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