No: Taofeek Owonikoko, MD, PhD Associate Professor Department of - - PowerPoint PPT Presentation

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

No:

Taofeek Owonikoko, MD, PhD Associate Professor Department of Hematology & Medical Oncology Winship Cancer Institute of Emory University

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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 chemotherapy

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

Prophylactic cranial irradiation (PCI)

Aupérin A et al.

• NEJM. 1999 Aug

12;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 XRT

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

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Evolution of treatment for SCLC

Extensive Stage SCLC

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

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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.

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

Disease progression evaluated according to RECIST v1.1.

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Median PFS: 101 days (3.32 months) vs 66 days (2.17 months) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Survival Probability 30 60 90 120 150 180 210 240 270 300 Survival Time (days) 89 65 45 27 19 12 8 4 3 3 89 74 55 41 28 13 10 6 3

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

Treatment group: Placebo + Paclitaxel Alisertib + Paclitaxel Censored Observations: Placebo + Paclitaxel Alisertib + 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

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PFS improvement in patients w ith c-Myc expression*

• *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.

Arm c-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)

Arm c-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 Survival Days 300 0.50 0.25 200 100 Alisertib + Paclitaxel Placebo + Paclitaxel 1.00 0.75 Survival 300 0.50 0.25 200 100 Alisertib + Paclitaxel Placebo + Paclitaxel Days c-Myc Positive, PFS c-Myc Negative, PFS

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PARP Inhibition: E2511 Study Design

ASCO Annual Meeting, 2017 Extensive stage SCLC Previously 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.

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Progression Free Survival

Unadjusted PFS HR: 0.75; 1-sided p=0.06 Adjusted PFS HR: 0.63; 1-sided p=0.01 Median 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.

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CALGB 30504 – Maintenance sunitinb

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

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PCI for extensive stage SCLC: One step forw ard 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.

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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 III Assumptions 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.

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

AMR IV 40 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

R A N D O M I Z E 2 to 1 Topotecan IV 1.5 mg/m2 1x daily on d 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)]

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Median OS in Sensitive and Refractory Patient Subgroups

Survival Probability Time (months)

Amrubicin Topotecan

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27

Survival Probability Time (months)

Amrubicin Topotecan

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 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 P Value* 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

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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 20

Nivolumab Number of patients at risk 4 6 7 7 12 17 21 26 35 39 56 98 1 3 7 14 16 19 21 24 28 33 43 61 Nivolumab + Ipilimumab

33 30 27 24 21 18 15 12 9 6 3 36 39

4 1 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.

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65 59 64 72

10 20 30 40 50 60 70 80 90

18 27 30 36

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 3 6 9 12 15 18 Month from first date of treatment PFS (probability) 45 17 9 5 2

• No. 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.

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Immunotherapy in SCLC

Phase II trial of ipilimumab + chemotherapy Phase III trial of ipilimumab + chemotherapy

Reck M, et al. Ann Oncol. 2012;24(1):75-83. Reck M, et al. J Clin Oncol. 2016 Jul 25 [Epub ahead of print].

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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

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Strategies for novel targeted therapies for SCLC

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

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SCLC – A Personalized Approach to Systemic Therapy

Newly diagnosed SCLC

• Chemotherapy

Platinum-doublet refractory (30%)

Predictive biomarker?

Platinum-doublet responsive (70%) 2nd line chemotherapy

• r immunotherapy

MYC amplified DLL 3 + Schalfen11+ Activating driver mutations AURKA inhibitor PARP inhibitor Rova-T Kinase inhibitor

Relapsed SCLC Re-biopsy

SCLC

VS.

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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].

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What w ill you do for your next new ly 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

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Conclusion

• Res ipsa loquitur

Thank you!