outline

32
WCLC 2013: Update On SCLC Raffaele Califano Department of Medical Oncology The Christie and University Hospital of South Manchester Manchester, UK [email protected]

Upload: trynt

Post on 30-Jan-2016

25 views

Category:

Documents


0 download

DESCRIPTION

WCLC 2013: Update On SCLC Raffaele Califano Department of Medical Oncology The Christie and University Hospital of South Manchester Manchester, UK [email protected]. Outline. Background Key studies Conclusion. Background. Aggressive disease Poor prognosis - PowerPoint PPT Presentation

TRANSCRIPT

Page 1: Outline

WCLC 2013:Update On SCLC

Raffaele Califano

Department of Medical Oncology The Christie and University Hospital of South

ManchesterManchester, UK

[email protected]

Page 2: Outline

Outline

Background

Key studies

Conclusion

Page 3: Outline

Background

Aggressive disease

Poor prognosis

Targeted agents have all failed so far...

No real progress in 20 years

Page 4: Outline

Key Studies

First-line treatment:Seckl et al (Abs O21.01)Glisson et al (Abs O21.05)

Pre-treated patients:Havel et al (Abs O21.06)

Page 5: Outline

Multicentre Phase III Randomised Multicentre Phase III Randomised Double Blind Placebo Controlled Double Blind Placebo Controlled Trial of Pravastatin added to First Trial of Pravastatin added to First Line Standard Chemotherapy in Line Standard Chemotherapy in SCLCSCLC

LungSt r

Michael J Seckl on behalf of the LungStar collaborators

Page 6: Outline

Statins:Kill SCLC in vitro + in vivo/additive with

chemo

May prevent cancer

Danish study: Longer OS for ca pts on statins

HCC: Pravastatin doubles survival

Rationale

Page 7: Outline

Placebo

Pravastatin 40 mg

ODPreviously untreated

LS/ ES SCLC, PS 0-3

No statins < 12m

(n=846)

R

Platinum/Etoposide plus placebo

Platinum/Etoposide plus pravastatin 40

mg OD

Primary endpoint: OS

Study Design

1:1 For 2 years

Page 8: Outline

Statistics

•Original sample size:•1300 patients (90% power, 5% significance level) to detect an increase from 10% to 15% in 2-yr survival with pravastatin •Equivalent to a median survival increase from 9 to 11 months in ES and 15 to 19 months in LS

•Revised sample size:•Reduced to 80% power, 5% significance level•842 patients with 792 events corresponds to detecting a HR of 0.82

Page 9: Outline

Baseline Characteristics

Pravastatin(N=422)

Placebo(N=424)

P-value

Male 219 (52%) 214 (51%) 0.681

Limited Stage 179 (42%) 178 (42%) 0.889

ECOG 0-1 316 (75%) 315 (74%) 0.813

Age (yrs) median [range]

64[41-86]

64[42-85] 0.621

Ipsiltateral SCN 97 (23%) 105 (25%) 0.573

Carboplatin/Etop.Cisplatin/Etop.

365 (87%) 57 (13%)

385 (91%)39 (9%)

0.0510.101

Page 10: Outline

  Pravastatin PlaceboMedian (mos) [95% CI]

10.7 [10.0-11.8]

10.8 [10.0-12.8]

1 Year OS [95% CI] 45.0% [40.3-49.8]

47.2% [42.4-51.9]

2 Year OS [95% CI] 15.9% [12.3-19.5]

17.3% [13.6-21.0]

HR: 1.08 (0.93-1.25) P=0.339

Overall Survival

Page 11: Outline

  Pravastatin Placebo

Median (mos) [95% CI]

7.8 [7.1-8.5] 7.4 [6.9-8.0]

1 Year PFS [95% CI] 26.8% [22.6-31.1]

27.3% [23.0-31.6]

2 Year PFS [95% CI] 10.0% [7.0-13.1] 11.8% [8.5-15.0]

HR: 1.03 (0.89-1.18) P=0.703

Progression-free Survival

Page 12: Outline

Toxicity

Page 13: Outline

Pravastatin Ineffective

Sub-group analyses / Translational studies?

A lot of patients/money wasted!

Conclusion/Comments

Page 14: Outline

A Randomized Phase 2 Study of Ganitumab or Rilotumumab with

Platinum-Based Chemotherapy as First-Line Treatment for Extensive-

Stage SCLC

B. Glisson, et al

Page 15: Outline

IGF1-RInhibition sensitizes cell lines to etoposide and carboplatin

High levels correlate with short survival

MET Expressed and functional in SCLC

Mutant in a subset of SCLC cell lines and tumor samples

Ganitumab and rilotumumabFully human mAbs targeting IGF1-R and hepatocyte growth factor (HGF)/scatter factor

Rationale

Page 16: Outline

Placebo

Ganitumab

Previously untreated ES SCLC,

PS 0-1No thrombosis

No diabetes(n=185)

R

Platinum/Etoposide plus placebo

Platinum/Etoposide plus Ganitumumab

Primary endpoint: OS

Study Design

1:1:1

Until PD

RilotumumabPlatinum/Etoposide plus Rilotumumab

Page 17: Outline

Full analysis setGanitumab

(n = 62)Rilotumumab

(n = 62)Placebo(n = 61)

Median age (range), y 60 (45–79) 61 (42–74) 61 (33–76)

Male, n (%) 48 (77) 47 (76) 47 (77)

Extensive disease stage at initial diagnosis, n (%)

60 (97) 62 (100) 58 (95)

ECOG performance status,a n (%)

0 13 (21) 19 (31) 12 (20)

1 48 (77) 43 (69) 49 (80)

Median baseline LDH (U/L) 345 388 432

Patients who received carboplatin, n (%) 41 (66) 40 (65) 40 (66)

Patients who received cisplatin, n (%) 21 (34) 22 (35) 21 (34)

Safety analysis setGanitumab

(n = 59)Rilotumumab

(n = 61)Placebo(n = 59)

Patients receiving prophylactic cranial irradiation, n (%)

34 (58) 25 (41) 27 (46)

Patients’ Charactheristics

Page 18: Outline

Ganitumab

(n = 62)

Rilotumumab

(n = 62)

Placebo(n = 61)

Complete response, n (%)

0 2 (3) 1 (2)

Partial response, n (%)

39 (63) 40 (65) 35 (57)

Stable disease, n (%) 13 (21) 12 (19) 16 (26)

Overall Response Rate

Page 19: Outline

Overall Survival

  Ganitumab

(n = 62)

Rilotumumab

(n = 62)

Placebo(n = 61)

Median (95% CI), mo

10.7 (8.1–14.1)

12.2 (8.8–14.6)

10.8(9.4–11.9)

Adjusted HRa

(95% CI)

1.01(0.67–1.52)

0.91(0.60–1.39)

 

Progression Free Survival

  Ganitumab

(n = 62)

Rilotumumab

(n = 62)

Placebo(n = 61)

Median (95% CI), mo

5.5(4.4–5.7)

5.4(4.4–5.7)

5.4(4.6–5.8)

Adjusted HRa

(95% CI)

1.03(0.70–1.52)

1.03(0.69–1.52)

 

Page 20: Outline

Ganitumab (n = 59)

Rilotumumab

(n = 61)

Placebo(n = 59)

Patients reporting ≥ 1 grade ≥ 3 AE, n (%) 41 (69) 44 (72) 47 (80)

Grade ≥ 3 AEs of interest reported in ≥ 1 patient, n (%)

Neutropenia 31 (53) 33 (54) 36 (61)Thrombocytopenia 8 (14) 9 (15) 2 (3)Venous thromboembolic events 3 (5) 2 (3) 2 (3)Hyperglycemia 3 (5) 2 (3) 1 (2)IP-related hepatic disorders 0 2 (3) 1 (2)Infusion reaction 1 (2) 0 0Arterial embolic/thromboembolic events

0 1 (2) 0

Cerebrovascular events 0 1 (2) 0

Gastric hemorrhage 0 0 1 (2)

Patients with a grade 5 AE, n (%) 7 (12) 6 (10) 3 (5)

Adverse Events

Page 21: Outline

Only available for IGF axis (Serum)

Low IGFBP-2 levels associated with increased response (but no OS) on ganitumab arm

Tumor biomarkers pending

Biomarker analysis

Page 22: Outline

No improvement in ORR, PFS, or OS

No pre-clinical data for activity in SCLC

Experimental agents only active in a targeted population?

Conclusion/Comments

Page 23: Outline

MLN8237 (ALISERTIB), An Investigational Selective Aurora

A Kinase (AAK) Inhibitor, In patients With

Relapsed/Refractory SCLC: PHASE 2 RESULTS

Havel et al

Page 24: Outline

Key mitotic regulator AAK is amplified or overexpressed in a variety of solid tumors

Inhibition of AAK results in:Chromosome misalignment and instabilityAbnormal spindle formationReduction in astral microtubule length/stability

Small molecule inhibitor of AAK with single-agent antitumor activity

Preclinical data support combination with taxanes, rituximab and other agents

Control

treated treated

treated

α−tubulin, DNA, Centrosomes

untreated

Rationale

Page 25: Outline

RP2D determined duringphase 1 portion of study

RP2D:MLN8237 50 mg BID for 7 days (21-day cycles)

Treatment for24 months, or until PD or unacceptable

toxicity

Study Design

SCLCN=45

H&NN=45

BreastN=45

GastricN=45

NSCLCN=45 ES SCLC

ECOG PS 0–1

≤2 prior lines

No symptomatic brain mets

Primary endpoint: ORR

Page 26: Outline

*Based on safety population (n=60) Data as of April 2013

All SCLC arm patients [response-evaluable]

(n=48)

Median age, years (range) 62 (46–76)

Male, n (%) 24 (50)

Race, n (%)WhiteBlack or African American

45 (94)3 (6)

Median time since diagnosis, years (range)*

1.0 (0.4–4.4)

ECOG PS, n (%)01

13 (27)35 (73)

Prior lines of therapy, n (%)1 2

25 (52)23 (48)

Demographics

Page 27: Outline

All patients (n=48)

Chemo-sensitive (n=36)

Chemo-refractory

(n=12)

First line, n (%)

Platinum/etoposide 45 (94) 33 (92) 12 (100)

Platinum/irinotecan 2 (4) 2 (5) –

Other 1 (2) 1 (3) –

Second line, n (%) n=23 n=19 n=4

Rechallenge 13 (56) 12 (63) 1 (25)

Topotecan 3 (13) 2 (11) 1 (25)

Paclitaxel 2 (9) 1 (5) 1 (25)

Platinum/Irinotecan 3 (13) 2 (11) 1 (25)

Other 2 (9) 2 (11) –Data as of April 2013

Previous Treatment

Page 28: Outline

Data as of September 2013

Efficacy and SafetyAll SCLC Patients

(N=48)Chemo-

sensitive (n=36)

Chemo-refractory

(n=12)

Median Cycles, n (range)

2 (1–15) 3.5 (1–15) 2 (2–6)

Best Response, n (%)ORR (PR)SDPD

10 (21)16 (33)22 (46)

7 (19)13 (36)16 (44)

3 (25)3 (25)6 (50)

Median PFS, months 2.11 2.58 1.74

Median TTP, months 2.6 2.8 1.4

Median DOR, months 4.1 4.4 3.1

Most common (≥5 %) grade ≥3 AEs, n (%)

Neutropenia 18 (30)

Anemia 10 (17)

Thrombocytopenia 6 (10)

Most common (≥5 %) grade ≥3 AEs, n (%)

Decreased WBC 7 (12)

Confusional state 4 (7)

Febrile neutropenia 5 (8)

Page 29: Outline

Biomarker analysis

53 tumor tissues available (6 responders, 2 SCLC)

Candidate biomarkers: amplification of Myc family genes and Aurora A, Ki-67)

Whole exome sequencing

Page 30: Outline

Mutated genes found in responders

Mutational landscape of SCLC

R

NR

R

NR

Highly mutated

Among 527 frequently mutated genes reported in SCLC, 122 genes found to be mutated in at least 1/6 patients

Fisher’s exact test identified 8 mutated genes associated with responders

Gene

Gene

Patie

nt

Patie

ntWhole exome sequencing:

Preliminary analysis

Page 31: Outline

Manageable safety profile

Activity similar to active agents in patients with relapsed SCLC

RPh2 study: Paclitaxel +/-MLN8237 to start soon

Conclusion/Comments

Page 32: Outline

No practice changing data

Need better understanding of molecular biology

Need tissue and possibly serum/plasma to be mandatory in trials

Take Home message