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definitions

Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with osimertinib. Evaluable for objective response: Only those patients who have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease reevaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.  
Disease Parameters Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as:  
- By chest x-ray: >20 mm
- By CT scan:
o Scan slice thickness 5 mm or under: >10 mm o Scan slice thickness >5 mm: double the slice thickness
- With calipers on clinical exam: ≥10 mm.
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are located in a previously irradiated area might or might not be considered measurable at the discretion of the PI. Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 6 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.
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post-lat lesions

Progression: As defined in Section 4.3.1 of the RECIST version 1.1 manuscript(69), at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Note: If patients progress only at the same site where LAT has been performed before, the progression will be considered to be a result of inadequate ablation and they will be considered for repeat LAT if clinically feasible by any of the previous modalities (surgery, RT, RFA, cryoablation) and again re-challenged with osimertinib. Progression only at the site of previous LAT will not be considered progression for the PFS2. Re-initiation of osimertinib treatment in this case has to be within one month.  
Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 28 days before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Conventional CT and MRI: CT and MRI - CT and MRI are the best currently available and reproducible methods to measure target lesions selected for response assessment. For this study helical multidetector CT will be performed with cuts of 5 mm in slice thickness for chest, abdomen and pelvis lesions and 2-3 mm thickness for head and neck lesions. Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases. The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. RECIST criteria will be used to determine disease progression unless there is cytological or histological confirmation of an alternative diagnosis such as pneumonia or inflammation. At the time of first progression when a biopsy is mandatory, biopsy will confirm disease progression. For instances of second progression when a biopsy is not mandatory, progression determined using RECIST criteria will be adequate to take patient off treatment. FDG-PET: New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up may be a sign of progressive disease. If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is progressive disease (PD). If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site. If so, the date of PD will be the date of the initial abnormal FDG-PET scan. If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. Note: A positive FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.  
Response Criteria 6.3.4.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of target lesions, taking as reference the baseline sum diameters. There can be no appearance of new lesions. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. 6.3.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis) Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 6.3.4.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Table 4. Evaluation of patients with measurable disease Target  Non-Target  New Lesions Overall                                                                                                                                                    | Best          | Overall   | Response                                           |                        |    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|-----------|----------------------------------------------------|------------------------|----|
| Lesions                                                                                                                                                                                                                                            | Lesions       | Response  | when                                               | Confirmation           | is |
| Required*                                                                                                                                                                                                                                          |               |           |                                                    |                        |    |
| CR                                                                                                                                                                                                                                                 | CR            | No        | CR                                                 | >4 wks. Confirmation** |    |
| CR                                                                                                                                                                                                                                                 | Non-CR/Non-PD | No        | PR                                                 | >4 wks. Confirmation** |    |
| CR                                                                                                                                                                                                                                                 | Not evaluated | No        | PR                                                 |                        |    |
| PR                                                                                                                                                                                                                                                 | Non-CR/Non               |           |                                                    |                        |    |
| PD/not evaluated                                                                                                                                                                                                                                   | No            | PR        |                                                    |                        |    |
| SD                                                                                                                                                                                                                                                 | Non-CR/Non               |           |                                                    |                        |    |
| PD/not evaluated                                                                                                                                                                                                                                   | No            | SD        | Documented at least once  >4 wks. from baseline*** |                        |    |
| PD                                                                                                                                                                                                                                                 | Any           | Yes or No | PD                                                 |                        |    |
| Any                                                                                                                                                                                                                                                | PD*           | Yes or No | PD                                                 | no prior SD, PR or CR  |    |
| Any                                                                                                                                                                                                                                                | Any           | Yes       | PD                                                 |                        |    |
| * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.  ** Only for non-randomized trials with response as primary endpoint.  *** In exceptional circumstances, unequivocal progression in non-target lesions may be |               |           |                                                    |                        |    |  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration"*. Every effort should be made to document the objective progression even after discontinuation of treatment.  
| Non-Target Lesions   | New Lesions   | Overall Response   |
|----------------------|---------------|--------------------|
| CR                   | No            | CR                 |
| Non-CR/non-PD        | No            | Non-CR/non-PD*     |  
| Not all evaluated   | No        | Not evaluated   |
|---------------------|-----------|-----------------|
| Unequivocal PD      | Yes or No | PD              |
| Any                 | Yes       | PD              |  
Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.  
Progression-Free Survival Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression.  
Overall Survival Overall survival is defined as the duration of time from start of treatment to death from any cause.
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6.4 safety assessments laboratory safety

Blood for determination of clinical chemistry, hematology and coagulation will be taken at the times indicated in the **Study Calendar**. Additional safety samples may be collected if clinically indicated at the discretion of the Investigator. The date, time of collection and results (values, units and reference ranges) will be recorded on the appropriate eCRF.  
Please refer to section 2.3 for the list of laboratory variables assessed.  
The Investigator should make an assessment of the available results with regard to clinically relevant abnormalities. The laboratory results should be signed and dated and retained at center as source data for laboratory variables. For information on how AEs based on laboratory tests should be recorded and reported, see Section **6.4.1** and section 7. In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to Appendix E 'Actions required in cases of combined increase of Aminotransferase and Total Bilirubin - Hy's Law', for further instructions.  
Physical examination A physical examination will be conducted at screening and at subsequent visits according to the schedule in section 3.6.
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ecg

Patients should be monitored for ECG changes according to the schedule in section 3.6 ECGs should be reviewed and any abnormalities noted.
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6.4.3.1 resting 12-lead ecg

Twelve-lead ECG will be obtained after the patient has been resting semi-supine for at least 10 minutes prior to times indicated. All ECGs should be recorded with the patient in the same physical position. A standardized ECG machine should be used and the patient should be examined using the same machine throughout the study if possible. The investigator or designated physician will review the ECG and may refer to a cardiologist if appropriate. A paper copy should be filed in the patient's medical records. If an abnormal ECG finding at screening or baseline is considered to be clinically significant by the investigator, it should be reported as a concurrent condition. For all ECGs, ECG intervals and an overall evaluation will be recorded.
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ophthalmologic exam

Full ophthalmic assessment, including slit lamp examination, should be performed at screening and if a patient experiences any visual symptoms (including blurring of vision), with additional tests if clinically indicated. Ophthalmology examination results should be collected in the eCRF. Any clinically significant findings, including those confirmed by the ophthalmologist must be reported as an AE. Photographs should be performed to record any clinically significant findings.
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6.5 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_40).
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7 nih reporting requirements/data and

Please refer to definitions provided in Policy 801: Reporting Research event found here.
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7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here.  
IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at dahutw@mail.nih.gov and to NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 nih required data and

The clinical research team will meet on a regular basis when patients are being actively treated on the trial to discuss each patient. All data will be collected in a timely manner and reviewed by the principal investigator or the lead associate investigator. Events meeting requirements for expedited reporting as described in section **7.2.1** will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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8 safety reporting criteria to

The PI or designee will send all reports to the manufacturer as described below.  
Expedited Adverse Event Reporting Criteria to the IND Manufacturer Any serious or unexpected adverse events occurring from the start of treatment until 30 days after the last dose of study medication will be faxed or emailed to AstraZeneca at the time the event is discovered. The PI or designee should send reports to jennifer.defrancisco@astrazeneca.com and AEMailboxClinicalTrialTCS@astrazeneca.com.  
* A *cover page* (see **Appendix F**) should accompany the *MedWatch* form indicating the following:
- Investigator Sponsored Study (ISS)  
- The investigator's name and address - The trial name/title and AstraZeneca ISS reference number
* The investigative site must also indicate, either in the SAE report or the cover page, the causality of events *in relation to all study medications* and if the SAE is related to disease progression, as determined by the principal investigator. * Send the SUSAR report and accompanying cover page by way of fax *or email* to AstraZeneca's designated fax line or by email as listed on the cover page in Appendix F
Additional Information Sent to AstraZeneca The following items must be provided to AstraZeneca:  
1. IRB approval of initial protocol 2. Any other information affecting the safety of human subjects research conducted under the CTA.  
3. Quarterly Reports Entered into the AstraZeneca Database a. Cumulative frequency table of adverse events in a table listing event name and CTC grade b. Number of subjects screened, enrolled, completed, withdrawn
Unless otherwise indicated, the information should be sent to by email to Jennifer DeFrancisco, Jennifer.defrancisco@astrazeneca.com
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9 clinical monitoring

Although this study is IND-exempt, the CCR will maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
- Informed consent process  
- Eligibility confirmation
- Drug administration and accountability
- Adverse events monitoring - Response assessment
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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10 statistical considerations 10.1 statistical

The primary objective is to determine PFS in patients with oligoprogressive disease after treatment with LAT followed by osimertinib. Patients who progress on their initial treatment with osimertinib and receive LAT therapy (surgery, radiation therapy, RFA, or cryoablation) followed by osimertinib will be evaluated for their time to second progression (PFS2). The objective will be to estimate the PFS2 for these patients and also to determine if the PFS2 results may be potentially superior to the expected results. Data from a recently published study indicated that patients with NSCLC who have progressed after receiving LAT would be expected to have approximately a 6.2 month median PFS2. With 41 evaluable patients receiving LAT, assuming accrual would take place over approximately 3 years, and that there would be at least 6 months of additional potential follow-up after the last patient has received the LAT followed by osimertinib , there would be 80% power to determine that there is a difference between a 6 month median PFS and an improved 10 month median PFS, with a one sided 0.10 alpha level test, using the method of Brookmeyer and Crowley as calculated via the following website: http://www.swogstat.org/stat/public/one_nonparametric_survival.html. The trial also aims to better define PFS in patients with *EGFR* mutation-positive NSCLC treated with osimertinib prior to LAT. Data from recently published studied indicated that patients with T790M-positive EGFR inhibitor-resistant NSCLC experienced a median 9.6 month PFS following osimertinib treatment and 83% of patients treated with osimertinib at a dose of 80 mg daily as a first-line treatment remained progression-free at 9 months. Using a combined population of patients who are chemo-naïve or who had progressive disease after prior EGFRTKI therapy, the present trial aims to treat both cohorts of patients with osimertinib in order to replicate the findings and to report the results in the two populations. In order to obtain 41 patients who receive LAT followed by osimertinib, it is anticipated that at least 100 patients would need to enroll onto the trial and receive treatment initially with osimertinib. These patients will all be followed for PFS and will have their initial PFS reported in an overall group as well as separately by prior treatment status (TKI naïve vs. prior 1st or 2nd generation EGFR TKI treatment). In order to recruit patients fast for the evaluation of LAT and re-treatment with osimertinib, a cohort of patients already treated with osimertinib in other institutions in on-going clinical trials and developed acquired resistance will be included in the trial. These patients will be enrolled in this study if they are eligible for LAT and be followed for PFS after LAT and re-treatment with osimertinib. In order to ensure that the trial does not continue to enroll patients in the event that outcomes are not adequate the following stopping rules will be implemented. For the patients initially receiving osimertinib on the trial, the initial median PFS would be expected to be approximately 9.6 months, with a lower two-sided 95% confidence interval bound of approximately 8.3 months. After 50 patients have been treated with osimertinib and potentially followed for at least one year, if the median PFS is below 8.3 months, then no further patients will be treated on the trial since the results associated with the first administration of osimertinib are substantially below what would be expected based on the previous study. For the patients who receive LAT, based on results from the prior published study, the median PFS would be 6.2 months, with a lower two-sided 95% confidence interval bound of 3.7 months. If after 20 patients on the present trial have received LAT followed by osimertinib and were followed for a potential of 9 months, the median PFS is 3.7 months or less, then no further patients will be enrolled on the trial since this would indicate results which are substantially below what would be expected based on the previous study. As re-treatment is allowed on this study, first treatment and second treatment patients will be included in the analysis of PFS as patients will not have been off osimertinib more than 1 month. Response criteria will be also assessed for both treatments as part of the analysis. In order to obtain 41 evaluable patients who receive LAT followed by osimertinib, the trial will have an initial accrual ceiling of 100 patients. When appropriate, based upon the fraction of all patients who are able to receive LAT, the trial will be amended to request additional patients expected to be necessary to result in 41 evaluable patients receiving LAT and osimertinib. It is anticipated that 3 to 5 years may be required to enroll adequate patients to obtain 41 who will receive LAT.
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10.2 methods for statistical analyses

The progression-free survival of patients with oligoprogressive disease after treatment with LAT followed by osimertinib will be estimated and plotted by the Kaplan–Meier method. In addition, the median progression-free survival will be reported along with the 95% confidence intervals. The results for the patients who undergo LAT are not expected to vary substantially according to whether they were initially EGFR TKI-naïve or not. However, the results will be evaluated including all patients who receive LAT as well as divided according to their initial EGFR TKI experience before treatment on this trial. The progression-free survival of patients treated with osimertinib prior to LAT will be estimated by the Kaplan-Meier method. Other important objectives include evaluating responses and overall survival (OS) in the patients who receive osimertinib after LAT, as well as determining the feasibility of evaluating EGFR mutation status using liquid biopsies (using blood or saliva samples). The response rate will be reported using a 95% confidence interval and OS will be reported using a Kaplan-Meier curve. The percentage of positive *EGFR* mutation in blood or saliva samples will be reported and the sensitivity and specificity of liquid biopsies will be assessed. Except for the evaluation of PFS2 in patients with oligoprogressive disease after treatment with LAT followed by osimertinib for which a one-sided 0.10 evaluation will be performed, all statistical tests will be two-sided and considered statistically significant when the p-value is <0.05. All statistical analyses will be performed using SAS (Version 9.4; SAS Institute, Cary, NC).
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11 collaborative agreements 11.1 clinical

A Clinical Trial Agreement (CTA \# 990-16) with AstraZeneca was executed on 02/05/2016 for the clinical development of AZD-9291.
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11.2 material transfer agreements

Human Materials Transfer Agreements with the following collaborators have been obtained or will be obtained prior to sending materials from NCI.  
1. Parker Cassidy at Mitra Biotech in order to perform the studies described in Section 5.1.1.3 2. Dr. David Wong's group at UCLA in order to perform the studies described in Section 5.1.3 3. Dr. Christopher Albanese at Georgetown University in order to perform the studies described in Section **5.4.2**.  
4. Dr. Amit Chaudhuri at Medgenome to perform the studies described in Section 5.1.1.3.10.  
5. Dr. Julia Beaver and Dr. Elliot Rosen at the Food and Drug Administration in order to perform the studies described in Section **5.1.1.5**.  
6. Dr. Olga Vitek at Northeastern University in order to perform the studies described in Section **5.1.1.3.5**.  
7. Dr. Greg Jones at Inivata in order to perform the studies described in Section **5.1.1.4**. 8. Dr. Haixu Tang at Indiana University to perform the studies described in Section **5.1.1.7**.  
9. Drs. James Sun and Jennifer Busby at Gritstone Oncology to perform the studies described in Section **5.1.1.8**.
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11.3 cooperative research and development

A Materials Cooperative Research and Development Agreement (CRADA) \#03288 with Aurigene was executed on 05/06/2019 and includes experiments described in the Experimental Plan - Section 5 which involve the use of patient-derived xenograft mouse models under this clinical protocol.
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12 human subjects protections 12.1

This study will be open to all individuals regardless of gender, ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are met. To date, there is no information that suggests that differences in drug metabolism or disease response would be expected in one sex, racial or ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, accrual may be expanded or a follow-up study may be written to investigate those differences more fully. This study will be recruited through internal referral, our local physician referral base, and through various websites (i.e., clinicaltrials.gov).
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12.2 participation of children

Patients under the age of 18 will be excluded from study due to the low occurrence of these oncologic histologies in the pediatric population. In addition, the risk of exposure to an investigational agent without proven benefit in the targeted histologies supports excluding children until additional safety and efficacy data is available.
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12.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **12.4.2**), all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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12.4 evaluation of benefits and

Potential risks include the possible occurrence of any of a range of side effects that are listed in section **13.1.2** and the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis as described earlier. 12.4.1.2 Non-physical risks of genetic research
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12.4.1.2.1 risk of receiving unwanted

Anxiety and stress may arise as a result of the anticipation that unwanted information regarding disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be clearly informed that the data related to DNA sequencing and genetic analysis is coded investigational and will not be shared with patients, family members or health care providers.
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12.4.1.2.2 risk related to possibility

This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the patients, family members or health care providers, this risk will be included in the informed consent document.  
As part of study efforts to provide confidentiality of subject information, this study has obtained a Certificate of Confidentiality which helps to protect personally identifiable research information. The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying information related to the research participants, should such disclosure have adverse consequences for subjects or damage their financial standing, employability, insurability or reputation. The informed consent includes the appropriate coverage and restrictions of the Certificate of Confidentiality.
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12.4.1.3 risks of biopsy

The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. Lung biopsies also present the risk for pneumothorax. Tumor biopsies will be done only if it is clinically safe and feasible. In addition, as up to 3 research biopsies may be collected under CT guidance, this will result in exposure to approximately 2.4 rem. This amount is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee.
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benefits

Taken together, benefits of combining osimertinib and local ablative therapy outweigh risks associated with the treatment. Patients should realize that we are hopeful that they may gain benefit from this study, but there is no objective evidence to support our optimism at this time. The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, which may or may not have a favorable impact on symptoms and/or survival.
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12.5 consent process and documentation

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of this trial. The patient will be provided an IRB-approved consent for review and signature and his/her questions will be answered. After a decision is made to enroll into the study, a signature will be obtained from the patient at a subsequent visit. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on study. The informed consent process will be documented on a progress note by the consenting investigator.
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telephone consent

For re-consent in the case of protocol amendments, the informed consent document may be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented in the medical record.
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13 pharmaceutical information 13.1 osimertinib

Note: The commercial drugs used in this study will not alter labelling of the FDA approved drugs nor does the investigation involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product. The FDA has determined that this protocol is IND exempt based on this.  
AZD9291 (osimertinib) 40mg Tablets 80mg Tablets AstraZeneca will supply AZD9291 as tablets for oral administration as a single daily dose of 80 mg. AZD9291 will usually be supplied as either bulk or unlabeled bottles for ISS/ESR studies.  
Toxicity Based on the phase I study by Janne et al., most of the adverse effects were grade 1 or 2(33).  
The incidences of grade 3-5 diarrhea, rash, nausea, and anorexia were 2%, 1%, 1%, and 2%, respectively. There were 6 cases of potential pneumonitis-like events. There were 6 patients who developed hyperglycemia, and 11 patients who had prolongation of QTc interval; none of these events led to discontinuation or reduction of AZD9291. Based on population pharmacokinetic analysis, no dose adjustment is recommended in patients with mild or moderate renal impairment as well as those with mild hepatic impairment(76). Exploratory analyses of clinical trials of AZD9291 suggest a higher incidence of Grade 3 or 4 adverse reactions (32% vs. 25%) and more frequent dose modification for adverse reactions (23% vs.  
17%) in patients 65 years or older as compared with those younger than 65 years(76). Based on the two retrospective studies and one prospective study, it has been shown that local ablative therapies are well tolerated in combination with EGFR-TKI(56-58).  
Administration Procedures Osimertinib is administered as 80 mg once daily for patients without leptomeningeal disease and 160 mg per day for those with leptomeningeal disease at baseline. Osimertinib can be taken without regard to food. Doses should be taken approximately 24 hours apart at the same time point each day. Doses should not be missed. If a patient misses taking a scheduled dose, within a window of 12 hours, it is acceptable to take the dose. If it is more than 12 hours after the dose time, the missed dose should not be taken, and patients should be instructed to take the next dose at the next scheduled time. If a patient vomits after taking their osimertinib, they should not make up for this dose, but should take the next scheduled dose. If a patient misses more than 5 scheduled doses of osimertinib within one cycle, this will be reported as a protocol deviation. If a patient misses 1-4 doses of osimertinib within one cycle, this will not be considered a deviation. If instructed by the study team to hold the investigational drug, held doses will not be considered a missed dose. A patient that interrupts therapy for more than 4 weeks will be taken off treatment.  
The dose of osimertinib can be reduced based on the rules described in Section 3.4. Further dose reductions are not possible. Once a dose has been reduced, it should not be re-escalated at future cycles. Any change from dosing schedule, dose interruptions, or dose reductions should be recorded. Patients may continue to receive osimertinib as long as they are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
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formulation

Osimertinib is presented for oral administration as a beige, film-coated tablet containing either 40 mg or 80 mg of osimertinib (expressed as the free base). Osimertinib tablets are packed in high-density polyethylene (HDPE) bottles. Bottles are secured with a child resistant closure; induction-sealed membranes provide tamper evidence.
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labelling

Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory guidelines. The labels will fulfill GMP Annex 13 requirements for labeling.  
Storage All study drugs should be kept in a secure place under appropriate storage conditions. The investigational product label on the bottle specifies the appropriate storage.  
Stability The investigational product label on the bottle specifies the stability/expiration date.  
Incompatibilities As CYP3A4 is the principal P450 protein responsible for the metabolism of osimertinib, AZ5104 and AZ7550, co-administration with a potent CYP3A4 inhibitor or inducer may affect their exposure. Osimertinib, AZ5104 and AZ7550 are substrates for P-gp and BCRP but are not substrates for OATP1B1 and OATP1B3. Osimertinib is a direct inhibitor of CYP 3A4/5 *in vitro* using nifedipine as the probe substrate (IC50 5.1 μM) although lower inhibition was observed with midazolam (IC50 >26.5 µM) and is a weak time-dependent inhibitor of CYP3A4 *in vitro* (KI and kinact of 1090 µM and 0.0617 min-1). The exposure of medications dependent on CYP3A4/5 may be increased when coadministered with osimertinib. Osimertinib is an inhibitor of BCRP *in vitro* (IC50 of 2.0 μM). The exposure of medications dependent on BCRP may be increased when co-administered with osimertinib due to BCRP inhibition. Osimertinib induces CYP3A4 and CYP1A2 *in vitro* in human hepatocytes. The exposure of medications dependent on CYPs 3A4 and 1A2 (also CYP2C and P-gp which may be induced) may be reduced when co-administered with osimertinib.  
Compliance The administration of all study drugs (including investigational products) should be recorded in the appropriate sections of the eCRF.
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14 references

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Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-42. 6. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-51. 7. Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis. JAMA. 2004;292(4):470-84. 8. D'Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a metaanalysis of the published literature. 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31. Uramoto H, Iwata T, Onitsuka T, Shimokawa H, Hanagiri T, Oyama T. Epithelialmesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res.  
2010;30(7):2513-7. 32. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046-61. 33. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689-99. 34. U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications 2015 [Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472565.htm. 35. Ramalingam SS, Yang JC-H, Lee CK, Kurata T, Kim D-W, John T, et al., editors.  
AZD9291, a mutant-selective EGFR inhibitor, as first-line treatment for EGFR mutationpositive advanced non-small cell lung cancer (NSCLC): Results from a phase 1 expansion cohort. ASCO Annual Meeting Proceedings; 2015. 36. Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016. 37. Yang J, editor Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): updated results from BLOOM, a Phase I study. Abstract 9002 [Oral Presentation]. annual meeting of the American Society of Clinical Oncology; 2016. 38. Yu HA, Riely GJ, Lovly CM. Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res. 2014;20(23):5898-907. 39. Oxnard GR, Lo P, Jackman DM, Butaney M, Heon S, Johnson BE, et al., editors. Delay of chemotherapy through use of post-progression erlotinib in patients with EGFR-mutant lung cancer. ASCO Annual Meeting Proceedings; 2012. 40. Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17(19):6298-303. 41. Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990-8. 42. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 7.2015) 2015 [Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp\#nscl. 43. Halmos B, Pennell NA, Fu P, Saad S, Gadgeel S, Otterson GA, et al. Randomized Phase II Trial of Erlotinib Beyond Progression in Advanced Erlotinib-Responsive Non-Small Cell Lung Cancer. Oncologist. 2015. 44. Schuler MH, Yang C-H, Park K, Bennouna J, Chen Y-M, Chouaid C, et al., editors. Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatanib plus paclitaxel (P) versus investigator's choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatanib--LUX-Lung 5 (LL5). ASCO Annual Meeting Proceedings; 2014. 45. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;advance online publication. 46. Rusthoven CG, Yeh N, Gaspar LE. Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer: Theory and Practice. Cancer J. 2015;21(5):404-12. 47. Rusthoven KE, Hammerman SF, Kavanagh BD, Birtwhistle MJ, Stares M, Camidge DR. Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol. 2009;48(4):578-83. 48. Simon R, Norton L. The Norton-Simon hypothesis: designing more effective and less toxic chemotherapeutic regimens. Nat Clin Pract Oncol. 2006;3(8):406-7. 49. Lo SS, Moffatt-Bruce SD, Dawson LA, Schwarz RE, Teh BS, Mayr NA, et al. The role of local therapy in the management of lung and liver oligometastases. Nat Rev Clin Oncol. 2011;8(7):405-16. 50. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-92. 51. Timmerman RD, Bizekis CS, Pass HI, Fong Y, Dupuy DE, Dawson LA, et al. Local surgical, ablative, and radiation treatment of metastases. CA Cancer J Clin. 2009;59(3):145-70. 52. Khan AJ, Mehta PS, Zusag TW, Bonomi PD, Penfield Faber L, Shott S, et al. Long term disease-free survival resulting from combined modality management of patients presenting with oligometastatic, non-small cell lung carcinoma (NSCLC). Radiother Oncol. 2006;81(2):163-7. 53. Pfannschmidt J, Dienemann H. Surgical treatment of oligometastatic non-small cell lung cancer. Lung Cancer. 2010;69(3):251-8. 54. Holy R, Piroth M, Pinkawa M, Eble MJ. Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer. Strahlenther Onkol. 2011;187(4):245-51. 55. Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, et al.  
Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J
Clin Oncol. 2009;27(10):1572-8. 56. Iyengar P, Kavanagh BD, Wardak Z, Smith I, Ahn C, Gerber DE, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol. 2014;32(34):3824-30. 57. Yu HA, Sima CS, Huang J, Solomon SB, Rimner A, Paik P, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8(3):346-51. 58. Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA, Jr., et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7(12):1807-14. 59. Porte H, Siat J, Guibert B, Lepimpec-Barthes F, Jancovici R, Bernard A, et al. Resection of adrenal metastases from non-small cell lung cancer: a multicenter study. Ann Thorac Surg. 2001;71(3):981-5. 60. Holy R, Piroth M, Pinkawa M, Eble MJ. Stereotactic body radiation therapy (SBRT) for treatment of adrenal gland metastases from non-small cell lung cancer. Strahlentherapie und Onkologie. 2011;187(4):245-51. 61. Luketich JD, Burt ME. Does resection of adrenal metastases from non-small cell lung cancer improve survival? Ann Thorac Surg. 1996;62(6):1614-6. 62. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322(8):494-500. 63. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363(9422):1665-72. 64. Furak J, Trojan I, Szoke T, Agocs L, Csekeo A, Kas J, et al. Lung cancer and its operable brain metastasis: survival rate and staging problems. Ann Thorac Surg. 2005;79(1):241-7; discussion -7.  
65. Burt M, Wronski M, Arbit E, Galicich JH. Resection of brain metastases from nonsmall-cell lung carcinoma. Results of therapy. Memorial Sloan-Kettering Cancer Center Thoracic Surgical Staff. J Thorac Cardiovasc Surg. 1992;103(3):399-410; discussion -1. 66. De Ruysscher D, Wanders R, van Baardwijk A, Dingemans AM, Reymen B, Houben R, et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450). J Thorac Oncol. 2012;7(10):1547-55. 67. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer. 2009;45(2):228-47. 68. Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidencebased, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol. 2000;18(20):3558-85. 69. Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.  
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15 appendices

| 15.1                                                                                                                                                            | APPENDIX A: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale   | Karnofsky Performance Scale                                                     |             |                 |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|---------------------------------------------------------------------------------|-------------|-----------------|-------------|
| Grade                                                                                                                                                           | Descriptions                                                            | Percent                                                                         | Description |                 |             |
| 100                                                                                                                                                             | Normal, no complaints, no evidence  of disease.                         |                                                                                 |             |                 |             |
| Normal activity. Fully active, able                                                                                                                             |                                                                         |                                                                                 |             |                 |             |
| 0                                                                                                                                                               | to                                                                      | carry                                                                           | on          | all             | pre-disease |
| performance without restriction.                                                                                                                                | 90                                                                      | Able to carry on normal activity;  minor signs or symptoms of disease.          |             |                 |             |
| Symptoms,                                                                                                                                                       | but                                                                     | ambulatory.                                                                     |             |                 |             |
| Restricted in physically strenuous  activity, but ambulatory and able to  carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                                      | Normal activity with effort; some  signs or symptoms of disease.                |             |                 |             |
| 1                                                                                                                                                               | 70                                                                      | Cares for self, unable to carry on  normal activity or to do active work.       |             |                 |             |
| In                                                                                                                                                              | bed                                                                     | <50%                                                                            | of          | the             | time.       |
| Ambulatory and capable of all selfcare, but unable to carry out any  work activities. Up and about more  than 50% of waking hours.                                                                                                                                                                 | 60                                                                      | Requires occasional assistance, but is  able to care for most of his/her needs. |             |                 |             |
| 2                                                                                                                                                               | 50                                                                      | Requires considerable assistance and  frequent medical care.                    |             |                 |             |
| 40                                                                                                                                                              | Disabled, requires special care and  assistance.                        |                                                                                 |             |                 |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                          |                                                                         |                                                                                 |             |                 |             |
| 3                                                                                                                                                               | 30                                                                      | Severely                                                                        | disabled,   | hospitalization |             |
| indicated. Death not imminent.                                                                                                                                  |                                                                         |                                                                                 |             |                 |             |
| 20                                                                                                                                                              | Very sick, hospitalization indicated.  Death not imminent.              |                                                                                 |             |                 |             |
| 100%                                                                                                                                                            | bedridden.                                                              | Completely                                                                      |             |                 |             |
| disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                                                                                 |                                                                         |                                                                                 |             |                 |             |
| 4                                                                                                                                                               | 10                                                                      | Moribund,                                                                       | fatal       | processes       |             |
| progressing rapidly.                                                                                                                                            |                                                                         |                                                                                 |             |                 |             |
| 5                                                                                                                                                               | Dead.                                                                   | 0                                                                               | Dead.       |                 |             |
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15.2 appendix b. guidance regarding

The use of any natural/herbal products or other "folk remedies" should be discouraged, but use of these products, as well as use of all vitamins, nutritional supplements, and all other concomitant medications must be recorded in the eCRF. Osimertinib is an investigational drug for which no data on in vivo interactions are currently available. Based on in vitro data and predicted clinical exposure data, osimertinib is considered unlikely to cause clinically significant drug interactions through inhibition or induction of cytochrome P450 enzyme activity. In vitro data have shown that the principal CYP enzymes responsible for the Phase I metabolism of osimertinib are CYP2C8, CYP3A4, and CYP3A5.
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1. drugs inhibiting cyp3a4 or

The contribution of Phase I metabolism to the total clearance of osimertinib is currently unknown but, to ensure patient safety, the following potent inhibitors of CYP3A4 should be avoided during this study if possible for any patient receiving osimertinib. If no alternative exists, the patient should be closely monitored for signs of toxicity.  
| Table 1. Drugs inhibiting CYP3A4  Contraindicated drugs Clarithromycin, telithromycin, troleandomycin                       | Consider withdrawing 1 week prior to osimertinib   |               |            |
|-----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|---------------|------------|
| Conivaptan                                                                                                                  | osimertinib start                                  |               |            |
| Indinavir,                                                                                                                  | lopinavir,                                         | nelfinavir,   | ritonavir, |
| Itraconazole,                                                                                                               | ketoconazole,                                      | posaconazole, |            |
| Mibefradil Nefazodone This list is not intended to be exhaustive, and a similar restriction will apply to other agents that |                                                    |               |            |
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2. drugs inducing cyp3a4 metabolism

The following potent inducers of CYP3A4 should be avoided during this study if possible for any patient receiving osimertinib because concomitant use may decrease osimertinib plasma concentrations.  
Table 2. Drugs inducing CYP3A4  
| Contraindicated drugs                   | start    |             |    |       |       |    |
|-----------------------------------------|----------|-------------|----|-------|-------|----|
| Carbamazepine, phenobarbital, phenytoin | Consider | withdrawing | 3  | weeks | prior | to |
| Rifampicin, rifabutin, rifapentine      |          |             |    |       |       |    |  
St John's Wort osimertinib start Phenobarbitone Consider withdrawing 5 weeks prior to osimertinib start This list is not intended to be exhaustive, and a similar restriction will apply to other agents that are known to strongly modulate CYP3A4 activity. Appropriate medical judgment is required.
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3. medicines whose exposures may

Table 3. Exposure, pharmacological action and toxicity may be increased or decreased by osimertinib  
| Warning of possible interaction                                                                                                                                                                                                                                                                                         | Advice   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| Alfentanil                                                                                                                                                                                                                                                                                                              | Drugs are permitted but caution should be  exercised and patients monitored closely for  possible drug interactions. Please refer to full  prescribing information for all drugs prior to coadministration with osimertinib.          |
| Amodiaquine  Repaglinide  Sirolimus  Tacrolimus  Torsemide  Fentanyl  Dihydroergotamine  Ergotamine  Simvastatin  Lovastatin  Atorvastatin  Rosuvastatin  Fluvastatin  Sulfasalazine  Warfarin  Phenytoin (also see Table 2)  s-Mephenytoin  Cyclosporine  Theophylline  Tizanidine  Aliskiren  Ambrisentan  Colchicine |          |  
Dabigatran etexilate  
| Digoxin  Fexofenadine  Maraviroc  Ranolazine  Talinolol  Tolvaptan  Maraviroc  Ranolazine  Talinolol  Tolvaptan   |
|-------------------------------------------------------------------------------------------------------------------|  
There are currently no data confirming that there is a pharmacokinetic (PK) interaction between these agents and osimertinib; *in vitro* data suggest osimertinib has the potential to cause drug interactions at the intestinal level through CYP3A4 and BCRP, it has also been shown to be an inhibitor of CYP2C8 and inducer of CYP3A4, CYP1A2 and CYP2C and p-glycoprotein. This list is not intended to be exhaustive, and a similar restriction will apply to other agents that are known to depend on CYP3A4, CYP2C8, CYP1A2 and CYP2C for metabolism or BCRP and p-glycoprotein for deposition disposition. Appropriate medical judgement is required.
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4. drugs that may prolong

The drugs listed in this section are taken from information provided by The Arizona Center for Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and Rockville, Maryland. Ref: http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm.
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4.1. drugs known to prolong

The following drugs are known to prolong QT interval or induce Torsades de Pointes and should not be combined with osimertinib. Recommended withdrawal periods following cessation of treatment with these agents are provided in the table.  
| Contraindicated drug                                                                                            | Withdrawal period prior to osimertinib start   |               |        |
|-----------------------------------------------------------------------------------------------------------------|------------------------------------------------|---------------|--------|
| Clarithromycin,                                                                                                 | droperidol,                                    | erythromycin, | 2 days |
| procainamide  Cisapride, disopyramide, dofetilide, domperidone,                                                 | 7 days                                         |               |        |
| ibutilide, quinidine, sotalol, sparfloxacin, thioridazine  Bepridil, chlorpromazine, halofantrine, haloperidol, | 14 days                                        |               |        |
| mesoridazine  Levomethadyl, methadone, pimozide                                                                 | 4 weeks                                        |               |        |  
| Arsenic trioxide        | 6 weeks*   |
|-------------------------|------------|
| Pentamidine             | 8 weeks    |
| Amiodarone, chloroquine | 1 year     |
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4.2. drugs that may possibly

The use of the following drugs is permitted (notwithstanding other exclusions and restrictions) provided the patient has been stable on therapy for the periods indicated.  
| Table 5. Drugs that may prolong QT interval Drug Minimum treatment period on medication  prior to osimertinib start  Alfuzosin, chloral hydrate, ciprofloxacin,  dolasetron, foscarnet, galantamine,  gemifloxacin, isradipine, ketoconazole,  levofloxacin, mexiletine, nicardipine,  octreotide, ofloxacin, ondansetron, quetiapine,  ranolazine, telithromycin, tizanidine,  vardenafil, venlafaxine, ziprasidone  2 days  Amantadine, amitriptyline, amoxapine,  clozapine, doxepin, felbamate, flecainide,  fluconazole, fosphenytoin, gatifloxacin,  granisetron, imipramine, indapamide, lithium,  moexipril/HCTZ, moxifloxacin, risperidone,  roxithromycin, sertraline, trimethoprim-sulfa,  trimipramine, voriconazole  7 days Azithromycin, citalopram, clomipramine,  itraconazole, nortriptyline, paroxetine,  solifenacin, tacrolimus  14 days  Fluoxetine 5 weeks  Protriptyline 6 weeks  Tamoxifen 8 weeks   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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15.3 appendix c osimertinib patient

1. Complete 1 diary for each 4-week (28-day) cycle of treatment.  
2. You will take your dose of osimertinib once daily at around the same time. You may take it with or without food. You should take the tablet whole with water. The tablet should not be crushed, split or chewed.  
3. Record the date, the number of osimertinib tablets you swallowed and the time you took the medicine.  
4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, do not make up the dose, but take the next scheduled dose.  
5. If you miss a dose of osimertinib and it is more than 12 hours after your usual dose time, the missed dose *should not* be taken, but take your next scheduled dose. If you miss taking a scheduled dose, within a window of 12 hours, it is acceptable to take the dose.  
6. If you have any comments or notice any side effects, please write them in the comments column.  
7. Please bring this diary and your bottle(s) of osimertinib when you return for each appointment.  
Today's Date:____________ Cycle:__________ OSIMERTINIB Dose:_________  
| Patient Study ID:_______________ DAY DATE TIME  DOSE                               | # OF TABLETS   | COMMENTS   |
|------------------------------------------------------------------------------------|----------------|------------|
| TAKEN                                                                              | TAKEN          | TAKEN      |
| 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. |                |            |  
| 24.   |
|-------|
| 2.26. |
| 27.   |
| 2.    |  
Patient Label
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15.4 appendix d. guidance for

Osimertinib is a potent irreversible small molecule inhibitor of both the single EGFRm (tyrosine kinase inhibitor (TKI) sensitivity conferring mutations) and dual EGFRm/T790M (TKI resistance conferring mutation) receptor forms of EGFR, with weaker inhibition towards wild type EGFR. Clinical experience with 80mg osimertinib has shown an association with the occurrence of dermatological adverse events (particularly rash and dry skin) and diarrhea. The considerable majority of these events have been mild, transient events that have not always required treatment. Based on experience with other EGFR and HER2 inhibitors, decreases in LVEF, anterior ocular effects and ILD/pneumonitis should be monitored for. Some guidance is provided in this document regarding these events. The purpose of these treatment guidelines is:  
- To prevent tolerable adverse events becoming intolerable for the patient and leading to discontinuation of treatment.  
- To promote consistency of treatment for specific adverse events across the osimertinib clinical program.
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1. skin events - rashes

Patients may consider applying over-the-counter moisturising cream to face, hands and feet twice daily from the start of treatment with osimertinib.  
Skin effects may occur at any time, but most likely to start within 2 weeks of starting treatment. Rashes and Acne  
  
  
| Topical steroid moderate strength bid      |
|--------------------------------------------|
| and                                        |
| ol of Oral antibiotic for 6 weeks - is     |
| Switch to broad spectrum/gram negative     |
| coverage if infection suspected (yellow    |
| crusts, purulent discharge, painful skin / |
| nares). Consider skin swab for bacterial   |
| culture                                    |
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dry skin / xerosis ctcae(v4)

- <10% body surface area (BSA)   - Face/Hands/Feet: over-the-counter ;  
  
  
moisturising cream or ointment bid - Body: ammonium lactate 12% cream bid or salicylic acid 6% cream bid  
  
  
| CTCAE(v4) Grade 2             |
|-------------------------------|
| - Treatment same as Grade 1   |
| - 10 to 30% BSA               |
| - Associated with erythema or |
| proper control and the c      |
| - Limiting instrumental       |  
  
  
CTCAE(v4) Grade ≥3  
  
  
| •>30% BSA                         | Treatment same as Grade 1/2, plus:   |
|-----------------------------------|--------------------------------------|
| - Associated with erythema or     | [[                                   |
| Eczematous areas of body: topical |                                      |
| pruritus                          | steroid moderate strength bid        |
| - Limiting self-care ADL          |                                      |
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pruritis

CTCAE(v4) Grade 1  
| - Mild or localised                    | Topical steroid moderate strength bid   |
|----------------------------------------|-----------------------------------------|
| - Topical intervention indicated       | or topical antipruritic bid             |
| ..                                     | ..                                      |
| CTCAE(v4) Grade 2                      |                                         |
| - Intense or widespread .              | - Topical steroid moderate strength     |
| - Intermittent                         | bid  or topical antipruritic bid        |
| - Oral antihistamine                   |                                         |
| - Skin changes from scratching         |                                         |
| (e.g. oedema, papulation, excoriation, |                                         |
| lichenification, oozing/crusts)        |                                         |
| - Oral intervention indicated          |                                         |
| - Limiting instrumental ADL            |                                         |
| CTCAE(v4) Grade ≥3                     |                                         |
| - Oral antihistamine                   |                                         |
| - Intense or widespread                |                                         |
| - Limiting self-care ADL or sleep      | - GABA agonist (gabapentin 300 mg or    |
| pregabalin 50-75 mg every 8 hours)     |                                         |
| - Oral corticosteroid or servic        |                                         |
| immunosuppressive therapy              |                                         |
| indicated                              |                                         |
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paronychia

Dermatologic Guidance Summary:  
  
- Patients may consider applying over-the-counter moisturising cream to face, hands and feet bid from the start of treatment.  
- Physicians may consider issuing a prescription for topical treatment to patients.  
However, topical steroids and topical or oral antibiotics should not be implemented prophylactically and treatment should only be started when confirmed by the treating physician.  
- As soon as an acneiform / papulopustular rash occurs, treatment with moderate strength topical steroids and antibiotics should be implemented.  
- The occurrence of non-papulopustular skin reactions should be treated appropriately, as defined by the treating physician, and in consultation with a dermatologist where necessary
- Use of topical benzoyl peroxides and other irritating anti-acne agents should be avoided.  
- Patients should be fully informed regarding skin reactions o may occur during treatment with osimertinib skin reactions are not contagious, and do not result from allergy to treatment o may consider applying over-the-counter moisturising cream to face, hands and feet bid from the start of treatment o to contact the study team to report any instances of skin reaction as soon as they arise so that appropriate treatment can be promptly initiated and, especially if the skin reaction changes (e.g. if it spreads or becomes painful)
o It may be beneficial to avoid irritating skin products (e.g. irritating soaps, products containing retinol or retinoic acid)
o Camouflage make-up (non-comedogenic or non-pore blocking) can be used during treatment
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diarrhea treatment guidance 2.

Patients should be fully informed regarding diarrhea May occur during treatment with osimertinib o  
diarrhea is not contagious, and does not result from allergy to treatment Contact the study team to report any instances of diarrhea as soon as they arise o so that appropriate treatment can be promptly initiated
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3. ophthalmic guidance

There is a known association between the use EGFR TKIs and the occurrence of ophthalmic adverse events. Patients on EGFR TKIs, including osimertinib, should be
- Fully informed that ophthalmic events may occur during treatment with osimertinib  
- Monitored periodically for these events - Osimertinib should not be administered on the first scheduled day if the patient has any clinically significant eye symptoms.  
- Encouraged to report any instances of ophthalmic symptoms and/or vision changes to allow the appropriate treatment to be initiated. Symptoms may include:
o Burning / itching / irritation / smarting o Redness with / without discharge o Blurred vision o Light sensitivity
Patients who wear contact lenses must discontinue wearing them if  
- They have any mild to moderate eye symptoms (CTCAE grade ≤2) until at least one week after symptoms have resolved.  
- Patient has a recurrence of eye symptoms or experiences any severe (CTCAE grade ≥3)
ocular events until at least one week after treatment with osimertinib is permanently discontinued.
Patients must not use any eye drops or ointment for treatment of eye symptoms, unless agreed by treating physician, at any time during the study until 1 week after osimertinib has been permanently discontinued.
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assessments during treatment

- If the patient reports any eye symptoms during treatment with osimertinib or if signs are observed during a study visit, the Investigator should perform a clinical examination including a best corrected near and distant visual acuity assessment as appropriate
- Findings should be documented in the patient's notes
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referral to ophthalmologist

Patients with ophthalmic AEs of CTCAE Grade > 3 or eye symptoms that are clinically significant and/or persistent (>7 days) should be referred to the ophthalmologist. For example:  
Deterioration in near or distant visual acuity by more than one level
.  
.  
Persistence or worsening of:
o Burning/ irritation/ smarting o Light sensitivity (photophobia)
o Itching o Blurred vision
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and

Considered causally related to osimertinib Initiate ophthalmic treatment as appropriate and withhold dose for up to 4 weeks  
- If event improves to CTCAE Grade <1 within 4 weeks, reinstate osimertinib at the current dose maintaining ophthalmic treatment as appropriate
- If event improves to CTCAE Grade 2 within 4 weeks, consider reinstating osimertinib at reduced dose of 40 mg daily, maintaining ophthalmic treatment as appropriate
- Permanently discontinue osimertinib and maintain ophthalmic treatment as appropriate, where o CTCAE Grade >3 or clinically significant or persistent adverse event does not improve to a lower CTCAE Grade within 4 weeks of osimertinib interruption, OR
o Any ulcerative event
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ophthalmic guidance summary

- It is important that patients are fully informed that ophthalmic events may occur during treatment with osimertinib.  
- Osimertinib should not be administered on the first scheduled day if the patient has any clinically significant eye symptoms.  
- Patients should be encouraged to report any instances of ophthalmic symptoms and/or vision changes to allow the appropriate treatment to be initiated (or ophthalmic referral).  
- Patients who wear contact lenses must discontinue wearing them if o They have any mild to moderate eye symptoms (CTCAE grade ≤2) until at least one week after symptoms have resolved.  
o Patient has a recurrence of eye symptoms or experiences any severe (CTCAE
grade ≥3) ocular events until at least one week after treatment with osimertinib is permanently discontinued.  
- Patients must not use any eye drops or ointment for treatment of eye symptoms, unless
agreed by a study doctor, at any time during the study until 1 week after osimertinib has been permanently discontinued  
- Osimertinib dose should be interrupted, modified or permanently discontinued as appropriate for any ophthalmic events
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4. left ventricular ejection fraction

Osimertinib and its active metabolite may also inhibit HER2. For this reason:  
- Measurement of LVEF should be performed if the investigator has clinical suspicion of new onset impaired cardiac function
- Patients are to be managed clinically according to standard of care
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5. interstitial lung disease (ild)

If you have clinical suspicion of interstitial lung disease (ILD), dosing with osimertinib should be interrupted while further investigations are performed. A diagnostic workup (including HRCT, blood and sputum culture, laboratory parameters) should be performed, to exclude conditions such as lymphangitic carcinomatosis, infection, allergy or pulmonary haemorrhage. In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have been excluded a diagnosis of interstitial lung disease should be considered and study treatment permanently discontinued.  
  
.  
Interrupt osimertinib dosing, if you have clinical suspicion of interstitial lung disease (ILD), while further investigations are performed.  
.  
Perform full diagnostic workup (including HRCT, blood and sputum culture, laboratory parameters to exclude conditions such as lymphangitic carcinomatosis, infection, allergy or pulmonary haemorrhage
.  
Contact the Medical Lead as soon as a potential pneumonitis event is identified.  
.  
Complete and submit pneumonitis questionnaire
- Resume osimertinib dosing as appropriate
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6. summary

- Patients should be fully informed of common adverse events associated with EGFR
TKIs, including AZD921. Counselling should include o Important aspects of preventative self-care measures o When to notify physician of symptoms that may require further evaluation or treatment o Appropriate treatments associated with EGFR TKIs adverse events o Importance of osimertinib dosing adherence or the importance of dose holds or reductions when appropriate
- Physicians should do the following:
o Review the protocol and all associated documents provided by the study team o Familiarize themselves with the clinical management of EGFR TKI toxicity and required reporting as outlined in study documents
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15.5 appendix e. potential drug

During the course of the study, the Investigator will remain vigilant for increases in liver biochemistry. The investigator is responsible for determining whether a patient meets potential Hy's Law (PHL) criteria at any point during the study. The Investigator assesses cases meeting PHL criteria to determine whether Hy's Law (HL) criteria are met. Hy's Law criteria are met if there is no alternative explanation for the elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP).
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2. definitions potential hy's law

A Potential Hy's Law (PHL) case is defined as a study patient with an increase in serum Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN irrespective of serum Alkaline Phosphatase (ALP), at any point during the study following the start of study medication.
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hy's law (hl)

An HL case is defined as a study patient with an increase in serum AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason can be found to explain the combination of increases, e.g., elevated serum ALP indicating cholestasis, viral hepatitis, another drug. For PHL and HL to be met the elevation in transaminases must precede or be coincident with (i.e., on the same day) the elevation in TBL, but there is no specified timeframe within which the elevations in transaminases and TBL must occur.
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3. identification of potential hy's

In order to identify cases of PHL it is important to perform a comprehensive review of laboratory data for any patient who meets any of the following identification criteria in isolation or in combination:  
- ALT ≥ 3xULN
- AST ≥ 3xULN
- TBL ≥ 2xULN
The Investigator will, without delay, review each new laboratory report and if the identification criteria are met, will:  
- Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for definition) by reviewing laboratory reports from all previous visits.  
- Promptly enter the laboratory data into the laboratory eCRF.
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4. follow-up 4.1. potential hy's

If the patient does not meet PHL criteria, the Investigator will: - Perform follow-up on subsequent laboratory results according to the guidance provided in the Clinical Study Protocol.
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4.2. potential hy's law criteria

If the patient does meet PHL criteria the Investigator will: - Determine whether PHL criteria were met at any study visit prior to starting study treatment in the presence of liver metastases (See Section 6).  
The Investigator will:  
- Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms and signs return to normal or baseline levels, or as long as medically indicated.  
- Investigate the etiology of the event and perform diagnostic investigations.  
- Complete the three Liver eCRF Modules as information becomes available.  
- If at any time the PHL case meets serious criteria, report it as an SAE using standard reporting procedures.
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5. review and assessment of

The instructions in this Section should be followed for all cases where PHL criteria are met. The Investigator will follow the instructions below.  
If there is an alternative explanation for the ALT or AST and TBL elevations, a determination of whether the alternative explanation is an AE will be made and subsequently whether the AE meets the criteria for a SAE:  
- If the alternative explanation is **not** an AE, record the alternative explanation on the appropriate eCRF.  
- If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF
accordingly.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations other than the IMP:  
- Record an SAE (report term 'Hy's Law').  
o The 'Medically Important' serious criterion should be used if no other serious criteria apply.  
o As there is no alternative explanation for the HL case, a causality assessment of
'related' should be assigned.
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6. actions required for repeat

This section is applicable to patients who meet PHL criteria on study treatment (including the 30 day follow-up period post discontinuation of study treatment) after having previously met PHL criteria at a study visit prior to starting study treatment. At the first 'on-study treatment' occurrence of PHL criteria being met, the Investigator will: Determine if there has been a significant change in the patient's condition compared with the last visit where PHL criteria were met:  
- If there is no significant change, no action is required.  
- If there is a significant change, follow the subsequent process described in Section 4.2 of this Appendix.
A 'significant' change in the patient's condition refers to a subsequent clinically relevant change in any of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in combination, or a clinically relevant change in associated symptoms such as fatigue, vomiting, rash, right upper quadrant pain, jaundice, and/or eosinophilia. The determination of whether there has been a significant change will be at the discretion of the Investigator; this may be in consultation with the Study Physician if there is any uncertainty.
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7. actions required for repeat

This section is applicable when a patient meets PHL criteria on study treatment (including the 30-day follow-up period) and has already met PHL criteria at a previous on study treatment visit. The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is based on the nature of the alternative cause identified for the previous occurrence. The investigator should determine the cause for the previous occurrence of PHL criteria being met and answer the following question:  
- Was the alternative cause for the previous occurrence of PHL criteria being met chronic or progressing malignant disease or did the patient meet PHL criteria prior to starting study treatment and at their first 'on-study treatment' visit as described in Section 6?
If No: Follow the process described in Section 6 of this Appendix. If Yes: Determine if there has been a significant change in the patient's condition compared with when PHL criteria were previously met.  
- If there is no significant change, no action is required. - If there is a significant change, follow the process described in Section 4.2 of this Appendix.
A 'significant' change in the patient's condition refers to a subsequent clinically relevant change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically relevant change in associated symptoms, such as fatigue, vomiting, rash, right upper quadrant pain, jaundice, and/or eosinophilia. The determination of whether there has been a significant change will be at the discretion of the Investigator; this may be in consultation with the Study Physician if there is any uncertainty.
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8. references

FDA Guidance for Industry (issued July 2009) 'Drug-induced liver injury: Premarketing clinical evaluation': http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM174090.pdf  
15.6 APPENDIX F. ASTRAZENECA SAE REPORT **COVER SHEET**
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us esr sae report coversheet

| Date: To:                                                   | AZ Patient Safety - TCS                             |
|-------------------------------------------------------------|-----------------------------------------------------|
| Fax #:                                                      | 1-302-886-4114 Jennifer.defrancisco@astrazeneca.com |
| Email:                                                      | and AEMailboxClinicalTrialTCS@astrazeneca.com       |
| Senders Name: Total number of pages: (including cover page) |                                                     |  
| D-code: ESSROS Number:  Sponsor Investigator/Site: Protocol Title: Initial or Follow Up:   |
|--------------------------------------------------------------------------------------------|  
Message: