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Debate 1—Are treatments for small cell lung cancer getting better?

No:Taofeek Owonikoko, MD, PhDAssociate ProfessorDepartment of Hematology & Medical OncologyWinship Cancer Institute of Emory University

2Winship Cancer Institute | Emory University

Evolution of SCLC treatment

1973 1992 1993 1999 2016

VA lung study established

limited stage category

Concurrent XRT

Pignon et al. NEJM 327 (1992), pp. 1618-

1624

High dose multiagent

chemotherapyArriagada et al. NEJM 1993; 329:1848-1852

Prophylactic cranial

irradiation (PCI)

Aupérin A et al. NEJM. 1999 Aug12;341(7):476-84

Limited Stage SCLC

1999

BID thoracic radiation

superior to QD fraction

Turrisi AT et al. NEJM 1999; 340:265-271

BEQ single daily fraction

not superior to bid radiation

Faivre-Finn C. et al. ASCO 2016

2002

Platinum doublet with

concurrent XRTSundstrom, S. et al. JCO; 20:4665-4672

3Winship Cancer Institute | Emory University

Evolution of treatment for SCLC

Extensive Stage SCLC

Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print].

4Winship Cancer Institute | Emory University

Different platinum doublet beyond etoposide

Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print]. Hanna N, et al. J Clin Oncol. 24(13):2038-2043. Lara P, et al. J Clin Oncol. 2009;27(15):2530-2535.

5Winship Cancer Institute | Emory University

AURORA Kinase inhibitor, Alisertib in SCLCPrimary endpoint: PFS (ITT population)

Disease progression evaluated according to RECIST v1.1. 5

Median PFS: 101 days (3.32 months) vs 66 days (2.17 months)1.00.90.80.70.60.50.40.30.20.1

0

Surv

ival

Pro

babi

lity

0 30 60 90 120 150 180 210 240 270 300Survival Time (days)

89 65 45 27 19 12 8 4 3 3 0

89 74 55 41 28 13 10 6 3 0 0

CORRECTEDHazard Ratio (95% CI): 0.71 (0.509–0.985)Log rank p-value: 0.038

Treatment group: Placebo + PaclitaxelAlisertib + PaclitaxelCensored Observations: Placebo + PaclitaxelAlisertib + Paclitaxel

Placebo + Paclitaxel

Alisertib + Paclitaxel

Owonikoko T, et al. Presented at: 17th World congress on Lung Cancer. December 4-7, 2016. Vienna, Austria. Abstract: MA11.07

6Winship Cancer Institute | Emory University

PFS improvement in patients with c-Mycexpression*

• *Archived tumor tissue available from 46 patients. • † Modal intensity for c-Myc positive = 1+, 2+, 3+ IHC score. • ‡ Modal intensity for c-Myc negative = 0 IHC score.

Armc-Myc positive†

n Median PFS (months)

Alisertib + Paclitaxel 17 4.64

Placebo + Paclitaxel 16 2.27

Hazard Ratio (95% CI) 0.29 (0.12–0.72)

Armc-Myc negative‡

n Median PFS (months)

Alisertib + Paclitaxel 6 3.32

Placebo + Paclitaxel 7 5.16

Hazard Ratio (95% CI) 11.8 (1.52–91.2)

Pbinary = 0.0006

1.00

0.75

Surv

ival

0Days

300

0.50

0.25

0200100

Alisertib + PaclitaxelPlacebo + Paclitaxel

1.00

0.75

Surv

ival

0 300

0.50

0.25

0200100

Alisertib + PaclitaxelPlacebo + Paclitaxel

Days

c-Myc Positive, PFS

c-Myc Negative, PFS

7Winship Cancer Institute | Emory University

PARP Inhibition: E2511 Study Design

ASCO Annual Meeting, 2017

Extensive stage SCLCPreviously untreated

Good renal and hepatic function

Cisplatin (75mg/m2) D1 Etoposide (100mg/m2) D1, 2, 3

Veliparib (100mg bid) D1-7

Cisplatin (75mg/m2) D1 Etoposide (100mg/m2) D1, 2, 3

Placebo (100mg bid) D1-7

Exclusion:Brain metastasis

ECOG PS ≥2

• Patients received a maximum of 4 cycles of therapy• Restaging scan obtained every 2 cycles and Q 3 months from end of treatment• PCI at the discretion of the treating physician• Consolidation TRT was not allowed

Stratification: • Gender (Male vs. Female)• LDH (≤ ULN vs. > ULN)

Owonikoko TK, et al. J Clin Oncol. 2017;35(suppl): Abstract 8505.

8Winship Cancer Institute | Emory University

Progression Free Survival

Unadjusted PFS HR: 0.75; 1-sided p=0.06 Adjusted PFS HR: 0.63; 1-sided p=0.01Median PFS: 6.1 vs. 5.5 months for CE+V and CE+P respectively

OS HR: 0.83 (80% CI 0.64-1.07); 1-sided p=0.17. Median OS: 10.3 vs. 8.9 months for CE+V and CE+P respectively

Owonikoko TK, et al. J Clin Oncol. 2017;35(suppl): Abstract 8505.

9Winship Cancer Institute | Emory University

CALGB 30504 – Maintenance sunitinb

Ready N, et al. J Clin Oncol. 2015;33(15):1660-1665.

10Winship Cancer Institute | Emory University

PCI for extensive stage SCLC: One step forward and back

Takahashi T, et al. Lancet Oncol. 2017;18(5):663-671. Slotman B, et al. N Engl J Med. 2007;357(7):664-672.

11Winship Cancer Institute | Emory University

Overall Sensitive Refractory

Jotte et al. PFS 4.5 vs. 3.3

4.5 vs. 3.3 NA

OS 9.2 vs. 7.6

9.2 vs. 7.6 NA

Inoue et al. PFS 3.5 vs. 2.2

3.9 vs. 3.0 2.6 vs. 1.5

OS 8.1 vs. 8.4

9.9 vs. 11.7 5.3 vs. 5.4

Phase IIIAssumptions

Phase III 97.5% power: 6.0 vs. 8.7 months (HR: 0.69)]Enrolled 295 refractory and 342 sensitive patients

Phase IIII PFS 4.1 vs. 3.5

OS 7.5 vs. 7.8 9.2 vs. 9.9 6.2 vs. 5.7

Phase II studies of Amrubicin vs. Topotecan in extensive stage SCLC

Inoue A, et al. J Clin Oncol. 2008;26(33):5401-5406. Jotte R, et al. J Clin Oncol. 2011;29(3):287-293.

12Winship Cancer Institute | Emory University

Phase III 2nd-line SCLC: ACT-1 Trial

AMR IV40 mg/m2

1x daily on d 1-3 q 3 w

• Small Cell Lung Cancer (SCLC)• Extensive or Limited Disease• Sensitive or refractory disease

(Progression ≥ 90 or <90 days after completion of 1st line chemotherapy, Response to 1st line chemo)

• 1 prior chemotherapy regimen• ECOG performance status 0-1• Stratified: Sensitive/Refractory;

Extensive/Limited

RANDOMIZE

2 to1

Topotecan IV1.5 mg/m2

1x daily ond 1-5 q 3 w

• Primary endpoint: Overall Survival• Secondary endpoints: ORR, PFS, TTP, quality of life, safety, sparse PK• Analyses: Interim (deaths = 294), Final (deaths = 490) [97.5% power: 6.0 vs. 8.7 months (HR: 0.69)]

13Winship Cancer Institute | Emory University

Median OS in Sensitive and Refractory Patient Subgroups

Sur

viva

l Pro

babi

lity

Time (months)

AmrubicinTopotecan

1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21 24 27

Sur

viva

l Pro

babi

lity

Time (months)

AmrubicinTopotecan

1.0

0.90.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 3 6 9 12 15 18 21 24 27 30 33

AMR Topo HR P Value*

N/events 199/168 96/86

OS (mo) 6.2 5.7 0.766 0.0469

95% CI 5.5-6.7 4.1-7.0 0.589 –0.997

* Unstratified log-rank test

Sensitive Patients

Refractory Patients

AMR Topo HR PValue*

N/events 225/168 117/89

OS (mo) 9.2 9.9 0.936 0.6164

95% CI 8.5-10.6 8.5-11.5 0.724 –1.211

14Winship Cancer Institute | Emory University

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC - Non-Randomized Cohort

Events/number at risk

Median OS, months (95% CI)

Minimum follow-up,a months

Nivolumab 82/98 4.1 (3.0, 6.8) 19.6

Nivolumab + Ipilimumab 47/61 7.8 (3.6, 14.2) 20.2

1-yr OS = 40%

1-yr OS = 27%

2-yr OS = 14%

Time (months)

OS

(%)

100

90

80

70

60

50

40

30

10

0

20

NivolumabNumber of patients at risk

46771217212635395698137141619212428334361Nivolumab + Ipilimumab

330 30272421181512963 36 39

0401

2-yr OS = 26%

OS = overall survival; aBetween first dose and database lock; follow-up shorter for patients who died prior to database lock

Antonia SJ, et al. Lancet Oncol. 2016;17(7):883-895.

15Winship Cancer Institute | Emory University

65 596472

0

10

20

30

40

50

60

70

80

90

182730

36

0

10

20

30

40

50

60

70

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC - 3-month PFSa and OS Rates

• Minimum follow-up time was 12 weeks at the time of database lock

Nivo randomized cohort Nivo + ipi randomized cohort Nivo non-randomized cohort Nivo + ipi non-randomized cohort

PFS = progression-free survival; Error bars indicate 95% CIs; aPer BICR

PFS

(%)

OS

(%)

n

Randomized cohort

147 95

Non-randomized cohort

98 61 n

Randomized cohort

147 95

Non-randomized cohort

98 61

Antonia SJ, et al. Lancet Oncol. 2016;17(7):883-895.

Phase II study of maintenance pembrolizumab in extensive stage small cell lung cancer patients Shirish M. Gadgeel, Jaclyn Ventimiglia, Gregory P. Kalemkerian, Mary J. Fidler, Wei Chen, Ammar Sukari, Balazs Halmos, Julie Boerner, Antoinette Wozniak, Cathy Galasso, Nathan A. Pennell

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Progression Free Survival

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18Month from first date of treatment

PFS

(pro

babi

lity)

45 17 9 5 2 0 0No. at risk

|

|

| | |

N = 45 90% CI

Median PFS 1.4 mo. 1.3-2.8

6-month PFS 21% 0.12-0.32

Gadgeel SM, et al. J Clin Oncol. 2017;35(suppl): Abstract 8504.

18Winship Cancer Institute | Emory University

Immunotherapy in SCLC

Phase II trial of ipilimumab + chemotherapy Phase III trial of ipilimumab + chemotherapyReck M, et al. Ann Oncol. 2012;24(1):75-83. Reck M, et al. J Clin Oncol. 2016 Jul 25 [Epub ahead of print].

19Winship Cancer Institute | Emory University

Progress in SCLC management: Is it just movement or real motion?

Facts do not cease to exist just because they are ignored!Aldous Leonard Huxley - British Author(1894 –1963)

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What does real progress look like

21Winship Cancer Institute | Emory University

Strategies for novel targeted therapies for SCLC

Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print].

22Winship Cancer Institute | Emory University

SCLC – A Personalized Approach to Systemic Therapy

Newly diagnosed SCLC - Chemotherapy

Platinum-doublet refractory (30%)

Predictive biomarker?

Platinum-doublet responsive (70%)

2nd line chemotherapyor immunotherapy

MYC amplifiedDLL 3 + Schalfen11+

Activating driver mutations

AURKA inhibitor PARP inhibitor Rova-T

Kinase inhibitor

Relapsed SCLC

Re-biopsySCLC VS.

23Winship Cancer Institute | Emory University

Ongoing studies of targeted therapy for extensive stage small-cell lung cancer

Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print].

24Winship Cancer Institute | Emory University

What will you do for your next newly diagnosed SCLC patient?

Doublet chemotherapy

and XRT

Consistent with SOC practice in 1992

Platinum doublet chemotherapy

Same as SOC practice in 1985

Limited stage SCLC Extensive stage SCLC

25Winship Cancer Institute | Emory University

Conclusion

•Res ipsa loquitur

Thank you!