The Evolving Role of

Immunotherapy as a Component
of Multimodal Therapy in Earlier
Stages of Lung Cancer

Rationale, Current Evidence, Key Trials, and

Implications for Multidisciplinary Care

This event will take place at the AATS International Thoracic Surgical Oncology Summit.
 Disclosures
Naiyer Rizvi, MD, has a financial interest/relationship
or affiliation in the form of:
Consultant for AstraZeneca; Bristol-Myers Squibb; Eli
Lilly and Company; F. Hoffmann-La Roche; Merck &
Co., Inc.; Novartis Pharmaceuticals Corporation; and
Pfizer Inc.
Stock Shareholder in Gritstone Oncology where Dr.
Rizvi is a Co-Founder.
Naiyer Rizvi, MD, does intend to discuss either non–
FDA-approved or investigational use for the following
products/devices: Immune checkpoint inhibitors as
monotherapies or as part of combinations.
Benny Weksler, MBA, MD, has a financial
interest/relationship or affiliation in the form of:
Other Financial or Material Support from Dr. Weksler
is a proctor for Intuitive Surgical Inc.
Benny Weksler, MBA, MD, does intend to discuss
either non–FDA-approved or investigational use for
the following products/devices: Immune checkpoint
inhibitors as monotherapies or as part of
combinations.

This CME/MOC/CE activity is jointly provided by Medical Learning Institute, Inc. and
PVI, PeerView Institute for Medical Education.
This activity is supported by an independent educational grant from AstraZeneca.
 Disclosures

CME Reviewer Medical Director

Siyang Leng, MD Kadrin Wilfong, MD
Siyang Leng, MD, has no financial PVI, PeerView Institute for Medical Education
interests/relationships or affiliations in relation to
this activity. Kadrin Wilfong, MD, has no financial
interests/relationships or affiliations in relation to
CE Reviewer this activity.
Janice Trainor-Tellier, MSN, RN 
Janice Trainor-Tellier, MSN, RN, has no
financial interests/relationships or affiliations in
relation to this activity.

The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for
Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest
related to the content of this CME/MOC/CE activity during the past 12 months.
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 MasterClass
Immunotherapy as a Component
of Multimodal Therapy of
Lung Cancer
Where Are We Now and
Where Are We Going Next?
 Module 1
Evolving Role of Immunotherapy in
Unresectable Stage III NSCLC
Naiyer Rizvi, MD
Price Family Chair Professor of Medicine
Director, Thoracic Oncology
Co-Director, Cancer Immunotherapy
Columbia University Medical Center
New York, New York
• How does cancer
immunotherapy work?

• What are the immune

checkpoint inhibitors?
 Adaptive Immune Response1

1. Topalian SL et al. Nat Rev Cancer. 2016;16:275-287.

 Ways to Enhance T-Cell Attack1

T-Cell

Turning
Blocking
Up the
the
Activating
Inhibiting

1. Mellman I et al. Nature. 2011;480:480-489.

 Mechanism of Checkpoint Inhibition1

T-Cell T-Cell T-Cell T-Cell

1. Adapted from Pallin DJ et al. Acad Emerg Med. 2018;25:819-827.

 Current Immune Checkpoint Inhibitors

Drug Mechanism
Ipilimumab Anti–CTLA-4
Nivolumab
Pembrolizumab Anti–PD-1
Cemiplimab-rwlc
Atezolizumab

Avelumab Anti–PD-L1

Durvalumab
 Current Immunotherapy-Based Combinations

Drugs Indication(s)

Melanoma (metastatic)
Nivolumab + ipilimumab Renal cell carcinoma
MSI-high or MMR-deficient colorectal cancer

Pembrolizumab + chemotherapy NSCLC

 Current Immunotherapy Landscape in NSCLC:
FDA Approvals of Checkpoint Inhibitors and Combinations
Pembrolizumab Pembrolizumab + Durvalumab
PD-L1+ pemetrexed/carboplatin stage III
mNSCLC 1L mNSCLC 1L NSCLC

Nivolumab Pembrolizumab Nivolumab

Atezolizumab
squamous PD-L1 + nonsquamous
mNSCLC 2L
mNSCLC 2L mNSCLC 2L mNSCLC 2L
• What is the rationale for using the immune
checkpoint inhibitors in locally advanced,
unresectable, stage III NSCLC?
 PACIFIC—Setting

> Unresectable Stage III NSCLC

 Tecemotide (L-BLP25) vs Placebo
After CRT for Stage III NSCLC (START)1
Tecemotide Placebo Tecemotide Placebo
(n = 829) (n = 410) (n = 829) (n = 410)

Median OS, mo (95% CI) 25.6 22.3 10.0 8.4

(22.5-29.2) (19.6-25.5) Median TTP, mo (95% CI) (9.1-11.5) (7.2-10.8)
HR (95% CI) 0.88 (0.75-1.03) 0.87
HR (95% CI) (0.75-1.00)
1-y OS, % (n) 77 (617) 75 (285)
2-y OS, % (n) 51 (301) 46 (127)
3-y OS, % (n) 40 (204) 37 (88)

1. Butts C et al. Lancet Oncol. 2014;15:59-68.

 Tecemotide (L-BLP25) vs Placebo
After CRT for Stage III NSCLC (START) (Cont’d)1
Overall Survival in Patients Who Received Concurrent Chemoradiotherapy
Tecemotide Placebo
(n = 538) (n = 268)
Median OS (95% CI), mo 30.8 (25.6-36.8) 20.6 (17.4-23.9)

HR (95% CI) 0.78 (0.64-0.95)

1. Butts C et al. Lancet Oncol. 2014;15:59-68.

 Addressing Unmet Needs: Emergence of
Immunotherapy in Stage III NSCLC
 Median PFS with standard SOC cCRT  ≈8-10 months and
only 15% are alive at 5 years1-6
 No major advances in locally advanced NSCLC for many years 
significant unmet need exists for novel therapeutic approaches to
improve outcomes beyond those achieved with cCRT

Immunotherapy is providing new hope and changing the

management of stage III NSCLC

1. Aupérin A et al. J Clin Oncol. 2010;28:2181-2190. 2. Yoon SM et al. World J Clin Oncol. 2017;8:1-20.
3. Ahn JS et al. J Clin Oncol. 2015;33:2660-2666. 4. Furuse J et al. Clin Oncol. 1999;17:2692-2699.
5. Belderbos J et al. Eur J Cancer. 2007;43:114-121. 6. Clamon G et al. J Clin Oncol. 1999;17:4-11.
 Radiation Can Be Immunogenic1

• 46 case reports between

1969 and 2014
• Wide variety of tumor
types, treatment sites,
dose schedules
• “Abscopal response”
occurred at 0 to 12 months

1. Abuodeh Y et al. Curr Probl Cancer. 2016;40:25-37.

 Radiation Can Induce Abscopal Response in Presence
of Immune Checkpoint Inhibition (Anti–CTLA-4)1

September 2013
PET/CT

August 2012 August 2012

PET/CT CT/sim
August 2012 January 2013
1. Golden EB et al. Cancer Immunol Res. 2013;1:365-372. PET/CT PET/CT
• In the context of KEYNOTE-001, patients were divided into subgroups to compare patients who
previously received radiotherapy with patients who had not
• 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first
cycle of pembrolizumab, (39%) extracranial, and (25%) thoracic radiotherapy
HR 0.58 (95% CI 0.36-0.94); P = .026

• Median overall survival:

10.7 months vs 5.3 months

• Extracranial radiotherapy:
HR 0·59, P = ·034
 Chemotherapy-Induced
Immunogenic Cell Death1

T-cell

1. Gotwals P et al. Nat Rev Cancer. 2017;17:286-301.

• What clinical evidence supports the use of
immune checkpoint inhibition in locally
advanced, unresectable, stage III NSCLC?
 Stage III NSCLC:
Key Immune Checkpoint Inhibitor Trials
• Design: Consolidation therapy

Phase Primary Endpoint Name ClinicalTrials.gov Identifier

Durvalumab 3 OS/PFS PACIFIC NCT02125461
Nivolumab 3 OS/PFS RTOG 3505 NCT02768558
Pembrolizumab 2 OS/PFS — NCT02343952
Pembrolizumab 1 Safety — NCT02621398

Atezolizumab 2 Safety/timing — NCT02525757

Nivolumaba 2 Safety NICOLAS NCT02434081

a
This trial also has a concurrent immunotherapy part.
 PACIFIC Trial: Design1,2
Phase 3 randomized, double-blind, placebo-controlled, multicenter, international study

• Stage III, locally advanced, Durvalumab

unresectable NSCLC 10 mg/kg Q2W (up to 12 mo)
• No progression following definitive n = 476
1-42 days
platinum-based cCRT (≥2 cycles) post-cCRT 2:1 randomization stratified by age,
• ≥18 years of age R sex, and smoking history
• WHO PS score 0 or 1 Placebo
• Estimated life expectancy ≥12 wk
10 mg/kg Q2W (up to 12 mo)
All-comers population n = 237

Endpoints
•Co-primary: PFS by BICRa (RECIST v1.1), and OS
•Key secondary: ORR per BICRb, DOR (per BICR), safety/tolerability, and PROs
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 1.
1. Paz-Ares L et al. 2017 European Society for Medical Oncology Annual Meeting (ESMO 2017). Abstract LBA1.
2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.
 Patient Characteristics1
Characteristic Durvalumab (N=476) Placebo (N=237) Total (N=713)
Age—yrs
Median 64 64 64
Range 31-84 23-90 23-90
Sex—No (%)
Male 334 (70.2) 166 (70.0) 500 (70.1)
Female 142 (29.8) 71 (30.0) 213 (29.9)
Disease stage—No (%)
IIIA 252 (52.9) 125 (52.7) 377 (52.9)
IIIB 212 (44.5) 107 (45.1) 319 (44.7)
Other 12 (2.5) 5 (2.1) 17 (2.4)
WHO performance status score—No (%)
0 234 (49.2) 114 (48.1) 384 (48.8)
1 240 (50.4) 122 (51.5) 362 (50.8)
1. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.
 PFS by BICR in the ITT Population1,2
Durvalumab Placebo
Median PFS (95% CI), mo 16.8 (13.0-18.1) 5.6 (4.6-7.8)
12-mo PFS, % (95% CI) 55.9 (51.0-60.4) 35.3 (29.0-41.7)
18-mo PFS, % (95% CI) 44.2 (37.7-50.5) 27.0 (19.9-34.5)

Stratified HRa = 0.52

(95% CI, 0.42-0.65)
Two-sided P < .001

a
Time from randomization to the first documented tumor progression, or death in the absence of progression.
1. Paz-Ares L et al. ESMO 2017. Abstract LBA1.
2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.
 Time to Death or Distant Metastasis
in the ITT Population1
Median Time to
No. of Events/
Death or Distant
Total No. of
Metastasis (95%
Patients
CI), mo

Durvalumab 182/476 28.3 (24.0-34.9)

Placebo 126/237 16.2 (12.5-21.1)

Stratified HR for death = 0.53 (95% CI, 0.41-0.68)

1. Antonia SJ et al. N Engl J Med. 2018 Sep 25 [Epub ahead of print].

 OS in the ITT Population1,2
No. of Events/ Median OS 12-mo OS Rate 24-mo OS Rate
Total No. of Patients (95% CI), mo (95% CI), % (95% CI), %

NR 83.1 66.3
Durvalumab 183/476
(34.7-NR) (79.4-86.2) (61.7-70.4)

28.7 75.3 55.6

Placebo 116/237
(22.9-NR) (69.2-80.4) (48.9-61.8)

Stratified HR for death = 0.68 (99.73% CI, 0.47-0.997)

Two-sided P = .0025

No. at Risk

1. Antonia SJ et al. 2018 IASLC 19th World Conference on Lung Cancer (WCLC 2018). Abstract PL02.01.
2. Antonia SJ et al. N Engl J Med. 2018 Sep 25 [Epub ahead of print].
 PFS and OS by Subgroup in the ITT Population 1
PFS HR (95% CI) OS HR (95% CI)
All patients
Sex Male
Female
Age at randomization <65 years
≥65 years
Smoker
Smoking status
Nonsmoker
Stage IIIA
Disease stage
Stage IIIB
Squamous
Tumor histologic type Nonsquamous
Cisplatin
Prior definitive CT Carboplatin
CR NA NA
Best response to PR
prior treatment SD
Positive NA
Negative
EGFR status
Unknown

0.25 0.50 1.00 2.00 0.25 0.50 1.00 2.00

Durvalumab better Placebo better Durvalumab better Placebo better
1. Antonia SJ et al. WCLC 2018. Abstract PL02.01.
 Subgroup Analysis by PD-L1 Status1

PFS HR (95% CI) OS HR (95% CI)

All patients
≥25%
PD-L1 status (prespecified)
<25%
Unknown
≥1%
PD-L1 status (post-hoc) 1-24%
<1%

0.25 0.50 1.00 2.00 0.25 0.50 1.00 2.00

Durvalumab better Placebo better Durvalumab better Placebo better

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 1% was part of an unplanned post-hoc analysis
requested by a health authority

1. Antonia SJ et al. WCLC 2018. Abstract PL02.01.

 Antitumor Activity by BICR
in the ITT Population1,2
Durvalumab Placebo
(n = 443)a (n = 213)a

Best OR, n (%)c

CR 6 (1.4) 1 (0.5)
PR 120 (27.1) 33 (15.5)
SD 233 (52.6) 119 (55.9)
PD 73 (16.5) 59 (27.7)
Non-evaluable 10 (2.3) 1 (0.5)
DOR, mo
Median (95% CI) NR 13.8 (6.0-NR) Treatment Effectb
HR = 0.43
Ongoing response at
(95% CI, 0.22-0.84)
data cutoff point, %d
At 12 mo 72.8 56.1
At 18 mo 72.8 46.8
a
Patients with measurable disease at baseline as determined by 1 of 2 independent central reviewers. b Placebo = reference group
when RR and HR were calculated—RR >1 in favor of durvalumab, HR <1 in favor of durvalumab. c One patient could not be included
in any best-OR categories because of inconsistency in baseline assessment for measurable disease between 2 independent central
reviewers. d Calculated by Kaplan–Meier method.
1. Paz-Ares L et al. ESMO 2017. Abstract LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.
 Safety Summary1,2

Durvalumab Placebo
Adverse Events, n %
(n = 475) (n = 234)
Any-grade all-causality AEs 460 (96.8) 222 (94.9)
Grade 3/4 142 (29.9) 61 (26.1)
Grade 5 21 (4.4) 13 (5.6)
Leading to discontinuation 73 (15.4) 23 (9.8)
Any-grade treatment-related AEs 322 (67.8) 125 (53.4)
SAEs 136 (28.6) 53 (22.6)

Any-grade immune-mediated AEs 115 (24.2) 19 (8.1)

Grade 3/4 16 (3.4) 6 (2.6)

1. Paz-Ares L et al. ESMO 2017. Abstract LBA1.

2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.
 Most Frequent AEs1,2
Durvalumab Placebo Durvalumab Placebo
Event, n (%) a (n = 475) (n = 234) Event, n (%) (n = 475) (n = 234)
Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4

Any event 460 (96.8) 142 (29.9) 222 (94.9) 61 (26.1) Pneumonia 62 (13.1) 21 (4.4) 18 (7.7) 9 (3.8)

Cough 168 (35.4) 2 (0.4) 59 (25.2) 1 (0.4) Arthralgia 59 (12.4) 0 26 (11.1) 61 (26.1)

Pneumonitis Pruritus 58 (12.2) 0 11 (4.7) 1 (0.4)

or radiation 161 (33.9) 16 (3.4) 58 (24.8) 6 (2.6)
pneumonitisb Rash 58 (12.2) 1 (0.2) 17 (7.3) 6 (2.6)
Fatigue 113 (23.8) 1 (0.2) 48 (20.5) 3 (1.3)
Upper RTI 58 (12.2) 1 (0.2) 23 (9.8) 3 (1.3)
Dyspnea 106 (22.3) 7 (1.5) 56 (23.9) 6 (2.6)
Constipation 56 (11.8) 1 (0.2) 20 (8.5) 6 (2.6)
Diarrhea 87 (18.3) 3 (0.6) 44 (18.8) 3 (1.3)
Pyrexia 70 (14.7) 1 (0.2) 21 (9.0) 0 Hypothyroidism 55 (11.6) 1 (0.2) 4 (1.7) 3 (1.3)
Decreased Asthenia 51 (10.7) 3 (0.6) 31 (13.2) 0
68 (14.3) 1 (0.2) 30 (12.8) 2 (0.9)
appetite
Back pain 50 (10.5) 1 (0.2) 27 (11.5) 2 (0.9)
Nausea 66 (13.9) 0 31 (13.2) 0
a
Occurring in >11% of patients in either treatment arm. b Assessed by investigators with subsequent review and adjudication by
study sponsor; pneumonitis includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis.
1. Paz-Ares L et al. ESMO 2017. Abstract LBA1.
2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.
 Immune-Related or Radiation Pneumonitis1,2

Pneumonitis (Grouped Term) Durvalumab Placebo

or Radiation Pneumonitis, n (%)a (n = 475) (n = 234)

Any grade 161 (33.9) 58 (24.8)

Grade 3/4 16 (3.4) 6 (2.6)

Grade 5 5 (1.1) 4 (1.7)

Leading to discontinuation 30 (6.3) 10 (4.3)

a
Assessed by investigators with subsequent review and adjudication by study sponsor; pneumonitis includes acute interstitial
pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis.
1. Paz-Ares L et al. ESMO 2017. Abstract LBA1.
2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.
 PACIFIC Trial Summary
• Durvalumab demonstrated statistically significant and robust improvement in PFS vs
placebo

• Durvalumab therapy resulted in significantly longer OS vs placebo

• Durvalumab demonstrated clinically meaningful benefit in ORR, with durable responses vs

placebo

• Patients receiving durvalumab had a lower incidence of new lesions, including new brain
metastases compared with patients receiving placebo

• Safety profile of durvalumab was consistent with other immunotherapies and with its own
safety profile as monotherapy in patients with more advanced disease; no new safety
signals were identified
 FDA Approved New SOC Option for Patients
With Unresectable Stage III NSCLC
• September 28, 2017: NCCN guidelines were updated to include durvalumab for
treatment of stage III locally advanced, unresectable NSCLC with no disease
progression after CRT
• October 17, 2017: FDA granted priority review status to sBLA for approval of
durvalumab for treatment of stage III locally advanced, unresectable NSCLC
with no disease progression after concurrent CRT
• February 16, 2018: FDA approved durvalumab for patients with unresectable
stage III NSCLC whose disease has not progressed following concurrent CRT
 Module 2
Potential Role of Immunotherapy
in Resectable NSCLC
Benny Weksler, MBA, MD
System Chief of Thoracic Surgery
Allegheny Health Network
Pittsburgh, Pennsylvania
• What is the rationale for using cancer
immunotherapy in resectable NSCLC?

• Are there any trials and data in

neoadjuvant or adjuvant settings?
 What About Resectable NSCLC?1

LACE (N = 4,584) Die Despite Alive Due Alive Due

Chemo to Surgery to Chemo
Stage IB
n = 1,371 HR = 0.92
5-y risk 36%

Stage II
n = 1,616 HR = 0.83
5-y risk 61%

Stage III
n = 1,247 HR = 0.83
5-y risk 74%
Note: 6th TNM edition staging was used.
1. Pignon JP et al. J Clin Oncol. 2008;26:3552-3559.
 Adjuvant Immunotherapy in Melanoma1
Primary Endpoint: Relapse-Free Survival
Nivolumab Ipilimumab
Events/N 154/453 206/453
Median RFS (95% CI), mo NR NR (16.6-NR)
HR (95% CI); log-rank P 0.65 (0.51-0.83); <.0001

1. Weber J et al. N Engl J Med. 2017;377:1824-1835.

 Selected Trials of Adjuvant Immunotherapy
for NSCLC
Primary
Trial Identifier Phase Stage Intervention
Endpoint
NCT02595944 3 IB-IIIA Nivolumab DFS, OS
NCT02486718 3 IB-IIIA Atezolizumab DFS
NCT02273375 3 IB-IIIA Durvalumab DFS
Durvalumab and Induced T-cell
NCT03130764 2 IB-IIIA
Tremelimumab response rate
NCT02504372 3 IB-IIIA Pembrolizumab DFS

NCT03053856 2 IIIA (N2) Pembrolizumab DFS

 Immunologic Effects of Chemotherapies1
Immunosuppressive cells Indirect immunostimulation
5-Fluorouracil Bevacizumab
Treg cells Cyclophosphamide Dasatinib
MDSCs
Docetaxel Decitabine
Gemcitabine Lapatinib
Best Studied
M2 Oxaliplatin Sorafenib
TAMs •Anthracycline
Paclitaxel Sunitinib
•Cyclophosphamide
Immune effector cells Direct immunostimulation
Gemcitabine Dasatinib
•Platinum
CTLs
Paclitaxel Imatinib (especially oxaliplatin)
NK Pemetrexed Sorafenib
cells •Gemcitabine
Poorly immunogenic tumor Increased immunogenicity •Taxanes
5-Fluorouracil Cetuximab
Doxorubicin Dabrafenib
Gemcitabine Decitabine
Idarubicin Erlotinib
Oxaliplatin Gefitinib
Radiation Trametinib

1. Galluzzi L et al. Cancer Immunol Res. 2016;4:895-902.

 Impact of Chemotherapy on TME in
Neoadjuvant Setting1
Methods
•FFPE surgical resections from 112 NSCLC cases with clinical
information
– 61 chemo-naïve
– 51 neoadjuvant-treated
• Multiplex IF: Opal-7 color kit™
• Image acquisition: Vectra™
• Image data analysis: InForm™, Spotfire™

1. Parra E et al. WCLC 2016. Abstract OA20.05.

 Neoadjuvant-Treated NSCLC Showed
Higher Inflammatory Infiltrate1
Median Values of Chemo-Naïve and Neoadjuvant Cases
NSCLC (N = 112)
Markers, mm2 Pa
Chemo Naïve (n = 61) Neoadjuvant (n = 51)
CD68+/PD-L1+ 194.46 307.32 .122
CD68+ 298.80 609.36 .059
CD3+/CD4+ 130.04 473.59 .050
CD3+/CD8+ 24.66 15.94 .588
CD3+ 903.21 1,501.99 .021
CD57+ 206.87 527.35 < .001
CD45RO+ 668.75 1,180.26 .019
CD45RO+/PD1+ 153.73 443.04 < .001
PD-1+ 336.02 795.21 < .001
FOXP3+ 5.38 8.37 .427
a
Mann Whitney U test.
1. Parra ER et al. J Immunother Cancer. 2018;6:48.
 Neoadjuvant Anti–PD-1 + Anti-CD137 is
Better Than Adjuvant (At Least in Mice)1

1. Liu J et al. Cancer Discov. 2016;6:1382-1399.

 Neoadjuvant Nivolumab Schema1

Nivolumab
Newly diagnosed SOC
3 mg/kg IV Surgical Resection
resectable stage I (post-operative
(day -14 and day - (day 0)
(>2 cm)/II/IIIA NSCLC treatment)
28)

Tumor Tumor and Lymph

Biopsy Node Assessment

• Primary endpoints: Safety and feasibility

• Also evaluated: Tumor pathological response; expression of PD-L1;
mutational burden; and mutation-associated, neoantigen-specific T-cell responses

1. Forde PM et al. N Engl J Med. 2018;378:1976-1986.

 Pathological Assessment of Response to
Neoadjuvant Nivolumab1
% of Pathological Regression According to Subgroup

• Major pathological response

occurred in 9/20 resected
tumors (45%; 95% CI, 23-68)
• Responses occurred in both
PD-L1–positive/–negative
tumors

1. Forde PM et al. N Engl J Med. 2018;378:1976-1986.

 Mutation Burden Is Associated With Pathologic
Response to Neoadjuvant Nivolumab1
Number of Sequence Alterations in Correlation Between # of Sequence Alterations
Pretreatment Tumor and % of Residual Tumor
400
400 Spearman’s rho, -0.75
350
350 P = .01 P = .008
300
300
250 250

200 200

150 150
AC
100 100 SCC
50 AS
50
0 0
6 8 5 6 9 4 1 2 4 4 7 0 20 40 60 80 100
01 00 00 00 01 00 01 01 01 02 00
1 6- 43- 0 1- 43- 01- 01- 43- 43- 16- 01- 1 6-
0 0 0 0
NY D M
D D0 MD M
D D0 D NY
0
M
D
NY Residual Tumor, %
M M M M

Major Pathological No Major Pathological

Response Response
(N = 3) (N = 8)

1. Forde PM et al. N Engl J Med. 2018;378:1976-1986.

 Neoadjuvant Atezolizumab in Resectable NSCLC:
Updated Results From a Multicenter Study (LCMC3)1
The efficacy-evaluable population comprised 45 patients who were treated with
atezolizumab and underwent surgical resection

Per protocol, 5 patients with

EGFR or ALK genetic
alterations were excluded from
the efficacy-evaluable
population
• 3 patients had pCR and 10
patients had a MPR
• No patients in the TC0 and IC0
subgroup had pCR or MPR
• Percent change in lesion size
from baseline did not appear to
associate with percent viable
tumor cells

TC1/2/3 or IC1/2/3 = PD-L1+ ≥1% on TC or IC; TC0 and IC0 = PD-L1+ <1% on TC and IC.
Pathological regression defined as viable tumor cells (%) – 100 (%).
Data cutoff: February 5, 2018.
1. Rusch V. WCLC 2018. MA04.09.
 NADIM: Neo-Adjuvant Immunotherapy
Chemo-Immunotherapy for Stage IIIA Resectable NSCLC: Phase 2 Study1
Adjuvant treatment initiated
between 3 and 8 weeks
Adjuvant after surgical resection
Neoadjuvant treatment
treatment
NSCLC Nivolumab
Nivolumab 360 mg + 240 mg Q2W for Follow
IIIA
paclitaxel 200 mg/m2 + 4 months and up
resectable
carboplatin AUC 6 nivolumab (3 years)
patients 480 mg Q4W for
IV, Q3W 8 months
3 cycles
IV (1 year)

• Phase 2
• Single arm
Blood Blood Blood
• Open label
extraction extraction extraction
(C1) (C3) (every 6 months) • Multicenter
• Resectable IIIA
NSCLC
• 46 patients

1. Provencio M et al. WCLC 2018. Abstract OA01.05.

 NADIM: Pathological Response1
The following were considered to identify factors
N % that potentially influence pathological response
Major responsea 24 80.0 (complete and major):
Complete response 18 75.0
<90% 6 20.0
Total 30 100.0

• Median patient follow-up: 4.1 months

(range 0.2-14.6 months)

• None of the patients have suffered

recurrence

a
Major pathological response defined as <10% viable tumor cells in the resected specimen.
1. Provencio M et al. WCLC 2018. Abstract OA01.05.
 Selected Trials of Neoadjuvant
Immunotherapy for NSCLC
Trial
Phase Stage Intervention Primary Endpoint
Identifier
Nivolumab with or
NCT02259621 2 IB-IIIA Safety and feasibility
without ipilimumab
Nivolumab and ipilimumab vs
NCT02998528 3 IB-IIIA MPR
chemotherapy
Nivolumab with or
NCT03158129 2 I-IIIA MPR
without ipilimumab
Pembrolizumab
NCT02818920 2 IB-IIIA Surgical feasibility rate
(neoadjuvant and adjuvant)
NCT02927301 2 IB-IIIA Atezolizumab MPR

NCT02572843 2 IIIA (N2) Durvalumab EFS

Nivolumab, carboplatin, and
NCT03081689 2 IIIA (N2) PFS
paclitaxel
 Practicum
Moving Immunotherapy Into
Earlier Stages of Lung Cancer
Practicalities, Challenges, Questions
 Let’s Consider a Case

64-year-old man with NSCLC

•History of 50 pack-years of smoking, but quit 10
years ago
•Found to have a 4.5-cm lung lesion in the right upper
lobe
 Case (Cont’d)

Pathological findings
•Adenocarcinoma
•No mutations in EGFR, ALK, ROS1, or BRAF
•PD-L1: 10% using the 22C3 antibody
•TMB status not available (not routinely tested)
 Case (Cont’d)

• Mediastinoscopy was performed

• Despite negative PET scan in the mediastinum, all 3
ipsilateral lymph node stations evaluated (level 2, 4,
and 7) had evidence of metastatic adenocarcinoma

Q Is this patient a candidate for resection?

Q Should neoadjuvant immunotherapy

protocol be considered?
 Case (Cont’d)

• Patient receives treatment: Cisplatin and etoposide

along with 65 Gy of radiation

What treatment would you recommend

Q
for this patient next?
Please remember to complete and submit your Post-Test
and Evaluation for CME/MOC/CE credit.
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