > 2 years prior to first day of study treatment.

• Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient's capacity to participate in the study.

• History of hypersensitivity to osimertinib (or drugs with a similar chemical structure or class to osimertinib) or any excipients of these agents.

• 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.

• 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.