david r. gandara, md university of california davis ... · “evolution” of personalized therapy...

“Evolution” of Personalized Therapy for Advanced Non-Small Cell Lung Cancer (NSCLC):

Status in 2016

David R. Gandara, MDUniversity of California Davis

Comprehensive Cancer Center

Disclosures

• Research Grants: AstraZeneca, BMS, Clovis,

Genentech, JNJ, Lilly, Merck, Novartis

• Consultant: Ariad, AstraZeneca, Boehringer-

Ingelheim, Celgene, Clovis, Genentech, Guardant

Health, Lilly, Liquid Genomics, Merck, Mirati,

Novartis, Peregrine, Pfizer, Synta

Theme: “Evolution” in NSCLC for 2016

• Evolution in Advanced NSCLC Therapeutic Landscape

• Evolution in Biomarker Testing Guidelines

• Evolution in understanding Mechanisms of Resistance to Therapy

• Evolution in Assessing Changes in Tumor Biology: Biopsy-Rebiopsy Strategies & Role of Plasma cfDNA

Patients with Advanced Stage NSCLC (PS 0-1)

Non-squamous Squamous

Oncogene-Driven

Non-Oncogene-

DrivenAll

1st line

1st lineMaintenance

2nd line

3rd line

TKI (targeted therapy)

EGFR MTALK

2nd-gen TKI

Chemo+/- TKI

Chemo

Chemo doublet+/- Bev

Chemo

Chemo

ChemoDoublet

Chemo

Or Erlotinib

Chemo

Compartmental Treatment Paradigm for Advanced NSCLC: 2014

Or Erlotinib

or Erlotinib

Chemo

Chemo

Or Erlotinib

Or Erlotinib

Or Erlotinib

Gandara et al:Clin Lung Cancer

(adapted)

Patients with Advanced NSCLC (PS 0-1)

Non-squamous Squamous

Oncogene-Driven

PD-L1+ PD-L1− PD-L1+ PD-L1−

1st line

1st lineMaintenance

2nd line

3rd line

TKI (targeted therapy)

3rd-gen TKI

Checkpoint

Chemo

Chemo doublet

Checkpoint + chemo

Checkpoint

Chemo

Chemo

Chemo doublet

Checkpoint + chemo

Checkpoint

Pem/bev

Checkpoint

Chemo (± Ramu)

Checkpoint

Or Erlotinib

Chemo

Checkpoint

± nab-paclitaxel

Checkpoint

Chemo

Checkpoint

Chemo

Chemo doublet(± Neci )

Checkpoint + chemo

Checkpoint

± nab-paclitaxel

Checkpoint

Chemo

Checkpoint

Or Afatinib

Chemo

Checkpoint

Checkpoint + chemo

Checkpoint

Checkpoint

Checkpoint

Compartmental Treatment Paradigm: 2016?? If all of the major PD-L1/PD-1 studies were positive (+ Neci & Ramu)

*Checkpoint does not include ipilimumab

TKI-checkpoint

Chemo( ± Ramu)

Chemo

Chemo(+/- Ramu)

Chemo(+/- Ramu)

Gandara et al: Clin Lung Cancer (adapted)

TKI-checkpoint

SQUIRE: Chemotherapy ± Necitumumab in Advanced Squamous Lung Cancer

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

OS

(%

)

Time Since Randomization (Months)

G

GC + N GC

Stratified HR (95% CI) 0.84 (0.74, 0.96)

Stratified P value (log-rank) 0.01

Median OS, months (95% CI) 11.5 (10.4, 12.6) 9.9 (8.9, 11.1)

CR, complete response; GC, gemcitabine-cisplatin; N, necitumumab; OS, overall survival;

PD, progressive disease; PR, partial response; R, randomization; SD, stable disease

1. Thatcher N, et al. Lancet Oncol. 2015;16:763-774

Overall Survival in Patients With EGFR FISH

Positive Squamous Lung Cancers

treated with EGFR MoABs plus Chemotherapy

SQUIRE (EGFR FISH+)1 S0819 (SqCLC-EGFR FISH+)2

FISH, fluorescent in situ hybridization; GC, gemcitabine and cisplatin; N, necitumumab

1. Hirsch F, et al. WCLC 2015;abstr ORAL32.05; 2. Herbst R, et al. WCLC 2015;abstr PLEN04.01

These data suggest that a biomarker strategy can be developed for EGFR MoAB-

based therapies in Squamous Lung Cancer

Maintenance

PD-L1Single Agent

PD-L1

PD-L1

PlatinumChemo

Targeted Therapy(EGFR)

TargetedTherapy

or Chemo

TargetedTherapy

or ChemoPD-L1

Combo

Sequential

Sequential

Combo

PD-L1

Strategies for Optimizing Development of New Therapies:Single Agents vs Combinations vs Sequential (e.g. PD-1/PD-L1 agents)

adapted from Gandara et al: IASLC APLCC 2016

Maintenance

√(2nd line)

√(1st line)

Marker positive Strategy:

PD-L1+

Phase III Trials of PD-1 therapy compared to Docetaxel in

2nd/3rd-Line Advanced/Metastatic NSCLC

Nivolumab Phase III Trials

Stage IIIB/IV Squam (017) NSCLC

non-squamous(057) NSCLC

Docetaxel

75 mg/m2 IV

Q3W

Nivolumab

3 mg/kg IV

Q2W

Treat until progression or

unacceptable toxicity or

withdrawal of consent

Overall Survival (OS)

Pembrolizumab Phase III Trial

Stage IIIB/IV NSCLC

Docetaxel

75 mg/m2 IV

Q3W

Pembro

10 mg/kg IV

Q3W




Overall Survival (OS)

Pembro

2 mg/kg IV

Q3W

“All comers” Strategy:

(PD-L1+ & PD-L1-)

CheckMate 017: Squamous

CheckMate 057: Non-Squamous

POSITIVE POSITIVE

KEYNOTE 010:

Squamous + Non-Squamous

Perspective on CheckMate Phase III Trials

Trial 017: Squamous Cell

Carcinoma

Trial 057: Non-Squamous Cell

Carcinoma

Two positive randomized phase III trials of

nivolumab vs. docetaxel,

but very different “Kinetics of Survival Curves”

“Kinetics of Survival Curves (OS)”

Trial 017 SQ: Early & continuous separation

Trial 057 Non-SQ: Cross-over but subsequent separation

Borghaei et al: NEJM 2015Brahmer et al: NEJM 2015

CheckMate 017: Nivolumab vs Docetaxel in Advanced Squamous NSCLC

Survival benefit of nivolumab was independent of PDL1 expression levels

in Squamous lung cancer

CheckMate 057: Nivo vs. Doc in advanced Non-Squamous NSCLC

Paz-Ares et al. ASCO 2015, LBA109.OS benefit correlates with PD-L1 expression in this Non-SQ trial.Contrasts with trial 017 in SQ.

KEYNOTE 10: Pembro versus Docetaxelin Advanced NSCLC (≥ 50% PD-L1)

OS, PD-L1 TPS ≥50% Stratum

Analysis cut-off date: September 30, 2015.

Treatment ArmMedian

(95% CI), moRate at

1 yHRa

(95% CI) P

Pembro 2 mg/kg 14.9 (10.4-NR) 53.4% 0.54 (0.38-0.77) 0.00024

Pembro 10 mg/kg 17.3 (11.8-NR) 58.1% 0.50 (0.36-0.70) 0.00002

Docetaxel 8.2 (6.4-10.7) 38.0% — —

aComparison of pembrolizumab vs docetaxel.

Herbst et al: Lancet 2015

CheckMate 026 -Phase III Trial

Stage IIIB/IV NSCLC

N=495

Platinum

Doublet

Q3W

Nivolumab

3 mg/kg IV

Q2W




Progression Free Survival (PFS)

Phase III Study of Anti-PD-L1 agents compared to Platinum

Chemotherapy in 1st-Line Advanced NSCLC (PD-L1+)

BMS-558 (Nivolumab)

Keynote 024 -Phase III Trial

Stage IIIB/IV NSCLC

N=300

Platinum

Doublet

Q3W

MK-3475

200 mg IV

Q3W




Progression Free Survival (PFS)

MK-3475 (Pembrolizumab)

Only PD-L1+ are eligible

(Marker+ strategy in both trials)

KEYNOTE-024: Pembro vs Chemotherapy in 1st-line therapy of Advanced NSCLC

• This trial will alter the SOC in 1st-line therapy of the great majority of patients with advanced NSCLC

• It confirms that this IO approach qualifies as “targeted therapy” using the PD-L1 biomarker

Maintenance

PD-L1Single Agent

PD-L1

PD-L1

PlatinumChemo

Targeted Therapy(EGFR)

TargetedTherapy

or Chemo

TargetedTherapy

or ChemoPD-L1

Combo

Sequential

Sequential

Combo

PD-L1

Strategies for Optimizing Development of New Therapies:Single Agents vs Combinations vs Sequential (e.g. PD-1/PD-L1 agents)

adapted from Gandara et al: IASLC APLCC 2016

Maintenance

?PD-1 agent

Post-PD

?With Chemo

?Chemo after

?Maintenance

Pembrolizumab

Induction Maintenance

2nd Line Treatment

Joint ECOG-SWOG Phase III proposal: Advanced Non-squamous Trial with Pembrolizumab

Carbo-Pemetrexed-

Pembro

Pembrolizumab

Pembro-Pemetrexed

Carbo-Pemetrexed-Pembrolizumab

Investigator Choice

Carbo-Pemetrexed>1

% T

PS

po

siti

ve

Ran

do

miz

atio

nArm 2

Co-Primary Objectives: OS in TPS >= 1% and >=50% TPS• Arm 3 versus Arm 1 (control)• Arm 2 versus Arm 1 (control)

Secondary Objectives: • PFS (Arm 3 versus Arms 2 and 3), • RR (Arm 3 versus Arms 2 and 3),• Immunosignature for Pembrolizumab:

o Primary PFS: Arms 1 and Arm 2• Immunosignature for Pembrolizumab versus carbo/Pemetrexed/Pembro

o Primary PFS: Arm 3 versus (Arms 1 and 2)

Stratify: PD-L1 >=50% versus < 50%

1st Line Treatment

Non-squamous NSCLC

Adv StageUntreated

PS 0-1

PD-L1 ≥ 1%

Pro

gre

ssiv

e D

ise

ase

Theme: “Evolutions” in NSCLC for 2016



• Evolution in understanding of Mechanisms of Resistance to Therapy


Evolution of NSCLC Subtyping from Histologic to Molecular-Based

NSCLC

as one

disease

Li, Mack, Gandara et al: JCO 2013 (adapted from Pao et al)

ALK

EGFR

Incorporation of Molecular Profiling into Therapeutic

Decision-Making Process for Advanced NSCLC

• Who to test?: Patients with NSCLC and adenocarcinoma (component)

• What to test for?: EGFR mutation and ALK fusion

• What specimen?: core needle biopsy (or multi-pass FNA), cytology cell block, surgical biopsy (bone biopsy problematic)

• How to test?: concurrently (not sequentially test-by-test)

• How long a turn-around time is acceptable?: <2 weeks

• When to test?: at the time of diagnosis (not just when treatment decision needed)

• When to re-test?: after PD from a targeted therapy intervention (to assess for clonal evolution in the molecular profile)

Summary Guidelines for 2013

Gandara Adaptation from: CAP/IASLC/AMP expert panel. Lindeman et al. JTO, 2013.

From Li, Gandara et al. JCO. 2013.

Evolution of Biomarker Testing in Clinical Practice: Past, Current & Future

Near-Future Approach (Patient-Based Therapy):Genomic profiling by high throughput next generation sequencing

for decision-making in individual patients

1. HistomorphologicalDiagnosis: Cancer

Evolving Approach (Target-Based Therapy V2.0):Multiplexed molecular tests with increased sensitivity & output

for decision-making in individual patients

Current Approach (Target-Based Therapy V1.0):Single gene molecular testing for decision-making in individual

patients

2. Molecular Diagnosis:Extract tumournucleic acids:

Archival cancer specimens

Archival FFPE tumourspecimens

Macro- or Micro-dissection of

Tumours

DNA and RNA

Empiric Approach (Past)(Compound-Based Therapy):

Clinical-histologic factors to select drugs for individual patients

Representative technologies:

Single Biomarker Tests:

• Sanger DNA Sequencing

• RT-PCR

• FISH

• IHC

Multiplex, Hot Spot Mutation Tests:

• PCR-based SNaPshot

• PCR-based Mass Array SNP

• Sequenom

Initial High-Throughput Technologies:

• SNP/CNV DNA microarray

• RNA microarray

Next-Generation Sequencing (NGS):

• Whole Genome or Exome Capture Sequencing (DNA)

• Whole or Targeted Transcriptome Sequencing (RNA)

• Epigenetic profilingPlasma cf DNA by NGS

The Growing List of Guideline Recommendationsfor Molecular Testing

http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdfNote: EGFR mutations too rare (<3.6%) to be routinely tested in squamous cell carcinoma 22

http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

RET: Cabozantinib : RR=40%

ALK: 65%RR to Crizotinib:~70% RR to 2° Gen TKI

Ceritinib in resistant cancers

METex14: RR >50% to Crizotinib

HER2 mutation:>50% RR to Afatinib;~20% to Dacomitinib

BRAF (V600E): >60% RR to BRAF + MEK

inhibitor combo

Translating Genomic Profiling Data into Therapeutic Strategies(Lung Adenocarcinoma)

KRAS:35% RR to MEK

inhibitors +Chemotherapy

ROS1: 70% RR toCrizotinib

HER2 mutation

EGFR: RR>70%to 1°-2° Gen TKIs;

~60% RR to 3° Gen TKIsin resistant cancers

ORAL06.07 - A. Kostenko

Single genes sequentially versus Multiplexed vs Next Gen Sequencing (NGS):

Cost Analysis

• Tissue requirement (10 ng per gene vs 50 ng for NGS panel)

• Sensitivity & Specificigy: NGS platforms now highly competitive

• Cost (multiplication of single test costs)

• NGS more cost effective if testing for 6 or more genes

EGFR E19del mutations detected by NGS in cases previously negative by other molecular testing techniques

Sherock, Peled et al.Clin Cancer Res. 2016

Targeted Therapies in Oncogene-Driven NSCLC:De Novo & Acquired Resistance

Oncogene-drivenNSCLC

Gandara et al: Clin Lung Cancer 2014

Best Response to Osimertinib in EGFR-Mutated T790M+Cancers

AZD9291(Osimertinib)

• Even in the subset of EGFR-mutated cancers with T790M+ acquired resistance, approximately 30% do not achieve RECIST response

• In about 5-10%, the best response is Progressive Disease (PD)• Combination trials of Osimertinib + modulating agents are ongoing

ETCTN Project Team Proposals: AZD9291 in EGFR-mutated NSCLC post-progression after Erlotinib

Schema for Multidisciplinary Integration of Biomarker Testing in Advanced Stage NSCLC: Looking for

“Actionable” Oncogenes

PulmonologistInterventional Radiologist

Surgeon

Identify Target Lesion

Biopsy

Histology Evaluation

Determine Therapy

Pathologist

Oncologist

MultidisciplinaryTeam

(Tumor Board)

Molecular Biomarker Testing

Identify Patient

Referring Physician

Med OncologistThoracic Surgeon

Radiation Oncologist Pulmonologist

RadiologistPathologist

When Progression Re-Biopsy

Treat

Determine New Therapy

Adapted from: Gandara: ASTRO/ASCO/IASLC Symposium on Molecular Testing, 2012

Treat


Emergence of ALK Resistance Mechanisms after Crizotinib

Doebele, Camidge et al: CCR 2012

• Secondary resistance ALK mutations• ALK Gene copy number increase• Transition to EGFR mutation• Transition to KRAS mutation

Consistent with mathematical models of Evolutionary Biology

Schema for Multidisciplinary Integration of Biomarker Testing in Advanced Stage NSCLC: Looking for

“Actionable” Oncogenes

PulmonologistInterventional Radiologist

Surgeon

Identify Target Lesion

Biopsy

Histology Evaluation

Determine Therapy

Pathologist

Oncologist

MultidisciplinaryTeam

(Tumor Board)

Molecular Biomarker Testing

Identify Patient

Referring Physician

Med OncologistThoracic Surgeon

Radiation Oncologist Pulmonologist

RadiologistPathologist


Treat

Determine New Therapy

Adapted from: Gandara: ASTRO/ASCO/IASLC Symposium on Molecular Testing, 2012

Treat


Plasma cfDNA Plasma cfDNA

Role of “Liquid Biopsy” (Plasma cf DNA) in determining mechanisms of Acquired Resistance

from Burrell and Swanton, Mol Oncol 2014

Advantages of plasma cf DNA over Tumor re-biopsy• Relatively non-invasive• Provides “global” perspective, abrogating issue of tumor heterogeneity• Can be repeated serially over time to monitor tumor response• Can detect resistance mutations in plasma prior to radiographic detection

Association between plasma EGFR mut+ at Cycle 3

and PFS/OS (from FASTACT Trial)

OSPFS

18.2 31.9

C3 mut+

C3 mut–

Median = 18.2 months

(95% CI: 14.2–27.4)

Median= 31.9 months

(95% CI: 23.5–undefined)

HR = 0.51

(95% CI: 0.31–0.84);

P=0.0066

7.2 12.0

C3 mut+

C3 mut–

Median = 7.2 months

(95% CI: 6.0–7.8)

Median =1 2.0 months

(95% CI: 9.6–16.5)

HR = 0.32

(95% CI: 0.21–0.48);

P<0.0001

Time (months)

OS

pro

bab

ilit

y

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Time (months)

PF

S p

rob

ab

ilit

y

C3 mut+ 42 42 35 28 14 7 6 4 1 1 1 1 0 0 0 0 0

C3 mut– 80 80 77 65 59 47 40 34 32 28 23 19 13 10 7 3 0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

C3 mut+ 42 42 42 41 37 32 30 28 23 21 18 14 14 12 9 4 3 2

C3 mut– 80 80 80 77 77 77 76 71 68 64 59 52 38 29 22 12 3 1

0

0

Patients, n Patients, n

Mok et al. WCLC 2013.

Phase II/III Trial of Afatinib With or Without Cetuximab in

1st-Line Therapy of EGFR-mutated NSCLC (S1403)

PIs: Goldberg, Lilenbaum, Politi.

Afatinib + Cetuximab*

Afatinib*

R

A

N

D

O

M

I

S

A

T

I

ON

Stage IIIB-IV NSCLC with EGFR mutation

(E19del, L858R)

1st Line

EGFR TKI naive

*at PD: Biopsy for tumor & cfDNA genomics & PDX development (selected patients)

PD: progressive diseasePDX: patient-derived xenograft

Genomics analysis (NGS)+ cfDNA analysis

Summary: “Evolution” in NSCLC for 2016





david r. gandara, md university of california davis ... · “evolution” of personalized therapy...

Documents