PAVING THE ATH TO PRECISION EDICINE IN NSCLCd2qrtshcpf0x30.cloudfront.net/nodes/285/Precision Medicine in NSCLC Grand Rounds... · • Biopsy/FNA specimen with a diagnosis of squamous

PAVING THE PATHTO PRECISION MEDICINE INNSCLCUsing Biomarkers to Determine Treatment Course

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Learning Objectives1) Review the molecular pathology of advanced non–small‐cell lung

cancer (NSCLC) and identify clinically relevant molecular mutationsthat impact treatment selection.

2) Examine strategies to coordinate care in the community setting toimprove adherence to guideline‐recommended molecular testingin NSCLC and discuss the utility of newer technologies, such asctDNA liquid biopsy, in clinical practice.

3) Evaluate targeted treatment options for actionable and acquiredmutations in NSCLC, such as EGFR/T790M, and assess the safetyand efficacy of these targeted therapies.

4) Using a case‐based approach, examine how to best incorporatemolecular testing to optimize targeted therapy selection in EGFR‐mutated NSCLC at initiation of therapy and upon diseaseprogression.

55.2%

28.0%

4.3% 7.4%

0%

20%

40%

60%

80%

100%

Percen

t

Stage

5‐Year Relative Survival

Lung Cancer

www.seer.cancer.gov/statfacts/html/lungb.html.

16%

22%

57%

5%

Percent of Cases by Stage

Localized (16%) Confined to Primary SiteRegional (22%) Spread to Regional Lymph NodesDistant (57%) Cancer Has MetastasizedUnknown (5%) Unstaged

Lung CancerClassification

Lung Cancer

Small‐Cell Lung Cancer 15%

Non‐Small Cell Lung Cancer85%

Squamous 30%

Non‐squamous70%

Large‐Cell Carcinoma (10%)• Large‐cell Neuroendocrine

Carcinoma

Adenocarcinoma (90%)• Mixed subtypes• Lepidic (non‐mucinous or

mucinous)• Acinar• Papillary• Micropapillary• Solid

Gridelli C, et al. Nat Rev Dis Primers. 2015.

Kenfield SA, et al. Tob Control. 2008.

SMALL‐CELL CARCINOMA

SQUAMOUS CELLCARCINOMA

Evolution of Genomic Alterations in Lung Adenocarcinoma

2009

2004

2018

1984–2003No known genotype

No known genotype

www.mycancergenome.org; Lindeman NI, et al. Arch Path Lab Med. 2018.

Why Genotype at the Time of Diagnosis?

• Helpful to confirm the diagnosis/provide the full diagnosis

• Helpful for prognostication

• Most important: can determine first‐line therapy in some cases (especially EGFR, ALK, ROS1, BRAFV600E); can provide additional options for salvage therapies in other cases

NCCN Guidelines Non–Small‐Cell Lung Cancer. Version 5.2018.

2018 Targeted Therapies in the United States

• EGFRmutation• Erlotinib*• Gefitinib*• Afatinib*• Osimertinib*

• ALK rearrangement• Crizotinib*• Ceritinib• Alectinib*• Brigatinib (second‐line)

• ROS1rearrangement

• Crizotinib• Ceritinib

• BRAFmutation• Dabrafanib + trametinib*

• MET amplification or MET exon 14 mutation• Crizotinib

• HER2 (ERBB2) mutations• Ado‐trastuzumab emtansine

• RET rearrangement• Cabozantinib• Vandetinib


*FDA approved in the first‐line setting.

Testing Methodologies• No such thing as a perfect test• Many different testing approaches

• Targeted mutation testing• Fluorescence in situ hybridization (FISH)• Next generation sequencing (NGS)• Others

• Every testing methodology has advantages and limitations

• The two major test features that describe these advantages and limitations are

• Clinical sensitivity• Analytical sensitivity

www.mycancergenome.org.

Think of Needles and Haystacks

Analytic SensitivityHow sensitively can the test detect a rare

change in a background of normal?

Clinical SensitivityHow many of the possible changes

does the test detect?

Looking for a needle in a haystack- The test can identify only a couple of

colors of needles, but can pick them out even when they are very rare

These two features are nearly always inversely related.

Advantage: A test with excellent clinical sensitivity can detect a wide range of alterations.Limitation: False negatives are mostly attributable to requiring a high level of any given mutation (requires a high proportion of tumor cells in the sample).

Advantage: A test with excellent analytic sensitivity can detect an alteration even when present at very low level.Limitation: False negatives are mostly attributable to an alteration not being part of test design (you can’t get an answer to something you don’t test).

Slide courtesy of Dara L. Aisner, MD, PhD.

Why Is This Important?

• Tumor samples consist of a mixture of tumor and non‐tumor

• If the sample has a high proportion of non‐tumor AND a testing method with poor analytic sensitivity is used, there is increased risk for false negatives

• Conversely, if a highly targeted test is used and a patient has a rare alteration, it may not be detected

Tumor Enrichment

• Tumor enrichment can overcome assay analytic sensitivity limitations

• No enrichment—all material in the specimen is included for testing

• Macrodissection—a broad area is isolated

• Microdissection—tumor cells are selectively isolated under a microscope

Lung adenocarcinomabefore and after manual microdissection

Many laboratories performing molecular testing utilize macrodissection...

…far fewer use microdissection


Examples of Methods & Analytic SensitivityMethod Analytic Sensitivity Can be used for Clinical Sensitivity

Sanger Sequencing Lowest (~15%) Highly enriched

tumor samplesUsually entire exons or regions of exons queried

Single Base Extension (SNaPshot, MassArray)

Moderate (~5%) Moderatelyenriched samples

Usually highly targeted to individual alterations

Real‐Time PCR Highest (1%–2%)

Samples in which enrichment is not feasible

Highly targeted to individual alterations

NextGeneration Sequencing

Moderate (5%–10%) Moderatelyenriched samples

Usually entire exons or regions of exons

Bottom line: Be familiar with the methodology employed by a laboratory, and whether it is paired with tumor enrichment.

What is Next Generation Sequencing?

• NGS is NOT a test—it is a platform

• Allows the evaluation of multiple regions simultaneously

• How in the world does this work?

How Does NGS Work?

• Each one of these blocks represents an unique stretch of a patient’s DNA

• Called a cluster

• DNA is freed from the tumor sample and selectively amplified

• Then, the clusters are spread across a flow cell to make each occupy a unique 2‐dimensional coordinate

Flow Cell


• Each flow cell is visualized by optical equipment to detect events at each cluster

• Nucleotide bases (A, T, G, C) are added—the optics determine which base is added at each cluster

• Typically, there are millions (10M–30M) of base reads on a single flow cell

• The view of the flow cell from above

• Each dot represents one cluster • Different colors represent different nucleotide bases (A, T, G, C)

How Does NGS Work?


Lots of Data

• Data comes out looking like this…

• This portion is the actual sequence data

• Next steps are bioinformatics, which is part of the reason NGS is more expensive than older tools


Bioinformatics of NGS DataMajor Steps

1) Assess the quality of the data• Poor quality NGS data is less reliable

2) Align the sequence with the reference• Human genome is reference for tumor NGS

3) Map the aligned sequence• What gene or where in the chromosomes?

4) Variant call• What is different between the reference sequence and the patient sequence?

5) Variant annotation• What is known about this specific alteration?

NGS is a Platform

• Each cluster is a unique stretch of a patient’s DNA

• Exactly which pieces of DNA are evaluated in the test is dependent on the NGS assay design


Targeted NGS Panels

Whole Exome Sequencing

Whole Genome

SequencingRNASeq

What is beingsequenced/ genotyped?

User defined,but typically 20–400

specific genes

All exons in all genes

~20,000 genes~350K exons

All exons and introns (non‐

coding regions) in all

genes

Messenger RNAs (gives data about

gene expression)

Size of read(how much data is generated)

Ranges0.1Mb–3Mb 60Mb 3.2Gb Ranges

20Mb–60Mb

Cost $ $$ $$$$$ $$

Some Examples of NGS

Clinical Considerations for Ordering Genotyping

Care CoordinationMaking Biomarker Testing Happen• Multi‐disciplinary conversations help to streamline processes

• Interventional radiology, pulmonology—acquiring enough tissue for all, not stopping when just one need is met

• Cytopathology—if called for rapid on‐site evaluation, request more tissue to ensure sufficient quantity for testing

• Pathology—establish tissue preservation mechanism

• If sending a patient for biopsy specifically for molecular testing, upfront discussion with pathology to request no IHC and tissue preservation

• Semi‐automated processes for all of the above can be established

Aisner DL, et al. Arch Path Lab Med. 2016.IHC, immunohistochemistry

Considerations for Testing in Early Stage NSCLC

Pro Con

• Test results are available immediately if the patient recurs

• Unnecessary if no recurrence

• Presence of a targetable alteration may signal suitability for an interventional trial• Example: ALCHEMIST

• Testing may evolve between diagnosis and recurrence

• Patient knowledge • Insurance may not cover testing

• Patient anxiety

Multifocal Disease

• Molecular testing can assist in resolving the relatedness of synchronous tumors

• Can alter staging considerations

• Panel‐based testing best for this purpose• Example: Same KRASmutation in two tumors is NOT proof that they are related (because KRASmutations are so common)

• Example: A complex mutation pattern with identical KRASand TP53mutations is much more convincing

Squamous—To Test or Not to Test?

• Low but appreciable incidence of targetable alterations in squamous cell carcinoma

• EGFR: 1%–4%• ALK: 0.5%–1%• Other abnormalities in chart are of unknown

significance for treatment

• Response to TKIs in squamous cell with EGFR or ALK alterations not as well defined

• However, sometimes squamous vs adeno distinction is hard to make and/or erroneous from a biopsy, especially if it is small

Drilon A, et al. Lancet Oncol. 2012.

These may represent misclassified squamous or adenosquamous

PIK3CA mutation,

4%

DDR2 mutation,

4%AKT1

mutation, 6%

PTEN mutation,

10%

FGFR1 amplification,

20%

Unknown, 56%

Squamous—To Test or Not to Test?

• Biopsy/FNA specimen with a diagnosis of squamous cell carcinoma

• Test in all never/light smokers

• Consider testing even if there is concern for an adenocarcinoma component

• Resected squamous cell carcinoma• Test in all never/light smokers

• Test even if any adenocarcinoma component is present• Dilemma: The presence/absence of adenocarcinoma component may not always be comprehensively evaluated

Recommendations for Testing Advanced‐Stage NSCLC

• At minimum, pursue testing for• EGFRmutations• ALK rearrangements• ROS1 rearrangements• BRAF p.V600E mutations

• NGS‐based testing can evaluate all of those while simultaneously evaluating for in‐development markers

• Can indicate clinical trial eligibility

• PD‐L1 IHC

Lindeman NI, et al. J Thorac Oncol. 2018; NCCN Guidelines Non–Small‐Cell Lung Cancer. Version 5.2018.

What about KRAS?

• There currently is no therapy specifically associated with improved outcomes in KRAS mutation positive tumors

• KRASmutation testing—should it happen?• Identification of a KRASmutation is very strong indicator that a targetable alteration (such as EGFRmutation or ALKrearrangement) is not present

• EGFR TKI should not be used in the setting of KRASmutation positive tumor

Lindeman NI, et al. J Thorac Oncol. 2018.

Guidelines for Testing• NCCN: 5.2018 (June, 2018)• CAP/IASLC/AMP joint guidelines (released January, 2018)• Major difference: NCCN endorses BRAF stand‐alone testing

• Common themes:• Do not use clinical features for selecting patients for biomarker testing

• EGFR, ALK, ROS1 should be considered standard of care for all advanced NSCLC patients

• Panel based testing which includes exploratory markers improves the chances for matching to a clinical trial

Lindeman NI, et al. J Thorac Oncol. 2018; NCCN Guidelines Non–Small‐Cell Lung Cancer. Version 5.2018.

USING BIOMARKERS TODETERMINE TREATMENTCOURSEFocus on EGFR Mutation Positive NSCLC

Case 1Newly diagnosed EGFR patient

• 62‐year‐old female with a 15 pack/year smoking history, who quit 25 years ago, presents with visual complaints

• Ophthalmologist found her to have choroidal metastasis

• Chest CT shows large left lung mass, as well as smaller bilateral nodules

• Lung CT‐guided biopsy = adenocarcinoma

• IHC shows PD‐L1 = 60%

• Genotyping shows EGFR exon 19 deletion

EGFR TKIs With FDA Approved First‐Line Indication

Study Agents N Median PFS Median OS

IPASS trial1,2 Gefitinib vs carbo‐paclitaxel 261 9.5 mo vs 6.3 mo 21.6 mo vs 21.9 mo

EURTAC3 Erlotinib vs platinum doublet 173 9.7 mo vs 5.2 mo 19.3 mo vs 19.5 mo

LUX‐Lung 34,5 Afatinib vs cisplatin‐pem 345 11.1 mo vs 6.9 mo 28.2 mo vs 28.2 mo

FLAURA6 Osimertinib vs erlotinib or gefitinib 556 19.0 mo vs 10.2 mo Not yet reported

1Fukuorka M, et al. J Clin Oncol. 2011; 2Wu YL, et al. Lung Cancer. 2017;3Rosell R, et al. Lancet Oncol. 2012; 4Sequist LV, et al. J Clin Oncol. 2013;

5Yang JC, et al. Lancet Oncol. 2015, 6Soria JC, et al. N Engl J Med 2018.

NCCN Guidelines Version 5.2018

EGFR mutation discovered during first‐line chemotherapy

Complete planned chemotherapy, including maintenance therapy, or interrupt, followed by erlotinib or afatinib or gefitinib or osimertinib

Erlotinib (category 1)or

Afatinib (category 1)or

Gefitinib (category 1)or

Osimertinib (category 1)

EGFR mutation discovered prior to first‐line chemotherapy

Sensitizing EGFR mutation

positive

FIRST‐LINE THERAPY


Ramalingam SS, et al. ESMO. 2017. Abstract LBA2_PR; Soria JC, et al. N Engl J Med. 2018.

FLAURA Double‐Blind Study Design

*≥20 years in Japan; #With central laboratory assessment performed for sensitivity; ‡Cobas EGFR Mutation Test (Roche Molecular Systems); §Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation; ¶Every 12 weeks after 18 months.

Stratification by mutation

status (Exon 19

deletion/L858R) and race(Asian/

non‐Asian)

Crossover was allowed for patients in the SoC arm, who could receive open‐label osimertinib upon central

confirmation of progression and T790M positivity

Patients with locally advanced or metastatic

NSCLCKey inclusion criteria • ≥18 years* •WHO performance status 0/1• Exon 19 deletion/L858R (enrolment by local# or central‡EGFR testing)

•No prior systemic anti‐cancer/EGFR‐TKI therapy

• Stable CNS metastases allowed

Endpoints• Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1)

• The study had a 90% power to detect a hazard ratio of 0.71 (representing a 29% improvement in median PFS from 10 months to 14.1 months) at a two‐sided alpha‐level of 5%

• Secondary endpoints: Objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported outcomes, safety

Randomised 1:1

RECIST 1.1 assessment every 6 weeks¶ until objective progressive

disease

EGFR‐TKI SoC§;

Gefitinib (250 mg po daily) or

Erlotinib (150 mg po daily)

(n=277)

Osimertinib(80 mg po daily)

(n=279)

Ramalingam SS, et al. ESMO. 2017. Abstract LBA2_PR; Soria JC, et al. N Engl J Med. 2018.

Median PFS, months (95% CI)18.9 (15.2, 21.4)10.2 (9.6, 11.1)

1.0

Prob

ability of p

rogression

‐free

survival

0.2

0.4

0.6

0.8

0.0

0 3 6 9 12 15 18 21 24 27Time from randomisation (months)

279277

262239

233197

210152

178107

13978

7137

2610

42

00

No. at riskOsimertinib

SoC

OsimertinibSoC

Primary EndpointPFS by Investigator Assessment

342 events in 556 patients at DCO: 62% maturity Osimertinib: 136 events (49%)SoC: 206 events (74%)

HR 0.46(95% CI 0.37, 0.57)

P<.0001

Soria JC, et al. N Engl J Med. 2018;Ramalingam SS, et al. ESMO. 2017. Abstract LBA2_PR.

FLAURA data cut‐off: June 12, 2017; Hazard ratio <1 implies a lower risk of progression on osimertinib 80 mg. Size of circle is proportional to the number of events.*By Investigator assessment; #Local or central test; ǂResult missing for 36 patients in the osimertinib arm and 37 patients in the SoC arm; §Result missing for 21 patients in the osimertinib arm and 29 patients in the SoC arm; ¶Subgroup categories with less than 20 events were excluded from the analysis.

PFS* Across SubgroupsFavours SoCSubgroup

Overall (n=556)Log Rank (primary)Cox PH

SexMale (n=206)Female (n=350)

Age at screening<65 (n=298)≥65 (n=258)

RaceAsian (n=347)Non‐Asian (n=209)

Smoking history Yes (n=199)No (n=357)

CNS metastasesYes (n=116)No (n=440)

WHO performance status0 (n=228)1 (n=327)

EGFR mutation at randomisation#Exon 19 deletion (n=349) L858R (n=207)

EGFR mutation by ctDNAǂ

Positive (n=359)Negative (n=124)

Centrally confirmed EGFR mutation§

Positive (n=500)Negative (n=6)¶

0.1 0.2 0.3 0.4 0.6 0.8

Hazard ratio (95% confidence interval)

0.46 (0.37, 0.57)0.46 (0.37, 0.57)

0.58 (0.41, 0.82)0.40 (0.30, 0.52)

0.44 (0.33, 0.58)0.49 (0.35, 0.67)

0.55 (0.42, 0.72)0.34 (0.23, 0.48)

0.48 (0.34, 0.68)0.45 (0.34, 0.59)

0.47 (0.30, 0.74)0.46 (0.36, 0.59)

0.39 (0.27, 0.56)0.50 (0.38, 0.66)

0.43 (0.32, 0.56)0.51 (0.36, 0.71)

0.44 (0.34, 0.57)0.48 (0.28, 0.80)0.43 (0.34, 0.54)NC (NC, NC)

2.0

PFS hazard ratio and 95% confidence interval

1.0

Favours Osimertinib

10.0

Ramalingam SS, et al. ESMO. 2017. Abstract LBA2_PR.

All Causality Adverse Events* (≥15% of patients)

AEs by preferred term, n (%)

Osimertinib (n=279) SoC (n=277)Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Any

Grade Grade 1 Grade 2 Grade 3 Grade 4

Diarrhoea 161 (58) 120 (43) 35 (13) 6 (2) 0 159 (57)* 116 (42) 35 (13) 6 (2) 0

Dry skin 88 (32) 76 (27) 11 (4) 1 (<1) 0 90 (32) 70 (25) 17 (6) 3 (1) 0Paronychia 81 (29) 37 (13) 43 (15) 1 (<1) 0 80 (29) 46 (17) 32 (12) 2 (1) 0Stomatitis 80 (29) 65 (23) 13 (5) 1 (<1) 1 (<1) 56 (20) 47 (17) 8 (3) 1 (<1) 0Dermatitis acneiform 71 (25) 61 (22) 10 (4) 0 0 134 (48) 71 (26) 50 (18) 13 (5) 0

Decreased appetite 56 (20) 27 (10) 22 (8) 7 (3) 0 51 (18) 24 (9) 22 (8) 5 (2) 0

Pruritis 48 (17) 40 (14) 7 (3) 1 (<1) 0 43 (16) 30 (11) 13 (5) 0 0Cough 46 (16) 34 (12) 12 (4) 0 0 42 (15) 25 (9) 16 (6) 1 (<1) 0Constipation 42 (15) 33 (12) 9 (3) 0 0 35 (13) 28 (10) 7 (3) 0 0AST increased 26 (9) 18 (6) 6 (2) 2 (1) 0 68 (25) 38 (14) 18 (6) 12 (4) 0ALT increased 18 (6) 11 (4) 6 (2) 1 (<1) 0 75 (27) 31 (11) 19 (7) 21 (8) 4 (1)

Median Duration of Exposure Osimertinib:16.2 months (range 0.1 to 27.4) SoC: 11.5 months (range 0‐26.2)

FLAURA data cut‐off: June 12, 2017. Grade 3 QTc prolongation based on collected digital ECGs values were recorded for 3 patients in the osimertinib arm and 2 patients in the SoC arm.*In the SoC arm there was one patient with Grade missing and one patient with Grade 5 diarrhoea

Ramalingam SS, et al. ESMO. 2017. Abstract LBA2_PR.

FLAURAEfficacy in Patients With CNS Metastasis

PFS in Patients WITH CNS Metastases PFS in Patients WITHOUT CNS Metastases

Soria JC, et al. N Engl J Med. 2018.

Sequencing of EGFR TKIsWhich Strategy is Best?

Erlotinib mPFS = 10mo Osimertinib mPFS = 10mo Chemo and others….

Osimertinib mPFS = 19mo Chemo and others….

T790M status

~40% ‐Chemo and others….

~60% +

Slide courtesy Lecia Sequist, MD.

How Many Make It to Second‐line Therapy After First‐line TKI?

Fukuoka M, et al. J Clin Oncol. 2011; Rosell R, et al. Lancet Oncol. 2012; Mitsudomi T, et al. ASCO. 2012. Abstract 7521; Sequist L, et al. J Clin Oncol. 2013;

Wu YL, et al. Lancet Oncol. 2014; Paz‐Ares L, et al. Ann Oncol. 2017; Mok TS, et al. ESMO. 2017. Abstract LBA50.

Study First‐line Therapy

N Eligible for Second‐line*

N (%) Receiving Any Second‐line Therapy

IPASS Gefitinib 129 97 (75%)

EURAC Erlotinib 56 38 (68%)

WJOG 3405 Gefitinib 86 60 (70%)

LUX Lung 3 Afatinib 184 144 (78%)


LUX Lung 7 Gefitinib 151 123 (81%)


FLAURA SOC (G & E) 206 (?) 62 got osimertinibAssuming 50% T790M, this means 60% treatedAssuming 60% T790M, this means 50% treated

Let’s assume in the real world, 70% of patients make it to

second line.

*Number who were no longer on first‐line treatment at the time of data cut‐off.

Erlotinib mPFS = 10mo Osimertinib mPFS = 10mo Chemo and others….

Osimertinib mPFS = 19mo Chemo and others….

~40% ‐

T790M status Chemo and others….

100

100

70% make it to second line

42~60% +

Sequencing of EGFR TKIsWhich Strategy is Best?

Slide courtesy Lecia Sequist, MD.

Summary of First‐line Recommendations for EGFR TKIs in 2018

• FLAURA has potentially defined a new standard of care with improved PFS, AE profile, and likely better CNS penetration for osimertinib

• NCCN has adopted first‐line osimertinib as a treatment option and osimertinib was granted FDA approved for use in the first‐line setting in April 2018.

Case 2Acquired Resistance• 55‐year‐old male, never smoker, presents with SOB and back pain. He is found to have a T‐spine vertebral lesion. Staging work‐up reveals bilateral lung nodules and a left pleural effusion.

• Thoracentesis = adenocarcinoma; genotyping = EGFR L858R mutation

• He begins erlotinib with good response • Resolution of back pain • Resolution of SOB• Radiographic response on his

first scans

• After 15 months, restaging shows innumerable new but tiny GGOs, all of which are too small to biopsy

“Liquid Biopsy”aka Cell‐free DNA Testing

• A non‐invasive approach to evaluation of tumor mutations (and other alterations)

• Methods can be highly targeted or more comprehensive

• Excellent specificity

• Sensitivity—up to 30% false negative

O'Leary B, Turner NC. Clin Oncol (R Coll Radiol). 2016.

Liquid Biopsy • Important to be aware of the major caveats

• Clear indications for use not established• Most studies show a consistent 20%–30% false negative rate

• Negative findings on liquid biopsy should be followed up with biopsy testing

• Best clinical case for use is in the setting of progression on EGFR TKI

• Targeted assays are best validated in this setting• Real‐time PCR • ddPCR

• Broader assays also can be used• e.g., NGS• Broader assays may compromise analytic sensitivity

Liquid Biopsy for T790M in AURA Study

Tissue T790M+ORR 62%

mPFS 9.7 moPlasma T790M+

ORR 63%mPFS 9.7 mo

Very similar outcomesif positive by either assay

Oxnard GO, et al. J Clin Oncol. 2016.

Liquid Biopsy for T790M in AURA Study

Tissue T790M+ORR 62%

mPFS 9.7 mo

Plasma T790M+ORR 63%

mPFS 9.7 mo

Very similar outcomesif positive by either assay

Oxnard GO, et al. J Clin Oncol. 2016.

But because ~1/3 of tumors don’t shed ctDNA, a negative plasma test does not mean

negative result!

Liquid Biopsy

• Bottom line

• cfDNA success is dependent on tumor shedding and, potentially, disease burden

• Negative results from cfDNA testing are uninformative

• If you are using liquid biopsy in the diagnostic setting, have a backup plan for what to do if uninformative

• Consider parallel biopsy order

Immunotherapy inEGFR Mutants

ImmunotherapyIt’s So Appealing…But Is It Right for EGFR Patients?

FDA Approvals To‐Date of Immune Checkpoint Inhibitors for NSCLC03/04/15 Second‐line nivolumab, squamous10/09/15 Second‐line nivolumab, any histology10/22/15 Second‐line pembrolizumab, PDL‐1> 1%10/18/16 Second‐line atezolizumab10/24/16 First‐line pembrolizumab, PDL‐1>50%05/10/17 First‐line carbo/pem/pembrolizumab02/16/18 Adjuvant durvalumab, stage III unresectable

Meta‐Analysis Shows Lack of Efficacy of Immune Checkpoint Inhibitors in EGFR Mutants (n=3025)

Lee CK, et al. JAMA Onc. 2018.

Possible Safety Concern with EGFR TKI and Immune Checkpoint Inhibitors

Oshima Y, et al. JAMA Oncol. 2018.

IP, interstitial pneumonitis

Immune Checkpoint Inhibitor Monotherapy in EGFR Mutants

• Preponderance of evidence suggests low activity for PD1 and PD‐L1 drugs alone in EGFR pts; second‐line docetaxel is superior to ICI monotherapy. Note first‐line KEYNOTE‐021 (for PD‐L1 >50%) did NOT include EGFR.

• There may be safety concerns for pts who receive both ICI and EGFR TKI in sequence (↑↑ pneumoni s)

• More data needed for IO combinations, either with chemo or a second IO agent

• Note KEYNOTE‐021 cohort G study with carboplatin/pemetrexed + pembrolizumab did not include EGFR pts, but IMpower 150 study did include

IMpower150: Study Design

Arm AAtezolizumabb + Carboplatinc

+ Paclitaxeld4 or 6 cycles

Atezolizumabb

Arm C (control)Carboplatinc + Paclitaxeld

+ Bevacizumabe4 or 6 cycles

Bevacizumabe

Survival fo

llow‐up

Stage IV or recurrent metastatic non‐squamous NSCLCchemotherapy‐naiveatumour tissue available for biomarker testingany PD‐L1 IHC status

Stratification Factors• Sex• PD‐L1 IHC expression• Liver metastases

N=1202

R1:1:1

Arm BAtezolizumabb +

Carboplatinc + Paclitaxeld+ Bevacizumabe4 or 6 cycles

Atezolizumabb+

Bevacizumabe

Maintenance therapy(no crossover permitted)

Treated with atezolizumab until PD by RECIST v1.1 or loss of

clinical benefitAND/OR

Treated with bevacizumab until PD by RECIST v1.1

The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit.

aPatients with a sensitising EGFRmutation or ALK translocation must have disease progression or intolerance of treatment with one or more approved targeted therapies. bAtezolizumab: 1200 mg IV q3w. cCarboplatin: AUC 6 IV q3w. dPaclitaxel: 200 mg/m2 IV q3w. eBevacizumab: 15 mg/kg IV q3w.

Socinski MA, et al. ASCO 2018. Abstract 9002; Socinski MA, et al. N Engl J Med. 2018.

The T‐effector (Teff) gene signature is defined by expression of PD‐L1, CXCL9 and IFNγ and is a surrogate of both PD‐L1 IHC expression and pre‐existing immunity (Kowanetz M, et al. WCLC, 2017).

IMpower150Study Populations and Objectives

Co‐primary objectives• Investigator‐assessed PFS in ITT‐WT• Investigator‐assessed PFS in Teff‐high WT• OS in ITT‐WT

ITTAll randomised

patients

Teff‐high WTaHigh T‐effector gene signature

expression

Teff‐low WTaLow T‐effector gene signature

expressionEGFR/ALK +

(13% of patients)

ITT‐WTa(87% of patients)

a WT refers to patients without EGFR or ALK genetic alterations

Key secondary objectives• Investigator‐assessed PFS and OS in ITT• Investigator‐assessed PFS in PD‐L1 IHC subgroups• Independent review facility (IRF)‐assessed PFS• ORR and DOR per RECIST v1.1 • Safety in ITT

Socinski MA, et al. ASCO 2018. Abstract 9002; Socinski MA, et al. N Engl J Med. 2018.

Updated PFS Analysis in the ITT‐WT (Arm B vs Arm C)

Socinski MA, et al. ASCO 2018. Abstract 9002.

• Statistically significant and clinically meaningful PFS benefit with atez + bev + chemotherapy vs bev + chemotherapy was previously observed (Reck M, et al. ESMO 2017. Abstract LBA1_PR) and continued to improve with additional follow‐up

Updated OS in the ITT‐WT (Arm B vs Arm C)


•Statistically significant and clinically meaningful OS benefit with atezo + bev + chemotherapy vs bev + chemotherapy was observed

OS in Key Subgroups(Arm B vs Arm C)


Median OS, mo

Safety Summary


Take Home Points• Biomarker testing is critical for optimal care of NSCLC patients. Please become familiar with 2018 CAP guidelines.

• Close, multidisciplinary conversations between medical oncology, pathology, and service obtaining diagnostic biopsies are key.

• Clinical pathways for EGFR‐mutants are changing in 2018.

• Osimertinib is a new choice for first‐line EGFR TKI therapy

• Push single agent immunotherapy off until after 2 lines of chemo

References and Suggested ReadingAisner D, Rumery M, Merrick D, et al. Do more with less: tips and techniques for maximizing small biopsy and cytology specimens for molecular and ancillary testing: the University of Colorado Experience. Arch Pathol Lab Med. 2016;140:1206–1220.

Drilon A, Rekhtman N, Ladanyi M, et al. Squamous‐cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 2012;13(10):e418–e426.

Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open‐label, first‐line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non–small‐cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866–2874.

Le D, Durham J, Smith K, et al. Mismatch‐repair deficiency predicts response of solid tumors to PD‐1 blockade. Science. 2017; 357(6349): 409–413.

Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non–small‐cell lung carcinoma: a systematic review and meta‐analysis. JAMA Oncol. 2018;4(2):210–216. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323–358.

Mitsudomi T, Morita S, Yatabe Y, et al. Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first‐line treatment for patients with non–small‐cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR). Abstract 7521. Presented at: ASCO; June 5, 2012; Chicago, Illinois. J Clin Oncol.2012;30 (15_Suppl):7521–7521.

Mok TS, Kim D, Wu Y, et al. Overall survival (OS) for first‐line crizotinib versus chemotherapy in ALK+ lung cancer: updated results from PROFILE 1014. Abstract LBA50. Presented at: ESMO; September 11, 2017; Madrid, Spain. Ann Oncol. 2017;28(Suppl 5):v605–649.

National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: non–small‐cell lung cancer. Version 5.2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July 2018.

O'Leary B, Turner NC. Science in focus: circulating tumour DNA as a liquid biopsy. Clin Oncol (R Coll Radiol). 2016;28(12):735–738.Oshima Y, Tanimoto T, Yuji K, et al. EGFR‐TKI‐associated interstitial pneumonitis in nivolumab‐treated patients with non–small‐cell lung cancer. JAMA Oncol. January 11, 2018 [Epub ahead of print].Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small‐cell lung cancer. J Clin Oncol. 2016;34(28):3375–3382.Paz‐Ares L, Tan EH, O'Byrne K, et al. Afatinib versus gefitinib in patients with EGFR mutation‐positive advanced non–small‐cell lung cancer: overall survival data from the phase IIb LUX‐Lung 7 trial. Ann Oncol. 2017;28(2):270–277.Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard‐of‐care (SoC) EGFR‐TKI as first‐line treatment in patients (pts) with EGFRm advanced NSCLC: FLAURA. Abstract LBA2_PR. Presented at: ESMO; September 9, 2017; Madrid, Spain. Ann Oncol.2017;28(suppl_5):v605–v649.Reck M, Socinski MA, Cappuzzo F, et al. Primary PFS and safety analyses of a randomized Phase III study of carbopla n + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non‐squamous metastatic NSCLC (Impower150). Abstract LBA1_PR. Presented at: ESMO Immuno‐Oncology Congress; December 7, 2017. Geneva, Switzerland.

References and Suggested Reading

Rosell R, Molina MA, Serrano MJ. EGFR mutations in circulating tumour DNA. Lancet Oncol. 2012;13(10):971–973.Sebastian M, Schmittel A, Reck M. First‐line treatment of EGFR‐mutated non–small‐cell lung cancer: critical review on study methodology. Eur Respir Rev. 2014;23(131):92–105.Sequist L, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013. 3327–3334.Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ±bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. Abstract 9002. Presented at: ASCO; June 4, 2018; Chicago, Illinois. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for First‐Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288‐2301.Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, et al; FLAURA Investigators. Osimertinib in untreated EGFR‐Mutated advanced non–small‐cell lung cancer. N Engl J Med. 2018;378(2):113–125.Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first‐line treatment of Asian patients with advanced non–small‐cell lung cancer harbouring EGFR mutations (LUX‐Lung 6): an open‐label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–222.

References and Suggested Reading

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