Successes and Challenges in Treating Squamous Cell

Successes and Challenges in Treating Squamous Cell Carcinoma of the Lung

Noemi Reguart,MD, PhD

Hospital Clinic de Barcelona

Barcelona, Spain

Boehringer Ingelheim’s Conversations in Oncology 2018 | Shanghai, China | 17-18 November 2018

Conversations in Oncology 2018 is a standalone medical education meeting by Boehringer Ingelheim

SC-CRP-02660

2

• Introduction

– Key Differences Between ADC and SqCC of the Lung

– Evolving Treatment Landscape for Metastatic NSCLC

• First-Line Immunotherapy Trials in Patients With SqCC of the Lung

– Pembrolizumab: KEYNOTE-407

– Atezolizumab: IMpower131

– Nivolumab: CheckMate-227, Part 1

• ErbB Receptor Family Is a Valid Therapeutic Target for SqCC of the Lung

– Afatinib: LUX-Lung 8

Outline

ADC = adenocarcinoma; SqCC = squamous cell carcinoma; NSCLC = non–small cell lung cancer..


3

Differences Between NSCLC Histologic Subsets:

ADC vs SqCC of the Lung1,2

aAdvances in 2015.

SOC = standard of care; PD-L1 = programmed death-ligand 1.

1. Gandara et al. Clin Cancer Res. 2015;21:2236; 2. Li et al. J Clin Oncol. 2013;31:1039.

ADC SqCC

Age Bimodal with

younger subset ~Older

Male/female ↑ Females ↑ Males

Smoking Never-smoker

subset ~Smokers

Therapies

contraindicated No

Yes

(pemetrexed,

bevacizumab)

Biomarker-driven

targeted therapy

as SOC

Yes

No

Good candidate:

PD-L1 therapy Yesa YESa

ADC 55%

SqCC [VALU

E]

[CATEGORY NAME] [VALU

E]


4

Genomic characterization of SqCC

The Cancer Genome Atlas Research Network. Nature. 2012;489:519-525.

The Cancer Genome Atlas (TCGA) initiative

Amplifications Mutations

MYCL MCL1

REL NFE2L2

SOX2 PDGFRA

EGFR FGFR1

CCND1

CRKL

ERBB2

MDM2

5

Evolution of NSCLC Subtyping From Histologic to

a Multitude of Genomically Defined Subsets

Li et al. J Clin Oncol. 2013;31:1039.

SqCC [VALUE]

[CATEGORY

NAME] [VALUE]

ADC

55%

NSCLC

as 1 disease

Histology-Based Subtyping

ADC

SqCC

ALK

HER2

BRAF

PIK3CA

AKT1

MAP2K1

NRAS

ROS1

RET

EGFR

KRAS

Unknown

EGFRvIII

PI3KCA

EGFR

DDR2

FGFR1 Amp

Unknown


6

PD-L1 expression in SqCC

Aggarwal et al. Ann Oncol. 2016;27(6):359-378

PD-L1 TPS ≥1%_67%

PD-L1 TPS ≥50%_ 28%

Pooled data from KEYNOTE-001, -010, and -024

7

ESMO

ESMO Guidelines Committee. Ann Oncol. 2018;29(suppl 4):iv193-iv237

Chemo

Antiangiogenics

EGFR inh

IO

Chemo

Chemo-IO

8

First-Line Immunotherapy Trials in Patients With SqCC of

the Lung Are Rapidly Changing the Treatment Landscape

1. Reck et al. N Engl J Med. 2016;375:1823; 2. Lopes et al. J Clin Oncol. 2018;36(suppl 18):LBA4; 3. Paz-Ares et al. J Clin Oncol. 2018;36(suppl):105; 4. Jotte et al. J Clin

Oncol. 2018;36(suppl):LBA9000; 5. Hellmann et al. Cancer Res. 2018;78(suppl 13):CT077; 6. Borghaei et al. J Clin Oncol. 2018;36(suppl):9001; 7. Hellmann et al. N Engl J

Med. 2018;378:2093.

Trial Name Histology Treatment Arms

KEYNOTE-0241 Mixed (N=305)

Squamous (n=56) Pembrolizumab vs chemotherapy (PD-L1 ≥50%)

KEYNOTE-0422 Mixed (N=1274)

Squamous (n=492) Pembrolizumab vs chemotherapy (PD-L1 ≥1%)

KEYNOTE-4073 Squamous (N=559) Pembrolizumab + chemotherapy vs chemotherapy

IMpower1314 Squamous (N=1021)

Arm A: atezolizumab + carboplatin + paclitaxel

Arm B: atezolizumab + carboplatin + nab-paclitaxel

Arm C: carboplatin + nab-paclitaxel

CheckMate 227, Part 15-7 Mixed (N=1739)

Squamous (n=487a)

Part 1a (PD-L1 ≥1%): nivolumab + ipilimumab; chemotherapy;

or nivolumab

Part 1b (PD-L1 <1%): nivolumab + ipilimumab; chemotherapy;

or nivolumab + chemotherapy

aSquamous histology in 28% of all randomised patients..


9

KEYNOTE-024 Study Design

Brahmer et al. WCLC 2017. Abstract OA 17.06.

10

KEYNOTE-024: updated OS


11

KEYNOTE-024: OS in subgroups


12

First Line, Stage IV Sq-NSCLC, PDL-1≥ 50%,

smoker…> 2 years on IO

Case report by N.Reguart, C.Cabrera

Aug 2017 Oct 2017 Sept 2018

ToT 13 mo

CR

13

KEYNOTE-407 Study Design

TPS = tumour proportion score; AUC = area under the concentration/time curve; Q3W = every 3 weeks; Q1W = every week; PFS = progression-free survival; RECIST = Response Evaluation Criteria in

Solid Tumors; BICR = blinded independent central review; OS = overall survival; ORR = objective response rate; DOR = duration of response; IHC = immunohistochemistry

Paz-Ares et al. ASCO 2018. Abstract 105.

..

aPercentage of tumor cells with membrabous PD-L1 staining assessed using the PD-L1 IHC 22C3 pharmDx assay. bPatients could crossover during combination therapy or monotherapy. To be eligible for crossover, PD must have been verified by BICR and all safety criteria had to be met.


14

KEYNOTE-407: PFS at Interim Analysis, ITT

Paz-Ares L, et al. ASCO 2018. Presented June 3, 2018.

15

KEYNOTE-407: OS at Interim Analysis

HR = hazard ratio; CI = confidence interval; NE = not evaluable; ITT = intention to treat.


ITT population.


16

KEYNOTE-407: OS at Interim Analysis by PD-L1 TPS



17

IMpower131 Study Design

Jotte et al. ASCO 2018. Abstract LBA9000.


18

IMpower 131: PFS in ITT Population

(Arm B vs Arm C, Investigator-Assessed)

CnP = carboplatin + nab-paclitaxel.


Data cutoff: January 22, 2018

aStratified HR


19

IMpower131: Interim OS (Arm B vs Arm C)



aStratified HR


20

Impower 131: Second OS Interim Analysis

Socinsky et al. ESMO 2018. Poster LBA65.

43% cross-over to IO

(other than atezolizumab)

21

IMpower131: Interim OS by PD-L1 Subgroups

(Arm B vs Arm C)

TC = tumour cell; IC = tumour-infiltrating immune cell.



aUnstratified HR


Impower 110

22

CheckMate-227, Part 1 Study Design

Borghaei et al. ASCO 2018. Abstract 9001.


23

CheckMate-227, Part 1 PFS in Patients With <1%

Tumor PD-L1 Expression


All Randomised Patients (Squamous and Nonsquamous)


24

CheckMate-227 Part 1 PFS Subgroup Analyses in

Patients With <1% Tumour PD-L1 Expression

TMB = tumour mutational burden.



25

PFS: Nivolumab + Chemotherapy vs Chemotherapy

By TMB

• TMB ≥10 mut/Mb: ORR was 60.5% with nivo + chemo and 20.8% with chemo

• TMB <10 mut/Mb: ORR was 27.8% with nivo + chemo and 22.0% with chemo

26

The ErbB Receptor Family Is a Valid Therapeutic

Target for SqCC of the Lung

1. Hirsch FR et al. J Clin Oncol. 2003;21:3798; 2. Lopez-Malpartida et al. Lung Cancer. 2009;65:25; 3. Lee et al. Lung Cancer. 2010;68:375; 4. Gately et al. Clin Lung Cancer. 2014;15:58; 5. Dacic et al. Am J Clin Pathol. 2006;125:860;

6. Ji et al. Proc Natl Acad Sci U S A. 2006;103:7817; 7. Dearden et al. Ann Oncol. 2013;24:2371; 8. Jaiswal et al. Cancer Cell. 2013;23:603; 9. Gorgoulis et al. Pathol Res Pract. 1995;191:973; 10. Kan et al. Nature. 2010;466:869;

11. Shepherd et al. N Engl J Med. 2005;353:123; 12. Clark et al. Clin Lung Cancer. 2006;7:389; 13. Leon et al. ESMO 2008. Abstract 1277; 14. Pirker et al. Lancet. 2009;373:1525; 15. Pirker et al. Lancet Oncol. 2012;13:33; 16. Thatcher

et al. ASCO 2014. Abstract 8008; 17. Li et al. J Clin Oncol. 2013;31:1039.

ErbB Receptor Frequency

(%)

EGFR overexpression2-5 26-86

EGFR amplification2,5 15-27

EGFRvIII mutation6 5

EGFR kinase domain mutation7 <5%

ERBB2 mutation/amplification2 5

ERBB3 mutation8 1

ERBB3 overexpression9 10

ERBB410 8

Frequency of known genetic drivers in SqCC17

• Dysregulation of the ErbB pathway is

frequently observed in SqCC of the lung

– EGFR overexpression and gene amplification

aberrations of other ErbB receptors and

dysregulation of the downstream pathways

have been implicated in the pathobiology

of SqCC1,2

– These findings likely account for the benefits

these patients derive from erlotinib11-13 and

other EGFR-directed therapies in different

treatment settings,14-16 despite the low

frequency of EGFR-activating mutations17

EGFRvIII

PI3KCA

EGFR

DDR2

FGFR1 Amp

Unknown

≈5%


27

Therapeutic targets in SqCC, defined by TCGA

The Cancer Genome Atlas Research Network. Nature. 2012;489:519-525.

Possible therapeutic

target in over 60% of

SqCC

Targets will need to

be validated

in pre-clinical

models

percent of cases (%)

inactivated050 50

activated

activation inhibitionProliferation, cell survival, translation

EGFR

9%

ERBB2

4%PIK3CA16%

PTEN15%

NRAS<1%

KRAS3%

BRAF4%

PI3K/RTK/RAS signaling

FGFR3

2%

HRAS3%

AKT316%

AKT24%

69% altered

STK112%

AKT1<1%

TSC13%

TSC23%

RASA14%

AMPK

MTOR

FGFR2

3%

NF111%

FGFR1

7%

ERBB3

2%

RTK

PI3K

Alteration pattern

RAS26%24%47%

28

Afatinib Is the First Irreversible ErbB Family

Blocker

1. Hirsh. BioDrugs. 2015;29:167; 2. Li et al. Oncogene. 2008;27:4702; 3. Solca et al. J Pharmacol Exp Ther. 2012;343:342.

• Afatinib covalently binds and

irreversibly blocks EGFR, HER2,

and ErbB41-3

• Targeting the whole ErbB Family

enhances the effect on important

signalling pathways2


29

Advanced SqCC in a non-smoker female

Case report, Noemi Reguart Hospital Clínic Barcelona

Progression

On Nivolumab

Response

On Afatinib

H-E: squamous cells p40 positive

30

LUX-Lung 8 Study Design:

Afatinib vs Erlotinib in SqCC of the Lung

PD = progressive disease; AE = adverse event; QD = once daily.

Soria et al. Lancet Oncol. 2015;16:897.

• Advanced SqCC NSCLC

(stage IIIB/IV)

• PD after ≥4 cycles of a first-line

platinum doublet

• ECOG PS 0 or 1

• No prior anti-EGFR therapy

• No active brain metastases

Afatinib (n=398)

40 mg QD

Erlotinib (n=397)

150 mg QD

Treatment

until disease

progression

or

unacceptable

AEs

Randomisation

1:1

(N=795)

• Stratification: East Asian vs non–East Asian

• Tumour tissue collected for correlative science

• Radiographic tumour assessment at baseline; weeks 8, 12, 16; every 8 weeks

thereafter

• Primary endpoint: PFS; key secondary endpoint: OS


31

1.0

LUX-Lung 8: Significant Improvement in PFS and

OS With Afatinib Compared With Erlotinib

1. Soria et al. Lancet Oncol. 2015;16:897; 2. Goss et al. ESMO 2018. Poster 1442P; 3. Boehringer Ingelheim Data on File.

397 99 34 17 10 2 0 1 1 1 Erlotinib

398 139 50 30 14 10 5 2 2 0

397 99 34 17 10 2 1 1 1 0

Afatinib

40 mg QD

(n=398)

Erlotinib

150 mg QD

(n=397)

Patients progressed or died, n (%) 299 (75.1) 306 (77.1)

Median PFS (mo) 2.6 1.9

HR 0.81; 95% CI: 0.69–0.96;

P=0.0103

Afatinib

40 mg QD

(n=398)

Erlotinib

150 mg QD

(n=397)

Patients died, n (%)3 307 (77.1) 325 (81.9)

Median OS (mo)2 7.8 6.8

HR 0.84; 95% CI: 0.73–0.97;

P=0.019

Pro

bab

ilit

y o

f P

FS

Updated PFS Analysis by Independent Review (n=795)1

3 6 9 12 15 18 21 24

0.2

0.4

0.6

0.8

0 0 27

Time (mo)

Afatinib

Erlotinib

No. at risk

Updated OS [Data Cutoff: March 2018] (n=795)2


Afatinib

(n=398)

Erlotinib

(n=397)

32

Retrospective Analysis of LUX-Lung 8 Patients

Deriving Long-Term Benefit

LTB = long-term benefit.

1. Yang et al. ELCC 2017. Poster 102P; 2. Soria et al. Lancet Oncol. 2015;16:897; 3. Goss et al. ESMO 2018. Poster 1442P.

OS: Primary Analysis

(ITT population)1 OS and PFS in Patients

Deriving Long-Term Benefit1-3

• 21 patients received ≥12 months of afatinib

treatment

– Median treatment duration was 19.0 months

(range: 12.3-51.3 months)

Afatinib

ITT

(n=398)

Afatinib

LTB

(n=21)

Median OS, mo 7.9 27.5

(range: 16.2-53.6)

Median PFS, mo 2.6 12.9

(range: 2.8-25.8)

0

36.4%

22.0%

28.2%

14.4%

Afatinib (n=398)

Erlotinib (n=397)

1.0

0.8

0.6

0.4

0.2

0 3 6 9 12 15 18 21 24 27 30

Time (months)

Es

tim

ate

d P

rob

ab

ilit

y o

f O

S


33

LUX-Lung 8 Long-Term Benefiters:

Treatment Response

VS = VeriStrat; VS-G = VeriStrat-Good; VS-P = VeriStrat-Poor.

Goss et al. ESMO 2018. Poster 1442P.

Median treatment

duration,

mo (range)

19.0

(12.3-51.3)

Median OS,

mo (range)

27.5

(16.2-53.6)

Median PFS,

mo (range)

12.9

(2.8-25.8)

Complete

response††, n (%) 1 (5)

Partial response††,

n (%) 6 (29)

Stable disease††,

n (%) 13 (62)

†Patients were ordered and numbered by treatment duration (at data cut-off), with patient 1 being on treatment longest; ‡Patient transferred to commercial drug on

discontinuation from study drug; §Patient also had rearrangements in two genes; ¶First observed response at time of tumour measurement; **≥1 SV present in at least

3/10 patients with long-term disease control, or part of the ErbB family (EGFR, ErbB2, ErbB3, ErbB4); ††One patient was not evaluable.


34

ErbB Family Mutations in SqCC of the Lung in the

LUX-Lung 8 Trial (Afatinib-treated Patients)

aNext-generation sequencing was undertaken in 10/21 LTRs and 132/398 afatinib-treated patients overall.

ErbB family mutations were more frequent in LTBs than in the overall afatinib-treated population.

WT = wild type.

Yang et al. ELCC 2017. Poster 102P.

Afatinib-Treated LTBs (n=10a)

ErbB3,

0% ErbB4,

10.0%

ErbB WT,

50.0%

ErbB2,

20.0%

EGFR,

20.0%

All Afatinib-Treated Patients (n=132a)

ErbB4,

2.3%

ErbB WT,

81.1%

ErbB2,

6.8% EGFR,

6.8%

ErbB3,

4.6%


35

Recent Additional Trial on Activity of Afatinib in

HER2 Exon 20–Mutated NSCLC

TTF = time to treatment failure; DCR = disease control rate; PR = partial response; SD = stable disease; ND = not determined as no assessments were available.

Peters et al. J Thorac Oncol. doi: 10.1016/j.jtho.2018.07.093.

All HER2

Mutation–Positive Patients

Patients With

p.A775_G776insYVMA

in Exon 20

Patients With M774dup

in Exon 20

n (%) 28 (100) 10 (36) 2 (7)

TTF

Median TTF, mo 2.9 9.6 1.9

TTF >1 y 8 (29) 4 (40) 0 (0)

Tumour response

Patients with response

data available 16 (57) 6 (60) 0 (0)

ORR 3 (19) 2 (33) ND

DCR 11 (69) 6 (100) ND

PR 3 (19) 2 (33) ND

SD 8 (50) 4 (67) ND


36

Summary and Conclusions

• Major differences exist between SqCC of the lung and ADC, including identification of

treatable oncogene subsets

• Immune checkpoint inhibitors have emerged as promising novel treatment options for

advanced SqCC

• ErbB receptor family is a valid therapeutic target for SqCC of the lung

• In LUX-Lung 8, patients with ErbB mutation–positive tumours showed a more

pronounced PFS and OS benefit with afatinib over erlotinib

• In the treatment of advanced SqCC, afatinib should be considered:

– As a treatment option in patients who have failed previous treatment with chemotherapy and

immunotherapy

– In the second-line setting in patients who are not eligible for immune checkpoint inhibitors


Documents

Successes and Challenges in Treating Squamous Cell