Targeted Therapies in the Management of Non-Small Cell Lung Cancer A Multi-Disciplinary Approach
Course Faculty Medical Oncologists: Dr. Barb Melosky British Columbia Cancer Agency, Vancouver, BC Dr. Jeff Rothenstein Lakeridge Health Oshawa, Oshawa, ON Dr. Sunil Verma Odette Cancer Center, Toronto, ON Radiation Oncologist: Dr. Patrick Cheung Odette Cancer Center, Toronto, ON Pathologists: Dr. Ming Tsao Princess Margaret Hospital, Toronto, ON
Disclosures Dr. Barb Melosky o Advisory Board Astra Zeneca, Roche, Boehringer Ingelheim, Pfizer, Lilly Dr. Jeff Rothenstein o Advisory Board Lilly, BMS; Grants/honorarium Novartis; Clinical trials Roche, BMS, AstraZeneca, Boehringer Ingelheim, Novartis Dr. Sunil Verma o Advisory Board AstraZeneca, Roche, Boehringer Ingelheim, Novartis, Lilly Dr. Patrick Cheung o None to declare Dr. Ming Tsao o Grants/honorarium Pfizer, Merck, Roche, AstraZeneca, Boehringer Ingelheim
Course Objectives 1. To review the evidence for use of biomarkers to help make treatment decisions for patients with advanced non small cell lung cancer 2. To discuss the current opportunities and challenges in integrating biomarkers in clinical care of lung cancer patients 3. To review the latest evidence on targeted therapies incorporating biomarkers 4. To discuss the emerging roles of radiotherapy in the management of metastatic NSCLC.
Course Outline Module 1: Case Study & NSCLC Treatment Overview Module 2: Molecular Testing in NSCLC Module 3: EGFR/TKI: Evidence Module 4: ALK Inhibitors: Evidence
Targeted Therapies in the Management of Non-Small Cell Lung Cancer: A Multi- Disciplinary Approach Module 1: Case Study & NSCLC Treatment Overview Dr. Patrick Cheung Radiation Oncologist, Odette Cancer Center, Toronto, ON
Module 1 Objectives Discuss a case study to illustrate best practices for patient diagnosis and treatment options in NSCLC. Describe appropriate treatment options for NSCLC patients based on their particular patient/tumour profiles. Review the clinical data for treatment options and management of NSCLC in patients.
Case Study 56 year old Caucasian male presents with two month history of shortness of breath and low back pain Previous medical history o Hypertension x 10 years - on Ramipril o Type II Diabetes x 8 years on Metformin o No previous Coronary disease/renal disease o Smoking History: 10 pack years
Case Study History of presenting illness o Cough and shortness of breath x 2 months o Dypnea with one flight of stairs o CXR confirms a suspicious R lower lung mass o Back pain x 2 months o Limiting activity increased with any activity o No neurological symptoms
Chest CT Scan
Other Related History Overall ECOG Performance Status of 1 Staging investigations: o CT Chest R lower lung mass and hilar adenopathy o CT Abdomen No evidence of Liver involvement o Bone Scan: Bone metastases T9, Left iliac bone, R ischium o MRI head multiple small volume (<1cm) brain metastases throughout brain with no significant edema o PET Scan evidence of FDG avid lung mass, hilar adenopathy and bone lesions
CT Scan Evidence of Bone Mets
MRI Brain Mets
MRI Brain Mets
Tissue is the Issue Pre-Test Question What is your investigation of choice for this patient to obtain tissue? 1. Bronchoscopy and Biopsy 2. Mediastinoscopy 3. Endobronchial Ultrasound 4. CT Guided Lung Biopsy 5. Bone biopsy
Case Study - Biopsy Results Core Biopsy of Right Lower Lung is performed: o Moderately differentiated adenocarcinoma
Biomarkers Who initiates the biomarker tests at your institution? 1. Surgeon 2. Respirologist 3. Interventional Radiologist 4. Pathologist 5. Radiation Oncologist 6. Medical Oncologist
Patient/Tumor Profile For which patients do you request biomarkers for? 1. All Advanced Non-Small Cell Lung Cancer 2. Non-Squamous Advanced Non-Small Cell Lung Cancer 3. Non-Smokers 4. Asian 5. Adenocarcinoma 6. Females 7. Combination of one of the above
Which Biomarker? When requesting biomarker profile test, what test do you usually request for in the first line setting? 1. EGFR 2. ALK 3. PDL-1 4. K-Ras 5. EGFR and ALK 6. All of the above
Molecular Profile How long does it take for you to get these results? 1. < 2 weeks 2. 2-3 weeks 3. 3-4 weeks 4. > 4 weeks
Case Study Treatment Decision The patient receives palliative radiation( 2000 cgy over five fractions, to T9) with good relief. How would you manage this patient now? 1. Initiate systemic chemotherapy 2. Wait to get biomarker test results prior to initiating therapy 3. Initiate radiotherapy for brain metastases
Treatment of NSCLC Brain Metastases in the EGFR +ve Patient No high level evidence comparing the efficacy of targeted agent alone vs upfront brain radiotherapy in molecularly selected EGFR +ve patients. Prospective phase 2 trials in EGFR +ve patients with brain metastases show >80% chance of response in the brain and up to 15 months of median intracranial PFS with erlotinib alone. In a molecularly non-selected patient population, a phase 3 trial comparing SRS + WBRT alone versus SRS + WBRT + erlotinib for patients with 1-3 brain metastases revealed significantly decreased OS and higher grade 3-5 toxicities when erlotinib was added. Only one retrospective study comparing outcomes of EGFR +ve NSCLC patients with brain metastases treated with up front erlotinib versus radiotherapy.
SUMMARY: o Patients treated with upfront WBRT had significantly longer intracranial PFS than those treated with erlotinib alone (median, 24 vs 16 mos, p=0.04), with no difference in OS o Patients treated with WBRT also had lower rate of failure in the brain compared to SRS
Treatment of NSCLC Brain Metastases in the ALK +ve Patient No high level evidence comparing the efficacy of targeted agent alone vs upfront brain radiotherapy in molecularly selected ALK +ve patients. Prospective trials in ALK +ve patients with brain metastases treated with crizotinib show >50% chance of intracranial control at 12 weeks and up to 7 months of median freedom from intracranial progression. One retrospective multi-institutional study revealing a high rate of intracranial progression in patients treated with targeted agents in ALK+ve NSCLC patients with brain metastases often requiring multiple lines of brain radiotherapy.
SUMMARY: o Brain metastases patients treated with upfront crizotinib have an intracranial disease control rate of 56% at 12 weeks and a median time to intracranial progression of 7 months o Brain metastases patients previously treated with brain radiotherapy and then with crizotinib have an intracranial disease control rate of 62% at 12 weeks and a median time to intracranial progression of 13.2 months
SUMMARY: o Patients presenting with brain metastases treated with targeted agent and brain radiotherapy have a median overall survival of 54.8 months and a median time to intracranial progression of 11.9 months o No survival difference between those who received SRS and WBRT o Strongly recommend choosing SRS over WBRT given the significant number of repeat brain treatments for these patients
Treatment of NSCLC Brain Metastases in the EGFR/ALK +ve Patient: Key Points Multi-disciplinary assessment should be performed in ALL patients with brain metastases, including assessment by Radiation Oncology, regardless of molecular mutation status. There is no doubt that targeted agents alone have efficacy against brain metastases with good response rates. Which patients are considered for treatment with systemic targeted agents alone without upfront brain XRT? o Small, non-bulky disease in non-eloquent areas of the brain o No significant vasogenic edema o Asymptomatic patient o Patient has to be compliant with regular follow-up imaging of the brain with MRI every 2-3 months so that early salvage with radiotherapy can be considered at time of progression.
Treatment of NSCLC Brain Metastases in the EGFR/ALK +ve Patient: Key Points Given no survival benefit and increased neurocognitive toxicities associated with WBRT, there is increasing interest to use SRS/SRT as treatment of brain metastases.