Paolo Bidoli

S.C. Oncologia Medica H S. Gerardo

Monza

NSCLC: Terapia medica nella fase avanzata

Food and Drug Administration. At http://www.fda.gov/cder/cancer/druglistframe.htm. Accessed August 28, 2006.; National Comprehensive

Cancer Network (NCCN). Practice Guidelines in Oncology. Non-small cell lung cancer v2.2006. Accessed August 28, 2006. Schrump et al.

Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

*Label does not include NSCLC-specific indication

First-line

Second-line

Third-line

Not approved

1970 1980 1990 2000

Median

overall

survival,

months

12+

~8–

10 ~6 ~2–

4

Best supportive care Single-agent platinum Doublets Bevacizumab + PC

Cisplatin*

1978

Carboplatin*

1989

Erlotinib

Pemetrexed

2004

Docetaxel

1999

Paclitaxel

Gemcitabine

1998

Vinorelbine

1994

Docetaxel

2002

Bevacizumab

2006

Gefitinib

2003

Standard Therapies

CT AND SILENT APPROVAL

Adeno LCC/NOS SCC SCLC

EGFR mutants ALK ROS/RET

HER2

b-raf

K-ras

K-ras

Courtesy G Scagliotti

THE FIRST HIT ON HISTOLOGY

Sandler NEJM 2006

THE SECOND HIT ON HISTOLOGY

Scagliotti JCO 2008

MAINTENANCE TREATMENT

Paz Ares JCO 2013

PS 0

PS 1

pemetrexed PS 0: 17.2 months versus placebo PS 0: 12.9, p =

0.059; pemetrexed PS 1: 12.9 months versus placebo PS 1: 10.7,

p = 0.121

Reck JTO JCO 2014

THE DRIVERS OF CHOICE

Benefit of first-line EGFR TKIs: 9 randomized phase III studies

Crizotinib in first line

Solomon BJ 2014

Second-line options for metastatic NSCLC in 2015

EGFR Mut+

pretreated

front-line

with EGFR-

TKIs

EGFR

WT/ALK-

non-

squamous

EGFR

WT/ALK-

squamous

Platinum

doublet +

bevacizumab

OR

platinum

+ pemetrexed

+/- bevacizumab

Erlotinib

or

Pemetrexed

or

Docetaxel

Erlotinib

or

Docetaxel

ALK+

pretreated

front-line

with

crizotinib

Ceritinib

or

Platinum

+ pemetrexed

+/- bevacizumab

Consider clinical trials with

new irreversible inhibitors

Consider platinum re-challenge or clinical trials

Consider clinical trials with

new inhibitors

CheckMate 017 (NCT01642004) - Study Design

• One pre-planned interim analysis for OS

• At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis)

• The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03

Patients stratified by region and prior paclitaxel use

Nivolumab 3 mg/kg IV Q2W

until PD or unacceptable toxicity n = 135

Docetaxel 75 mg/m2 IV Q3W

until PD or unacceptable toxicity n = 137

Ran

do

miz

e 1

:1

• Primary Endpoint:

– OS

• Additional Endpoints:

Investigator-assessed ORR

Investigator-assessed PFS

Correlation between PD-L1 expression and efficacy

Safety

Quality of life (LCSS)

• Stage IIIb/IV SQ NSCLC

• 1 prior platinum doublet-based chemotherapy

• ECOG PS 0–1

• Pre-treatment (archival or fresh) tumor samples required for PD-L1 analysis

N = 272

LCSS = Lung cancer symptom scale

Brahmer J, et al. NEJM 2015

CheckMate 017: Overall

Survival Nivolumab

n = 135 Docetaxel

n = 137

mOS, months (95% CI)

9.2 (7.33, 12.62)

6.0 (5.29, 7.39)

# events 103 122

HR = 0.62 (0.48, 0.81); P = 0.0004

0 6 14 25 37 51 57 69 86 113 135 0 Nivolumab

Number of Patients at Risk

0 3 7 11 15 22 33 46 69 104 137 Docetaxel 1

OS

(%

)

Time (months)

100

90

80

70

60

50

40

30

10

0

20

33 27 24 21 18 15 12 9 6 3 0 30

Nivolumab

18-month

OS rate = 28% 12-month

OS rate = 42%

Docetaxel

18-month

OS rate = 13%

12-month OS rate = 24%

Based on August 2015 DBL.

Minimum follow-up for survival: 18 months

mOS = median overall survival. Symbols refer to censored observations.

Reckamp K, et al. Presented at the 16th World Conference on Lung Cancer; September 6–9, 2015; Denver, Colorado, USA. Oral 02.01.

17

CheckMate 057 (NCT01673867) Study Design

• PD-L1 expression measured using the Dako/BMS automated IHC assay14,15

– Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness

a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator.

Ran

do

miz

e 1

:1

• Stage IIIB/IV non-SQ NSCLC

• Pre-treatment (archival or recent) tumor samples required for PD-L1

• ECOG PS 0–1

• Failed 1 prior platinum doublet

• Prior maintenance therapy alloweda

• Prior TKI therapy allowed for known ALK translocation or EGFR mutation

N = 582

Nivolumab 3 mg/kg IV Q2W

until PD or unacceptable toxicity

n = 292

Docetaxel 75 mg/m2 IV Q3W

until PD or unacceptable toxicity

n = 290

• Primary Endpoint – OS • Additional Endpoints – ORRb

– PFSb

– Safety – Efficacy by tumor PD-L1 expression – Quality of life (LCSS)

Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line)

Paz-Ares L, et al. ASCO 2015

H. Borghaei, L. Paz-Ares, N Engl J Med. 2015 Sep 27

Nivolumab

(n = 292)

Docetaxel

(n = 290)

mOS, mo 12.2 9.4

HR = 0.73 (96% CI: 0.59, 0.89);

P = 0.0015

CheckMate 057 (NCT01673867)- OS

Anti PD1/PD-L1 agents: open

questions

• How to select patients?

• Clinical characteristics?

• PD-L1 expression or other biomarkers?

• Treatment duration

• Best tool(s) to assess drug activity?

• Patient communication

AURA (AZD9291):

best % change in target-lesion

size

Janne PA, NEJM 2015

For p

erson

al use o

nly

Alectinib: Best systemic and best tumor response

ORR = 55%

Gadgeel SM et al; Lancet Oncology 2014; 15: 1119-28

Second-line options for metastatic NSCLC in 2016

EGFR Mut+

pretreated

front-line

with EGFR-

TKIs

EGFR

WT/ALK-

/ROS1-

non-

squamous

Squamous

Osimertinib

(T790M+)

NIVOLUMAB

DOCETAXEL

+ANTIANGIO

GENIC

AGENTS

ALK+

pretreated

front-line

with

crizotinib

Ceritinib or

alectinib

Consider clinical trials with

new irreversible inhibitors

Consider platinum re-challenge or clinical trials

Consider clinical trials with

new inhibitors

NIVOLUMAB

“Benchè i dottori lo

curassero,

gli cavassero sangue e gli

facessero prendere molte

medicine, tuttavia guarì”.

LEV NIKOLAEVIC TOLSTOJ