Neoadjuvant Immunotherapy for NSCLCs

Neoadjuvant Immunotherapy for NSCLCs

William N. William Jr., MD

Director of Oncology and Hematology, Hospital BP, a Beneficência Portuguesa de São Paulo

Adjunct Associate Professor, The University of Texas MD Anderson Cancer Center

Outline

• Background and rationale

• Neoadjuvant immunotherapy-based trials• IO monotherapy• IO combo• IO-chemo combo

• Challenges

• Future directions

Outline



• Challenges


The primary goal of adjuvant treatment is to eliminate micrometastatic disease

primary

micromets

Surgery

(primary)

Adjuvant

therapy

XX

Courtesy of Heymach JV, AACR 2018 (modified)

Neoadjuvant treatment can “downstage” the primary tumor

Neoadjuvant

therapy

X

surgery

X

XX

Courtesy of Heymach JV, AACR 2018 (modified)

Advantages of neoadjuvant therapy:• Downstage the tumor• Assess the biology of the disease• Impact micromets at an earlier

time point• Better tolerated before surgery

than after surgery • Assessment of response to

therapy• Translational analyses on tumors

at baseline and surgery • Evaluate potential surrogate

endpoints that may correlate with clinical benefit

Use of surrogate endpoints after induction therapy for neoadjuvant drug development in resectable NSCLC

• “FDA may grant traditional approval if a drug shows a direct clinical benefit or based on an improvement in an established surrogate”

• “The surrogate endpoint should be correlated with the clinical outcome, and should capture the complete net effect of the treatment on the clinical outcome”

Hellmann, ... William WN et al. Lancet Oncology 2014

Blumenthal G et al, J Thorac Oncol 2018 Pataer A, …, William WN et al., J Thorac Oncol, 2012

Major pathological response may represent a suitable surrogate for improved survival after neoadjuvant therapy

A. Overall Survival C.

D.

Overall Survival

Disease-Free Survival

Pataer A, William WN, … et al., J Thorac Oncol, 2012

MPR rate to neoadjuvant chemotherapy

in historical controls (MDACC): 19%

Recurrence-Free SurvivalB.

Cascone T, William WN, et al. Ann Thorac Surg, 2018

Chen L, Gibbons D et al, Nat Commun 2014

Genetic targeting of PD-L1 on cancer cells reverses the CD8+ TIL dysfunction and suppresses metastasis

Neoadjuvant IMT is superior to adjuvant in eradicating metastases in murine breast cancer model

Liu et al, Cancer Discovery 2016

Outline



• Challenges


Neoadjuvant anti-PD1 blockade is safe and

active in resectable NSCLC patients

Forde P et al, NEJM 2018

MPR (≤10% viable tumor cells) Rate: 45%

LCMC3 Study: Neoadjuvant Atezolizumab produces MPRs in 19% of resected NSCLC patients

Pathologic regression defined as % viable tumor cells – 100%. pCR, pathologic complete response. a 1 EGFR+ patient had aborted surgery. * Pathologic response could not be assessed. + EGFR+. + ALK+.

Patients in intended surgery population (n = 90)

• PR: 6 (7%); SD: 80 (89%); PD: 4 (4%)

• 3 of 8 EGFR/ALK+ had 40% to 50% pathological regression

Primary efficacy population (n = 77)

• MPR: 15 of 77 (19%; 95%CI: 11%, 30%)

• pCR: 4 of 77 (5%) patients

• 38 of 77 (49%) had ≥ 50% pathological regression

MPR

0% to −49% −50% to −89% −90% to −99% (MPR) −100% (MPR and pCR)

Kwiatkowski DJ, ASCO Annual Meeting 2019 Abstract 8503

LCMC3 Study: Adverse Eventsa

TRAEs

With ≥ 5% Incidence, n (%)

Safety Population

(N = 101)

Fatigue 20 (20%)

Infusion-related reaction 11 (11%)

Pyrexia 10 (10%)

Decreased appetite 8 (8%)

AST increased 7 (7%)

Nausea 7 (7%)

Arthralgia 6 (6%)

Influenza-like illness 6 (6%)

Diarrhea 5 (5%)

Grade ≥ 3 TRAEs

Pneumonitis 3 (3%)

Nasal congestion 1 (1%)

Decreased lymphocyte count 1 (1%)

Anemia 1 (1%)

Adverse Events, n (%)Safety Population

(N = 101)

All-cause AEs 98 (97%)

Grade 3-4 29 (29%)

Grade 5b 2 (2%)

TRAEs 58 (57%)

Grade ≥ 3* 6 (6%)

Serious AE 30 (30%)

AE leading to treatment

withdrawal5 (5%)

AST, aspartate aminotransferase; TRAE, treatment-related adverse event. a AEs during neoadjuvant treatment. b 2 patients with Grade 5 AE not related to study treatment:

cardiac death post-surgical resection and death due to disease progression.

Data cutoff: September 5, 2018.

Kwiatkowski DJ, ASCO Annual Meeting 2019 Abstract 8503

Days after Cell Injection

Adjuvant vs. Neoadjuvant combo

Neoadjuvant superior

HR=0.33

P=.028

0 1 0 2 0 3 0 4 0 5 0 6 0

0

2 0

4 0

6 0

8 0

1 0 0

3 4 4 S Q O V A+-1 2 9 s v M ic e S u rv iv a l:

N e o a d ju v a n t IO -S u rg e ry A rm # 2

D a y s a fte r tu m o r c e ll in je c tio n

Pe

rc

en

t s

urv

iva

l

N e o a d ju v a n t a n t i-P D -1 +

a n t i-C T L A - 4

A d ju v a n t a n t i-P D -1 +

a n t i-C T L A - 4

Cascone, William WN et al, AACR 2018

**Microscopic lung mets

0

5

1 0

1 5

2 0

2 5

3 0

3 5

4 0

4 5

M ic ro s c o p ic L u n g M e ta s ta s e s

in 3 4 4 S Q -O V A+ N S C L C

Nu

mb

er o

f M

icro

sc

op

ic

Lu

ng

Me

tas

tas

es

/H&

E s

lid

e

N e o a d ju va n t IO -

S u rg e ry a rm

S u rg e ry -

A d ju v a n t IO a rm

IgG

a n ti-C T L A -4

a n t i-C T L A -4 +

a n ti-P D -1

a n ti-P D -1

0

5

1 0

1 5

2 0

2 5

3 0

3 5

4 0

4 5

M ic ro s c o p ic L u n g M e ta s ta s e s

in 3 4 4 S Q -O V A+ N S C L C

Nu

mb

er o

f M

ic

ro

sc

op

ic

Lu

ng

M

eta

sta

se

s/H

&E

s

lid

e

N e o a d ju va n t IO -

S u rg e ry a rm

S u rg e ry -

A d ju v a n t IO a rm

IgG

a n ti-C T L A -4

a n t i-C T L A -4 +

a n ti-P D -1

a n ti-P D -1* *

***

***

Neoadjuvant combined ICB prolongs survival and reduces mets vs. monotherapy or adjuvant combo in a preclinical model of NSCLC

CheckMate 012, a phase I study in stage

IIIB/IV NSCLC pts: higher ORRs and PFS

with combo nivo + ipi vs. nivo monotherapy

Hellmann MD et al, Lancet Oncol. 2017

N= 44

Eligibility NSCLC Stage I-IIIA

N2 single station

(AJCC7th)

Contralateral 2

and/or 4 node eval

to exclude N3

Surgical candidate

ECOG PS 0-1

Stratification Stage

R1:1

Arm B n=21:

Nivolumab

3 mg/kg

D1,15,29 +

Ipilimumab

1 mg/kg D1

D1 D15 D29

D1 D15 D29

Surgery

BIOMARKERS

EVALUATION

Arm A n=23:

Nivolumab

3 mg/kg

D1,15,29

CT

PET/CT

Blood

Stool

Tumor

Uninvolved

lung

CT, PET/CT

Tumor

(Archival/fresh)

Blood, Stool

SOC

Postop therapy

Primary endpoint:

≤10% viable tumor (MPR)

(within 3-6 weeks

after last dose)

NEOSTAR: phase II study of induction checkpoint blockade for untreated stage I-IIIA NSCLC amenable for surgical resection

Cascone T, William WN, et al. ASCO Annual Meeting 2019 Abstract 8504

NCT03158129

PI: Cascone

co-PI: Sepesi

NCT03158129

Primary endpoint: MPR rate NI meets the pre-specified trial efficacy boundary

Overall ITT

Resected + not resected

Total

n = 44

N

n = 23

NI

n = 21

MPR + pCR 11 (25%)4 (17%)

(95% CI:5%,39%)

7 (33%)

(95% CI:15%,57%)

0% viable tumor (pCR) 8 (18%) 2 (9%) 6 (29%)

1-10% viable tumor 3 (7%) 2 (9%) 1 (5%)

% v

iab

le t

um

or

N (n = 21) NI (n = 16)

Evaluable

Resected on trial

Total

n = 37

N

n = 21

NI

n = 16

MPR + pCR 11 (30%) 4 (19%) 7 (44%)

0% viable tumor (pCR) 8 (22%) 2 (10%) 6 (38%)

1-10% viable tumor 3 (8%) 2 (10%) 1 (6%)

70

N (n = 23) NI (n = 21)

Pre-specified trial efficacy

boundary: ≥ 6 MPRs

Pa

tie

nt

co

un

t

MPR + pCR

>10 % viable tumor

1-10 % viable tumor

0 % viable tumor

20

Median (min, max)

70 (0,100)

Median (min, max)

20 (0,100)


Grade 1-2 TRAE*

N (23) NI (21)

n n/23 (%) n n/21 (%)

Fatigue 8 35% Rash acneiform 11 52%

Rash acneiform 6 26% Fatigue 7 33%

Anemia 3 13% Nausea 7 33%

Hyponatremia 3 13% Cough 6 29%

Diarrhea 2 9% Diarrhea 6 29%

Increased Alanine

Aminotransferase 2 9% Chills 3 14%

Flu like symptoms 2 9% Anemia 2 10%

Headache 2 9% Dyspnea 2 10%

Hypomagnesemia 2 9% Hyperthyroidism 2 10%

Pruritus 2 9% Pruritus 2 10%

Vomiting 2 10%

Grade 3-5 TRAE

N (23) NI (21)

n n/23 (%) n n/21 (%)

Hypermagnesemia (G3) 1 4% Diarrhea (G3) 1 4%

Hypoxia (G3) 1 4% Hyponatremia (G3) 1 4%

Pneumonia (G3)* 1 4%

Pneumonitis (G5)* 1 4%

* From the same patient

* The maximum grade of TRAE from a patient is considered

Median follow-up time after randomization: 8.4 months

Arm A: 1 pt (IIB) died of steroid-treated pneumonitis 4.1 months after randomization

Arm B: 1 pt (IIIA) had PD 2 months after randomization, and died of disease 17 months after randomization

Treatment-related adverse events (TRAEs) and follow up


Neoadjuvant chemotherapy increases expression of PD-L1 vs. untreated tumors

Parra ER, …, William WN et al, JITC 2018

Study design & Endpoints(Within 3 to 8 weeks after

surgical resection)

Mariano Provencio, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.

Primary Endpoint:

PFS at 24 months

Secondary Endpoints:

Down-staging rate,

complete resection rate,

ORR, safety, TTP, OS

at 3 years

Study start: April 2017

Enrollment completion: August 2018

Data analysis cut-off: 27th June 2019

1 Two patients were not resected due to their own decision, 3 patients did not fulfill resectability criteria according to the surgeons’ opinion2 Three patients did not receive adjuvant treatment due to toxicity, 1 patient exceeded the time per protocol to start adjuvant treatment

Patient Disposition


51 pts assessed for eligibility

46 eligible pts included and received neoadjuvant treatment (ITT)

5 pts did not meet all inclusion/exclusion

criteria

5 pts were not resected after neoadjuvant

treatment1

41 ptsunderwent surgery

37 pts receivedadjuvant treatment

4 pts did notreceive adjuvant treatment2

Patient baseline characteristics N=46 (ITT)

Age (median, range) 63(41-77)

Male, N (%) 34 (74 %)

ECOG PS

0 N (%)

1 N (%)

25 (54%)

21 (46%)

Smoking status, N (%)

Former/current 46 (100%)

Adenocarcinoma, N (%) 28 (61)

Co-morbidities, N (%) 43 (93,5)

N2 33 (89.2)

Multiple station 25 (75.8)

Pathological response

To identify factors influencing pathological response (complete and major) the following potential influencing factors were

considered:

• Comorbidities.

• Clinical stage.

• Tumor size mm

• Primary tumour site (right vs left).

• Histology (adenocarcinoma vs squamous).

• Node involvement (yes/no).

Each one of the factors were compared between the patients with a pathological response.

No statistically significant differences were observed


Pathologic response N=41 % (CI 95%)

Major Pathological Response (MPR)

Complete Response (CR)

34/41

24/41

83 (68-93)

59 (42-74)

> 10% residual viable tumor 7/41 17 (7-32)

• Age.

• Gender.

• Performance status.

• Smoking status.

• N2: Unique vs Multiple

• Toxicities

• Nodes N1 vs N2

Outline



• Challenges


The optimal cutoff percentage of viable tumor for predicting survival may differ between ADC and SCC in response to NAC

Qu, et al. J Thorac Onc 2019

65% VT correlated with survival in adenocarcinoma

≤10% VT correlated with survival in SCC

Weissferdt A and Pataer A 2019, under revisions

Strong Interobserver Agreement on MPR in NSCLC Patients Receiving Neoadjuvant Chemotherapy

A distinct pattern of immune-mediated tumor regression in NSCLC specimens with MPR to IO, with features of immune activation, tumor cell death, and tissue repair

Adapted from Cottrell TR et al. Ann Oncol. 2018

Neoadjuvant CT and IO are associated with similar histopathological changes compared to untreated resected tumors but result in lower proportions of viable tumor and higher degrees

of fibrosis

Parameter of PTR Untreated cohort

(mean values)

CT cohort(mean values)

IO cohort (mean values)

P value

Viable tumor 66.4% 40.9% 34% 0.0027

Fibrosis 27.4% 45.9% 59.2% 0.0033

Necrosis 6.2% 13.1% 6.6% 0.8817

Inflammation 2.32 1.50 1.85 0.2088

TLS 0.90 0.95 1.00 0.3552

Macrophages 0.10 0.66 0.81 0.0639

LVI 0.26 0.21 0.30 0.9113

Cholesterol clefts 0.083 0.87 0.91 0.0003

Giant cells 0.35 0.75 0.65 0.0300

Neovascularization 0.05 0 0.10 0.3679

Weissferdt A et al., ESMO Congress 2018

TMB and PD-L1 correlations with MPR and pathological regression in neoadjuvant ICI studies

n = 68

ρ = −0.24a

P = 0.04

Kwiatkowski DJ, ASCO 2019 Abstract 8503

(n = 40) (n = 10)

P =

0.48a

TMB by MPR (n = 50)

Forde P et al, NEJM 2018

Elevated baseline tumor PD-L1 expression is associated with radiographic and pathologic responses in NEOSTAR

Tina Cascone, MD, PhD

Ba

se

lin

e %

PD

-L1

CR/PR SD/PD

60

80

40

20

0

P = 0.015

Baseline % PD-L1 and RECIST responses

% v

iab

le t

um

or

<1% >1%

60

80

100

40

20

0

Baseline % PD-L1

P = 0.046

Baseline % PD-L1 and % viable tumor

Baselin

e %

PD

-L1

MPR No MPR

60

80

40

20

0

P = 0.015

Baseline % PD-L1 and MPR


Nivo plus Ipi combo is associated with increased T cell repertoire diversity and reactivity in the tumor at surgery

Reuben A. et al, ASCO 2019 Abstract 8532

Tu

mo

r rich

ne

ss s

urg

ery

Blood richness baseline

R = 0.82

P = 0.023

10000 30000 50000 70000

0

5000

10000

15000

G0

Tum

or S

N

NI

Uninvolved

lung

Resected

tumor

Clo

na

lity

Ric

hn

ess

Uninvolved

lung

Resected

tumor

Div

ers

ity

Reacti

vit

y

Ric

hn

ess

Pre-

therapy

Pre-

therapy

Surgery Surgery

N NI

Pre-

therapy

Pre-

therapy

Surgery SurgeryC

lon

alit

y

N NI

Div

ers

ity

Re

ac

tivit

y

Cascone T, ASCO Annual Meeting 2019 Abstract 8504

Early ctDNA clearance is associated with pathologic response to anti-PD1 therapy in early-stage NSCLC

Anagnostou V, Forde P et al, Cancer Res 2019

Updated long-term follow up following neoadjuvant nivolumab:• At median follow up of 30 m, 15/20 pts are

disease-free and alive. 2 pts have died, 1 of disease relapse.

• Median RFS unreached. The 24m RFS rate is 69% (95% CI: 51-93).

• Presence of ctDNA at diagnosis and MPR do not associate with RFS.

Reuss JE et al, J Clin Oncol 37, no. 15_suppl, 2019 Abstract 8524

Outline



• Challenges


NEOSTAR: a platform phase II study to test induction checkpoint blockade-based strategies for untreated and resectable stage I-IIIA NSCLC

NCT03158129

N total = 44

Eligibility

NSCLC Stage I-

IIIA (AJCC7th)

Surgical

Candidate

Stratification

Stage

Surgery

R1:1

Arm B:

Nivolumab

3 mg/kg

D1,15,29 +

Ipilimumab

1 mg/kg D1

D1 D15 D29

D1 D15 D29

SurgeryWithin 8 weeks

post surgery

Within 8 weeks

post surgery

Arm A:

Nivolumab

3 mg/kg

D1,15,29

SOC

Postop therapy

SOC

Postop therapy

Primary endpoint:

≤10% viable tumor (MPR)Arm C:

Nivolumab

360 mg IV +

Chemotherapy

IV q3 weeks

X 3 cycles

D1 D22 D43

SurgeryWithin 8 weeks

post surgery

SOC

Postop therapy

N = 22

Eligibility

NSCLC

Stage IB (≥4cm)-

IIIA (AJCC 7th)

Surgical

Candidate PI: Cascone

co-PI: Sepesi

Primary endpoint:

≤10% viable tumor (MPR)

Surgical

resection

Arm D: Durvalumab 1500 mg IV + danvatirsen

200 mg IV

Arm A: Durvalumab 1500 mg IV monotherapy

Patients stratified by

lymph node

involvementR

an

do

miz

e 1

:1:1

:1

(up

to

40

pa

tie

nts

pe

r a

rm)

Week 0 Week 1 Week 2 Week 3 Week 4

ECOG PS, Eastern Cooperative Oncology Group performance

status; NSCLC, non-small-cell lung cancer

Days 29 to

42

Follow-up

Day 105

Durv

alu

mab

Durv

alu

mab

Danvatirs

en

Danvatirs

en

Danvatirs

en

Danvatirs

en

Danvatirs

en

Danvatirs

en

Danvatirs

en

Arm B: Durvalumab 1500 mg IV +

oleclumab 3000 mg IV

Durv

alu

mab

Ole

clu

mab

Ole

clu

mab

Arm C: Durvalumab 1500 mg IV + monalizumab

750 mg IV

Durv

alu

mab

Monaliz

um

ab

Monaliz

um

ab

Tumor sample obtained

prior to treatment

Resectable, early

stage

(I [> 2 cm] to IIIA)

NSCLC

ECOG PS 0/1

NeoCOAST: Platform study testing the safety and activity of neoadjuvant Durvalumab with or without novel immunotherapies

Primary endpoint

MPR rate

Secondary endpoints

Feasibility of surgery within planned window

Safety: AEs, SAEs etc.

pCR rate, PK, ADAs

Garcia Campelo R, Cascone T et al, WCLC 2019, P2.04-28

Trial identifier Phase Sponsor Stage Intervention/Disease space Primary endpoint

NCT02259621 (NA_00092076) 2 Sidney Kimmel Comprehensive Cancer Center

IB–IIIA Nivo with or without ipi Safety and feasibility

NCT02818920 (TOP 1501) 2 Duke University Medical Center IB–IIIA Pembrolizumab (neoadjuvant and adjuvant) Surgical feasibility rate

NCT02927301 (LCMC-3) 2 Genentech IB–IIIA Atezolizumab (neoadjuvant and adjuvant) MPR

NCT02572843 2 Swiss Group for Clinical Cancer Research

IIIA (N2) Durvalumab (neoadjuvant, following chemotherapy, and adjuvant)

EFS

NCT03794544 (NeoCOAST) 2 MedImmune I [> 2 cm]-IIIA Durvalumab with or without novel I-O agents MPR

NCT03158129 (NEOSTAR) 2 MD Anderson Cancer Center I–IIIA Nivo with or without ipi or chemo MPR

NCT03197467 (NEOMUN) 2 AIO-Studien-gGmbH II-IIIA Pembrolizumab (neoadjuvant) Feasibility, safety, clinical, path responses

NCT03081689 (NADIM) 2 Spanish Lung Cancer Group IIIA (N2) Nivolumab, carboplatin, paclitaxel PFS

NCT03838159(NADIM II)

2 Fundación GECP IIIA/IIIB (T3N2) Neoadjuvant Nivo, Paclitaxel, Carbo and adjuvant Nivo vs. neoadj Paclitaxel, Carbo

pCR

NCT02716038 2 Columbia University IB-IIIA Neoadjuvant Atezo, Carbo, Nab-paclitaxel MPR

NCT03237377 2 Sidney Kimmel Comprehensive Cancer Center

IIIA Neoadjuvant Durvalumab/RT or Durvalumab/Tremelimumab/RT

Toxicities, Feasibility of Preoperative ImmunoRT

NCT02904954* 2 Weill Medical College of Cornell University

I-IIIA Durvalumab With or Without SBRT DFS

NCT02998528 (CheckMATE 816) 3 Bristol-Myers Squibb IB-IIIA Nivo plus ipi or chemotherapy vs. chemo EFS and pCR rate

Selected ICI trials in the neoadjuvant/perioperative space for resectable NSCLC

https://clinicaltrials.gov/

*Altorki et al., IASLC 2019, P2.04-92: 34 pts randomized to Durva vs. Durva+SBRT: Grade 3/4 AEs: 11%. Resectability rate: 88% (30/34; 28R-0:87%). Grade 3/4 perioperative AEs: 31% (10/32). MPR Arm-2: 47% (8/17) vs. 0 in Arm-1. Excluding 4 EGFR mutant pts, MPR 61.5% (8/13%) in Arm-2.


Ongoing phase 3 periadjuvant studies with I-O in resectable NSCLC

Key Eligibility Criteria

• Stage II-III* resectableNSCLC

• ECOG PS 0–1

I-O +Chemotherapy

4 cycles†

I-O

13-16 cycles†

Chemotherapy† Placebo/BSC

Surgery

R

Surgery

Checkmate 77T1 KEYNOTE-6712 IMpower0303 AEGEAN4,5

I-O agent Nivolumab Pembrolizumab Atezolizumab Durvalumab

Primary endpoint(s) EFS EFS, OS MPR, EFS MPR

PCD May 2023 Jan 2024 March 2025 July 2020

Stages II-IIIB‡ II-IIIB‡ II-IIIB‡ IIA-IIIB‡

Target enrollment 452 786 374 300

*Stages included differ between trials. †Dosage, timing, duration, and chemotherapy backbones differ between trials; information not available for Checkmate 77T or AEGEAN. ‡Includes stages IIIB patients with N2 disease that is considered resectable.1. Clinicaltrials.gov. NCT04025879. Accessed August 7, 2019. 2. Clinicaltrials.gov. NCT03425643. Accessed August 7, 2019. 3. Clinicaltrials.gov. NCT034056063. Accessed August 7, 2019. 4. Clinicaltrials.gov. NCT03800134. Accessed August 7, 2019. 5. Heymach JV et al. Poster presentation at WCLC 2019. P1.18-02.

Trial identifier Phase Sponsor Stage Intervention Primary endpoint

NCT02595944(ANVIL)

3 National Cancer Institute (NCI)

IB–IIIA Nivolumab DFS, OS

NCT02486718(IMpower010)

3 Hoffmann-La Roche IB–IIIA Atezolizumab DFS

NCT02273375 (BR31)

3 Canadian Cancers Trials Group

IB-IIIA Durvalumab DFS

NCT02504372 (KEYNOTE-091) (PEARLS)

3 EORTC, Merck IB–IIIA Pembrolizumab DFS

NCT03053856 2 Samsung Medical Center

IIIA (N2) Pembrolizumab DFS

NCT03447769CANOPY-A

3 Novartis Pharmaceuticals

IIA-IIIA and IIIB (T > 5cm N2) completely resected

Canakinumab or placebo

DFS

Selected ICI trials in the adjuvant space for operable NSCLC



ALCHEMIST Adjuvant ICI trial post ANVIL

Study Chair: Jacob Sands - ALLIANCE

Courtesy of Jacob Sands

ICI trials in the perioperative space: what we have learned and future directions

Role of neoadjuvant/perioperative ICIs for stage I-III resectable NSCLC

Best therapy timing, # doses, sequence vs combination, spatiotemporal modulation of the immune TME by therapy are under investigation (preclinical models as platform)

Investigate safety/feasibility and activity of novel neoadjuvant IO-based combinations: STING agonists, intratumoral IOs, anti-CTLA-4-based combos?

Biomarker discovery/patient selection in neoadjuvant studies: PD-L1, TMB, scRNA-seq, ctDNA, microbiome, oncogenic drivers, TCR/neoantigen repertoire, sex/age, radiomics

Validation of surrogate clinical endpoints in phase 3 studies

Harmonization/standardization of methods for path response assessment (tumor, nodes) Does type of therapy matter? Does histology matter? Guidelines being developed by IASLC Interobserver agreement on path responses: IASLC efforts; industry-academia collaboration; FDA input/guidance MPR in IIT population vs. resected patients only, exclusion of oncogenic drivers

Surgical challenges after neoadjuvant therapies

Documents

Neoadjuvant Immunotherapy for NSCLCs