Thoracic Malignancies
Committee
Objectives
1. To develop new strategies to treat lung cancer
2. To develop novel agents with a strong emphasis
on biomarker discovery
3. To incorporate novel imaging methods as an
integral component of drug development and
cancer care
Thoracic Committee Leadership • Chair: Suresh S. Ramalingam ,MD
• Co-Chair: Charles Rudin, MD
• Lung Biology Committee Chairs: David Carbone MD, Jill
Kolesar PhD
• Imaging Co-Chair: Caroline Chiles, MD
• Thoracic Surgery: Steve Keller, MD
• Pathology Co-Chair: Seena Aisner, MD
• Biostatistics: Suzanne Dahlberg, PhD
Ongoing Studies
ECOG 1505
• Phase III study to evaluate the role of
bevacizumab in early stage NSCLC
• Stage IB, II & IIIA
– Stage IB >4cm primary tumor
• Primary endpoint: Overall survival
• Study Chair: Heather Wakelee, MD
E1505
Early stage NSCLC
S/P Curative Surgery
N=1500 patients
Chemotherapy
X 4 cycles
Chemotherapy
X 4 cycles
+
Bevacizumab (1 year)
Chemotherapy: Cisplatin+ Docetaxel Cisplatin+ pemetrexed, Cisplatin + Gemcitabine, Cisplatin + Vinorelbine
Present Status
• > 1200 patients enrolled
• Anticipated to complete accrual in June 2013
• Interim analysis revealed no unanticipated
toxicity concerns with the addition of
bevacizumab to chemotherapy
– Wakelee et al, ASCO 2011.
E5508
• Phase III study to define the optimal
maintenance therapy strategy for non-
squamous NSCLC
• Primary endpoint: Overall survival
• Study chair: Suresh Ramalingam
ECOG 5508: Schema
IIIB/IV NSCLC PS0/1
No Prior Tx
N=1288
Carboplatin Paclitaxel
Bevacizumab X 4 cycles
CR PR SD
N=897
R A N D 0 M I Z A T I
O N
Bevacizumab
Pemetrexed
Bevacizumab Pemetrexed Stratification Factors:
Smoking status, Gender Histology, Best response, Stage
Primary endpoint Overall Survival
Study Status
• Activated in August 2010
• Current accrual = 350 patients
• Averaging approximately 25 patients/month
over the past 7 months
E3508
• To evaluate the therapeutic utility of
combining of an IGF-1R antibody to standard
chemotherapy for first-line therapy of
advanced NSCLC
• Primary endpoint: PFS
• Study chair: Ethan Argiris, MD
Rand Ph II Study Scheme
Non-squamous NSCLC
‘Bevacizumab eligible’
Stage IV
N=180 patients
Carboplatin
Paclitaxel
Bevacizumab
IMC-A12
Carboplatin
Paclitaxel
Bevacizumab
Current accrual: 120 patients
E4508
Hanna et al, ASCO 2012.
E4508: Results
-Excess number of on-study deaths in arms A and C -Prompted early closure of study
E6508
• Phase II study in stage III NSCLC
• Rationale: To evaluate BLP25 vaccine in
combination with bevacizumab following
chemoradiotherapy
• Sample size=55 pts
• PI: Jyoti Patel, MD & David Carbone, MD
Upcoming Studies
Optimal Follow-up for Resected NSCLC
• There are no standard guidelines for follow-up of
patients with resected early stage NSCLC
• In the era of CT screening, the number of early
stage NSCLC patients will increase
• Critical need to develop evidence-based
approach
STILL Study
• Randomized study for stage II and III NSCLC
• Two broad approaches to be evaluated
• Approach 1: Comparison of CT versus CXR
• Approach 2: Timing of CT scan
• Study chairs: Larry Kessler, PhD & Elizabeth
Loggers, MD
Approach 1
Stage II & III A
Chest X-Ray
Q 3 months X 2 years, then annual CXR
CT scan
Q6 months X 2 years, then annual CT
Approach 2
Stage II & III A
CT Chest
Q 3 months X 2 years, then annual CT
CT scan
Q6 months X 2 years, then annual CT
Study Endpoints
• Primary: To determine the impact of surveillance
modality and frequency in overall survival
• Secondary endpoints:
– To evaluate the effects of surveillance on
psychosocial function
– To study the impact on healthcare costs
– To collect bio-specimens
Natural History of ALK+ Early Stage NSCLC
• Mayo Clinic study
• Stage I-III NSCLC (Adeno)
• N= 225 pts
• ALK+ patients had a HR of 2.1 for DFS
compared to ALK- patients
DFS in Early Stage NSCLC
Yang et al, J Thorac Oncol, 2012.
E3511: Study Scheme
Stage I- IIIA
NSCLC
ALK +
Surgical Resection
Adjuvant Chemotherapy
(if indicated)
Crizotinib
X
2 years
Placebo
Registration
Primary endpoint: DFS Stratification: Chemotherapy(Yes or No) Stage (IA, IB<4 cm vs. IB>4 cm, II vs. IIIA) Prior radiotherapy (Yes or No) Sex
Registration: prior to randomization < 6 months from surgery Prior radiotherapy allowed
Statistical design
• T0 detect a 33% reduction in the hazard rate for DFs
• 6 patients/month
• Power 80%
• 1-sided type 1 error rate of 2.5%
• Estimated sample size is 336 patients
Translational Endpoints
• To compare outcomes based on ALK
positivity by FISH versus IHC/RT-PCR
• To study the prognosis for ALK positive
NSCLC patients based on the type of fusion
protein
FGFR1 amplification in squamous NSCLC
Weiss et al., Sci Transl Med 2010
Focal gene amplification of FGFR1 Amplification correlates with FGFR inhibitor sensitivity
ECOG 2512: AZD 4547 With docetaxel in FGFR amplified Squamous Cell Carcinoma
Recurrent NSCLC
FGFR Amplification
N=68 patients
Docetaxel AZD 4547
Docetaxel
AZD 4547
Includes a run-in phase I component; AZD 4547 will be given at 80 mg BID on days 1-14. Primary endpoint: PFS Study chair: Charles Rudin, MD
FGFR1 FISH considerations
• Centralized assay by Quintiles (Chicago)
– 1 week turnaround
• 2-stage consent
– Consent for FISH testing (before/during/after 1st line therapy)
– Consent for treatment
30
E1512: Cabozantinib + Erlotinib
Background
• XL184 (cabozantinib) inhibits MET, VEGFR2, and RET
• HGF/MET signaling important in primary and acquired resistance to
erlotinib
• XL184 + erlotinib is active in a preclinical NSCLC model w/ acquired
resistance to EGFR inhibitors due to amplified MET
• With erlotinib at 150 mg daily, MTD of XL184 was 50 mg daily
• DLT was diarrhea and mucositis in 3/17 patients
31
Best Time Point Response of Patients with at Least One Post-
Baseline Tumor Assessment Correlated with Genotyping (N = 44)
• 8 of 53 evaluable patients had a best time point response of > 30% tumor shrinkage
• 4 of 53 evaluable patients (8%) had a confirmed partial response (PR)
• Two patients had confirmed MET gene copy number gain – both experienced tumor shrinkage
• Of the 20 patients with an activating EGFR mutation, 9 also had a T790M mutation; 7 of these patients had SD as their best response
E1512: Study Scheme
Non-Squamous NSCLC
2nd or 3rd line of therapy
ECOG PS 0-2
No known EGFR mutation
No prior erlotinib
RANDOMIZE
N=35 per arm
- Stratify by PS and line of therapy
- Require tissue collection for MET
expression
Cabozantinib alone
60 mg PO QD
Erlotinib alone
150 mg PO QD
Cabozantinib
40 mg PO QD
Erlotinib
150 mg PO QD Primary endpoint: Target PFS 2.6 months to 4.6 months
N=105; enroll 2.5 q wk (1.5 yr accrual, 6 mo follow up)
Study chairs: Joel Neal, MD & Heather Wakelee, MD
Small Cell Lung Cancer
E1508: Comparing Hedgehog Inhibition and IGF-1R inhibition
Extensive Stage SCLC
No Prior Chemotherapy
N=180 patients
Cisplatin
Etoposide
GDC 0449
Cisplatin
Etoposide
IMC-A12
Cisplatin
Etoposide
Primary endpoint: PFS Study chairs: Charles Rudin & Chandra Belani Accrual completed
E2511: Background
• Combination of platinum and topoisomerase inhibitors
remains the standard frontline therapy for SCLC
• Cytotoxicity and clinical efficacy results primarily from
DNA damage
• Innate and acquired resistance to DNA damage limits
clinical efficacy of these well-established frontline agents
ABT-888 (Veliparib)
• Orally administered PARP inhibitor
• More than 90% inhibition of PARP enzyme activity at the 10mg bid
in a phase 0 study established this dose as biologically meaningful
• Well tolerated when combined with platinum doublets (carboplatin
AUC6; paclitaxel 200mg/m2) with MTD established at 120mg bid
Kumar et al. JCO, volume 27 (16): 2705 2009 Ramalingam et al. unpublished data
In vivo combination of veliparib and cisplatin in 2 independent SCLC xenografts experiments
Owonikoko et. al. Proc AACR Annual Meeting; Orlando 2011
E2511: Scheme
Extensive Stage SCLC 150 Patients
1:1 randomization
Stratification: Age
Gender LDH
67 patients Cisplatin 75mg/m2 day 1
Etoposide100mg/m2 Days 1-3 +
Veliparib 60mg BID Days 1-7 4 cycles
67 Patients Cisplatin 75mg/m2 day 1
Etoposide100mg/m2 Days 1-3 +
Placebo pills BID Days 1-7 4 cycles
Primary endpoint: PFS Study chair: Taofeek Owonikoko, MD, PhD
www.ecog-acrin.org