WCLC 2013:Update On SCLC

Raffaele Califano

Department of Medical Oncology The Christie and University Hospital of South

ManchesterManchester, UK

raffaele.califano@christie.nhs.uk

Outline

Background

Key studies

Conclusion

Background

Aggressive disease

Poor prognosis

Targeted agents have all failed so far...

No real progress in 20 years

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)

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

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

chemo May prevent cancerDanish study: Longer OS for ca pts on statinsHCC: Pravastatin doubles survival

Rationale

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

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

Baseline CharacteristicsPravastatin

(N=422)Placebo(N=424)

P-value

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

Limited Stage 179 (42%) 178 (42%) 0.889ECOG 0-1 316 (75%) 315 (74%) 0.813Age (yrs) median [range]

64[41-86]

64[42-85] 0.621

Ipsiltateral SCN 97 (23%) 105 (25%) 0.573Carboplatin/Etop.Cisplatin/Etop.

365 (87%) 57 (13%)

385 (91%)39 (9%) 0.051

0.101

  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

  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

Toxicity

Pravastatin Ineffective

Sub-group analyses / Translational studies?

A lot of patients/money wasted!

Conclusion/Comments

A Randomized Phase 2 Study of Ganitumab or Rilotumumab with

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

Stage SCLCB. Glisson, et al

IGF1-RInhibition sensitizes cell lines to etoposide and carboplatinHigh levels correlate with short survival

MET Expressed and functional in SCLCMutant 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

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

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 432Patients 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

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

Overall Survival  Ganituma

b(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  Ganituma

b(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)  

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) 0Gastric hemorrhage 0 0 1 (2)

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

Adverse Events

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

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

MLN8237 (ALISERTIB), An Investigational Selective Aurora

A Kinase (AAK) Inhibitor, In patients With

Relapsed/Refractory SCLC: PHASE 2 RESULTSHavel et al

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

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 linesNo symptomatic brain mets

Primary endpoint: ORR

*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

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

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 1.74Median TTP, months 2.6 2.8 1.4Median 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)

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

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

Manageable safety profile

Activity similar to active agents in patients with relapsed SCLC

RPh2 study: Paclitaxel +/-MLN8237 to start soon

Conclusion/Comments

No practice changing data

Need better understanding of molecular biology

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

Take Home message