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Moderator Neil Love, MD Faculty

Management of Locally Advanced Non-Small Cell Lung Cancer

Tuesday, September 15, 2020 5:00 PM – 6:00 PM ET

Kelly EH Goodwin, MSN, RN, ANP-BC David R Spigel, MD Heather Wakelee, MD Elizabeth S Waxman, RN, MSN, ANP-BC

You may submit questions using the Zoom Chat

• ption below

Dr Love and Faculty Encourage You to Ask Questions

Feel free to submit questions now before the program begins and throughout the program.

Familiarizing Yourself with the Zoom Interface How to answer poll questions

When a poll question pops up, click your answer choice from the available options. Results will be shown after everyone has answered.

Commercial Support

This activity is supported by an educational grant from AstraZeneca Pharmaceuticals LP.

Dr Love — Disclosures

Dr Love Dr Love is president and CEO of Research To Practice. Research To Practice receives funds in the form of educational grants to develop CME activities from the following commercial interests: AbbVie Inc, Acerta Pharma — A member of the AstraZeneca Group, Adaptive Biotechnologies Corporation, Agendia Inc, Agios Pharmaceuticals Inc, Amgen Inc, Array BioPharma Inc, a subsidiary of Pfizer Inc, Astellas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Biodesix Inc, bioTheranostics Inc, Blueprint Medicines, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Clovis Oncology, Daiichi Sankyo Inc, Dendreon Pharmaceuticals Inc, Eisai Inc, EMD Serono Inc, Exelixis Inc, Foundation Medicine, Genentech, a member of the Roche Group, Genmab, Genomic Health Inc, Gilead Sciences Inc, GlaxoSmithKline, Grail Inc, Guardant Health, Halozyme Inc, Helsinn Healthcare SA, ImmunoGen Inc, Incyte Corporation, Infinity Pharmaceuticals Inc, Ipsen Biopharmaceuticals Inc, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Jazz Pharmaceuticals Inc, Kite, A Gilead Company, Lexicon Pharmaceuticals Inc, Lilly, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Merck, Merrimack Pharmaceuticals Inc, Myriad Genetic Laboratories Inc, Natera Inc, Novartis, Oncopeptides, Pfizer Inc, Pharmacyclics LLC, an AbbVie Company, Prometheus Laboratories Inc, Puma Biotechnology Inc, Regeneron Pharmaceuticals Inc, Sandoz Inc, a Novartis Division, Sanofi Genzyme, Seattle Genetics, Sirtex Medical Ltd, Spectrum Pharmaceuticals Inc, Sumitomo Dainippon Pharma Oncology Inc, Taiho Oncology Inc, Takeda Oncology, Tesaro, A GSK Company, Teva Oncology, Tokai Pharmaceuticals Inc and Verastem Inc.

RESEARCH TO PRACTICE CME/NCPD PLANNING COMMITTEE MEMBERS, STAFF AND REVIEWERS

Planners, scientific staff and independent reviewers for Research To Practice have no relevant conflicts of interest to disclose.

Dr Goodwin — Disclosures

No relevant conflicts of interest to disclose.

Dr Spigel — Disclosures

Consulting Agreements Aptitude Health, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Celgene Corporation, Dracen Pharmaceuticals, EMD Serono Inc, Evelo Biosciences Inc, Genentech, a member of the Roche Group, GlaxoSmithKline, Iksuda Therapeutics, Illumina, Merck, Molecular Templates, Nektar, Novartis, Pfizer Inc, PharmaMar, Roche Laboratories Inc, Seattle Genetics, Takeda Pharmaceutical Company Limited, Triptych Health Partners, TRM Oncology Contracted Research Aeglea BioTherapeutics, Astellas, AstraZeneca Pharmaceuticals LP, BIND Therapeutics Inc, Bristol-Myers Squibb Company, Celgene Corporation, Celldex Therapeutics, Clovis Oncology, Daiichi Sankyo Inc, Eisai Inc, EMD Serono Inc, G1 Therapeutics, Genentech, a member of the Roche Group, GRAIL, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, ImmunoGen Inc, Ipsen Biopharmaceuticals Inc, Janssen Biotech Inc, Lilly, Merck, Molecular Partners, Nektar, Neon Therapeutics, Novartis, Takeda Oncology, Transgene, UT Southwestern Medical Center

Dr Wakelee — Disclosures

Consulting Agreements Cellworks, Daiichi Sankyo Inc, Genentech, a member of the Roche group, Helsinn Healthcare SA, INC Pharma, Janssen Biotech Inc, Merck, Mirati Therapeutics Contracted Research ACEA Biosciences Inc, Arrys Therapeutics, a wholly owned subsidiary

• f Kyn Therapeutics, AstraZeneca Pharmaceuticals LP, Bristol-Myers

Squibb Company, Celgene Corporation, Clovis Oncology, Daiichi Sankyo Inc, Exelixis Inc, Genentech, a member of the Roche group, INC Pharma, Lilly, Merck, Novartis, Pfizer Inc, Xcovery

Ms Waxman — Disclosures

No relevant conflicts of interest to disclose.

Moderator Neil Love, MD Faculty Kelly EH Goodwin, MSN, RN, ANP-BC David R Spigel, MD Heather Wakelee, MD Elizabeth S Waxman, RN, MSN, ANP-BC

Management of Locally Advanced Non-Small Cell Lung Cancer

Tuesday, September 15, 2020 5:00 PM – 6:00 PM ET

Live Webinar Faculty

Kelly EH Goodwin, MSN, RN, ANP-BC Thoracic Cancer Center Massachusetts General Hospital Boston, Massachusetts David R Spigel, MD Chief Scientific Officer Program Director, Lung Cancer Research Sarah Cannon Research Institute Nashville, Tennessee Heather Wakelee, MD Professor of Medicine, Division of Oncology Faculty Director Stanford Cancer Clinical Trials Office Stanford University School of Medicine Stanford Cancer Institute Stanford, California Elizabeth S Waxman, RN, MSN, ANP-BC Nurse Practitioner in the Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Steering Committee

Ramaswamy Govindan, MD Professor of Medicine Director, Section of Oncology Anheuser-Busch Endowed Chair in Medical Oncology Washington University School of Medicine St Louis, Missouri Alison Holmes Tisch, MSN, RN, ANP-BC, AOCNP Clinical Operations Manager Thoracic, Neuro, Uro and Radiation Oncology Nurse Practitioner, Thoracic Oncology Stanford Health Care Palo Alto, California Project Chair Neil Love, MD Research To Practice Miami, Florida

What Advanced Practice Professionals Need to Know: Locally Advanced Non- Small Cell Lung Cancer: Thursday, November 5, 2020, 5:00 PM to 6:00 PM ET

Rasheda Persinger, NP-C Medical Oncology Lead Nurse Practitioner The Sidney Kimmel Comprehensive Cancer Center at Sibley Memorial Hospital Johns Hopkins Medicine Washington, DC Matthew Gubens, MD, MS Associate Professor, Thoracic Medical Oncology University of California, San Francisco San Francisco, California

We Encourage Clinicians in Practice to Submit Questions

You may submit questions using the Zoom Chat

• ption below

Feel free to submit questions now before the program commences and throughout the program.

Familiarizing Yourself with the Zoom Interface How to answer poll questions

When a poll question pops up, click your answer choice from the available

• ptions. Results will be shown after everyone has answered.

Moderator Neil Love, MD Faculty Kelly EH Goodwin, MSN, RN, ANP-BC David R Spigel, MD Heather Wakelee, MD Elizabeth S Waxman, RN, MSN, ANP-BC

Management of Locally Advanced Non-Small Cell Lung Cancer

Tuesday, September 15, 2020 5:00 PM – 6:00 PM ET

Management of Locally Advanced Non-Small Cell Lung Cancer

Module 1: Use of Consolidation Durvalumab for Patients with Locally Advanced NSCLC

• Overview of locally advanced NSCLC; traditional treatment paradigm
• Educating patients regarding the mechanism of action and potential benefits of consolidation

durvalumab

• Clinical and biologic considerations for the incorporation of consolidation durvalumab in the

management of locally advanced NSCLC

• Practical factors surrounding the administration of consolidation durvalumab

Module 2: Tolerability Considerations with Consolidation Durvalumab

• Common and uncommon adverse events observed with the use of consolidation durvalumab
• Counseling patients on immune-related adverse events
• Management of common clinical syndromes: gastritis, pneumonitis and colitis

Management of Locally Advanced Non-Small Cell Lung Cancer

Module 1: Use of Consolidation Durvalumab for Patients with Locally Advanced NSCLC

• Overview of locally advanced NSCLC; traditional treatment paradigm
• Educating patients regarding the mechanism of action and potential benefits of consolidation

durvalumab

• Clinical and biologic considerations for the incorporation of consolidation durvalumab in the

management of locally advanced NSCLC

• Practical factors surrounding the administration of consolidation durvalumab

Module 2: Tolerability Considerations with Consolidation Durvalumab

• Common and uncommon adverse events observed with the use of consolidation durvalumab
• Counseling patients on immune-related adverse events
• Management of common clinical syndromes: gastritis, pneumonitis and colitis

Lung Anatomy: Distribution of Lymph Nodes

Staging Regional Lymph Nodes in Lung Cancer

NX Regional lymph nodes cannot be assessed N0 No regional node metastasis N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastasis in the contralateral mediastinal, contralateral hilar, ipsilateral

• r contralateral scalene or supraclavicular lymph node(s)

Lung Cancer Stage Grouping (AJCC 8th Edition)

Detterbeck FC et al. Chest 2017;151(1):193-203.

Stage Distribution at Diagnosis of Patients with Lung Cancer

SEER Analysis: (2004-2010, N = 344,797)

Chen VW et al. Cancer 2014;120:3781-92. Siegel RL et al. CA Cancer J Clin. 2019 Jan;69(1):7-34.

Stage at diagnosis (AJCC, 7th edition) I II III IV Unknown % of patients 18% 7% 19% 49% 5% Est no. of patients in USA, 2019 41,067 15,971 43,349 111,794 11,408

Occult disease accounts for approximately 1.5%

Treatment Received for NSCLC (2000-2012, N = 780,294)

Based on the National Cancer Data Base (NCDB) according to TNM 8th Edition

Chansky K et al. J Thorac Oncol 2017;12(7):1109-21.

Unknown No Treatment Chemo only ChemoRT RT only Surgery followed by RT Surgery followed by ChemoRT Surgery followed by Chemo Surgery only % of Patients within Subgroup Best Stage

Selected Negative Trials after Concurrent Chemotherapy + Radiation

TRIAL DESIGN MEDIAN OS HR P VALUE CALGB 398011 Induction chemo à CRT vs cCRT 14 vs 12 N/R 0.3 LUN 01-242 cCRT à docetaxel vs cCRT 23.2 vs 21.2 N/R 0.883 SWOG S00233 cCRT à docetaxel à placebo vs cCRT à docetaxel à gefitinib 35 vs 23 0.63 .0013 RTOG 06174 cCRT à chemo vs cCRT + cetuximab à chemo 24 vs 25 1.07 0.29 START5 Sequential or cCRT à placebo vs Sequential or cCRT à tecemotide 25.6 vs 22.3 0.88 .123

• 1. Vokes et al J Clin Oncol 2007
• 2. Hanna et al J Clin Oncol 2008
• 3. Kelly et al J Clin Oncol 2008
• 4. Bradley et al Lancet Oncol 2015
• 5. Butts et al Lancet Oncol 2014

Courtesy of Benjamin Levy, MD

Proposed Mechanism for the Abscopal Effect

a) Primary kill by radiation

Wani SQ et al. Cureus 2019;11(2):e4100.

b) Metastasis destroyed by abscopal effect Destroy secondary b) Antigen-presenting cells (APCs) present tumor antigens to CD8 T cells c) CD8 T cells circulate through the body, destroying both directly irradiated tumor and metastasis by abscopal effect

Dendritic cell TUMOR Activated T cell Resting T cell LYMPH NODE TCR CD28 MHC B7 Tumor antigen Release of cancer cell antigens: chemotherapy, radiation, targeted therapy Cancer antigen presentation: vaccines Priming and activation: anti–CTLA-4 Killing of cancer cells: anti–PD-1, anti–PD-L1

Courtesy of Julie R Brahmer, MD, MSc

A Road Map of Immunotherapy Agents in the Cancer-Immune System Interaction

Rationale of checkpoint inhibitors after chemoradiation1–6

• 1. Deng L, et al. J Clin Invest 2014;124:687–695; 2. Dovedi SJ, et al. Cancer Res

2014;74:5458–5468; 3. Chacon JA, et al. Vaccines (Basel) 2016;4:E43; 4. Formenti SC, Demaria S. J Natl Cancer Inst 2013;105:256–265; 5. Funaki S, et al. Oncol Rep 2017;38:2277−2284; 6. Antonia SJ, et al. N Engl J Med 2017;377:1919–29.

Antigens

Chemotherapy Radiation

Antigen- presenting Cell Antigens Active T cell PD-L1 PD-1 Inactive T cells Tumor

PD-1/PD-L1 inhibitors reverse immune suppression and lead to a systemic antitumor response

CHECKPOINT INHIBITOR CHEMORADIATION

Chemoradiation induces tumor antigen release and an adaptive immune response PD-L1 overexpression leads to immune cell evasion Checkpoint inhibitors

Courtesy of Benjamin Levy, MD

PACIFIC: Study Design

Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study1

*Using the Ventana SP263 immunohistochemistry assay

†Defined as the time from randomization until the date of objective disease progression or death by any cause in the absence of progression. BICR, blinded independent central review;

cCRT, concurrent CRT; PFS2, time to second progression; RECIST, Response Evaluation Criteria in Solid Tumors; TTDM, time to death or distant metastasis. ClinicalTrials.gov number: NCT02125461

• Unresectable, Stage III NSCLC

without progression after definitive platinum-based cCRT (≥2 cycles)

• 18 years or older
• WHO PS score 0 or 1
• If available, archived pre-cCRT

tumor tissue for PD-L1 testing* All-comers population (i.e. irrespective of PD-L1 status) N=713 randomized Durvalumab 10 mg/kg q2w for up to 12 months N=476 Placebo 10 mg/kg q2w for up to 12 months N=237 2:1 randomization, stratified by age, sex, and smoking history Key secondary endpoints

• ORR, DoR and

TTDM by BICR

• PFS2 by

investigator

• Safety
• PROs

Primary endpoints

• PFS by BICR using

RECIST v1.1†

• OS

R

1–42 days post-cCRT

• 1. Antonia SJ, et al. N Engl J Med 2017;377:1919–29.

Courtesy of Benjamin Levy, MD

PACIFIC: Updated Progression-free Survival by BICR* (ITT)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39

Probability of Progression-free Survival Time from Randomization (months)

• No. at Risk

Durvalumab 476 377 302 268 213 188 163 143 116 83 43 23 1 Placebo 237 163 106 86 67 55 46 39 32 24 10 5 *Median duration of follow-up was 25.2 months (range 0.2–43.1)

†No formal statistical comparison was made because the study had achieved significance for PFS at the first planned IA (data cutoff of Feb 13, 2017)

PFS HR = 0.51

95% CI, 0.41–0.63† 34.4% 49.5% 55.7% 26.7%

• No. of events /
• No. of patients (%)

Median PFS (95% CI) months Durvalumab 243/476 (51.1) 17.2 (13.1–23.9) Placebo 173/237 (73.0) 5.6 (4.6–7.7) Antonia SJ et al. N Engl J Med 2018;379(24):2342-50.

Courtesy of Benjamin Levy, MD

Gray JE et al. J Thorac Oncol 2020;15(2):288-93.

Probability of OS Time from randomization (months)

• No. at risk
• No. of events/

total no. of patients (%) Median OS (95% CI) months 12-month OS rate (95% CI) % 24-month OS rate (95% CI) % 36-month OS rate (95% CI) % Durvalumab 210/476 (44.1) NR (38.4-NR) 83.1 (79.4-86.2) 66.3 (61.8-70.4) 57.0 (52.3-61.4) Placebo 134/237 (56.5) 29.1 (22.1-35.1) 74.6 (68.5-79.7) 55.3 (48.6-61.4) 43.5 (37.0-49.9) Stratified hazard ratio for death, 0.69 (95% CI, 0.55-0.86) Stratified hazard ratio for death from the primary analysis, 0.68 (95% CI, 0.53-0.87) Durvalumab Placebo

PACIFIC: 3-Year Overall Survival Analysis in the Intention-to-Treat Population

PACIFIC: Outcomes by Time to Initiation of Durvalumab

Antonia SJ et al. N Engl J Med 2017;377(20):1919-29; Gray JE et al. J Thorac Oncol 2020;15(2):288-93.

Progression-free Survival Overall Survival

Placebo Durvalumab

• no. of patients

Unstratified Hazard Ratio (95% CI)

Favors durvalumab Durvalumab Better Placebo Better

Placebo Durvalumab

• No. of events/
• no. of patients (%)

Unstratified Hazard Ratio for Death (95% CI)

PACIFIC Trial: Subgroup Analysis by PD-L1 Status

Note: PFS data based on data cutoff of Feb 13, 2017, and OS data based on data cutoff of March 22, 2018

• Important facts regarding PD-L1 status:

− PD-L1 testing was not required − 37% of patients with unknown PD-L1 status − PD-L1 status was obtained pre-CRT (getting a sample post-CRT medically not feasible) − PD-L1 expression-level cutoff of 1% was part of an unplanned post-hoc analysis requested by a health authority

Antonia SJ et al. N Engl J Med 2018;379(24):2342-50.

Courtesy of Benjamin Levy, MD

Progression-free and Overall Survival by Subgroup (ITT)

Note: PFS data based on data cutoff of Feb 13, 2017, and OS data based on data cutoff of March 22, 2018 *Not calculated if subgroup has <20 events NA, not available

Antonia SJ et al. N Engl J Med 2018;379(24):2342-50.

Courtesy of Benjamin Levy, MD

In general, should durvalumab be recommended as consolidation treatment for a patient with locally advanced NSCLC who underwent surgical excision and chemoradiation therapy as initial treatment?

At what point after the completion of chemoradiation therapy do you typically begin treatment with consolidation durvalumab in your patients with locally advanced NSCLC? (Dr Govindan)

14 – 42 days 21 – 28 days 14 – 42 days 14 – 21 days 7 – 14 days 21 days 42 days 1 – 7 days

Should imaging studies be obtained for all patients with locally advanced NSCLC after the completion of chemoradiation therapy but prior to initiating consolidation durvalumab? (Dr Spigel)

Yes Yes Yes Yes No Yes Yes No

Should PD-L1 levels generally be tested in patients with locally advanced NSCLC? (Dr Spigel)

Should patients with locally advanced NSCLC generally undergo testing for targetable tumor mutations? (Ms Waxman)

In general, do you believe durvalumab should be used as consolidation treatment after chemoradiation therapy for patients with locally advanced NSCLC with an EGFR tumor mutation? (Dr Spigel)

No Yes Yes Yes No Yes Yes No

What do you consider to be the absolute and relative contraindications to the use of consolidation durvalumab in the management of locally advanced NSCLC? (Ms Goodwin)

Absolute: severe/symptomatic pneumonitis; Relative: stable autoimmune illnesses Absolute: lupus, organ transplant; Relative: other autoimmune diseases, poor PS Absolute: pneumonitis, auto-immune disease; Relative: poor PS after CRT Transplant and any auto immune disease not well controlled Absolute: pneumonitis; Relative: underlying auto-immune disorders Severe autoimmune medical history and/or severe pneumonitis from radiation Preexisting autoimmune disorders (eg, myasthenia gravis) Underlying autoimmune disorders

In which situations, if any, do you administer sequential rather than concurrent chemoradiation therapy to your patients with locally advanced NSCLC? (Dr Spigel)

In general, should durvalumab be recommended as consolidation treatment for an older, frail patient who is unable to tolerate chemotherapy and receives only radiation therapy for unresectable locally advanced NSCLC?

Management of Locally Advanced Non-Small Cell Lung Cancer

Module 1: Use of Consolidation Durvalumab for Patients with Locally Advanced NSCLC

• Overview of locally advanced NSCLC; traditional treatment paradigm
• Educating patients regarding the mechanism of action and potential benefits of consolidation

durvalumab

• Clinical and biologic considerations for the incorporation of consolidation durvalumab in the

management of locally advanced NSCLC

• Practical factors surrounding the administration of consolidation durvalumab

Module 2: Tolerability Considerations with Consolidation Durvalumab

• Common and uncommon adverse events observed with the use of consolidation durvalumab
• Counseling patients on immune-related adverse events
• Management of common clinical syndromes: gastritis, pneumonitis and colitis

PACIFIC: Incidence and Time to Onset of Pneumonitis, and Treatment Exposure

Pneumonitis Durvalumab (N = 475) Placebo (N = 234) Any grade pneumonitis or radiation pneumonitis 96.8% 94.9% Grade 3/4 pneumonitis or radiation pneumonitis 29.9% 26.1% Median time to onset from 1st dose 55.0 days 55.0 days Median time to onset from radiotherapy 73.0 days 76.5 days Median duration 64.0 days 57.0 days

Vansteenkiste JF et al. Proc IASLC/WCLC 2018;Abstract MA05.02.

• Overall treatment exposure was similar for patients with or without pneumonitis

10 20 30 40 50 60 70 80 90 100 ≥16 ≥32 ≥48 ≥54

% of patients Weeks of treatment

10 20 30 40 50 60 70 80 90 100 ≥16 ≥32 ≥48 ≥54

% of patients Weeks of treatment Placebo with pneumonitis (n = 58) Placebo without pneumonitis (n = 176) Durvalumab with pneumonitis (n = 161) Durvalumab without pneumonitis (n = 314)

Real-World Rates of Pneumonitis After Consolidation Durvalumab

Real-World Survey of Pneumonitis/Radiation Pneumonitis in LA-NSCLC After Approval of Durvalumab: HOPE-005/CRIMSON Retrospective Cohort Study

• >80% developed pneumonitis
• More than half of them were asymptomatic, but 5% needed HOT and 1.5% developed fatal

pneumonitis

• V20 was an independent risk factor for symptomatic pneumonitis (Grade ≥2)
• With careful consideration, durvalumab-rechallenge could be an option after corticosteroid therapy

for pneumonitis Incidence of Pneumonitis in US Veterans with NSCLC Receiving Durvalumab After Chemoradiation Therapy

• In this real-world cohort, clinical significant pneumonitis was:

– More frequent compared to clinical trial reports

• Asymptomatic infiltrates on imaging: 39.8%
• Clinically significant pneumonitis: 21.1%

– Grade 2 (7.3%), Grade 3 (11.4%), Grade 4 (1.6%), Grade 5 (0.8%) – Not associated with increased risk of death

Saito et al. ASCO 2020; Abstract 9039. Thomas T et al. ASCO 2020; Abstract 9034.

Immune-Mediated Toxicity

• Use of checkpoint inhibitors (including durvalumab)

– Restore the ability of a patient’s T-cells to attack tumors – Generate an immune-mediated antitumor response – The same checkpoints also prevent autoimmunity – Inhibiting those checkpoints can lead to autoimmune toxicity

June, Nat Med 2017

Courtesy of Stephen V Liu, MD, PhD

Immune-Mediated Toxicity

• Any organ/system can be

affected

– Special concern in stage III NSCLC for the lungs – Radiation alone can cause pneumonitis – Generally low grade, if any – Potential for serious toxicity – Early recognition is the key to avoiding poor outcomes

June, Nat Med 2017

Courtesy of Stephen V Liu, MD, PhD

Pneumonitis

• Pneumonitis differential

– Radiation pneumonitis (consider radiation fields) – Immune-mediated pneumonitis (consider timing) – Pneumonia or infection (consider other symptoms)

• If non-infectious, initial management of radiation

pneumonitis and immune-mediated pneumonitis is similar (steroid therapy)

Courtesy of Stephen V Liu, MD, PhD

Pneumonitis Management

• Symptoms must be monitored closely

– Engage entire medical team and caregivers – New dyspnea/cough, new hypoxia warrant workup

• Low threshold to hold therapy for evaluation
• Management guided by grade of pneumonitis

– Grade 1: asymptomatic, no intervention needed – Grade 2: symptomatic, intervention required – Grade 3: severe symptoms, limiting ADLs, oxygen indicated – Grade 4: life threatening

Brahmer, JCO 2018

Courtesy of Stephen V Liu, MD, PhD

Pneumonitis Management

• Grade 2 symptomatic pneumonitis

– Hold immunotherapy – Radiographic imaging – Steroids: prednisone 1-2 mg/kg/d, taper over 4-6 weeks – Consider antibiotics – Monitor every 3 days, should improve in 2-3 days

Brahmer, JCO 2018

Courtesy of Stephen V Liu, MD, PhD

Pneumonitis Management

• Grade 3 severe pneumonitis

– Inpatient management – Permanently discontinue therapy – CT scan – Start IV steroids (methylprednisolone 1-2 mg/kg/d)

• Escalate immunosuppression if not improving within 48h

– Pulmonary and ID consultations

Brahmer, JCO 2018

Courtesy of Stephen V Liu, MD, PhD

Other Immune-Mediated Adverse Events

• Non-pneumonitis immune-mediated events with durvalumab

– 56.3% occur within 3 months; 83.1% within 6 months – Thyroid disorders (seen in 11.4% of patients) – Rash/dermatitis (seen in 1.9%) – Diarrhea/colitis (seen in 1.1%)

Naidoo, ASCO 2020

Thyroid Rash Diarrhea Time to Onset 85 days 37 days 61 days Duration 63.5 days 117 days 74 days Time to Resolution 56 days 104 days 47.5 days

Courtesy of Stephen V Liu, MD, PhD

Immune-Mediated Adverse Events

• Hormone replacement if indicated
• For severe immune-related side effects, treatment is

immune suppression (steroids)

– Early and aggressive intervention important for severe cases – When steroids tapered off, side effects may return

• Long courses of steroids may be needed
• Potential risk of infection and other complications of steroid use

– Lowering the dose or changing schedule is not effective

Roth, JCO 1992

Courtesy of Stephen V Liu, MD, PhD

Monitoring with Immunotherapy

• History and physical

– New symptoms, new findings, vital signs

• Regular blood tests when receiving immunotherapy

– CBC, BMP, LFTs, TSH

• Symptom-directed evaluation as needed

– Cortisol, troponin, CPK, gonadotropins

• Direct and open communication with the team

– Not just during treatment visits

• Anything notable and new needs to be reported!

Courtesy of Stephen V Liu, MD, PhD

A patient undergoing concurrent chemoradiation therapy for locally advanced NSCLC is scheduled to receive treatment tomorrow but has a neutrophil count of 650 with no fever or other symptoms. What would you recommend? (Dr Gubens)

Skip chemotherapy tomorrow but administer radiation therapy Skip chemotherapy tomorrow but administer radiation therapy Skip chemotherapy tomorrow but administer radiation therapy Skip chemotherapy tomorrow but administer radiation therapy Skip chemotherapy tomorrow but administer radiation therapy Skip chemotherapy tomorrow but administer radiation therapy Skip chemotherapy tomorrow but administer radiation therapy Skip chemotherapy tomorrow but administer radiation therapy

Do you routinely administer growth factors during concurrent chemoradiation therapy in your patients with locally advanced NSCLC? (Ms Goodwin)

No No No No No No No No

Do you routinely recommend the placement

• f enteral feeding tubes prior to the initiation
• f chemoradiation therapy in your patients

with locally advanced NSCLC? (Dr Spigel)

A patient who successfully received chemoradiation therapy for locally advanced NSCLC is about to start durvalumab but is experiencing mild

• esophagitis. Should durvalumab be started?

Yes Yes Yes Yes Yes Yes Yes Yes

What are the most common immune-mediated adverse events that you

• bserve in your patients who are receiving consolidation durvalumab?

(Ms Goodwin)

Hypothyroidism, rash, myalgias/rheum side effects, pneumonitis, hepatitis, colitis Fatigue, pneumonitis, thyroiditis Dermatitis, thyroiditis, pneumonitis Fatigue, arthralgias, thyroid abnormalities Hypothyroidism, rash/pruritus, pneumonitis, colitis, transaminitis Pneumonitis, rash, colitis Thyroiditis Hypothyroidism, pneumonitis

What would you estimate to be the likelihood that a patient who is started on consolidation durvalumab for unresectable locally advanced NSCLC will be able to complete 1 year of therapy, assuming there is no recurrence?

A patient with locally advanced NSCLC has been receiving consolidation durvalumab and faring well. His wife calls saying that over the past week he has developed a dry cough that has worsened but no fever. He is also increasingly short of breath and is having trouble walking short distances. What would you recommend? (Dr Gubens)

Same day clinic evaluation including O2 sats, PE-CT to eval for pneumonitis Send him to the emergency room for a CT scan now Send him to the emergency room for a CT scan now Send him to the emergency room for a CT scan now Clinic visit w/ O2 sats, determine need for ER versus outpatient management Obtain a CT scan before his next scheduled office visit Send him to the emergency room for a CT scan now Send him to the emergency room for a CT scan now

A patient with locally advanced NSCLC has completed 6 months of consolidation

• durvalumab. She feels well, remains active, has no cough and her vital signs show

her respiratory rate to be 14 and her oxygen saturation to be 98%. Chest CT shows possible pneumonitis in her right lower lobe near the radiation field. What would you recommend? (Dr Gubens)

Hold durvalumab and obtain next CT in 1 month Hold durvalumab and administer corticosteroids Continue durvalumab and obtain next CT in 1 month Hold durvalumab with short threshold for holding and/or starting prednisone Continue durvalumab and obtain next CT in 3 months Continue durvalumab and obtain next CT in 3 months Continue durvalumab and obtain next CT in 1 month Continue durvalumab and obtain next CT in 3 months

A 68-year-old man develops dyspnea 2 months after completion of concurrent chemoradiation therapy while receiving consolidation durvalumab. He is diagnosed with pneumonitis, which is felt to be radiation related. Durvalumab is held and he is started on steroids. After 1 month, his symptoms have resolved, and he has been tapered down to 5 mg daily of prednisone. Would you restart durvalumab? (Dr Wakelee)

Yes Yes Yes Yes Yes Yes Yes No

A 60-year-old woman with locally advanced NSCLC has completed 3 cycles of cisplatin/pemetrexed with concurrent radiation therapy. She starts consolidation durvalumab but after 5 days calls in complaining of diarrhea (4 loose bowel movements in the past 24 hours without any abdominal pain). Do you advise her to take the loperamide that was prescribed to her? (Dr Wakelee)

No Yes Yes Yes Yes Yes Yes Yes

A 75-year-old woman with locally advanced NSCLC has completed chemoradiation therapy and is receiving consolidation durvalumab. Her morning labs, which are fasting, have shown progressively higher glucose levels (210 mg/dL after her first cycle and 300 mg/dL after her second). Do you believe this could be related to the durvalumab? (Dr Wakelee)

Yes No Yes Yes Yes Yes Yes Yes

In general, how often should thyroid function tests be performed in patients with locally advanced NSCLC who are receiving durvalumab consolidation? (Dr Wakelee)

Every 4 weeks Every 12 weeks Every 4 weeks Every 4 to 6 weeks Every 6 weeks Every 4 weeks Every 4 weeks Every 4 weeks

A patient with locally advanced NSCLC has completed 3 months of consolidation durvalumab and is faring well but on routine labs is noted to have a TSH level of 14 mU/L and a free T4 level of 3 ng/dL. What would you recommend? (Dr Gubens)

Continue durvalumab and start thyroid hormone supplementation Continue durvalumab and continue to monitor thyroid function Continue durvalumab and start thyroid hormone supplementation Continue durvalumab and start thyroid hormone supplementation Continue durvalumab and start thyroid hormone supplementation Continue durvalumab and start thyroid hormone supplementation Continue durvalumab and start thyroid hormone supplementation Continue durvalumab and continue to monitor thyroid function

A 63-year-old man receives chemoradiation therapy and has completed 10 cycles of consolidation durvalumab. Upon arrival for his next cycle of treatment, his AST and ALT, which have been normal to this point, are 160 and 190, respectively. Would you authorize treatment? (Dr Wakelee)

No Yes No Yes No No Yes Yes

A 55-year-old woman with locally advanced NSCLC with an EGFR exon 19 deletion mutation has been receiving consolidation durvalumab for 6 months when repeat imaging shows metastatic disease in her liver. What would you estimate is the likelihood that this patient will develop pneumonitis if osimertinib is administered immediately after durvalumab? (Dr Wakelee)

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