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New Developments in the Treatment of SCLC

Alan Sandler, MD

Oregon Health & Science University

Outline

• Amrubicin vs topotecan in second-line SCLC

• Randomized Phase II study of carboplatin & etoposide with or without pan-BCL-2 antagonist obatoclax in ES-SCLC

• Bendamustine in previously treated SCLC

Randomized Phase 3 Trial of Amrubicin versus Topotecan as Second-line Treatment for SCLC• Although SCLC is often responsive to 1st-line

chemotherapy, relapse remains common and prognosis is poor with 5-year OS of 6%

• Topotecan (Topo) is approved in the US and EU for 2nd-line SCLC treatment based on response rates of 11-31% in sensitive pts

• Amrubicin (AMR) is a 3rd-generation anthracycline and potent topoisomerase II inhibitor approved in Japan for treatment of SCLC and NSCLC

• Efficacy and safety of AMR and Topo were compared as 2nd-line treatment in patients with SCLC sensitive or refractory to 1st-line platinum-based chemotherapy

Jotte, et al ASCO 2011

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

AMR IVAMR IV40 mg/m40 mg/m22 1x daily on 1x daily on d 1-3 q 3 w d 1-3 q 3 w

• Small Cell Lung Cancer (SCLC)Small Cell Lung Cancer (SCLC)

• Extensive or Limited DiseaseExtensive or Limited Disease

• Sensitive or refractory disease Sensitive or refractory disease (Progression ≥90 or <90 days after (Progression ≥90 or <90 days after completion of 1completion of 1stst-line chemotherapy, -line chemotherapy, Response to 1Response to 1stst-line chemo)-line chemo)

• 1 prior chemotherapy regimen1 prior chemotherapy regimen

• ECOG performance status 0-1ECOG performance status 0-1

• Stratified: Sensitive/Refractory; Stratified: Sensitive/Refractory; Extensive/LimitedExtensive/Limited

RRAANNDDOOMMIIZZEE

2 2 toto11

Topotecan IVTopotecan IV1.5 mg/m1.5 mg/m22 1x daily on1x daily on

d 1-5 q 3 w 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)]

Baseline Characteristics

AMR, N=424 n (%)

Topo, N=213n (%)

Age (Median)

Range

Age ≥ 65 years

62

22-81

169 (39.9)

61

30-81

74 (34.7)

Sex

Male

Female

244 (57.5)

180 (42.5)

127 (59.6)

86 (40.4)

Performance Status

0

1

2

126 (29.7)

289 (68.2)

9 (2.1)

72 (33.8)

137 (64.3)

4 (1.9)

Sensitivity to first-line therapy

Sensitive

Refractory

225 (53.1)

199 (46.9)

117 (54.9)

96 (45.1)

PFS – ITT Population

Amrubicin

N=424

Topotecan

N=213HR p-value*

N/Events 424/367 213/167

Median PFS (months)

4.1 3.5 0.802 0.0182

95% CI 3.5 – 4.3 2.9 – 4.2 0.667 – 0.965

* Unstratified log-rank test

RR = 31.1 (A) vs 16.6% (T) p= 0.0001

OS – ITT Population

AMR Topo HR p-value*

N/Events 424/336 213/175

Median OS

(months)7.5 7.8 0.880 0.1701

95% CI 6.8 – 8.5 6.6 – 8.5 0.733 – 1.057

* Unstratified log-rank test

Median OS in Sensitive and Refractory Patient Subgroups

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

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

Sensitive Patients

Refractory Patients

Most Frequently Observed Grade 3 or 4 TEAEs (≥ 5% in Any Treatment Group) by System Organ Class (Safety Population)

System Organ Class

Preferred Term

Number (%) of Patients

Amrubicin(N=408)

Topotecan (N=197)

Patients with at least 1 Grade 3 or 4 TEAE 296 (72.5) 174 (88.3)

Blood and Lymphatic System Disorders 216 (52.9) 152 (77.2)

Anemia 65 (15.9) 60 (30.5)

Febrile Neutropenia 38 (9.3) 7 (3.6)

Leukopenia 62 (15.2) 43 (21.8)

Neutropenia 168 (41.2) 105 (53.3)

Thrombocytopenia 86 (21.1) 107 (54.3)

General Disorders and Administration Site Conditions

74 (18.1) 30 (15.2)

Fatigue 43 (10.5) 24 (12.2)

Infections 54 (13.2) 17 (8.6)

Pneumonia 22 (5.4) 5 (2.5)

Metabolism and Nutrition Disorders 67 (16.4) 24 (12.2)

Hyponatremia 21 (5.1) 11 (5.6)

Respiratory, Thoracic, and Mediastinal Disorders 43 (10.5) 19 (9.6)

Dyspnea 18 (4.4) 13 (6.6)

Transfusions

Blood and related products 131 (32.1) 104 (52.8)

P<0.05 for highlighted values.

Randomized Phase II Study of Carboplatin & Etoposide with or without pan-BCL-2

Antagonist Obatoclax in Extensive Stage Small Cell Lung Cancer (ES-SCLC)

C. Langer, I. Albert, P. Kovacs, J. Blakely, G. Pajkos, P. Petrov, A. Somfay, A. Szczesna, P.

Zatloukal, A. Kazarnowicz, M. Moezi, M. Schreeder, J. Schnyder, M. S. Berger, and GEM017 ES-SCLC

Investigators

Obatoclax (Ob)

NHN

HN

OCH3

CH3

CH3

NHN

HN

OCH3

CH3

CH3

• Pro-apoptotic small molecule

• Mimetic of BCL-2 family BH3 proteins

• Synergistic with cisplatin and etoposide in vitro

Obatoclax Phase 2b: Trial Design

Investigational Arm (CbEOb) N=77

Obatoclax 30 mg flat dose/3 hr days 1, 2 and 3

Carboplatin AUC 5 IV day 1

Etoposide 100 mg/m2 days 1, 2, 3

Tx every 3 wks X 6, followed by

Maintenance obatoclax [single-agent - same schedule until PD]

Control Arm (CbE) N=78 R

Carboplatin AUC 5 IV day 1

Etoposide 100 mg/m2 days 1, 2, 3

Tx every 3 wks X 6

Primary endpoint - Response rate based on RECIST criteria

Eligibility Criteria

• Extensive-stage SCLC

• No prior chemotherapy exposure

• PS 0-2

• Age ≥ 18 yrs

• Adequate end-organ indices

• No symptomatic brain metastases

Relevant Non-hematologic Toxicities (%)AEs ≥10% Difference Between Arms

* Transient - During infusion

Adverse Event Obatoclax Arm (%) Control Arm (%)

Grade All (Grade 3 or 4) All (Grade 3 or 4)

Somnolence 46* (8) 0

Euphoric Mood 31* (4) 0

Dizziness 25 (0) 13 (0)

Ataxia 13* (0) 1 (1)

Confusional State 13* (1) 1 (0)

Diarrhea 27 (1) 10 (1)

Anorexia 25 (3) 8 (0)

Hematologic and Lab Toxicity

Toxicity CbEOb (%) CbE (%)

Grade All 3+4 All 3+4

Neutropenia 85 61 77 58

Anemia 77 8 78 15

Thrombocytopenia

65 17 71 10

SGOT 32 5 19 0

Alk Phos 36 4 15 0

Bili 25 3 11 1

Creat 8 0 9 0

Response Rate Analysis

CbEOb CbE p-value (Fisher’s; 1-sided)

PS 0-2 CR/PR 50/7765%

42/78 54%

0.107

PS 0-2 CR/PR/SD

64/77 83%

54/78 69%

0.033

PS 0-1 CR/PR 47/69 68%

41/72 57%

0.116

PS 0-1 CR/PR/SD

61/69 88%

53/72 74%

0.021

• All responses, including SD, confirmed by 2nd evaluation 6 + wks later• CR/PR/SD = disease control rate

Overall Kaplan-Meier Actuarial Estimated PFS

• CbE, 5.4 mos

• CbeOb, 6.0 mos

– Overall HR (CbEOb/CE) = 0.795

– p = 0.084

Kaplan-Meier Actuarial Estimated Survival

• CbE, 9.9 mos

• CbeOb, 10.6 mos

– Overall HR (CEOb/CE) = 0.724

– One-sided p-value = 0.052

Kaplan-Meier Actuarial Estimated Survival in PS 0-1 Patients (PS at Screening)

• CbE, 10.1 mos

• CbeOb, 11.9 mos

– Overall HR (CEOb/CE) = 0.711

– One-sided p-value = 0.054

Survival by Chemotherapy Sensitivity Status in PS 0-1 Patients (PS at Screening)

Sensitive = Alive without progression after 6 cycles combination chemotherapy

• CE Sensitive, 12.8 mos

• CbEOb Sensitive, 15.4 mos

– Sensitive HR (CbEOb/CE) = 0.732

– One-sided p-value = 0.146

Bendamustine in SCLC

• Bendamustine is an alkylating agent

• Bendamustine in combination with carboplatin has shown efficacy as first line therapy in extensive stage SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster, et al, JTO 2007].

Lovely, et al ASCO 2012

Bendamustine in 2nd/3rd line SCLC

• Single-arm, multicenter phase II trial

• Eligible patients had previously treated ES-SCLC, up to 2 prior regimens, ECOG performance status 0-2, evaluable/measurable disease, and adequate marrow, renal and hepatic function.  Patients with stable treated brain metastases were allowed

• Patients were treated with bendamustine (120mg/m2 IV days 1 and 2 every 3 weeks) for up to 6 cycles

• Primary endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity

Results

• 48 patients were enrolled and 33 patients were evaluable for response.

• 56% were male and 96% were Caucasian.

• There was 1 CR, 9 PR, 13 SD (48% disease control rate).

• Median TTP was 3.37 months (95% CI 2.30 to 4.47 months).

• Median overall survival of 4.77 months (95% CI 3.67 to 6.07 months). 

Toxicity

• Grade 3/4 AEs included fatigue (18.8%), dyspnea (14.5%), infection without neutropenia (12.5%), anemia (8.3%), neutropenia (8.3%) and diarrhea (8.3%).

• 5 patients (10.4%) required dose reductions due to AEs, 2 due to fatigue, 1 due to neutropenia, 1 due to pancytopenia and 1 due to pneumonia.

Conclusions

• Primary endpoint of OS in ITT was not significantly different (7.5 mo amrubicin vs. 7.8 mo topotecan, HR 0.880, p=0.1701).

• An improvement in OS in refractory patients was observed (6.2 mo amrubicin vs. 5.7 mo topotecan, HR 0.766, p=0.0469).

• In ES-SCLC, obatoclax in combination with carboplatin/etoposide (CbEOb) demonstrated a trend for improved ORR, PFS, and OS compared to CbE.

Sunday, February 12, 2012Hollywood, Florida

Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD

Co-Chair and ModeratorNeil Love, MD

Faculty

Walter J Curran Jr, MDDavid Jablons, MDMark G Kris, MD

Suresh Ramalingam, MDAlan B Sandler, MD