wclc 2013: update on sclc raffaele califano department of medical oncology the christie and...
DESCRIPTION
Background Aggressive disease Poor prognosis Targeted agents have all failed so far... No real progress in 20 yearsTRANSCRIPT
WCLC 2013:Update On SCLC
Raffaele Califano
Department of Medical Oncology The Christie and University Hospital of South
ManchesterManchester, 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