Current status of (neo)

adjuvant immunotherapy in
early stage NSCLC
Are we there yet?

Lizza Hendriks, MD, PhD

Pulmonologist, Maastricht UMC+, The Netherlands
Lizza.hendriks@mumc.nl
@HendriksLizza
 DISCLOSURE INFORMATION

Affiliation / Financial interest Commercial Company

Grants/research support: Roche, Boehringer Ingelheim, AstraZeneca (institution)

Honoraria or consultation fees: Advisory boards BMS, Roche, Boehringer Ingelheim, Lilly, Takeda,
Amgen, Pfizer (institution)
Participation in a company NA
sponsored bureau:
Stock shareholder: NA
Spouse / partner: NA
Other support / potential conflict of Interviews for Roche (institution), mentorship program with key
interest: opinion leaders funded by AstraZeneca, PI pharma studies
AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda,
Blueprint Medicines, (all institution), travel support Roche, BMS
(self), speaker bureau MSD (institution) webinars Medtalks (self)
 Outline

Where do we come from in early stage NSCLC?

Rationale for immune checkpoint inhibitors (ICI) in early stage NSCLC?

Summary of current data: adjuvant and neoadjuvant

Challenges and future directions

 Outline

Where do we come from in early stage NSCLC?

Rationale for immune checkpoint inhibitors (ICI) in early stage NSCLC?

Summary of current data: adjuvant and neoadjuvant

Challenges and future directions

 Where do we come from?

+4% OS @5year with chemo TNM8: <70% 5year OS from stage ≥IB

TKI and beva also no benefit

Arriagada NEJM 2004 *Goldstraw JTO 2015 *Goss JCO 2013 * Wakelee Lancet Oncol 2017
 First attempt with immunotherapeutical compound
MAGRIT
MAGE-A3 vs placebo
N=2312 Possible reasons no benefit
- Low level CD8 response
- Immunosuppression post surgery:
loss of benefit of MAGE-A3

WE NEED TO DO
BETTER

Vansteenkiste Lancet Oncology 2016 *Atanackovic J Immunol 2004

 Outline

Where do we come from in early stage NSCLC?

Rationale for immune checkpoint inhibitors (ICI) in early stage NSCLC?

Summary of current data: adjuvant and neoadjuvant

Challenges and future directions

 ICI give hope in (locally) advanced NSCLC

KN024 5 year OS

PACIFIC 4 year OS

Brahmer ESMO 2020 *Faivre-Finn ESMO 2020

 What do we need from ICI in early stage NSCLC?
Eradicate micrometastatic disease: improve OS
Early surrogate endpoint that correlates with OS would be ideal

Preferably increase compliance and tolerability

Preferably downstaging – increase resectability

No or acceptable increase in (late) toxicity,

including 2nd cancers

No overtreatment, minimize financial toxicity

 Outline

Where do we come from in early stage NSCLC?

Rationale for immune checkpoint inhibitors (ICI) in early stage NSCLC?

Summary of current data: adjuvant and neoadjuvant

Challenges and future directions

 We don’t have data for NSCLC (yet!)
Promising melanoma data with adjuvant ICI

100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 Years
O N Number of patients at risk
264 475 283 217 77184 161
Ipilimumab 10 mg/kg vs nivolumab Ipilimumab 10 mg/kg
323 476 261 199 65
vs1317 placebo
154
1
133
0
Ipilimumab
Placebo Pembrolizumab vs placebo
Stage IIIB-C + IV Stage IIIA-C Stage IIIA-C
RFS HR 0.68 RFS HR: 0.76 RFS HR 0.57
OS HR: 0.72

Weber – ESMO 2019 * Long - NEJM 2018 * Weber - NEJM 2018 * Eggermont -NEJM 2018 (slide courtesy of prof Besse, modified)
Overview ongoing adjuvant ICI trials in NSCLC

Patience needed!

Is neoadjuvant better?

slide courtesy J Remon

 Is neoadjuvant ICI better?

DO WE HAVE TRIAL DATA FOR NSCLC?

Cascone AACR 2018
 Overview neoadjuvant ICI-(ICI) trials
Trial Stage N Treatment

Forde I-IIIA 22 2 cycles nivo / SoC adjuvant

LCMC3 IB-IIIA 101 2 cycles atezo /SoC adjuvant, optional atezo

MK3475-223 I-II 15 1-2 cycles pembro / SoC adjuvant

Gao IA-IIIA 40 2 cycles sintilimab / adjuvant chemo, ICI or combo

NEOSTAR I-IIIA 44 3 cycles nivo ± ipi 1 cycle / SoC adjuvant

Reuss IB-IIIA 9 3 cycles nivo + ipi 1 cycle / SoC adjuvant

IONESCO IB-IIIA 50 3 cycles durva

PRINCEPS I-IIIA 30 1 cycle atezo / SoC adjuvant

Reviewed in Benitez CCR 2020, Uprety JTO 2020 *Reuss JITC 2020 * Besse ESMO 2020 * Wislez ESMO 2020
 Overview neoadjuvant ICI-(ICI) trials

Trial Primary endpoint Surgical feasibility / complications

Forde Safety, feasibility No delay / all surgery / 5% gr≥3 TRAE / 0 death

LCMC3 MPR 11% no surgery / 6% gr≥3 TRAE / 1 death

MK3475-223 Safety, RR 13% delay / 33-27% (non)surgical SAE / 0 death

Gao Safety, feasibility 5% delay / 8% no surgery / 10% gr≥3 TRAE / 2 deaths

NEOSTAR MPR 11% no surgery / 8-12% gr≥3 TRAE / 1 death

Reuss Safety, feasibility No delay / 33% no surgery / 10% gr≥3 TRAE / 1 death

IONESCO % R0 7% no surgery / no gr≥3 TRAE / 4 death

PRINCEPS 2 month tolerance No delay / all surgery / 23% surgical complication / 0 death

Reviewed in Benitez CCR 2020, Uprety JTO 2020 *Reuss JITC 2020 * Besse ESMO 2020 * Wislez ESMO 2020
 How to improve: rationale for neoadjuvant chemo & ICI

Tumor
growth

Martin-Ruiz Sci rep 2020

 Overview neoadjuvant chemo-ICI trial results

Trial Stage N Treatment End- Surgical feasibility /

point complications
NADIM IIIA N2 46 3 cycles nivo – paclitaxel – carbo / PFS No delay / 11% no surgery / 30%
adjuvant nivo 1 year @24m TRAE/ no deaths
Columbia IB-IIIA 30 2-4 cycles atezo – nab-paclitaxel – MPR No delay / 3% no surgery / total
carbo / no adjuvant therapy % TRAE not specified / no
deaths
SAKK IIIA N2 68 3 cycles cisplatin – docetaxel / EFS@ Delay and tox not specified in
16/14 adjuvant durva 1 year 12m presentation
Zinner I-IIIA 13 3 cyles nivo + platinum doublet MPR No delay / 15% preop gr ≥3
chemo (histology based) TRAE / 1 death

Reviewed in Benitez CCR 2020, Uprety JTO 2020 *Rothschild ESMO 2020 *
Zinner ASCO 2020 * Provencio Lancet Oncol 2020 * Shu Lancet Oncol 2020
Surgical outcomes – feasibility – response rate - MPR

Slide courtesy J Remon - updated

 Ongoing phase III neoadjuvant ICI trials

KEYNOTE 671 CT+pembro Pembro 39W

Tislelizumab CT+tislelizumab Tislelizu*
NCT04379635 EFS
NCT03425643 S
EFS R S
N=786
R OS N=380 MPR
CT+placebo Placebo 39W Stage II-IIIA CT+placebo Placebo*
Stage II-IIB (N2)

CT+nivo JS001-028-III
CheckMate 816 CT+toripalimab Toripali^^
EFS NCT04158440 EFS
NCT02998528 R R
N=350
Nivo + ipi S pCR N=406 S MPR
Stage IB-IIIA Stage IIIA CT+placebo Placebo^^
CT

IMpower 030 CT+atezo Atezo 48W CheckMate 77T CT+nivo Nivo 1 yr

EFS NCT04025879 EFS
NCT03456063 R S MPR R S
N=450 N=452
Stage II-IIIB(N2) CT+placebo Placebo 48W Stage IIA-IIIB (N2) CT+placebo Placebo 1 yr

AEGEAN CT+durva Durva 48W CT: chemotherapy ; S: surgery

NCT03800134 R EFS
S MPR *: up to 12 cyles of 21 or 42 days; ^^ duration not specified
N=800
Stage IIA-IIIB(N2) CT+placebo Placebo 48W Search date clinicaltrials.gov sept 27 2020, data presented
according to trialregistry information
 Outline

Where do we come from in early stage NSCLC?

Why could immune checkpoint inhibitors (ICI) work in early stage NSCLC?

Summary of current data: neoadjuvant vs adjuvant

Challenges and future directions

Multiple challenges!

Benitez CCR 2020

 Major pathological response challenges
Standardization needed

Correlation with OS in Melanoma: correlation

neoadjuvant chemo irPR and OS
3 = MPR (≤10% viable tumor) + at
least 3 features of irPR)

Travis JTO 2020 *Stein Ann Oncol 2019 *Cottrell Ann Oncol 2019 * Pataer JTO 2012
 Nodal immune flare and surgical challenges

NEOSTAR: nodal immune flare in 11%

5% additional invasive mediastinal staging
7% change surgical plan. All N0!

Increased complexity of resection and 17-

54% rate of thoracotomy conversion

Cascone ASCO 2019 *Sepesi WCLC 2019 * Bott J Thor Cardiovasc Surg 2019 *Stiles AATS 2019
 Challenge: timing neoadjuvant ICI and role adjuvant ICI

Preclinical breast cancer data: timing and sequence do matter!

4-5 days from neoadjuvant ICI to surgery optimal
10 too long, 2 too short
Adjuvant ICI no added value after 2 cycles neoadjuvant (but more complications)

Do we need adjuvant ICI after

neoadjuvant ICI?
Duration of (neo)adjuvant ICI?

Liu Oncoimmunology 2019 *Brahmer JCO 2010

Challenge: radiotherapy & ICI synergistic & safe?

ASCO 2020 N=9

2 inoperable
Feasibility criteria NOT met

Dutch INCREASE trial

ongoing NL8435
cT3-4N0-1M0

Lemmon ASCO 2020 * Dickhoff BMC Cancer 2020

 Conclusions and take home messages
What are our aims with (neo)adjuvant ICI and what do we know?
Eradicate micrometastatic disease: improve OS ?
Early surrogate endpoint that correlates with OS would be ideal MPR?

Preferably increase compliance and tolerability Discrepant results

Preferably downstaging – increase resectability Discrepant results

No or acceptable increase in (late) toxicity, incl 2nd cancers ?

No overtreatment, minimize financial toxicity Challenge!

 Thank you

Jordi Remon
Biomarkers needed!
Jessica Menis

Benjamin Besse