Edward B. Garon, MD, MS, Jamie E. Chaft, MD, and Matthew D. Hellmann, MD, prepared useful Practice Aids pertaining to lung cancer management for this CME/MOC/CE activity titled "Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Cancer Continuum: State of the Science and Implications for Practice." For the full presentation, monograph, complete CME/MOC/CE information, and to apply for credit, please visit us at http://bit.ly/2ATq0qp. CME/MOC/CE credit will be available until November 21, 2019.

1. a
Time from randomization to the first documented tumor progression, or death in the absence of progression. b
ORR as measured from baseline scan post-CRT completion.
BIRC: blinded independent review committee; cCRT: concurrent chemoradiation therapy; DOR: duration of response; NSCLC: non–small-cell lung cancer; ORR: objective response rate; PD-L1: programmed death ligand 1; PRO: patient-reported outcome; PS: performance status;
SOC: standard of care.
1. Paz-Ares L et al. 2017 European Society for Medical Oncology Congress. LBA1. 2. Antonia SJ et al. N Engl J Med. 2017 Sep 8. [Epub ahead of print]. 3. Antonia SJ et al. WCLC 2019. Abstract PL02.01.
Access the activity, “Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Cancer
Continuum: State of the Science and Implications for Practice,” at www.peerview.com/CVU40.
OTHER IMMUNOTHERAPY TRIALS IN STAGE III NSCLC
• Stage III, locally advanced,
unresectable NSCLC
• No progression following definitive
platinum-based cCRT (≥2 cycles)
• ≥18 years of age
• WHO PS score 0 or 1
• Estimated life expectancy ≥12 wk
Cough
(35.4% vs 25.2%)
Durvalumab Placebo
vs
16.8 mo
(95% CI, 13-18.1)
5.6 mo
(95% CI, 4.6-7.8)
Co-primary
• PFS by BIRC (RECIST v1.1)
• OS
Secondary
• ORR per BIRC
• DOR per BIRC
• Safety/tolerability
• PROs
Durvalumab
10 mg/kg 1x/2 wk
up to 12 mo
n = 476
Placebo
10 mg/kg 1x/2 wk
up to 12 mo
n = 237
2:1 randomization
stratified by age, sex,
and smoking history
48% reduction in risk of progression
or death vs placebo (HR = 0.52)
(95% CI, 0.42–0.65)
Benefit irrespective of PD-L1 expression or EGFR mutation status
1-42 days
post-cCRT
Design: consolidation therapy
Nivolumab
Pembrolizumab
Pembrolizumab
Atezolizumab
Nivolumab
3
2
1
2
2
Treatment Phase
RTOG 3505
−
−
−
NICOLAS
Name
NCT02768558
NCT02343952
NCT02621398
NCT02525757
NCT02434081
ClinicalTrials.gov Identifier
OS/PFS
Time to death or distant metastasis
Safety
Safety/timing
Safety
Primary Endpoint
Grade 3/4 AEs:
Durvalumab
Placebo
Durvalumab
Placebo
28.4%
95% CI, 24.28-32.89
16.0%
95% CI, 11.31-21.59
P < .001P < .001
PACIFIC TRIAL1-3 The first phase 3 trial to test an immune checkpoint inhibitor as sequential treatment in patients with stage III
NSCLC who had not progressed following platinum-based chemotherapy concurrent with radiation therapy
Statistically-significant OS benefit with clinically meaningful improvement
in patients receiving durvalumab compared with placeboOS
Most frequent AEs Grade 3/4 AEsDurvalumab vs Placebo
29.9% 26.1%Fatigue
(23.8% vs 20.5%)
Pneumonitis/
radiation pneumonitis
(33.9% vs 24.8%)
Dyspnea
(22.3% vs 23.9%)Diarrhea
(18.3% vs 18.8%)
Safety
Median PFSa
ORRb
EndpointsPatients
All-comers population
FDA approved on February 16, 2018; indicated for:
Recommended Dosage
Patients with unresectable stage III NSCLC whose disease
has not progressed following concurrent platinum-based
chemotherapy and radiation therapy
10 mg/kg administered as an intravenous infusion over
60 minutes every 2 weeks until disease progression,
unacceptable toxicity, or a maximum of 12 months
New SOC
IMMUNE CHECKPOINT INHIBITION AS A KEY
TREATMENT STRATEGY IN STAGE III NSCLC
Current Evidence and Ongoing Trials

2. 1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768.
Access the activity, “Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Cancer
Continuum: State of the Science and Implications for Practice,” at www.peerview.com/CVU40.
• In general, checkpoint inhibitor therapy should be continued with close monitoring, with the
exception of some neurologic, hematologic, and cardiac toxicities
(Minimalornosymptoms;diagnosticchangesonly)
Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic
enhancement can also lead to a unique spectrum of immune-related adverse effects (irAEs)
Grade 1
What is the spectrum of potential irAEs?Why do irAEs occur?
General recommendations and management principles include the following:
IrAEs are often diagnosed by exclusion;
other causes should be ruled out
(including AEs of other therapies
used), but immunotherapy-related
toxicity should always be included
in the differential
There should be a high level of suspicion
that new symptoms are treatment-
related; early recognition, evaluation,
and treatment of irAEs plus patient
education are essential for best outcome
Depending on severity of irAE,
management may require corticosteroid
or other immunosuppressive treatment
and interruption or discontinuation
of therapy
If appropriate immunosuppressive
treatment is used, patients generally
recover from irAEs
Use of immunosuppressive therapy
to manage irAEs does not impact
response to immunotherapy
How should irAEs be diagnosed and managed?
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or lab values revert ≤ grade 1
• Corticosteroids (initial dose of 0.5-1 mg/kg/day of prednisone or equivalent) may be administered
Grade 3 toxicities:
• Hold checkpoint inhibitor therapy
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/day or methylprednisolone IV 1-2 mg/kg/day)
• If symptoms do not improve with 48-72 hours of high-dose corticosteroid, infliximab may be offered
for some toxicities
• Taper corticosteroids over the course of at least 4-6 weeks
• When symptoms and/or laboratory values revert to ≤ grade 1, rechallenging with immunotherapy
may be offered; however caution is advised, especially in those patients with early-onset irAEs;
dose adjustments are not recommended
Grade 4 toxicities:
• In general, permanent discontinuation of checkpoint inhibitor therapy is warranted, with the exception
of endocrinopathies that have been controlled by hormone replacement
Brahmer JR et al. Management of Immune-Related Adverse Events in PatientsTreated
With Immune Checkpoint InhibitorTherapy: American Society of Clinical Oncology
Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768.
For organ-specific assessment and management of irAEs, please see the ASCO guidelines:
Additional resources available on the ASCO website:
https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/supportive-care-and-treatment-related-issues#/29866
Grade 2
(Mild to moderate symptoms)
(Severe or life-threatening symptoms)
Grades 3/4
Any organ system can be affected; more commonly occurring are pulmonary
(pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, vitiligo),
gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis),
and endocrine (thyroiditis, hypophysitis, adrenal insufficiency) irAEs
The precise pathophysiology is unknown, but translational studies have
shown that T-cell, antibody, and cytokine responses may be involved
Q
Q
Q
A
A
A
Pancreatitis,
autoimmune diabetes
Colitis
Enteritis
Encephalitis, aseptic menigitis
Thyroiditis, hypothyroidism,
hyperthyroidism
Dry mouth, mucositis
Hypophysitis
Uveitis
Pneumonitis
Thrombocytophenia,
anemia
Hepatitis
Adrenal insufficiency
Nephritits
Vasculitis
Arthralgia
Neuropathy
Rash, vitiligo
Myocarditis
Increasing T-cell
activity against
antigens that
are present in
tumors and
healthy tissue
Activated T cell
Antithyroid
antibodies
Increasing
levels of
inflammatory
cytokines
Increasing levels
of preexisting
autoantibodies
Enhancing
complement-mediated
inflammation due to
direct binding of an
anti–CTLA-4 antibody
with CTLA-4
expressed on
normal tissue
Activated T cell
Anti–CTLA-4 antibody
CTLA-4 on pituitary Complement-
mediated
inflammation
Cytokines
Tumor with antigen
and activated T cells
IMMUNE-RELATED ADVERSE EFFECTS
ASSOCIATED WITH IMMUNE
CHECKPOINT INHIBITORS
Underlying Mechanisms, Spectrum of Presentation, & Management1, 2

3. ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; NSCLC: non–small-cell lung cancer; PD-L1: Programmed death-ligand 1; PFS: progression-free survival; OS: overall survival; SOC: standard of care; TKI: tyrosine kinase inhibitor; TMB: tumor mutational burden.
1. Lopes G et al. 2018 American Society of Clinical Oncology Annual Meeting (ASCO 2018). Abstract LBA4. 2. Gandhi L et al. N Engl J Med. 2018;378(22):2078-2092. 3. Paz-Arez LG et al. ASCO 2018. Abstract 105. 4. Socinski M et al. N Engl J Med. 2018;378:2288-2301.
5. https://www.roche.com/media/releases/med-cor-2018-05-29.htm. Accessed September 12, 2018. 6. Jotte RM et al. ASCO 2018. Abstract LBA9000. 7. Hellmann MD et al. N Engl J Med. 2018;378:2093-2104.
Access the activity, “Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Cancer
Continuum: State of the Science and Implications for Practice,” at www.peerview.com/CVU40.
Select First-Line Immunotherapy Trials With Recent Data Read-Outs1-7
Select First-Line Immunotherapy Trials With Upcoming Data Read-Outs
Driver mutation absent
Squamous Non-Squamous
Driver mutation present
Pembrolizumab
PD-L1
≥50%
PD-L1
<50%
Pembrolizumab
or pemetrexed +
carboplatin +
pembrolizumab
Pemetrexed +
carboplatin +
pembrolizumab
Chemotherapy
ALK/EGFR
TKIs
or other targeted Rx
PD-L1
≥50%
PD-L1
<50%
OS benefit for pembrolizumab vs doublet chemotherapy in patients
with squamous/non-squamous NSCLC with PD-L1 ≥1%KEYNOTE-042
OS/PFS benefit for pembrolizumab + chemotherapy (pemetrexed/
platinum) vs chemotherapy in patients with non-squamous NSCLC
regardless of PD-L1 expression
KEYNOTE-189
OS benefit for pembrolizumab + chemotherapy (carboplatin/paclitaxel
or nab-paclitaxel) vs chemotherapy in patients with squamous NSCLCKEYNOTE-407
OS/PFS benefit for atezolizumab + bevacizumab + chemotherapy vs
bevacizumab + chemotherapy in patients with non-squamous NSCLC*
*All prespecified exploratory biomarker-selected subgroups (incl. EGFR+ and ALK+, varying levels of PD-L1 expression)
IMpower150
OS benefit for atezolizumab + chemotherapy (carboplatin/nab-paclitaxel)
vs chemotherapy in patients with nonsquamous NSCLCIMpower130
PFS benefit for atezolizumab + chemotherapy (carboplatin/
nab-paclitaxel) vs chemotherapy in patients with squamous NSCLCIMpower131
PFS benefit for nivolumab + ipilimumab vs chemotherapy in patients
with NSCLC and highTMB, irrespective of PD-L1 expressionCheckMate -227
MYSTIC
NCT02453282
Patients with EGFR and ALK wild-type locally advanced or metastatic NSCLC
Durvalumab + tremelimumab vs platinum-based SOC chemotherapy
Durvalumab monotherapy versus platinum-based SOC chemotherapy
Combination arm: PFS + OS
Monotherapy arm: OS
Primary endpoints
OS
Primary endpoint
PFS
Primary endpoint
NEPTUNE
NCT02542293
Patients with EGFR and ALK wild-type advanced or metastatic NSCLC
Durvalumab + tremelimumab vs platinum-based SOC chemotherapy
POSEIDON
NCT03164616
Patients with metastatic NSCLC lacking activating EGFR mutations or ALK fusions
Durvalumab + tremelimumab + SOC chemotherapy vs durvalumab +
SOC chemotherapy vs SOC chemotherapy
Current First-Line Treatment Algorithm for Stage 4 NSCLC
THE EVOLVING IMMUNOTHERAPY
LANDSCAPE IN ADVANCED NSCLC
Single-Agent and Combinatorial Approaches in the First-Line Setting