Neo-Bio-ADAURA: a Phase II Study to Evaluate Mechanisms of Resistance to Neoadjuvant Osimertinib

Inclusion Criteria:

• Be willing and able to provide written informed consent for the trial prior to anystudy specific procedures. The subject must also provide consent for correlativetranslational study.

• Male or female subjects who are ≥18 years of age on the day of signing the informedconsent.

• Histologically or cytologically documented non-squamous NSCLC with completelyresectable (Stage II-III) disease.

Note: thick needle biopsy of endobronchial ultrasound (EBUS)/bronchoscopy is acceptable.

• Complete surgical resection of the primary NSCLC must be deemed achievable, asassessed by a multi-disciplinary team evaluation (which should include a thoracicsurgeon, specialised in oncologic procedures).

• Performance status (ECOG) 0-1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.

• Lung function test results allowing curative surgery by thoracic surgeon'sassessment.

• Cardiac function by ECHO cardiography results allowing curative surgery by thoracicsurgeon's assessment.

• Have adequate normal organ and marrow function, including the following:

• Absolute neutrophil count ≥1.5×109/L.

• Platelet count ≥ 100×109/L.

• Haemoglobin ≥ 9.0 g/dL. Note: The use of granulocyte colony stimulating factor (G-CSF) support, platelet transfusion and blood transfusions to meet thesecriteria is not permitted.

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 timesthe upper limit of normal (ULN).

• Total bilirubin (TBL) ≤1.5 times the ULN or for patients withdocumented/suspected Gilbert's disease, bilirubin ≤2 times the ULN.

• Creatinine ≤1.5 times the ULN or creatinine clearance ≥50 mL/min (creatinineclearance can be measured or calculated by Cockcroft and Gault equation). Ifneoadjuvant chemotherapy is part of the neoadjuvant treatment regimen3,calculated creatinine clearance must be ≥60 mL/min.

• Body weight >30 kg.

• Life expectancy of >6 months prior to enrolment.

• A tumour which harbours one of the 2 common EGFR mutations known to be associatedwith EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination withother EGFR mutations (ie, T790M, G719X, S7681 and L861Q). Exon 20 insertionco-mutation are not permitted.

• Female patients who are not abstinent (in line with the preferred and usuallifestyle choice of the patient) and intend to be sexually active with a malepartner must use highly effective contraceptive measures. Women of child-bearingpotential must have a negative urine or serum pregnancy test within 72 hours priorto receiving the first dose of study medication. If the urine test is positive orcannot be confirmed as negative, a serum pregnancy test will be required prior tothe first dose of any study treatment if they are of child-bearing potential; ormust have evidence of non-child-bearing potential by fulfilling 1 of the followingcriteria at screening:

• Post-menopausal, defined as 50 years of age or more and amenorrhoeic for atleast 12 months following cessation of all exogenous hormonal treatments.

• Women under 50 years old would be considered as postmenopausal if they havebeen amenorrhoeic for 12 months or more following cessation of exogenoushormonal treatments and have luteinizing hormone (LH) and follicle-stimulatinghormone (FSH) levels in the post-menopausal range for the institution.

• Documentation of irreversible surgical sterilization by hysterectomy, bilateraloophorectomy or bilateral salpingectomy but not tubal ligation (Furtherinformation is available in Appendix B (Definition of Women of ChildbearingPotential and Acceptable Contraceptive Methods).

• Male patients must be willing to use barrier contraception.

Exclusion Criteria:

• Known active infection with hepatitis C virus (HVC) or tuberculosis. Patientspositive for HCV antibody are eligible only if the polymerase chain reaction isnegative for HCV RNA. Screening for chronic conditions is not required.

• Known active or uncontrolled infection with hepatitis B virus (HBV) (i.e., knownpositive HBV surface antigen [HBsAg] result).

Participants with HBV infection may be included only if they meet all the following criteria:

• Demonstrated absence of HCV co-infection or history of HCV co-infection

• Demonstrated absence of HIV infection

• Participants with active HBV infection are eligible if they are:

• Receiving anti-viral treatment for at least 6 weeks prior to study treatment

• HBV DNA is suppressed to <100 IU/mL

• transaminase levels are below ULN.

• Participants with a resolved or chronic infection HBV are eligible if they are:

• Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG].

• Receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (to be determined by a hepatologist) post-treatment or

• Positive for HBsAg, but for >6 months have had transaminases levels below ULNand HBV DNA levels below <100 IU/mL (i.e., are in an inactive carrier state).

• Receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (to be determined by a hepatologist) post-treatment.

• HIV active infection (e.g. patients receiving treatment for infection)

Should participants with HIV infection be included, patients are only eligible if they meet all the following criteria:

• Undetectable viral RNA load for 6 months

• CD4+ count of >350 cells/μL

• No history of AIDS-defining opportunistic infection within the past 12 months'

• Stable for at least 4 weeks on the same anti-HIV medications

• Past medical history of interstitial lung disease (ILD), drug-induced ILD,radiation pneumonitis which required steroid treatment, or any evidence ofclinically significant ILD.

• A history of another primary malignancy, except for the following:

• Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of osimertinib and of low potential riskfor recurrence

• Adequately treated non-melanoma skin cancer or lentigo malignancy withoutevidence of disease

• Adequately treated carcinoma in situ without evidence of disease.

• Has pre-operative radiotherapy treatment as part of the care plan.

• Refractory nausea and vomiting, chronic gastrointestinal diseases causinginability to swallow osimertinib, or previous significant bowel resection thatwould preclude adequate absorption of osimertinib.

• Mixed small cell and NSCLC histology.

• T4 tumours infiltrating the aorta, the oesophagus and/or the heart; and/or anybulky N2 disease.

• Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc) > 470 msec obtained from 3electrocardiograms (ECGs), using the screening clinic ECG machine-derivedQTcF value

• Any clinically important abnormalities in rhythm, conduction or morphologyof resting ECG, e.g., complete left bundle branch block, second-degreeheart block, and third-degree heart block.

• Patient with any factors that increase the risk of QTc prolongation orrisk of arrhythmic events such as heart failure, electrolyte abnormalities (including serum/plasma potassium below the lower limit of normal [LLN];serum/plasma magnesium <LLN; serum/plasma calcium <LLN , congenital longQT syndrome, family history of long QT syndrome, or unexplained suddendeath under 40 years of age in first-degree relatives or any concomitantmedication known to prolong the QT interval and cause Torsade de Pointes (TdP).

• Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

• Any unresolved toxicities from prior therapy greater than Common TerminologyCriteria for Adverse Events (CTCAE) grade 1 at the time of starting studytreatment with the exception of alopecia and grade 2 prior platinum-therapyrelated neuropathy.

• Prior treatment (within the previous 12 months) with any systemic anti-cancertherapy for NSCLC including chemotherapy, biologic therapy, immunotherapy,hormonal therapy or any investigational drug/product.

• Prior treatment (within the previous 12 months) with EGFR-TKI therapy.

• Current use of medications or herbal supplements known to be strong inducers ofcytochrome P450(CYP)3A4, or unable to stop use of such medications at least 3weeks prior to receiving the first dose of study treatment.

• Ongoing treatment with immune suppressing drugs (e.g., methotrexate forrheumatoid disease, continuous systemic steroids for chronic obstructivepulmonary disease, etc.).

• Any major surgical procedure (as defined by the Investigator) which occurredwithin 28 days prior to the first dose of osimertinib. Procedures such asplacement of vascular access, biopsy via mediastinoscopy or biopsy viavideo-assisted thoracoscopic surgery (VATS) are permitted.

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

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

• Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of aninterventional study.

• Prior randomization or treatment in a previous osimertinib clinical studyregardless of treatment arm assignment.

• Previous enrolment in the present study.

• Known allergy or hypersensitivity to any of the study drugs, study drugexcipients, drugs with a similar chemical structure or class, or anaesthetics.

• Inability of the patient, in the opinion of the investigator, to understandand/or comply with study medications, procedures and/or follow-up OR anyconditions that, in the opinion of the investigator, may render the patientunable to complete the study.

• Any condition that, in the opinion of the Investigator, would interfere withthe evaluation of patient safety or study results, including, but not limitedto, ongoing or active infection, uncontrolled hypertension, active bleedingdiatheses, unstable angina pectoris, significant cardiac arrhythmia,interstitial lung disease, or psychiatric illness/social situations that wouldlimit compliance with study requirement, substantially increase risk ofincurring AEs from study treatment, or compromise the ability of the patient togive written informed consent.