deputy chair of therapeutics programs, · 2016-08-09 · ecog-acrin 5152 thoracic concept by joel...

Suresh S. Ramalingam, MD

Chair of Thoracic Committee

Deputy Chair of Therapeutics Programs, ECOG-ACRIN

17th International Lung Cancer Congress

Objectives

1. Integration of targeted agents to the treatment of lung cancer with strong emphasis on biomarker discovery

2. Development of individualized treatment options for patients based on specific genotypic aberrations

3. Development of novel agents for SCLC

4. Incorporation of novel imaging biomarkers

3


Thoracic Committee Leadership

4

Chair: Suresh Ramalingam (Emory U)

Imaging Co-Chair: Caroline Chiles (Wake Forest U)

Therapeutic Co-Chair: Charles Rudin (MSKCC)

Pathology Co-Chair: Seena Aisner (Rutgers U)

Statistician: Suzanne Dahlberg (Dana Farber)

Thoracic Surgery: Steve Keller (Albert Einstein)

Lung Biology Co-Chairs: David Carbone (Ohio St) & Jill Kolesar (U Wisconsin)

17th International Lung Cancer Congress 5

Early Stage NSCLC: Strategies to Improve Cure Rate


E1505

6.

*Specified regimens

• Cisplatin and pemetrexed

• Cisplatin and docetaxel

• Cisplatin and vinorelbine

• Cisplatin and gemcitabine

Primary endpoint: overall survival

Secondary endpoints: disease-free survival,

safety [bleeding and arterial thromboembolic

events (ATEs)]

Eligibility

•Resected IB–IIIA

• ≥ lobectomy

•No prior chemotherapy

•No planned XRT

•No CVA/TIA

•No ATE in 12 months

N = 1500

RANDOMI

ZE

Chemotherapy* x 4 cycles

Chemotherapy* x 4 cycles +bevacizumab x 1 year

OS +/- Bevacizumab DFS+/- BevacizumabOS hazard ratio (ChB:Ch): 0.99

95% CI: (0.82-1.19) ; p=0.90

Med OS Ch NR

Med OS ChB 85.8 (74.9-NA) mo

DFS hazard ratio (ChB:Ch): 0.99

95% CI: (0.86-1.15) ; p=0.95

Med DFS Ch 42.9 (95% CI 36.7-57.0) mo

Med DFS ChB 40.6 (95% CI 35.5-49.5) mo

Abstr 8507: E1505 Chemotherapy subsets: Presented by: H. Wakelee

OS= overall survival, DFS = disease free survival: median f/up 50.3 months; 475 deaths

OS by chemo group; Non-squamous OS by chemo group; Squamous

Logrank p=0.19 Logrank p=0.96

Abstr 8507: E1505 Chemotherapy subsets: Presented by: H. Wakelee


ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker

Identification and Sequencing Trial)

Trial

Category

A151216

ALCHEMIST E4512 A081105

Target Registry/Interve

ntion with

biopsy at

recurrence

ALK+ EGFRmut

Prevalence all comers ~5% ~10%

Total Sample

Size

6000 – 8000 378 (5%

ineligible)

430 (5%

ineligible)

Primary

Endpoint

N/A Overall Survival Overall Survival

Power N/A 80% 85%

One-sided α N/A 0.025 0.05

Hazard Ratio N/A 0.67 0.67


EA4512: Schema

10

Stage I- IIIA

NSCLC

ALK + *

Surgical Resection

Adjuvant Chemotherapy

± Radiation Tx

(if indicated)

Crizotinib

X

2 years

Placebo

Registration

Primary endpoint: OS

Stratification: Chemotherapy (Yes or No)StagePrior radiotherapy (Yes or No)Sex

*by FISH

Chairs: David Gerber & Corey Langer


EA5142: Adjuvant Nivolumab in Resected Lung Cancers (ANVIL) – A randomized, double-blinded, placebo-controlled, Phase 3 study of nivolumab

after surgical resection and adjuvant chemotherapy in NSCLC

11


Treatment/Follow-up

•Randomized 1:1 to nivo vs placebo

•Stratified by stage, histology, chemo/no chemo,

PDL-1 expression

•Nivolumab 3 mg/kg q2 wks x 1 year

•Surveillance scans q3 months x 2 years then q6

months x 3 years then annually

Resected

IB(>4cm)-

IIIA

NSCLC

Nivolumab

q2 weeks x 1

year

Observation

1o co-endpoints of median

OS and DFS

EGFR, ALK

wt

Completed

adjuvant

therapy

EA5142: Schema

Study Chairs:

Jamie Chaft,

Martin Edelman & John Heymach


Stage III (N2) Disease

• Induction therapy is recommended before surgery

• Chemotherapy or Chemo-RT?

• Can we predict the mediastinal nodal clearance by imaging?

– Can early PET/CT predict mediastinal nodal clearance?

13


EA5123: Schema

14

Stage IIIA(N2)

PS 0/1

Resectable

N=90 pts

Confirmation of nodal involvement

PET/CT- baseline

Cisplatin-based induction therapy

X 3 cycles

PET/CT after

cycle 1

PET/CT scan

Surgical Resection

Pathological confirmation of

nodal status

Primary endpoint:Ability of cycle 1 PET to predict nodal clearance

Study chairs:Leora HornCaroline ChilesSteven Keller


Advanced Stage NSCLC

15


ECOG 5508: Schema

IIIB/IV NSCLCPS0/1

No Prior TxN=1515

CarboplatinPaclitaxel

BevacizumabX 4 cycles

CRPRSD

N=897

RANDOMIZE

Bevacizumab

Pemetrexed

BevacizumabPemetrexed

Stratification Factors:Smoking status, GenderHistology, Best response, Stage Primary endpoint

Overall Survival

http://clinicaltrials.gov/show/NCT01107626

EA5152: A Randomized Phase II Trial of Nivolumab versus

Cabozantinib plus Nivolumab in Patients with

Previously Treated Non-Squamous NSCLC

Joel Neal, Suzanne Dahlberg, Heather Wakelee, Suresh Ramalingam

E1512: Overall Survival

* 1-sided p values

** Follow up currently shorter on this arm c/w other arms

Median

(mo)

HR

(vs Erlotinib)

p*

(vs Erl)

Erlotinib (n=38) 5.1 - -

Cabozantinib n=39) 9.2 0.68 [0.49-0.95] 0.07

Erlotinib+Cabo (n=36) 13.3** 0.51 [0.35 - 0.74] 0.01

Rationale for Cabo+Nivo

• More than half of patients progress on nivolumab within the first 3 months of therapy (PFS 2.3m, compared with 4.2m on E1512 for cabo)

• Cabozantinib has immunostimulatory properties:

• In a colon cancer mouse model, cabozantinib causes IFN-g and TNF-a release, plus CD4 and CD8 T-cell tumor infiltration1, and

• Cabozantinib plus CEA vaccination cures 50% of these tumors2

• In prostate cancer, cabozantinib leads to tumor regression in a MET-independent, neutrophil-mediated manner3

1 Kwilas et al. J Transl Med 2014 2 Kwilas et al Cancer Cell Microenviron 2015 3 Patnaik AACR 2015 Ab 5497

EA5152 Phase 2 Study: Cabozantinib/Nivolumab vs Nivolumab

Key eligibility criteria

• Metastatic non-squamous

NSCLC

• Failed platinum therapy and

up to 2 other prior treatments

for metastatic disease (No

prior MET or PD-1/PD-L1

inhibitors)

• PS 0 - 2

• Treated brain mets OK

• Paraffin tissue available

• No known EGFR/ALK/

METe14/METamp/ROS1/RET

R

A

N

D

O

M

I

Z

E

Phase 2 PFS Endpoint

PFS HR target 0.56 (44% reduction in PFS HR)

• Nivo: expect 4 mo (PFS 2.3 but curve steep, 4 is conservative)

• Nivo + Cabo: goal 7.2 mo

• N=96 (target 43 evaluable per arm, 10 pts per month enrollment)

• 89% power, 44% reduction in PFS HR 0.173->0.096 (1-sided p=0.10)

• (Corresponds to median PFS 4 mo to 7.2 mo)

• PFS events = 74

Primary endpoint reporting in 18 months

Biomarkers

PD-L1 IHC 28-8 pharmDx test (requesting company support)

MET assessment, retrospective

Cabozantinib: 60 mg PO daily

Nivolumab: 3 mg/kg every 2 weeks

Arm A:

Nivolumab

Arm B:

Cabozantinib +

Nivolumab

Stratification

Performance Status

• 0 / 1 vs 2

Line of therapy

• 2 vs 3 / 4

ECOG-ACRIN 5152 Thoracic concept by Joel Neal, Suzanne Dahlberg, Heather Wakelee, Suresh Ramalingam

Best response to erlotinib or gefitinib

Yasuda, et al. Lancet Oncol, 2011.Yasuda, et al. Science Trans Med, 2014.

EGFR Exon 20 Insertions

• Exon 20 insertions make up ~4-10% of all EGFR mutations in NSCLC

• Exon 20 insertions are generally refractory to currently-available EGFR TKIs– mPFS on erlotinib and

gefitinib: 1.5-2 mos– mPFS on afatinib: 2.9 mos

• No effective targeted therapies exist for pts with EGFR ins20

EGFR Ins20 in vitro models: osimertinib is active with a favorable therapeutic window

Hirano, et al. Oncotarget 2015.

• Simon two-stage design

• Primary endpoint- response rate (RECIST 1.1)

• Planned sample size – 40 patients (we expect ~36/40 to be eligible and treated)

• This design assumes goal RR of 30% and null hypothesis 10% and will have 91% power with a one-sided significance of 0.0527

• Projected accrual 1-2 patients/month

• Study will be considered positive if 7/36 responses are seen.

• Following completion of accrual, the study could be amended to allow a 3rd stage if the two-stage tests rejects the null hypothesis

Statistical considerations

Stage I Stage II

20 pts(~18 eligible/

treated)> 3/18 responses

20 pts(~18 eligible/

treated)

Harnessing the Immune System

• Checkpoint inhibitors have demonstrated activity in advanced NSCLC

• Search for predictive biomarkers are ongoing

• This class of agents have potential to provide breakthrough in many settings in lung cancer

Harnessing the Immune System: Key Questions

• Can immunotherapy be used to greater success in patients with minimal disease burden?

• Is it better to give immunotherapy and chemotherapy in a sequential or concurrent manner?

• Can the abscopal effect be leveraged to improve disease control?

• Can immunotherapy improve the outcome of patients with driver mutations?


Small Cell Lung Cancer

26


Veliparib + Platinum

Cisplatin Carboplatin

Donawho et al, Clin Cancer Res, 2007


Phase 1 Results

• Unconfirmed best response in 7 evaluable patients as assessed by local investigators:– Progressive Disease (0)

– Stable Disease (2; 28.6%)

– Partial Response (4; 57.1%)

– Complete Response (1; 14.3%)

• Median follow up time: 6.0 months

28

Owonikoko et al, ASCO 2014

Cancer Imaging

1. Integrate quantitative imaging biomarkers into treatment trials– CT based: volumetrics, textural analysis

– PET-CT: SUV, metabolic tumor volume

– MRI: apparent diffusion coefficient (ADC)

2. Role of imaging biomarkers in trial design– Response assessment

– Adaptive trial design (modify treatment based on during-therapy imaging)

– Targeted treatment based on imaging biomarker

18

PrE0504A Phase I/II Study of Glembatumumab Vedotin in Patients

with gpNMB-Expressing, Advanced or MetastaticSquamous Cell Carcinoma of the Lung

Protocol Version 1.0:

23December2015

Background

• Glycoprotein NMB (gpNMB) is a type I transmembrane protein.

• Expressed on osteoclasts, osteoblasts, macrophages and dendritic cells

• Breast cancer, melanoma, SCC and glioblastoma overexpress gpNMB.

Phase II Study Schema

REGISTRATION

Treat until diseaseprogression or intolerance

33Confidential - PrE0504 Initiation Training 05Apr2016

1 MTD as determined during the dose-escalation phase.

Y Treatment should begin within 10 working days of study entry (registration).Y In Stage 1, approximately 20 eligible, treated patients will be enrolled. If ≥ 2

patients achieve a tumor response [Partial Response (PR) or Complete Response(CR)], an additional 15 eligible, treated patients will be enrolled in Stage 2, for amaximum total of 35 eligible, treated patients. To assure sufficient eligible, treatedpatients, up to 2 additional patients may be enrolled (total of 37 patients).

NOTE: Before proceeding to Phase II, the protocol will be amended to specify the finaldose and schedule selected from Phase I. Patients that participate in Phase I will not beeligible to participate in Phase II.

Phase II Stage

Dosing (IV q3 weeks over 90 minutes)

Patients (n)

1 MTD1 18

2 MTD1 19

PrE505Open Label, Phase II Study of Anti - Programmed

Death – Ligand 1 Antibody, Durvalumab(MEDI4736), in Combination with Chemotherapy

for the First-Line Treatment of UnresectableMesothelioma

Patrick Forde & Julie Brahmer

Rationale - PD-L1 & Mesothelioma

• 69.7% of samples were PD-L1 positive (≥5% expression) while 40.6% had ≥50% staining4

• Recent study of 224 mesotheliomas also confirms high expression levels – 40% PD-L1 positive5

• Pembrolizumab has activity in pretreated mesothelioma6

4. Cowen M, Forde PM, Brahmer JR, Illei PB. PD-L1 is highly expressed by immunohistochemistry in malignant pleural mesothelioma. Presented at: USCAP Annual Meeting, March 1-7, San Diego, Ca.

5. Mansfield A et al. PD-L1 expression and association with survival in mesothelioma. Presented at: European Lung Cancer Conference, March 26-29, Geneva, Switzerland.

Schema & Key Points

Consent &

Screening

≤14 days

PemCis q 3 weeks x 4-6

cycles

Concurrent durvalumab q

3 weeks x 4-6 cycles

Subjects

with

partial

response

or stable

disease

Durvalumab q 3

weeks until PD

(max 1 year

treatment)

• Primary endpoint – increase median OS from 12 to 19 months

• Secondary – Safety, BORR, irPFS, Correlates including WES/cfDNA,

Cytokines, PBMC analyses, IHC on baseline tumor sample

Summary

1. Harnessing the immune system

– Adjuvant therapy study of Nivolumab

– Pembrolizumab in 1st line setting

2. Development of novel agents

– Cabozantinib in salvage therapy of advanced NSCLC

3. Individualized treatment approaches for SCLC

– Biomarkers for PARP inhibition

4. Evaluation of imaging biomarkers

– Early PET for N2 disease

deputy chair of therapeutics programs, · 2016-08-09 · ecog-acrin 5152 thoracic concept by joel...

Documents