checkpoint inhibitors in sclc - oncologypro.esmo.org · • neuroendocrine origin •

Luis Paz-Ares

Hospital Universitario Doce de Octubre,Madrid, Spain

Checkpoint Inhibitorsin SCLC

• Neuroendocrine origin

• <15% of all lung cancers, mostly diagnosed in smokers

• Early spread (stage IV at diagnosis 70%) and short doubling time

• High chemosensitivity but rapid emergence of resistance

• Autoinmunity – paraneoplastic syndromes

• 5 yr survival rate 6%;

• LS-SCLC median OS -15-20 months

• ES-SCLC median OS – 8-13 months

First line Treatment Options1. Platinum + etoposide/irinotecan2. Clinical trial

Second line Treatment Options1. Topoisomerase 1 inhibitor2. Clinical trial 3. Palliative care

Clinical Characteristics of SCLC

0%

20%

40%

60%

80%

100%

0 5 10 15Years After Enrollment

IAIBIIAIIBIIIAIIIBIV

Deaths / N17 / 2514 / 198 / 15

84 / 101332 / 384424 / 481

1400 / 1439

Medianin Months

3135681713128

SCLC - TNM stage

ES Small Cell Lung Cancer: Evolution of Therapy

Alkylating Based

Chemotherapy

(CMV)

Anthracycline Based

Chemotherapy

(CAV)

1970s 1980s

Platinum Based

Chemotherapy

(EP/IP)

1990s

Targeted Therapy

and Sequencing

2000s

Immunotherapy

and ADCs?

2010s

L Horn, WLCC 2016

George J et al, Nature 2015, 524:47-53.;Ross JS et al; J Clin Path 2014

Biological Characteristics of SCLC• SCLC sequencing on 110 whole genomes found evidence for a nearly universal and

biallelic loss of TP53 and RB1 (left panel).• SCLC sequencing on 98 patient samples revealed 53% had > 1 actionable mutation (right

panel)• Low frequency targetable mutations: NOTCH1, BRAF, PIK3CA, and KIT. • Amplification of FGFR1 and MYC family genes.• Mutation frequency is high.

• Non-synonymous mutation rate 5.5-7.4/Mb (melanoma 6-6.5)• 180-240 mutations per tumor

Mutation Load and SCLC

Alexandrov LB, Nature 2013

Mutational catalogues of 7,042 primary cancers (507 from whole genome and 6,535 from exome sequences)

Alexandrov LB, Nature 2013

7J. Gorge et al..Nature.2015 524(7563): 47–53

Genomic Landscape

Drug Development for SCLC

Bunn PA Jr et al, J Thorac Oncol 2016, 11:453-74

Numerous negative trials

Mutation burden, smoking signature in predicting response in

NSCLC patients

Naiyer A. Rizvi et al. Science 2015;348:124-128

Clinical trials of cancer vaccines for lung cancer

Li Yang et al. Am J Clin Exp Immunol 2016;5(1):1-20

Checkpoint Inhibitors

• Anti-CTLA-4

• Anti-PD-1

• Anti-PD-L1

11

CTLA-4 Inhibitors in SCLC

CA184-041: Phase II Ipilimumab + Chemotherapy for 1L ED -SCLC*

N=130Concurrent

Ipilimumab (10 mg/kg) +

Paclitaxel (175 mg/m2)/carboplatin (AUC 6)

Q3W

(n=43)Key Inclusion Criteria

≥18 years of age

ED-SCLC*

ECOG PS ≤1

No prior systemic therapy for lung cancer

No symptomatic CNS metastases or autoimmune disease

R

ControlPlacebo + paclitaxel (175 mg/m2)/carboplatin

(AUC 6)

(n=45)

• Primary outcome measure: irPFS• Key secondary outcome measures: OS,

PFS, BORR, safety

Phased †

Ipilimumab (10 mg/kg) +

Paclitaxel (175 mg/m2)/carboplatin (AUC 6)

Q3W

(n=42)

MTNIpi‡

MTNIpi‡

MTNplacebo

* This trial also included 204 NSCLC patients.† 2 doses of paclitaxel/carboplatin prior to start of ipilimumab.‡ 10 mg/kg intravenous.

PFS and BORR in the ED -SCLC Population: CA184-041

ResponseControl

Pbo + chemo(n=45)

ConcurrentIpi + chemo

(n=43)

Phased *

Ipi + chemo(n=42)

irPFSMedian (mo)

5.3 5.7(HR=0.75, P=0.11)

6.4(HR=0.64, P=0.03†)

mWHO-PFSMedian (mo)

5.2 3.9(HR=0.93, P=0.38)

5.2(HR=0.93, P=0.37)

irBORR 53% 49% 71%

irWHO-BORR 49% 33% 57%* Phased regimen: 2 doses of paclitaxel (175 mg/m2)/carboplatin (AUC=6) prior to start of ipilimumab.† P-values are based on an unstratified log-rank test with a one-sided α of 0.1.

See slide notes for references and abbreviations.

OS in ED-SCLC: CA184 -041

OS of Phased vs Control

Months

Control Phased *

Median

HRP

9.9 mo----

12.9 mo0.750.13

ControlConcurren

t

Median

HRP

9.9 mo----

9.1 mo0.950.41

0 3 6 9 12 15 18 21

1.0

0.8

0.6

0.4

0.2

0.0

OS

(p

rob

ab

ilit

y)

0 3 6 9 12 15 18 21 24

1.0

0.8

0.6

0.4

0.2

0.0

OS

(p

rob

ab

ilit

y)

* Phased regimen: 2 doses of paclitaxel (175 mg/m2)/carboplatin (AUC=6) prior to start of ipilimumab.

OS of Concurrent vs Control

Months

See slide notes for references and abbreviations. Reck et al, Ann Oncol, 2013.

Safety: Treatment-Related AEs in ≥15% Patients - CA184 -041

ConcurrentIpilimumab

(n=42)

Grade 1/2, % Grade 3/4, %

PhasedIpilimumab

(n=42)

Grade 1/2, % Grade 3/4, %

Control

(n=44)

Grade 1/2, % Grade 3/4, %/%

Total treatment-related AEs

41 43 45 50 61 23/7

Anemia† 87 5 81 10 84 7/0

Thrombocytopenia† 44 3 50 7 61 2/0

Alopecia 57 n/a 67 n/a 59 n/a/n/a

Neutropenia† 41 8 40 10 40 2/0

Arthralgia 24 0 36 10 32 0/0

Peripheral sensory neuropathy*

24 0 33 0 32 0/0

Fatigue 24 7 17 12 20 5/0

Nausea 24 0 29 0 20 2/0

Diarrhea 21 4 24 10 11 5/0

Peripheral neuropathy 14 0 24 0 11 0/0

Pruritis 24 0 17 2 5 0/0

ALT† 36 18 36 4 21 0/0

AST† 39 13 33 7 33 0/0

* As reported by investigators. † Based on laboratory results.

Adverse events listed were those (any grade) reported in at least 5% of treated patients in any arm. Patients could have more than one adverse event. One death

in the concurrent ipilimumab arm was attributed to treatment-related hepatotoxicity.

Adapted from Reck et al, Ann Oncol, 20131

CA184-156: Phase III Ipilimumab + Chemotherapy for 1L ED -SCLC

N=1414

Ipilimumab +

Pt/Etoposide

Key Inclusion Criteria

� ≥18 years of age

� ED-SCLC

� ECOG PS ≤1

� No prior systemic therapy for lung cancer

� No symptomatic CNS metastases or autoimmune disease

R

Placebo +

Pt/Etoposide

• Primary outcome measure: OS• Secondary outcome measure: PFS

Start Date: December 2011Estimated Study Completion Date: March 2017Estimated Primary Completion Date: March 2015Status: Ongoing, but not recruitingStudy Director: Bristol-Myers Squibb

PE ± Ipilimumab

Reck M et al, JCO 2016 [Epub ahead of print]

• N = 1132• Documented ED-SCLC• ECOG PS 0-1• No brain mets requiring tx• No autoimmune disease• No systemic immunosuppression

PE + Ipilimumab

10/mg/kg IV Q3Wn = 478

PE + Placebo Q3Wn = 476

R1:1 N = 954

Why was this study negative?• Drug delivery

• 15% randomly assigned pts did not receive study drug.

• Only 13% of ipilimumab pts lived long enough to receive this drug

for maintenance

• Correct neoantigens not expressed sufficiently to drive

immunogenicity.

• Anti-CTLA-4 agent may not be the best drug to use after

chemotherapy (cytotoxic T cell effect occurs during priming phase).

• Trial populaton not enriched enough for patient population that

benefit from immunotherapy.

• Exclude rapid disease progressors

• Need for biomarker.

• Combined anti-CTLA-4 and anti-PD-1/PD-L1 may be more effective.

19

20LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES.

.

NCT01331525 / ICE: Phase II Ipilimumab + Chemotherapy for 1L ED -SCLC

* 3-monthly maintenance ipilimumab planned.† Assessed by investigators. ‡ Fatal event presented like anti-Hu syndrome; both events occurred in patients with positive baseline anti-neuronal antibodies. §At 1 year.

1L ED-SCLC[1,2]

Chemo-immunotherapy with ICE was feasible, but with appreciable immune-related AEs [1]

− 61% of patients experienced >Grade 3 AEs, 42% possibly ipi-related †

− 6% (2 pts) had ipi-related neurological events ‡ (1 case was fatal)

Immuno-Oncology for SCLCImmuno-Oncology for SCLC

Ipilimumab(Cycles 3–6, in

responding patients*)

EC

N=42

• Primary outcome measure: PFS§

• Secondary outcome measures: tumor response and toxicity

Start Date: June 2011

Estimated Study Completion Date: June 2015Estimated Primary Completion Date: June 2015Status: CompletedStudy Director: University Hospital Southampton NHS

Foundation Trust collaboration with Bristol-Myers Squibb and

others

See slide notes for references and abbreviations.

NCT02046733 / STIMULI: Phase II Ipilimumab with nivolumab vs Observation for 1L L D-

SCLC

* ≤ 1 for enrollment, ≤ 2 for randomization.† Except fatigue, appetite, esophagitis, and renal impairment (≤ Grade 2 allowed) and alopecia (any grade allowed).

N=260

• Primary outcome measure: OS, PFS• Secondary outcome measures: OR,

TTF, AEs

Start Date: July 2014

Estimated Study Completion Date: January 2022Estimated Primary Completion Date: October 2019Status: Active, recruitingStudy Director: European Thoracic Oncology Platform

collaboration with Bristol-Myers Squibb and others

Ipilimumab +

nivolumab

R

Observation

Key Inclusion Criteria

� ≥18 years of age

� Untreated LD-SCLC

� ECOG PS ≤1 or 2*

� Non PD after completion of CRT, PCI

� Adequate hematological, renal, and liver function

� Recovery of all AEs to Grade ≤1†

CRT + PCI

PD-1/PD-L1 Inhibitors in SCLC

PD-L1 Expression in SCLC

Retrospective Sample Analysis

# Patients 43 102 99

PD-L1+ 085% (LS)62% (ES)

83%

Schultheis AM et al, Euro J Cancer, 2015; Ishii H et al, JTO, 2015; Komiya T et al, Euro J Cancer, 2015; Chae YK et al, Clin Lung Can, 2016

Trial NPD-L1 Expression

Status

Nivolumab

40PD-L1+* (32%)PD-L1- (68%)

46PD-L1+* (33%)PD-L1- (67%)

Pembrolizumab 137PD-L1+* (29%)PD-L1- (71%)

* Positive expression > 1%

Nivolumab ± Ipilimumab in Recurrent SCLC:

Phase 1/2 CheckMate 032 Study

• Based on data from the previous database lock, the nivolumab-3 and nivolumab-1 + ipilimumab-3 arms were selected for

further development in SCLC; updated data from these arms are presented here

24

aIncludes 3 patients from nivolumab-1 + ipilimumab-1 arm; bMedian follow-up of 15.7 months; cMedian follow-up of 21.0 monthsDOR = duration of response; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survival

– Patients with SCLC (N = 217)a

– ≥1 prior line of therapy– PD-L1 unselected

Until disease progression or unacceptable toxicity

Primary objective: ORR per RECIST v1.1Secondary objectives: safety, OS, PFS, DORExploratory objective: biomarker analysis

Database lock: August 09, 2016

Nivolumab 3 mg/kg IV Q2W(n = 98)b

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV Q3W for 4 cycles

(n = 61)c


(n = 55)

Nivolumab 3mg/kg IV Q2W until disease progression or unacceptable toxicity

S Antonia et al., Lancet Oncol 2016

* Three patients in the nivolumab 3 mg/kg group, two patients in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four patients in the nivolumab 3

mg/kg plus ipilimumab 1 mg/kg group did not receive first-line platinum therapy and did not meet eligibility criteria, although they were treated and included

in the analysis. †Defined as a patient who relapsed <90 days after chemotherapy.

Baseline Patient Characteristics:

CheckMate 032 SCLC Cohort

Nivolumab3 mg/kg(n = 98)

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg

(n = 61)


(n = 54)

Median age, years(range)

Age ≥75 years63 (57–68)

9 (9%)66 (58–71)

7 (11%)61 (56–65)

0

Male, % 62 57 59

Race, %WhiteBlack/African AmericanOther Not reported

93340

98200

96022

Number of prior treatment regimens, %12–3>3

41563

523810

43526

First-line platinum-treated patients*, %Platinum-sensitivePlatinum-resistant†

Unknown

563110

413818

393915

See slide notes for references and abbreviations. PERMISSION NOT OBTAINED Antonia et al, ASCO 20161


*Percentage of PD-L1 evaluable patients; may exceed 100% due to rounding.

Nivolumab3 mg/kg(n = 98)


(n = 61)


(n = 54)

Smoking Status, %Current/former smokerNever smokedUnknown

9730

9370

8992

PD-L1 expression level*≥ 1%< 1%≥ 5%< 5%Indeterminate, not evaluable, or missing

14866

9430

24765

9539

13883

9826

Baseline Patient Characteristics:

CheckMate 032 SCLC Cohort


Nivolumab 3

(n = 98)

Nivolumab 1 + Ipilimumab 3

(n = 61)

Nivolumab 3 + Ipilimumab 1

(n = 54)

ORR, % 10 23 19

Platinum-sensitivea 11 28 19

Platinum-resistanta 10 17 10

Complete response 0 2 0

Partial response 10 21 19

Stable disease 22 21 17

Progressive disease 53 38 54

Unable to determine 12 13 11

Not evaluableb 2 5 0

Time to objective response, months 2.0 (1.3–2.8) 2.1 (1.4–2.8) 1.4 (1.3–2.7)

aPlatinum sensitivity was unknown for 29 patients as follows: nivolumab-3, n=10; nivolumab-1/ipilimumab-3, n=11; nivolumab-3/ipilimumab-1, n=8. 3

patients in the nivolumab-3 arm, 2 patients in the nivolumab-1/ipilimumab-3 arm and 4 patients in the nivolumab-3/ipilimumab-1 arm did not receive

first-line platinum therapy and did not meet eligibility criteria, although they were treated and included in the analysis.bNo tumor assessment follow-up.

Summary of Clinical Activity: CheckMate 032 SCLC Cohort


Safety: Treatment-Related AEs in ≥10% Patients

• Treatment-related deaths

• Two patients in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group (myasthenia gravis and worsening of renal failure, respectively)

• One patient in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort died from pneumonitis, regarded as treatment-relatedAnalysis included all patients enrolled at least 90 days prior to database lock. Patients with AEs after crossover from nivolumab 3 mg/kg to combination treatment excluded. Some

patients had more than one AE.

Nivolumab 3 mg/kg(n=98)

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n=61)

Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n=54)

Grade 1–2

Grade 3 Grade 4Grade 1–

2Grade 3 Grade 4

Grade 1–2

Grade 3 Grade 4

Total treatment-related AEs, n (%)

39 (40%) 9 (9%) 4 (4%) 30 (49%) 14 (23%) 4 (7%) 30 (56%) 8 (15%) 2 (4%)

Fatigue 10 (10%) 1 (1%) 0 16 (26%) 0 0 12 (22%) 0 0

Pruritus 11 (11%) 0 0 11 (18%) 1 (2%) 0 5 (9%) 0 0

Diarrhea 7 (7%) 0 0 10 (16%) 3 (5%) 0 8 (15%) 1 (2%) 0

Nausea 7 (7%) 0 0 6 (10%) 1 (2%) 0 4 (7%) 0 0

Decreased appetite 6 (6%) 0 0 4 (7%) 0 0 6 (11%) 0 0

Hypothyroidism 3 (3%) 0 0 9 (15%) 1 (2%) 0 4 (7%) 0 0

Hyperthyroidism 2 (2%) 0 0 7 (11%) 0 0 3 (6%) 0 0

Rash 2 (2%) 0 0 10 (16%) 2 (3%) 0 4 (7%) 0 0

Rash, maculopapular 1 (1%) 0 0 6 (10%) 2 (3%) 0 2 (4%) 0 0

Treatment-related AEs leading to

discontinuations6 (6%) 7 (11%) 4 (7%)

See slide notes for references and abbreviations. S Antonia et al., Lancet Oncol 2016

Nivolumab ± Ipilimumab in Recurrent SCLC:

Phase 1/2 CheckMate 032 Study

• Based on data from the previous database lock, the nivolumab-3 and nivolumab-1 + ipilimumab-3 arms were selected for

further development in SCLC; updated data from these arms are presented here

29

aIncludes 3 patients from nivolumab-1 + ipilimumab-1 arm; bMedian follow-up of 15.7 months; cMedian follow-up of 21.0 monthsDOR = duration of response; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survival

– Patients with SCLC (N = 217)a

– ≥1 prior line of therapy– PD-L1 unselected

Until disease progression or unacceptable toxicity

Primary objective: ORR per RECIST v1.1Secondary objectives: safety, OS, PFS, DORExploratory objective: biomarker analysis

Database lock: August 09, 2016

Nivolumab 3 mg/kg IV Q2W(n = 98)b


(n = 61)c


(n = 55)

Nivolumab 3mg/kg IV Q2W until disease progression or unacceptable toxicity

MD Hellmann et al, WLCC 2016

CheckMate 032: Nivolumab ± Ipilimumab in Recurrent SCLC

Summary of Efficacy

30

Nivolumab-3

(n = 98)

Nivolumab-1 + Ipilimumab-3

(n = 61)

ORR

Overall, % (95% CI)

Platinum-sensitive,b % (n/N)

Platinum-resistant,b % (n/N)

Patients with 1 prior regimen, % (n/N)

Patients with ≥2 prior regimens, %

(n/N)

11 (6, 19)

13 (7/56)

8 (3/37)

10 (4/40)

12 (7/58)

25a (15, 37)

25 (7/28)

24 (6/25)

28 (9/32)

21 (6/29)

Best overall response, %

CR

PR

SD

PD

Unable to determine

0

11

24

53

11

3

21

25

38

13

Median DOR, months (95% CI)

Ongoing responses lasting ~>18 monthsc after

treatment initiation, % (n/N)d

NR (4.4, NR)

27 (3/11)

11.7 (4.0, NR)

33 (5/15)

aValue to 1 decimal point: 24.6; bPlatinum sensitivity was unknown for 13 patients (nivolumab-3, n = 5; nivolumab-1 + ipilimumab-3, n = 8); c>72 weeks; dPercentage of respondersCR = complete response; NR = not reached; PD = progressive disease; PR = partial response; SD = stable disease



CheckMate 032: Nivolumab ± Ipilimumab in Recurrent SCLC 2-Year Overall Survival

Additional follow-up since ASCO 2016: 4.6 months

31

Events/number

at risk

Median OS, Months (95%

CI)

Medianfollow-up

time,a months

Nivolumab-3 71/98 4.1 (3.0, 9.1) 15.7

Nivolumab-1 + ipilimumab-3

40/61 7.9 (3.6, 14.2) 21.0

Months

OS

(%

)100

90

80

70

60

50

40

30

10

0

20

330 30272421181512963

0144810102435385498Nivolumab-3

Number of patients at risk

0013512192428334361Nivolumab-1 + ipilimumab-3

1-yr OS = 30%

2-yr OS = 17%c

2-yr OS = 30%b

1-yr OS = 42%


7

• 66-year-old male with <1% tumor PD-L1 expression

• Platinum-sensitive disease; treated with 1 prior platinum-based regimen

CT scan at week 72 after cycle 33 of treatment – CR

Baseline pretreatment CT scan

Adrenalmetastasis

Adrenalmetastasis

Lymph nodemetastasis

Lymph nodemetastasis

CT = computed tomography

0 10 20 30 40 50 60 70 80

Weeks

Cha

nge

from

bas

elin

e (%

)

–100

–80

–60

–40

–20

20

40

60

80

100

0

Confirmed PR or CR

Complete Response in SCLC Patient Treated With Nivolumab + Ipilimumab


Across cohorts, 73% evaluable for PD-L1 expression at baseline; 17% (of PD-L1 evaluable samples) with ≥1% tumor PD-L1 expression

33

Nivolumab-3


aKaplan–Meier estimates, with error bars indicating 95% CIs

0

10

20

30

40

50

60

70

80

30

98n

All patients

OS

rat

e (%

)

Overall PD-L1 expression

42

61

32

65

<1%

44

31

30

10

≥1%

50

10

26

23

Unknown

35

20

Nivolumab ± Ipilimumab in Recurrent SCLC 1-Year OS Rates a by PD-L1 Expression


No additional treatment-related deaths were reported; at prior disclosure, 2 treatment-related deaths occurred with nivolumab-1 + ipilimumab-3: one due to myasthenia gravis and one due to worsening of renal failure

Grade 3–4 treatment-related limbic encephalitis occurred in 1 patient in the nivolumab-3 arm

Treatment-related pneumonitis occurred in 4 patients in the nivolumab-3 arm (2 grade 3–4 events) and 2 patients in the nivolumab-1 + ipilimumab-3 arm (1 grade 3–4 event)

34

Grade 1−2

Grade 3−4

Pat

ient

s w

ith a

n ev

ent,

%

Nivolumab-3

(n = 98)


(n = 61)

13

DC = discontinuation


Treatment-Related AEs in ≥10% of Patients


Presentation Number: Presentation Title – Presenting Author

CheckMate 032: Nivolumab ± Ipilimumab in Recurrent SCL C Summary

• ORR was 25% with nivolumab + ipilimumab and 11% with nivolumab– Responses remained durable, with ~1/3 of responses ongoing ~>18 months– Responses occurred regardless of platinum sensitivity and prior lines of therapy

• Survival remains encouraging with additional follow-up– Nivolumab + ipilimumab estimated 2-year OS rate: 30%– Nivolumab estimated 2-year OS rate: 17% – OS rates were similar in patients with or without PD-L1 expression

• Safety profiles are consistent with other tumor types– Treatment-related discontinuation rates remained low for nivolumab (5%) and nivolumab + ipilimumab (11%)– With longer follow-up, no new safety concerns or additional treatment-related deaths were noted

• Ongoing CheckMate 032 randomized expansion study: nivolumab alone (n = 150) vs nivolumab-1 + ipilimumab-3 (n = 100)

35

CHECKMATE 451

Ready. ASCO 2016 Abstract TPS 8579.

CheckMate 451

Nivolumab and SCLC

Trial population Intervention

CHECKMATE 331

Relapse/refractory SCLC

[NCT02481830]

Randomised phase 3 study.

2nd line

Nivolumab vs Topotecan

STIMULI

LD-SCLC

[NCT02046733]

Randomised phase 2 study. LD-SCLC.

Nivolumab +Ipilimumab v no Tx following CRT


[NCT02247349]

BMS-986012 anti- fucosyl GM1, alone and in

combination with nivolumab


[NCT02472977]

Advanced solid tumours incl SCLC. Phase 1 study

of Ulocuplumab (anti-CXCR4 mab) alone or in

combination with Nivolumab

Nivolumab in SCLC

6198 – PA Ott

KEYNOTE-028 (NCT02054806): Phase 1b Multicohort Stud y of Pembrolizumab for PD -L1–Positive Advanced Solid Tumors

aIf clinically stable, patients are to remain on pembrolizumab until progressive disease is confirmed on a second scan performed ≥4 weeks later.

aResponse assessment : Every 8 weeks for the first 6 months; every 12 weeks thereafter

Primary end points: ORR per RECIST v1.1 (investigator assessed) and safety

Secondary end points: PFS, OS, duration of response

Pembrolizumab 10 mg/kg IV

Q2W

Complete or partial response or stable disease

Treat for 24 months or until progression a

or intolerable toxicity

Confirmed progressive disease a

or unacceptable toxicity

Discontinue pembrolizumab

ResponseAssessment a

Patients•Small cell lung cancer•Failure of or inability to receive standard therapy•ECOG PS 0 or 1•≥1 measurable lesion•PD-L1 positivity•No autoimmune disease or interstitial lung disease

PA Ott et al., WLCC 2016

6198 – PA Ott

Analysis of PD -L1 Expression

• Samples: archival or newly obtained core or excisional biopsy of a nonirradiated lesion

• Immunohistochemistry: performed at a central laboratory using a prototype assay and the 22C3 antibody clone (Merck & Co., Inc., Kenilworth, NJ, USA)

• Positivity: membranous PD-L1 expression in ≥1% of tumor and associated inflammatory cells or positive staining in stroma

• SCLC cohort: of 147 evaluable samples, 42 PD-L1 positive (28.6%)

Examples of PD-L1 Staining in SCLC Specimens From K EYNOTE-028

PD-L1 Negative PD-L1 Positive


6198 – PA Ott

Patient and Disease Characteristics

Characteristic, n (%) N = 24

Age, median (range), years

60.5 (41-80)

Male 14 (58.3)

RaceWhiteAsianNot specified

13 (54.2)3 (12.5)8 (33.3)

ECOG performance status01

7 (29.2)17 (70.8)

Stable brain metastases 5 (20.8)

HistologySmall cellNeuroendocrine

23 (95.8)1 (4.2)

Characteristic, n (%) N = 24

Type of prior therapya

ChemotherapyRadiotherapyInvestigational TKIOther investigational therapy

24 (100)

1 (4.2)1 (4.2)1 (4.2)

Specific prior therapiesa,b

Cisplatin/carboplatin + etoposideIrinotecan or topotecanTaxane

24 (100)

11 (45.8)

7 (29.2)

Previous lines of therapyc

12

3 (12.5)

12

aPatients could have received ≥1 type of prior therapy. bNot all prior

therapies are listed. cIncludes adjuvant and neoadjuvant therapies.

Data cutoff date: June 20, 2016.

6198 – PA Ott

Antitumor Activity (RECIST v1.1, investigator review, confirmed)

Best Overall Response n % 95% CI

Complete response 1 4.2 0.1-21.1

Partial response 7 29.2 12.6-51.1

Stable disease 1 4.2 0.1-21.1

Progressive disease 13 54.2 32.8-74.4

No assessmenta 2 8.3 1.0-27.0

Duration of response, median (range), monthsb 19.4 (3.6+ to 20.0+)

Objective response rate: 33.3% (95% CI, 15.6%-55.3% )

Clinical benefit rate (CR + PR + SD ≥6 months): 33.3% (95% CI, 15.6%-55.3%)aFor “No Assessment,” the patient discontinued before postbaseline assessment.bCalculated using the Kaplan-Meier method for censored data.


Change From Baseline in Tumor Size (RECIST v1.1, investigator review)

Bar lengths are best target lesion changes, bar colors are best overall responses.

Data cutoff date: June 20, 2016.PA Ott et al., WLCC 2016

6198 – PA Ott

Treatment Duration and Duration of Response (RECIST v1.1, investigator review)

0 20 40 60 80 100

Duration of Treatment, Weeks

Treatment discontinuation

Progressive disease

Stable disease

Partial response

Complete response

Treatment ongoing

The length of each bar corresponds to the duration of treatment.

Response symbols represent time to first report and not best overall.



6198 – PA Ott

Progression-Free Survival(investigator review)

PFS N = 24

Events, n (%) 20 (83.3)

PFS, median (95% CI), months

1.9 (1.7–5.9)

28.6%23.8%


6198 – PA Ott

Overall Survival

OS N = 24

Events, n (%) 15 (62.5)

OS, median (95% CI), months

9.7 (4.1-NR)

66.0%

37.7%


6198 – PA Ott

Treatment-Related Adverse Events

aOccurred in the same patient.


Any Grade, Occurring in ≥3 Patients

N = 24n (%)

Any 16 (66.7)

Arthralgia 4 (16.7)

Asthenia 4 (16.7)

Rash 4 (16.7)

Diarrhea 3 (12.5)

Fatigue 3 (12.5)

Grade 3-5, Occurring in ≥1 Patient

N = 24

n (%)

Any 2 (8.3)

Astheniaa 1 (4.2)

Blood bilirubin increased 1 (4.2)

Colitisa 1 (4.2)

Intestinal ischemiaa 1 (4.2)

AEs of Interest Based on Immune Etiology Occurring in ≥1 Patient

N = 24

n (%)

Any3

(12.5)

Autoimmune thyroiditis 1 (4.2)

Infusion site reaction 1 (4.2)

Cytokine release syndromea 1 (4.2)

Colitisa 1 (4.2)

• Median follow-up duration• 9.8 months (range, 0.5-24 months)

• No cases of pneumonitis


Pembrolizumab and SCLC


Refractory SCLC

[NCT 02551432]

Pembrolizumab + Paclitaxel (single arm phase 2)

Second line SCLC

[NCT 02963090]

Pembrolizumab vs Topotecan [phase 2]

REACTION; First line ED-SCLC

[NCT 02580994]

platinum-etoposide chemotherapy +/- pembro [phase 2]

LD-SCLC

[NCT 02402920]

Pembrolizumab & Platinum-Etoposide, plus concurrent

radiotherapy [phase 1]

ED-SCLC

[NCT 023312251]

Pembrolizumab & chemotherapy in advanced solid tumours, incl

SCLC – Irinotecan & Pembrolizumab

ED-SCLC

[NCT 02661100]

Pembrolizumab in advanced solid tumours, incl SCLC. Treated with

CDX-1401 (tumour specific antigen) & Poly-ICLC (Toll-like receptor

agonist) & Pembrolizumab

KEYNOTE 158

[NCT 02628067]

Pembrolizumab in advanced solid tumours, incl SCLC.

Pembrolizumab in SCLC

Atezolizumab and SCLC


IMpower133

First line ED-SCLC

[NCT02763579]

Carboplatin-etoposide +/- Atezolizumab or Placebo

(phase 3)

Untreated ED-SCLC

[NCT 02748889]

Carboplatin-etoposide +/- Atezolizumab

(phase 1 / 2)

Atezolizumab in SCLC

Durvalumab and SCLC


Relapse SCLC

[NCT 02701400]

Durvalumab & Tremelimumab +/- Radiotherapy

Platinum-refractory

ED-SCLC

[NCT 02937818]

Durvalumab & novel combination therapies (e.g. XXX)

First line treatment in

solid tumours, incl

SCLC

[NCT 02658214]

Durvalumab & Tremelimumab

Advanced solid

tumours, incl SCLC

[NCT 02734004]

Durvalumab & Olaparib

No trials registered with Avelumab in Small cell lung cancer

Durvaluumab in SCLC

• Combination with first line platinum based chemotherapy or as maintenance therapy following induction therapy (pembrolizumab, atezolizumab and nivolumab)

• Compared to second line chemotherapy (nivolumab and pembrolizumab)

• Combined with paclitaxel as second line therapy (pembrolizumab)

• Following concurrent chemo-radiation therapy (nivolumab and pembrolizumab)

• Ipi+Nivo or Treme+Durva combos (+/- Chemo) in the first line setting

Ongoing Trials with PD -1/PD-L1 Inhibitors

BMS-986012 in Relapsed/Refractory SCLC (CA001-030 / NCT02247349)

Purpose

Determine the safety, tolerability, PK,

immunogenicity, antitumor activity,

and pharmacodynamics of BMS-

986012 alone and in combination with

nivolumab in patients with

relapsed/refractory SCLC

Primary Endpointa

• Safety (AEs, SAEs, AEs leading to

discontinuation, deaths), until

resolution of AEs or 100 days after last

study dose

Secondary Endpointsa

• BOR, ORR, DOR, PFS, PFS rate, OS, OS

rate

• Anti-drug antibodies (ADA) response to

BMS-986012 in combination with

nivolumab, at approximately 3 years

• PK and immunogenicity

• Changes in the QTcF

Study Specific Eligibility Criteria

• Histologically or cytologically

confirmed SCLC

• Measurable disease

• No grade ≥2 peripheral neuropathy

• No brain metastases, uncontrolled

cardiovascular disease, or concomitant

malignancies

AE=adverse event; BOR=best overall response; DOR=duration of response;

ORR=objective response rate; OS=overall survival; PFS=progression free survival;

PK=pharmacokinetics; SAE=serious adverse event; SCLC=small cell lung cancer.

Study Start Date: October 2014

Estimated Study Completion Date: October 2018

Estimated Primary Completion Date: October 2018

Phase I/II trial

N=172

Safety

BMS-986012 IV q3w

(4 dose levels)

Cohort A

(refractory

)

BMS-

986012 IV

q3w

Cohort C

(sensitive)

BMS-

986012 IV

q3w

Cohort B

(refractory

)

BMS-

986012 IV

q3w

Cohort D

(sensitive)

BMS-

986012 IV

q3w

BMS-986012 IV

q3w

+

Nivolumab

(2 dose levels)

Combination

(refractory and

sensitive)

BMS-986012 IV

q3w

+

Nivolumab

Dose Escalation

Cohort Expansion

Trial of BMS -986012 in Combination With Platinum and Etoposide (CA001-044 /

NCT02815592)

Phase I/II trial

N=120

Safety and tolerability,

PFS

ARM 1

BMS-

986012

+

Cisplatin

+

Etoposide

ARM 2

BMS-

986012

+

Carboplati

n

+

Etoposide

ARM 3A

BMS-

986012

+

Platinum

+

Etoposide

ARM 3B

Platinum

+

Etoposide

Purpose

To administer BMS-986012 in combination with

platinum and etoposide as first-line therapy in

extensive-stage SCLC

Primary Endpointsa

• Number of patients with AEs

• Number of patients with SAEs

• Number of patients discontinuing due to AEs

• Number of AE-related deaths

• Number of patients with laboratory toxicity

grade shift from baseline

• PFS up to 2 years

Secondary Endpointsb

• Pharmacokinetic parameters

• Immunogenicity


• Histologically or cytologically documented

SCLC

• Extensive-stage disease (stage IV)

• No prior systemic therapy for lung cancer

• No symptomatic brain metastases

• No grade 2 peripheral neuropathy

Study Start Date: September 2016

Estimated Study Completion Date: July 2019

Estimated Primary Completion Date: July 2019

Safety and Efficacy Study of Ulocuplumab and Nivolumab in Patients With Solid Tumors (CXCR4

inhibitor, NCT02472977)

Purpose

To determine whether the combination of

ulocuplumab and nivolumab is safe and

effective in the treatment of pancreatic

cancer and SCLC

Primary Endpointsa

DLT

ORR

OS

Secondary Endpointsa

Safety and tolerability

PFS


Advanced, metastatic SCLC or pancreatic cancer

At least one prior chemotherapy

ECOG PS ≤1

No brain metastases

No prior treatment with checkpoint inhibitors

Phase I/II trial

N=195

SCLC Arm

Nivolumab

+

Ulocuplumab

DLT, ORR, and OS

Pancreatic Arm

Nivolumab

+

Ulocuplumab

Study Start Date: July 2015

Estimated Study Completion Date: February 2018

Estimated Primary Completion Date: February 2018

Study of BMS-986158 in Patients With Select Advanced

Solid Tumors (CA011-001 / NCT02419417)

Purpose

Determine the safety, tolerability, pharmacokinetics,

and pharmacodynamics of BMS-986158 in patients

with select advanced solid tumors

Primary Endpoint

• Safety (rate of AEs and SAEs), 30 days from last dose

or until AEs are grade ≤1 or have returned to baseline

Secondary Endpoints

• BOR, ORR, DOR, PFS, PFS rate, every 8 weeks until last

dose, expected average of 4 months

• PK, at c1 d1 to c8 d8 of dosing for dose escalation

phase and c1 d1 to c2 d8 for dose expansion phase

• BET expression, at c1 d1 through c2 d15 of dosing

• Changes in QTcF, at c1 d1 to c8 d8 of dosing for dose

escalation phase and c1 d1 to c2 d8 for dose

expansion phase


• TNBC, ovarian (serous histology for expansion phase),

SCLC, or other solid tumors

• Life expectancy ≥3 months

• ≥1 measurable lesion by RECIST v1.1

• No uncontrolled medical conditions, second

malignancy, or uncontrolled cardiovascular disease

Study Start Date: June 2015

Estimated Study Completion Date: December 2018

Estimated Primary Completion Date: December 2018

Phase I/II trial

N=150

Safety

Arm A

BMS-986158

Dose Escalation Phase

Dose Expansion Phase

Arm B

BMS-986158

Arm C

BMS-986158

Arm A

BMS-986158

Arm B

BMS-986158

Arm C

BMS-986158

KEYNOTE 078 (AIO Thoraxoncology) - M. ReckPembrolizumab Maintenance Following First-Line

Platinum Based Chemotherapy Metastatic Squamous -

NSCLC

Primary endpoint Progression-free survival (RECIST 1.1)

Secondary endpoints Overall response rate

Overall survival

PD-L1 expression in tumor samples

Tolerability and safety

Quality of life (FACT-L, LCSS)

Metastatic

Squamous

NSCLC (n = 130)

First line

metastatic

Measurable

disease

ECOG PS 0-1

Any PD-L1

status

EML4/ALK (-)

EGFR wild type

Pembrolizumab

200 mg Q3W x 2 yrs

Placebo

Q3W 2 yrs

Carbo/Cis

platin

Combination

Min 2-6

cycles

C

R

o

r

P

R

R

1:1

Primary endpoint

Progression-free survival @ 6 months

Secondary endpoints

Overall response rate (ORR)

Progression Free Survival (PFS)

Immune-Related Disease Control Rate (iDCR)

Overall survival

Tolerability and safety

KEYNOTE 068 (REACTION - EORTC 1416) - B. BesseA phase II study of etoposide and cis/carboplatin with or

without pembrolizumab in untreated extensive SCLC

Metastatic SCLC

(n = 152)

First line metastatic

Measurable

disease

ECOG PS 0-1

PD-L1 status

Pembrolizumab200 mg Q3WPD/Death*

Carbo/

Cis

Etopos

ide

(2

cycles)

C

R

o

r

P

R

Carbo/Cis EtoposidePembrolizumanb(4 cycles)

Carbo/Cis

Etoposide

(4 cycles)

R

1:1

PD

End

Study

PD

* Patients receiving pembrolizumab are allowed to stop after one year. Should they progress more than 3

months after stopping therapy, retreatment will be allow provided they are meeting all inclusion criteria.

CCTG Protocol Number: IND.227A phase II randomized study of pembrolizumab in

patients with advanced malignant pleural

mesothelioma

Cisplatin/Pemetrexed

Pembrolizumab

R

1:

1

Malignant pleural mesothelioma(n = 126)

No prior therapy

Unresectable

disease

ECOG PS 0-1

PD-L1 status

End

Study

Primary Endpoint:Progression Free Survival

Secondary Endpoints: Overall Survival, QOL, Safety

Cisplatin/Pemetrexed/Pembrolizumab + Pembrolizumab maintenance PD

Stratifications:Epitheloid vs other subtypes

Gracias

[email protected]

6198 – PA Ott

Summary and Conclusions

• Pembrolizumab demonstrated meaningful antitumor activity in previously treated patients with PD-L1–positive SCLC

– 33.3% ORR (1 CR, 7 PR) and 37.7% 12-month OS

– Responses were durable, with a median duration of response of 19.4 months

• Safety profile was consistent with previous experience for pembrolizumab in other tumor types

– Safety profile did not change with longer follow-up

• Ongoing trials of pembrolizumab for extensive-stage SCLC– NCT02359019: phase 2 study of pembrolizumab maintenance therapy following

combination chemotherapy

– NCT02580994: phase 2 study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive-stage SCLC

Immunotherapy TrialsDrug Trial

Pembrolizumab

Phase I trial of MK-3475 and concurrent chemo/radiation for the elimination of small cell lung cancer

Study of pembrolizumab and chemotherapy with or without radiation in small cell lung cancer (SCLC)

Pembrolizumab plus chemotherapy in untreated extensive SCLC

Pembrolizumab and paclitaxel in refractory small cell lung cancer

Pembrolizumab in treating patients with extensive stage small cell lung cancer after completion of combination chemotherapy

Nivolumab

Small cell lung carcinoma trial with nivolumab and ipilimumab in limited doses

Effectiveness study of nivolumab compared to chemotherapy in patients with relapsed small-cell lung cancer ChekMate 331

A study of nivolumab, or nivolumab in combination with ipilimumab, or placebo in patients with ED-SCLC after completion of platinum-based chemotherapy CheckMate 451

AtezolizumabA study of carboplatin plus etoposide with or without atezolizumab in participants with untreated extensive-stage small cell lung cancer

DurvalumabDurvalumab and Tremelimumab with or without radiation in relapsed SCLC

Take Home Messages

ED 14: Small Cell Lung Cancer and Neuroendocrine Tu mors: Immunotherapy of Lung Cancer: Nevin Murray MD Canada

• Rovalpituzumab tserine demonstratates encouraging single agent

activity in relapsed SCLC (DLL3 first SCLC biomarker for Rx).

• Chemotherapy with phased Ipilimumab not more effective than

chemotherapy alone first line.

• Anti-PD-1 (nivolumab and pembrolizumab) active in previously treated

SCLC.

• Combined nivolumab and ipilumimab more toxic but possibly more

effective.

• No first-line data for immunotherapy without chemotherapy (can we

wait for response??).

• Approval of new agents expected (2nd line Rx SCLC “soft target”).

More and better targeting is needed!!

Conclussion

T cell mediated immune rejection of tumours

Therapeutic intervention

Presentation of

tumour-specific/associated Ag

Activation of

Tumour-specific

T cells

Co-stimulatory

T cell

Signals

Negative

Regulatory signals

(immune check-points)

Other

immunosuppressive

factors environment

CD137

CD28

IL-2

IL-15CTLA-4

PD1

B7-1

Agonists Antagonists

T regulatory cellsMyeloid supp cellsIL-10, TGFbeta

Tumour vaccine

e.g. MAGE

or intrinsic (unknown)

checkpoint inhibitors in sclc - oncologypro.esmo.org · • neuroendocrine origin •

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