Leveraging the Growing Arsenal of Adjuvant Therapies for Early-Stage NSCLC

Leveraging the Growing Arsenal of Adjuvant
Therapies for Early-Stage NSCLC
Helena A. Yu, MD
Associate Attending Physician
Memorial Sloan Kettering Cancer Center

Provided by i3 Health
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Disclosures
Advisory board/panel: AbbVie, AstraZeneca, Black Diamond,
Blueprint, C4 Therapeutics, Cullinan, Daiichi Sankyo, Janssen, Taiho,
Takeda
Grants/research support: AstraZeneca, Black Diamond, Blueprint,
Cullinan, Daiichi Sankyo, Erasca, Janssen, Novartis, Pfizer
i3 Health has mitigated all relevant financial relationships

Learning Objectives
NSCLC = non–small cell lung cancer.
Identify the correct tumor stage and appropriate management
approach for NSCLC based on the latest evidence
Distinguish biomarkers for early-stage NSCLC that can inform
individualized treatment strategies
Appraise efficacy and safety data of novel adjuvant therapies for
patients with NSCLC as elucidated by recent clinical trials
Apply strategies to prevent and mitigate adverse events associated
with novel adjuvant therapies for early-stage NSCLC

Outline
Early-stage lung cancer introduction
Biomarker testing
Perioperative treatment
Pivotal trials
Targeted therapies
Case explorations

Lung Cancer Is a Public Health Problem
Second most frequently diagnosed cancer among men and women
12% and 13% of estimated new cancer cases, respectively
Leading cause of cancer-related mortality
21% of deaths in both men and women
NSCLC accounts for up to 85% of all lung cancers
Stage at diagnosis remains high
20% at stage I or II
30% at stage III (locally advanced disease)
50% at stage IV
Siegel et al, 2023; Provencio et al, 2022.

Early-Stage Lung Cancer: Outcomes Are Poor
NR = not reported; MST = median survival time.
Goldstraw et al, 2016.
Clinical Stage
Pathological Stage
Events/N MST 24 Months 60 Months
IA1 68/781 NR 97% 92%
IA2 505/3,105 NR 94% 83%
IA3 546/4,217 NR 90% 77%
IB 560/1,928 NR 87% 68%
IIA 215/585 NR 79% 60%
IIB 605/1,453 66.0 72% 53%
IIIA 2,052/3,200 29.3 55% 36%
IIIB 1,551/2,140 19.0 44% 26%
IIIC 831/986 12.6 24% 13%
IVA 336/484 11.5 23% 10%
IVB 328/398 6.0 10% 0%
Events/N MST 24 Months 60 Months
IA1 139/1,389 NR 97% 90%
IA2 823/5,633 NR 94% 85%
IA3 875/4,401 NR 92% 80%
IB 1,618/6,095 NR 89% 73%
IIA 556/1,638 NR 82% 65%
IIB 2,175/5,226 NR 76% 56%
IIIA 3,219/5,756 41.9 65% 41%
IIIB 1,215/1,729 22.0 47% 24%
IIIC 55/69 11.0 30% 12%

What Is the Potential IMPACT of Adjuvant Therapy After Surgery?
Salazar et al, 2017; Raman et al, 2020.
Eliminates residual disease Cure
Suppresses residual disease
Disease control
and delay recurrence
Does neither
(ineffective or intolerable)
Unnecessary and toxic

Adjuvant Therapy for Early-Stage Disease
HR = hazard ratio; CALGB = Cancer and Leukemia Group B; ALPI = Adjuvant Lung Project Italy; IALT = International Adjuvant Lung Cancer Trial;
ANITA = Adjuvant Navelbine International Trialist Association; LACE = Lung Adjuvant Cisplatin Evaluation.
Pignon et al, 2008; Pisters et al, 2008.
Benefit of Adjuvant Platinum-Doublet Chemotherapy
5.4% benefit at 5 years
HR 0.89, P<0.005 Die Live Live b/c of chemo

Targeted Therapy and Immunotherapy
KN189 = KEYNOTE-189; IO = immuno-oncology; erl/gef = erlotinib/gefitinib.
Howlader et al, 2020; Gandhi et al, 2018; Ramalingam et al, 2020.
Improving Survival
N Howlader et al. N Engl J Med 2020;383:640-649.
KN189
Chemo vs
Chemo/IO
FLAURA
Osimertinib vs
Erl/Gef

Diagnosis and Clinical Stages of NSCLC
H&P = history and physical; CT = computed tomography; CBC = complete blood count; NCCN = National Comprehensive Cancer Network; LN = lymph node.
NCCN, 2023.
Pathologic Diagnosis
NSCLC
Initial Evaluation Clinical Stages
NSCLC
• H&P (include performance status)
• CT chest and upper abdomen with
contrast, including adrenals
• CBC
• Chemistry profile
• Smoking cessation advice, counseling,
counseling, and pharmacotherapy
• Integrate palliative care (NCCN
Guidelines for Palliative Care)
• Stage I: small, lung only
• Stage II: larger tumor and/or hilar LN involvement
involvement
• Stage III: larger tumor with invasion, and/or
mediastinal LN involvement or separate nodules
nodules ipsilateral side
• Stage IV: extrathoracic mets including pleural
metastases

TNM Staging System for NSCLC
ACS, 2023.
Main tumor size and extent (T): How
large has the tumor grown? Has it
infiltrated nearby structures or organs?
Spread to nearby lymph nodes (N): Is
the cancer in nearby lymph nodes?
(see image)
Spread to distant sites (M): Has the
cancer spread to distant organs such
as the brain, bones, adrenal glands,
liver, or the other lung?
Numbers or letters after T, N, and M
provide details regarding each factor
American Joint Committee on Cancer (AJCC) Definitions for T, N, M
Trachea
Lung
Lung
Supraclavicular
(collarbone)
lymph nodes
Upper
mediastinal
lymph nodes
Bronchial
lymph nodes
Subcarinal
mediastinal
Lower mediastinal
lymph nodes
Hilar
lymph nodes
Bronchus

Molecular Testing in Lung Cancer
SCLC = small cell lung cancer; EGFR = epidermal growth factor receptor; 1L = first-line; FDA = US Food and Drug Administration.
Blackhall et al, 2020.
FDA approved targeted therapy in 1L metastatic setting:
First-line: EGFR, ALK, ROS1, RET, MET exon 14, NTRK
Second-line: BRAF V600E, KRAS G12C, HER2, EGFR exon 20
FDA-approved targeted therapy in early-stage setting
Adjuvant after resection: EGFR

Biomarkers for Immunotherapy
PD-L1 = programmed death-ligand 1; IHC = immunohistochemistry; TIL = tumor-infiltrating lymphocytes;
MSI = microsatellite instability; TSG = tumor suppressor gene.
Slide adapted from Dr. Kurt Schalper, Yale Cancer Center.
Phenotype markers
Genomic markers
PD-L1 IHC
TILs
Microbiome
MSI
Mutational burden
Oncogenes/TSGs
(LKB1/KEAP1)
TCRβ clonality
Topalian et al, 2012, NEJM
Herbst et al, 2014, Nature
Garon et al, 2015, NEJM
Weber et al, 2015, Lancet Oncol
Snyder et al, 2014, NEJM
Van Allen et al, 2015, Science
Rizvi et al, 2015, Science
Hugo et al, 2016, Cell
Taube et al, 2014, CCR
Tumeh et al, 2014, Nature
Le et al, 2015, NEJM
Tumeh et al, 2014, Nature
Robert et al, 2014, CCR
Vétizou et al, 2015, Science
Sivan et al, 2015, Science
Gopalakrishnan et al, 2018, Science
Le et al, 2015, NEJM
Overman et al, 2017, JCO
Zaretzky et al, 2016, NEJM
Gao et al, 2016, Cell
Gettinger et al, 2017, Can Discovery
Pan et al, 2018, Science
Miao et al, 2018, Science
Regulatory
approved as
biomarkers
by the FDA

PD-L1 Testing
CDx = companion diagnostic.
Hirsch et al, 2017; McLaughlin et al, 2016; Hong et al, 2020; Doroshow et al, 2021.
Different Antibodies
22C3 PharmDx
0
10
20
30
40
50
60
70
80
90
100
%
Tumor
Staining
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39
Cases
SP263
SP142
28-8
22C3
CDx: 22c3, 28-8
CDx: SP263
CDx: SP142
Blue-Print Study (N=40)
Heterogeneity
Intertumoral
Intratumoral
≥1% <1%
Malignant
Cells
Several Scoring Systems

Guidelines on Biomarker Testing
NGS = next-generation sequencing.
NCCN, 2023.
Histology: helps guide
chemotherapy
Squamous
Adenocarcinoma
Large cell
Small cell
PD-L1 testing
PD-L1 0
PD-L1 >1%
Molecular testing
Ideally a platform assay like
NGS
Minimum EGFR testing
since there is approved
EGFR-targeted adjuvant
therapy

Goal of Adjuvant Treatment
Provencio et al, 2022.
To Eliminate Micrometastatic Disease
Primary
Micromets
Surgery
(primary)
Adjuvant
therapy
X
X
X

Neoadjuvant Therapy Is Better Tolerated
MPR = major pathologic response; pCR = pathologic complete response.
May Be More Efficacious
Neoadjuvant
therapy Surgery
X
X
X
X
X
Other potential
advantages of
neoadjuvant treatment
• Analysis of tumor
response (MPR, pCR)
• Enhance antitumor
immunity when greater
burden of tumor and
tumor antigens are
present
• Earlier treatment of
micromets and
increased compliance

Different Perioperative Treatment Options
ICI = immune checkpoint inhibitor.
NCCN, 2023.
Platinum chemo
Surgery
Induction Surgery Adjuvant
ICI + platinum chemo
Supportive care
Neoadjuvant R
Surgery
Surgery Adjuvant
ICI
Supportive care
Adjuvant
Adjuvant chemo
R
Platinum chemo
Surgery
ICI
Supportive care
Neoadjuvant
+ Adjuvant
R
Platinum chemo
ICI + platinum chemo

Guideline-Recommended Therapy
Adapted from NCCN, 2023.
Adjuvant Therapy
Preferred
(nonsquamous)
• Cisplatin + pemetrexed
Preferred
(squamous)
• Cisplatin + gemcitabine
• Cisplatin + docetaxel
Other
recommended
• Cisplatin + vinorelbine
• Cisplatin + etoposide
Useful in certain
circumstances
• Carboplatin + paclitaxel
• Carboplatin + gemcitabine
• Carboplatin + pemetrexed
Single agent pembrolizumab following pembro + chemo
chemo neoadjuvant therapy and surgery
Systemic Therapy Following Adjuvant
Osimertinib
Atezolizumab
Pembrolizumab
Neoadjuvant Therapy
Candidate for
for checkpoint
checkpoint
inhibition
Nivolumab + platinum doublet
Pembrolizumab + platinum doublet
Platinum doublet
doublet includes:
includes:
• Carboplatin + paclitaxel (any histology)
• Cisplatin + pemetrexed (nonsquamous)
• Cisplatin + gemcitabine (squamous)
• Cisplatin + paclitaxel (any histology
• Carboplatin + pemetrexed (nonsquamous)
(nonsquamous)
• Carboplatin + gemcitabine (squamous)
Not a
candidate for
for checkpoint
checkpoint
inhibition
Preferred
(nonsquamous)
• Cisplatin + pemetrexed
Preferred
(squamous)
• Cisplatin + gemcitabine
• Cisplatin + docetaxel
Other
recommended
• Cisplatin + vinorelbine
• Cisplatin + etoposide
Useful in certain
circumstances
• Carboplatin + paclitaxel
• Carboplatin + gemcitabine
• Carboplatin + pemetrexed

IMpower010: Adjuvant Atezolizumab for Early-Stage NSCLC
ECOG = Eastern Cooperative Oncology Group; UICC = Union for International Cancer Control; AJCC = American Joint Committee on Cancer;
Q21D = every 21 days; BSC = best supportive care; DFS = disease-free survival; OS = overall survival; ITT = intention-to-treat; TC = tumor cells.
Felip et al, 2021.
Primary end points
Investigator-assessed DFS tested hierarchically:
• PD-L1 TC ≥1% (per SP263) stage
II-IIIA population
• All-randomized stage II-IIIA population
• ITT population (stage IB-IIIA)
Secondary end points
• OS in ITT population
• DFS in PD-L1 TC ≥50% (per SP263) stage
II-IIIA population
• 3-year and 5-year DFS in 3 populations
Stratification factors
• Male/female
• Stage (IB vs II vs IIIA)
• Histology
• PD-L1 tumor expression status:
TC2/3 and any IC vs TC0/1 and
IC2/3 vs TC0/1 and IC0/1
R N=1,005
Key Eligibility Criteria
• Completely resected stage IB-IIIA
NSCLC per UICC/AJCC v7
• Stage IB tumors ≥4 cm
• ECOG 0–1
• Lobectomy/pneumonectomy
• Tumor issue for PD-L1 analysis
Atezolizumab
1,200 mg Q21D
16 cycles
BSC
Survival follow-up
Cisplatin + pemetrexed,
gemcitabine, docetaxel, or
vinorelbine
1-4 cycles
(N=1,280)

IMpower-010: Adjuvant Atezolizumab (cont.)
NE = not evaluable.
Felip et al, 2021; FDA, 2021.
Disease-Free Survival
HR 0.66
(P=0.0039)
13.6%
improvement in 2-
year DFS
October 15, 2021: FDA approves adjuvant atezolizumab for
resectable stage II-IIIA NSCLC with PD-L1 >1%
PD-L1 >1%
Stage II-IIIA

Felip et al, 2021.
All stage II-IIIA:
HR 0.79 (P=0.0039)
8.6% improvement in
2-year DFS
DFS
All stages
All PD-L1
TC <1%:
no benefit
(HR 0.97)

aInterstitial lung disease, multiple organ dysfunction syndrome, myocarditis, and acute myeloid leukemia (all 4 events related to atezolizumab), and
pneumothorax, cerebrovascular accident, arrhythmia, and acute cardiac failure. bPneumonia; pulmonary embolism; and cardiac tamponade and septic shock in
the same patient. cAtezolizumab-related.
Felip et al, 2021.
Atezolizumab-related
adverse events:
Hypothyroidism (11%)
Pruritus (9%)
Rash (8%)
Safety
Atezolizumab
(n=495)
Best supportive care group
(n=495)
Adverse event
Any grade 459 (93%) 350 (71%)
Grade 3-4 108 (22%) 57 (12%)
Serious 87 (18%) 42 (8%)
Grade 5 8 (2%)a 3 (1%)b
Led to dose interruption of
atezolizumab
142 (29%) --
Led to atezolizumab
discontinuation
90 (18%) --
Immune-mediated adverse events
Any grade 256 (52%) 47 (9%)
Grade 3-4 39 (8%) 3 (1%)
Required the use of systemic
corticosteroidsc 60 (12%) 4 (1%)
Led to discontinuation 52 (11%) 0

KEYNOTE-91/PEARLS
aAdjuvent chemotherapy recommended for stage II–IIIA, to be considered for stage IB.
Q3W = every 3 weeks.
O’Brien et al, 2022.
Adjuvant Pembrolizumab for Early-Stage NSCLC: Study Design
Primary end points
• DFS in the overall population
• DFS in the TPS ≥50% population
• Confirmed stage IB (≥4 cm)–
IIIA NSCLC per AJCC v7
• Complete surgical resection
with negative margins (R0)
• Provision of tumor tissue for
PD-L1 testing
• Any PD-L1 level
N=1,177
PD-L1 testing
done centrally
using PD-L1
IHC 22C3
pharmDx
Key Randomization Criteria
• No evidence of disease
• ECOG PS 0–1
• Adjuvant chemotherapya
• Considered for stage IB (≥4
cm) disease
• Strongly recommended for
stage II and IIIA disease
• Limited to ≤4 cycles
Pembrolizumab 200 mg Q3W
≤18 administrations
(~1 year)
Placebo Q3W
≤18 administrations
(~1 year)
R

KEYNOTE-91/PEARLS: Adjuvant Pembrolizumab (cont.)
O’Brien et al, 2022; FDA, 2023b.
Stage IB-IIIA
HR=0.76 (P=0.0014,
95% CI, 0.63-0.91)
PD-L1>50%
HR=0.82 (P=0.14,
95% CI, 0.57-1.18)
January 26, 2023: FDA approves adjuvant pembrolizumab for
resectable stage IB (T2a ≥4 cm), II, or IIIA NSCLC

KEYNOTE-91/PEARLS: Adjuvant Pembrolizumab (cont.)
IRAEs = immune-related adverse events.
O’Brien et al, 2022.
Adverse events associated with pembrolizumab vs placebo
Potentially immune-related and infusion reactions: 39% vs 13%
Of these, requiring corticosteroids: 37% vs 23%
Hypothyroidism: 21% vs 5%
Hyperthyroidism: 11% vs 3%
Pneumonitis: 7% vs 3%
Grade 3 or worse IRAEs in the pembrolizumab group: severe skin
reactions, hepatitis, pneumonitis
Safety

Benefits of Neoadjuvant Therapy
Image courtesy of Helena A. Yu, MD.
Better tolerated
Predictive biomarker data can be obtained
pre-treatment
IO may be more effective with the tumor
in situ
Chance for a lesser lung resection
Possible shorter duration of therapy
Pathologic data to guide post-op
prognosis and possibly further therapy

CheckMate 816: Neoadjuvant Nivolumab for Early-Stage NSCLC
RT = radiation therapy; BICR = blinded independent central review; EFS = event-free survival; BIPR = blinded independent pathology review;
ORR = objective response rate; AEs = adverse events; path = pathologic.
Forde et al, 2022.
Path CR: 24.0 vs 2.2% (P<0.001)
• Newly diagnosed, resectable,
stage IB (≥4 cm)–IIIA NSCLC
(per TNM 7th edition)
• ECOG PS 0-1
• No known sensitizing EGFR
mutations or ALK alterations
N=358
NIVO 360 mg Q3W
+
Chemo Q3W (3 cycles)
Chemo Q3W (3 cycles)
R
Surgery
(within 6 weeks
post-treatment)
Optional
adjuvant
chemo, RT, or
chemoRT
Radiologic
restaging Follow-up
Primary end points
• pCR by BICR
• EFS by BICR
• MPR by BIPR
• OS
• Time to death or distant
metastases
Exploratory end points
• ORR by BICR
• Feasibility of surgery;
peri- and post-operative
surgery–related AEs
Stratified by stage (IB/II vs IIIA),
PD-L1 (≥1% vs <1%), and sex

Patients (n=144) Patients (n=126)
Increasing
depth
of
response
pCR in primary tumor
(0% viable tumor cells)
pCR in primary tumor
(0% viable tumor cells)
Regression
in
tumor
area
with
viable
tumor
cells
(%)
Regression
in
tumor
area
with
viable
tumor
cells
(%)
CheckMate 816: Neoadjuvant Nivolumab (cont.)
Spicer et al, 2021.
Efficacy

Forde et al, 2022.
Event-Free Survival
EFS HR: 0.63 (P=0.005)
18.5% improvement in 2-year EFS

aPrespecific interim OS analysis did not cross boundary for statistical significance.
Forde et al, 2022; FDA, 2022.
Adverse events in nivo
group vs
chemotherapy group
Grade ≥3:
33.5% vs 36.9%
Neutropenia:
8.5% vs 11.9%
Rash:
8.5% in nivo group
Pneumonitis:
1.1% in nivo group
Overall Survival
OS HR: 0.57 (P=0.008)a
12.1% improvement in 2-year OS
March 4, 2022: FDA approves neoadjuvant nivo/chemo
for resectable NSCLC

aPrespecified interim OS analysis did not cross boundary for statistical significance.
Forde et al, 2022; FDA, 2022.
Efficacy
OS HR: 0.57 (P=0.008)a
12.1% improvement in 2-year OS
March 4, 2022: FDA approves neoadjuvant nivo/chemo for
resectable NSCLC
EFS HR: 0.63 (P=0.005)
18.5% improvement in 2-year EFS

AEGEAN: Perioperative Durvalumab for Early-Stage NSCLC
wt = wild-type; HRQOL = health-related quality of life; PRO = patient-reported outcomes.
Heymach et al, 2023.
Study Design
R
• Resectable NSCLC
• Stage IIA–select IIIB
• EGFR wt / ALK wt
• Planned for lobectomy,
bilobectomy, or sleeve resection
(N=800)
Durvalumab +
platinum-based chemotherapy
Placebo +
platinum-based chemotherapy
Surgery
Surgery
Durvalumab
Placebo
Q3W x 4 cycles Q4W x 12 cycles
Pathological evaluation of
surgical specimen by central review
Stratification Factors
• Disease stage (II vs III)
• PD-L1 TC expression status
(<1% vs ≥1%)
Primary end points
• pCR
• EFS
• mPR, DFS, OS
• pCR, mPR, EFS, DFS, OS
(PD-L1 TC ≥1% group)
• HRQOL/PRO
• Pharmacokinetics
• Immunogenicity

aHR <1 favors the durvalumab arm versus the placebo arm. Median and landmark estimates calculated using the Kaplan-Meier method; HR calculated using
a stratified Cox proportional hazards model; and P value calculated using a stratified log rank test. Stratification factors: disease stage (II vs III) and PD-L1
expression status (<1% vs ≥1%). Significance boundary = 0.009899 (based on total 5% alpha), calculated using a Lan-DeMets alpha spending function with
O'Brien Fleming boundary.
D = durvalumab; PBO = placebo.
Efficacy
D arm PBO arm
No. events / no. patients
(%)
98/366 (26.8) 138/374 (36.9)
mEFS, months (95% CI) NR (31.9–NR) 25.9 (18.9–NR)
Stratified HRa (95% CI) 0.68 (0.53–0.88)
Stratified log-rank P-value 0.003902
Time from randomization (months)
1.0
0
Probability
of
EFS
0.8
0.6
0.4
0.2
0.0
3 21 45 48
No. at risk:
D arm 366 336 271 194 140 90 78 50 49 31 30 14 11 3 1 1 0
PBO arm 374 339 257 184 136 82 74 53 50 30 25 16 13 1 1 0 0
Censored
0.9
0.7
0.5
0.3
0.1
42
39
36
33
30
27
24
18
15
12
9
6
73.4%
64.5%
63.3%
52.4%
Median follow-up (range) in censored
patients: 11.7 months (0.0–46.1)
EFS maturity: 31.9%
AEGEAN regimen
achieved primary end
point of EFS (HR 0.68)
with 11% improvement
in 2-year EFS
AEGEAN: Perioperative Durvalumab (cont.)

CR = complete response.
Grade ≥3 AEs: 42.3%
in durvalumab arm,
43.4% in
chemotherapy arm
No unexpected AES
related to treatment
Efficacy
17.2
4.3
0
10
20
30
40
33.3
12.3
0
10
20
30
40
pCR
rate
(%)
MPR
rate
(%)
Difference = 13.0%
(95% CI: 8.7–17.6)
pCR (Central Lab) MPR (Central Lab)
Difference = 21.0%
(95% CI: 15.1–26.9)
D arm
(N=366)
PBO arm
(N=374)
D arm
(n=366)
PBO arm
(n=374)
P value = 0.000036
based on interim
analysis (n=402)‡
P value = 0.000002
based on interim
analysis (n=402)
Achieved primary end point of significant improvement in path
CR as well as MPR
AEGEAN: Perioperative Durvalumab

KEYNOTE-671: Perioperative Pembrolizumab in Early-Stage NSCLC
IV = intravenous.
Wakelee et al, 2023a.
Study Design
Pembrolizumab 200 mg IV Q3W
+
Cisplatin and gemcitabine
or
Cisplatin and pemetrexed
for up to 4 cycles
Placebo IV Q3W
+
Cisplatin and gemcitabine
or
Cisplatin and pemetrexed
for up to 4 cycles
• Pathologically confirmed,
resectable stage II, IIIA, or IIIB
(N2) NSCLC per AJCC v8
• No prior therapy
• Able to undergo surgery
• Provision of tumor sample for
PD-L1 evaluation
• ECOG PS 0 or 1
(N=786)
Pembrolizumab 200 mg IV Q3W
for up to 13 cycles
Placebo IV Q3W
for up to 13 cycles
Surgery
Surgery
R
Primary end points
• EFS per investigator review
• OS
• mPR and pCR per blinded independent
pathology review, and safety
• Disease stage (II vs III)
• PD-L1 TPS (<50% vs ≥50%)
• Histology (squamous vs nonsquamous)
• Geographic region (east Asia vs not east Asia)

Pembro = pembrolizumab.
Wakelee et al, 2023a; Wakelee et al, 2023b; FDA 2023a.
Event-Free Survival and Overall Survival
Pts w/
Event
Median
(95% CI), mo
Pembro arm 35.0% NR (34.1-NR)
Placebo arm 51.3% 17.0 (14.3-22.0)
HR 0.58 (95%
CI: 0.46-0.72)
P<0.00001
Pts w/
Event
Median
(95% CI), mo
Pembro arm 19.1% NR (NR-NR)
Placebo arm 25.3% 45.5 (42.0-NR)
HR 0.73 (95%
CI: 0.54-0.99)
P=0.02124
KEYNOTE-671: Perioperative Pembrolizumab (cont.)
October 16, 2023: FDA approves perioperative
pembro/chemo for resectable NSCLC

a Per IASLC criteria, defined as ≤10% viable tumor cells in resected primary tumor and lymph nodes.
b Per IASLC criteria, defined as absence of residual invasive cancer in resected primary tumor and lymph nodes (ypT0/Tis ypN0).
Data cutoff date for IA1: July 29, 2022.
Efficacy
0
5
10
15
20
25
30
35
40
45
50
Pembro Arm Placebo Arm
mPR,
%
(95%
CI)
30.2%
(25.7-35.0)
11.0%
(8.1-14.5)
Pembro
Arm
(n=397)
Placebo
Arm
(n=400)
Δ 19.2 (13.9-24.7)
P<0.00001
mPRa
0
5
10
15
20
25
30
35
40
45
50
Pembro Arm Placebo Arm
pCR,
%
(95%
CI)
18.1%
(14.5-22.3)
4.0%
(2.3-6.4)
Pembro
Arm
(n=397)
Placebo
Arm
(n=400)
Δ 14.2 (10.1-18.7)
P<0.00001
pCRb

Potentially immune-related AEs in pembrolizumab group vs placebo
group:
Any, including infusion reactions: 25.3% vs 10.5%
Any grade ≥3: 5.8% vs 1.5%
Included: hypothyroidism, hyperthyroidism, pneumonitis
Safety

Perioperative Timing of
Chemotherapy and
Immunotherapy

ICI for Early-Stage Disease
ICB = immune checkpoint blockade; MRD = minimal residual disease.
Provencio et al, 2022; Heymach et al, 2023; Wakelee et al, 2023a; Forde et al, 2022; Chae & Oh, 2019; Pantel & Alix-Panabières, 2019; Campelo et al, 2019.
Both neoadjuvant (nivolumab) and adjuvant ICB (atezolizumab, pembrolizumab) significantly
improve outcomes and are FDA-approved; neoadjuvant may give more benefit with shorter
duration
Perioperative ICB (durvalumab in AEGEAN; pembrolizumab in KEYNOTE-671) improve
outcomes, although advantages vs neoadjuvant or adjuvant will require longer follow-up
Next step is to risk stratify patients by pathologic response
Monitor risk using MRD assays
Surgery
ICB+ platinum chemo ICB
Biomarker-driven
neoadjuvant combos with
rapid path readout (eg,
Neocoast)
Identify who really
needs 1 year adjuvant
ICB
(vs none? Or longer?)

Using Pathological Response To Guide Treatment
Forde et al, 2022.
pCR vs no pCR
patients for
nivo + chemo:
HR 0.13 (arm)
If the pCR group is
benefitting so much,
shouldn’t they
continue?
(still >20% chance
of recurrence)
If the no pCR group
hasn’t responded as
well, should they get
a different type of
therapy?

Use of MRD To Identify Patients at Risk
ctDNA= circulating tumor DNA.
Chae & Oh, 2019; Pantel & Alix-Panabières, 2019.
Local therapy with or
without (neo)adjuvant
therapy for non-
metastatic disease
Adjuvant or post-
adjuvant therapy for
occult disease
recurrence
Systemic therapy for
overt metastatic
recurrence
Cancer
progression
Clinical
diagnostic
threshold
MRD
diagnostic
threshold
Standard-of-Care Management
With MRD: Adjuvant Treatment
No MRD: Monitor Off-Treatment
R
Intervention
Control
ctDNA

Targeted Therapy in the
Adjuvant Setting

Adjuvant Osimertinib
D’Angelo et al, 2012; Pi et al, 2018.

ADAURA: Adjuvant Osimertinib
WHO = World Health Organization.
Herbst et al, 2023.
Phase 3 Study Design
• ≥18 years (Japan/Taiwan ≥20)
• WHO performance status 0/1
• Confirmed primary non-squamous NSCLC
• Exon 19 deletion/L858R
• Brain imaging, if not completed pre-operatively
• Complete resection with negative margins
• Maximum interval between surgery and
randomization:
• 10 weeks without adjuvant chemotherapy
• 26 weeks with adjuvant chemotherapy
(N=682)
Osimertinib 80 mg
once daily
Placebo
once daily
Planned treatment duration:
• 3 years
Treatment continued until:
• Disease recurrence
• Treatment completion
• Discontinuation criterion met
Follow-up:
• Until recurrence: Week 12 and
24, then every 24 weeks to 5
years, then yearly
• After recurrence: every 24
weeks for 5 years, then yearly
• Stage (IB vs II vs IIIA)
• EGFRm (Ex19del vs L858R)
• Race (Asian vs non-Asian)
Primary end points
• DFS by investigator assessment in
stage II-IIIA patients
• DFS in the overall population (stage
IB-IIIA)
• Landmark DFS rates
• OS
• Safety
• Health-related quality of life
R

Herbst et al, 2023.
Adjuvant osimertinib demonstrated highly statistically significant and
clinically meaningful improvement in DFS in completely resected EGFR-
mutated NSCLC vs placebo in both the primary (stage II-IIIA) and overall
(IB-IIIA) populations, along with a tolerable safety profile
Adjuvant Osimertinib Has Significantly Improved DFS
ADAURA: Adjuvant Osimertinib (cont.)

Herbst et al, 2023.
Adjuvant osimertinib demonstrated a statistically and clinically significant
improvement in OS vs placebo in the primary population of stage II-IIIA
disease
Patients With Stage II/IIIA Disease: Overall Survival

Herbst et al, 2023.
Adjuvant osimertinib demonstrated a statistically and
clinically significant improvement in OS vs placebo in the
overall population of stage IB-IIIA disease
Patients With Stage IB/II/IIA Disease: Overall Survival
Most
common
(≥20%)
Osimertinib
(n=337):
any grade (%)
Placebo (n=343):
any grade (%)
Diarrhea 47% 20%
Paronychia 27% 1%
Dry skin 25% 7%
Pruritus 21% 9%
Cough 20% 18%

NeoADAURA: Neoadjuvant Osimertinib for EGFR-Mutated NSCLC
QD = every day; AUC = area under the curve.
Aredo et al, 2023; Tsuboi et al, 2021.
Genomic testing has improved such that these approaches are
feasible
Phase 3, Randomized, Controlled Study (NCT04351555)
• Resectable
• Stage II–IIIB NSCLC
• EGFR-mutated
NSCLC (exon 19
deletion/L858R)
(N=51)
Osimertinib + chemo
Q3W, 3 cycles
Placebo + chemo
Q3W, 3 cycles
Osimertinib
9 weeks
Surgery MPR & pCR
Adjuvant:
Investigator choice
(optimal care)
EFS & OS
• Stage II/III
• Non–Asian/Chinese/Other Asian
• Ex19del/L858R
Double-Blind Treatment Arms
1. Placebo + investigator’s choice of pemetrexed 500 mg/m2 plus carboplatin AUC5 mg/mL min or
cisplatin 75 mg/m2
2. Osimertinib 80 mg QD + investigator’s choice of pemetrexed 500 mg/m2 plus carboplatin AUC5
mg/mL/min or cisplatin 75 mg/m2
Open-Label (Sponsor-Blind) Treatment Arm
3. Osimertinib 80 mg QD
Adjuvant Therapy at Investigator’s Discretion
• Up to 5 years until disease recurrence or withdrawal of consent
• Osimertinib will be offered to all patients who complete surgery (±
post-surgical chemotherapy) for up to 3 years
• Follow-up at 12- and 24-weeks post-surgery, then every 24 weeks
IO is less effective (or not indicated) in most oncogene-driven lung
cancer subsets (few exceptions: KRAS, BRAF)
Effectively shrinking cancers may spare lung tissue at surgery
Data here from CheckMate 816
R

Aredo et al, 2023.
Primary End Point: Major Pathologic Response Rate
Primary end point
• mPR rate
(powered to detect mPR ~50%)
• Safety, surgical complications,
unrespectability rate
• Efficacy, lymph node downstaging,
pathological response rate, pCR rate,
5-year DFS/OS
Exploratory end point
• Identify mechanisms underlying
disease persistence
Neoadjuvant Osimertinib

SD = standard deviation; IQR = interquartile range.
Aredo et al, 2023.
Primary End Point: Major Pathologic Response Rate = 15%
Characteristic All (N=27)
Age at diagnosis (years), mean (SD) 66.5 (11.4%)
Sex, n (%)
• Female 22 (81.5%)
• Male 5 (18.5%)
Race/ethnicity, n (%)
• White 15 (55.6%)
• Asian 11 (40.7%)
• Hispanic 1 (3.7%)
Clinical stage, n (%)
• IA 5 (18.5%)
• IB 3 (11.1%)
• IIA 3 (11.1%)
• IIB 7 (25.9%)
• IIIA 9 (33.3%)
EGFR mutation, n (%)
• L858R 16 (59.3%)
• Exon 19 deletion 11 (40.7%)
Serious AEs included:
dyspnea, pulmonary embolism, atrial fibrillation, pneumonitis
Neoadjuvant Osimertinib (cont.)

Managing Adverse Events: Osimertinib
echo = echocardiogram.
Vogel & Jennifer, 2016; Maeda et al, 2022; Patel et al, 2020.
Pneumonitis
Low threshold to scan
Cardiomyopathy
Baseline echo
Low threshold to re-image
Dry skin/rash
Moisturizer
Topical steroids
Topical antibiotics
Oral antibiotics
Mucositis
Dexamethasone rinses
Oral mouth care
Diarrhea
Loperamide

Managing Adverse Events: Immunotherapy
DRESS = drug reaction with eosinophilia and systemic symptoms.
Martins et al, 2019.
Early identification, proactive
labs, review of toxicities
Hold therapy, consider
treatment of IRAE
Mainstay of treatment are
corticosteroids

Case Study 1: Mr. ES
CXR = chest radiography; PET = positron emission tomography; MRI = magnetic resonance imaging.
Images courtesy of Helena A. Yu, MD.
77-year-old male, 60 pack-year history of smoking, gets a pre-op CXR
before a knee replacement, which identified a R lung nodule
Bronchoscopy with biopsy confirms primary lung adenocarcinoma, and
PET/MRI indicate no distant metastatic disease

Case Study 1: Mr. ES (cont.)
Do you recommend neoadjuvant treatment?
What info do you want before you decide?
The surgeon feels that Mr. ES is immediately resectable, and he
undergoes a lobectomy and lymph node dissection. Final pathology
indicates a T2AN1M0 lung adenocarcinoma, stage IIB (PD-L1 60%)
He recovers from surgery well and presents to your office to discuss any
postoperative treatment
What do you recommend?

Case Study 2: Ms. LT
41-year-old woman, never smoker, develops a dry cough. The CT scan
shows a left-sided lung nodule
Bronchoscopy with biopsy confirms primary lung adenocarcinoma, and
PET/MRI indicate no distant metastatic disease but ipsilateral hilar lymph
node involvement
Images courtesy of Helena A. Yu, MD.

Case Study 2: Ms. LT (cont.)
Do you recommend neoadjuvant treatment?
What info do you want before you decide?

Key Takeaways
New standard of care for perioperative immunotherapy and
chemotherapy in addition to surgical resection
Biomarker testing is very important to dictate perioperative treatment
There are benefits to neoadjuvant therapy: tolerability, better immune
response with intact tumor, information about path response
Suspect next generation of studies will incorporate path response and
MRD plasma assays to personalize treatment plans

Key Takeaways (cont.)
Molecular testing
PD-L1 testing
Diagnosis of early-
stage lung cancer
EGFR-negative
EGFR-positive
Chemo
ICI
Chemo
if appropriate
Surgery
± chemo
Adjuvant ICI
± chemo
Adjuvant osimertinib
Path response
MRD assays to dictate
further care

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