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Learning Objectives1) Review the molecular pathology of advanced non–small‐cell lung cancer (NSCLC)
and identify clinically relevant molecular mutations that impact treatmentselection.
2) Examine strategies to coordinate care in the community setting to improveadherence to guideline‐recommended molecular testing in NSCLC and discuss theutility of newer technologies, such as ctDNA liquid biopsy, in clinical practice.
3) Evaluate targeted treatment options for actionable and acquired mutations inNSCLC, such as EGFR/T790M, and assess the safety and efficacy of these targetedtherapies.
4) Using a case‐based approach, examine how to best incorporate molecular testingto optimize targeted therapy selection in EGFR‐mutated NSCLC at initiation oftherapy and upon disease progression.
Lung Cancer
www.seer.cancer.gov/statfacts/html/lungb.html.
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Lung CancerClassification
Lung Cancer
Small‐Cell Lung Cancer 15%
Non–Small‐Cell Lung Cancer85%
Squamous 30% Non‐squamous
70%
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
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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 6.2018.
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2018 Targeted Therapies in the United States• EGFRmutation
• Erlotinib*
• Gefitinib*
• Afatinib*
• Osimertinib*
• Dacomitinib*a
• ALK rearrangement• Crizotinib*
• Ceritinib
• Alectinib*
• Brigatinib (second‐line)
• ROS1 rearrangement• 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 first‐line settingaApproved 9/27/18
FDA Prescribingg Information;NCCN Guidelines Non–Small‐Cell Lung Cancer. Version 6.2018.
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.
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Think of Needles and HaystacksAnalytic Sensitivity
How 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
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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.
Slide courtesy of Dara L. Aisner, MD, PhD.
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Examples of Methods & Analytic Sensitivity
Method Analytic Sensitivity Can be used for Clinical Sensitivity
Sanger Sequencing
Lowest (~15%)Highly enriched tumor samples
Usually entire exons or regions of exons queried
Single Base Extension (SNaPshot, MassArray)
Moderate (~5%)Moderately enriched 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
Next Generation Sequencing
Moderate (5%–10%)Moderately enriched 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?
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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
Slide courtesy of Dara L. Aisner, MD, PhD.
• 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?
Slide courtesy of Dara L. Aisner, MD, PhD.
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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
Slide courtesy of Dara L. Aisner, MD, PhD.
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?
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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
Slide courtesy of Dara L. Aisner, MD, PhD.
Targeted NGS Panels
Whole Exome Sequencing
Whole Genome Sequencing
RNASeq
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 3.2GbRanges
20Mb–60Mb
Cost $ $$ $$$$$ $$
Some Examples of NGS
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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.
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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 aninterventional 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
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• 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 EGFRor 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
Squamous—To Test or Not to Test?
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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 6.2018.
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 ALK rearrangement) is not present
• EGFR TKI should not be used in the setting of KRASmutation positive tumor
Lindeman NI, et al. J Thorac Oncol. 2018.
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Guidelines for Testing
• NCCN: 6.2018 (August, 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 6.2018.
USING BIOMARKERS TO DETERMINE
TREATMENT COURSEFocus on EGFR Mutation Positive NSCLC
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EGFR TKIs–With FDA Approved First‐Line Indication
Study Agents N Median PFS Median OS
IPASS trial1,2Gefitinib vs carbo‐paclitaxel
261 9.5 mo vs 6.3 mo 21.6 mo vs 21.9 mo
EURTAC3Erlotinib vs platinum doublet
173 9.7 mo vs 5.2 mo 19.3 mo vs 19.5 mo
LUX‐Lung 34,5Afatinib 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
ARCHER 10507,8Dacomitinib vs gefitinib
452 14.7 mo vs 9.2 mo 34.1 mo vs 26.8 mo
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; 7Wu YL, et al. Lancet Oncol. 2017; Mok TS, et al. J Clin Oncol. 2018.
NCCN Guidelines Version 6.2018
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)orAfatinib (category 1)orGefitinib (category 1)orOsimertinib (category 1)
EGFR mutation discovered prior to first‐line chemotherapy
Sensitizing EGFR mutation positive
FIRST‐LINE THERAPY
NCCN Guidelines Non–Small‐Cell Lung Cancer. Version 6.2018.Note: Dacomitinib was approved by the FDA on 9/27/2018 for first‐line use
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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; ‡CobasEGFR 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, whocould receive open‐label osimertinib upon central
confirmation of progression and T790M positivity
Patients with locally advanced or metastatic NSCLC
Key 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 qd) or Erlotinib (150 mg po qd)
(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.SoC=standard of care
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Median PFS, months (95% CI)
18.9 (15.2, 21.4)
10.2 (9.6, 11.1)
1.0Probab
ility of progression‐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
Osimertinib
SoC
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<0.0001
Soria JC, et al. N Engl J Med. 2018;Ramalingam SS, et al. ESMO. 2017. Abstract LBA2_PR.
PFS Across SubgroupsFavours SoCSubgroup
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)
Favours Osimertinib
0.1 0.2 0.3 0.4 0.6 0.8 2.0
PFS hazard ratio and 95% confidence interval1.0 10.0
Overall (n=556)Log Rank (primary)Cox PH
Age at screening<65 (n=298)≥65 (n=258)
SexMale (n=206)Female (n=350)
CNS metastasesYes (n=116)No (n=440)
RaceAsian (n=347)Non‐Asian (n=209)
Centrally confirmed EGFR mutationPositive (n=500)Negative (n=6)
Smoking history Yes (n=199)No (n=357)
EGFRmutation at randomizationExon 19 deletion (n=349) L858R (n=207)
WHO performance status0 (n=228)1 (n=327)
EGFRmutation by ctDNAPositive (n=359)Negative (n=124)
Soria JC, et al. N Engl J Med. 2018.
Hazard ratio (95% confidence interval)
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Adverse EventsFLAURA
Soria JC, et al. N Engl J Med. 2018.
Adverse Event n (%)
Osimertinib (n=279) SoC (n=277)Any Grade
Grade 1 Grade 2 Grade 3 Grade 4Any Grade
Grade 1 Grade 2 Grade 3 Grade 4
Any adverse event 273 (98) 34 (12) 144 (52) 83 (30) 6 (2) 271 (98) 22 (8) 125 (45) 103 (37) 11 (4)
Diarrhea 161 (58) 120 (43) 35 (13) 6 (2) 0 159 (57)* 116 (42) 35 (13) 6 (2) 0
Rash or acne 161 (58) 134 (48) 24 (9) 3 (1) 0 216 (78) 110 (40) 87 (31) 19 (7) 0
Dry skin 88 (32) 76 (27) 11 (4) 1 (<1) 0 90 (32) 70 (25) 17 (6) 3 (1) 0
Paronychia 81 (29) 37 (13) 43 (15) 1 (<1) 0 80 (29) 46 (17) 32 (12) 2 (1) 0
Stomatitis 80 (29) 65 (23) 13 (5) 1 (<1) 1 (<1) 56 (20) 47 (17) 8 (3) 1 (<1) 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 0
AST increased 26 (9) 18 (6) 6 (2) 2 (1) 0 68 (25) 38 (14) 18 (6) 12 (4) 0
ALT increased 18 (6) 11 (4) 6 (2) 1 (<1) 0 75 (27) 31 (11) 19 (7) 21 (8) 4 (1)
*In the SoC arm there was one patient with Grade missing and one patient with Grade 5 diarrhea
Adverse EventsARCHER 1050
Adverse Event n (%)
Dacomitinib (n=227) Gefitinib (n=224)
Grade 1‐2 Grade 3 Grade 4 Grade 5 Grade 1‐2 Grade 3 Grade 4 Grade 5
Any adverse event 83 (37) 116 (51) 5 (2) 22 (10) 128 (57) 67 (30) 5 (2) 20 (9)
Diarrhea 178 (78) 19 (8) 0 1 (<1) 123 (55) 2 (1) 0 0
Paronychia 123 (54) 17 (7) 0 0 42 (19) 3 (1) 0 0
Dermatitis acneiform 80 (35) 31 (14) 0 0 64 (29) 0 0 0
Rash 30 (13) 10 (4) 0 0 24 (11) 0 0 0
Maculopapular rash 18 (8) 10 (4) 0 0 26 (12) 1 (<1) 0 0
Dermatitis 21 (9) 4 (2) 0 0 8 (4) 1 (<1) 0 0
Pustular rash 6 (3) 8 (4) 0 0 3 (1) 0 0 0
ALT increased 42 (19) 2 (1) 0 0 69 (31) 19 (8) 0 0
AST increased 42 (19) 0 0 0 72 (32) 9 (4) 0 0
Hypokalemia 11 (5) 9 (4) 2 (1) 0 9 (4) 4 (2) 0 0
Overall 150 patients (66%) in the dacomitinib group required a dose reduction due to toxicity. Wu YL, et al. Lancet Oncol. 2017.
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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.
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 6 Afatinib 194 123 (63%)
LUX Lung 7 Gefitinib 151 123 (81%)
LUX Lung 7 Afatinib 146 108 (74%)
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.
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Erlotinib mPFS = 10mo Osimertinib mPFS = 10mo Chemo and others….
Osimertinib mPFS = 19mo Chemo and others….
~40% ‐
T790M status
Chemo and others….
100
100
Only ~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 approval for use in the first‐line setting in April 2018
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“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.
• 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
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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.
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
But because ~1/3 of tumors don’t shed ctDNA, a negative plasma test does not mean negative result!
Oxnard GO, et al. J Clin Oncol. 2016.
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• 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
Liquid Biopsy
Immunotherapy in EGFR Mutants
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ImmunotherapyIt’s so Appealing…but Is It Right for EGFR Patients?
FDA Approvals To‐Date of Immune Checkpoint Inhibitors for NSCLC
03/04/15 Second‐line nivolumab, squamous
10/09/15 Second‐line nivolumab, any histology
10/22/15 Second‐line pembrolizumab, PDL‐1> 1%
10/18/16 Second‐line atezolizumab
10/24/16 First‐line pembrolizumab, PDL‐1>50%
05/10/17 First‐line carbo/pem/pembrolizumab
02/16/18 Adjuvant durvalumab, stage III unresectable
Meta‐Analysis (n=3025) Shows Lack of Efficacy of Immune Checkpoint Inhibitors in EGFR mutants
Lee CK, et al. JAMA Onc. 2018.
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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
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IMpower150: Study Design
Arm AAtezolizumabb + Carboplatinc +
Paclitaxeld
4 or 6 cycles
Atezolizumabb
Arm C (control)Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Bevacizumabe
Survival follo
w‐up
Stage IV or recurrent metastatic non‐
squamous NSCLCchemotherapy‐naivea
tumour tissue available for biomarker testing
any PD‐L1 IHC status
Stratification Factors• Sex• PD‐L1 IHC expression• Liver metastases
N=1202
R1:1:1
Arm BAtezolizumabb + Carboplatinc +
Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Atezolizumabb
+ Bevacizumabe
Maintenance therapy(no crossover permitted)
Treated with atezolizumab until PD by RECIST v1.1 or loss of clinical
benefit
AND/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.
Socinski MA, et al. ASCO 2018. Abstract 9002; Socinski MA, et al. N Engl J Med. 2018.
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.
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 WTa
High T‐effector gene signature expression
Teff‐low WTa
Low T‐effector gene signature expression
EGFR/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.
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Updated PFS Analysis in the ITT‐WT (Arm B vs Arm C)
Socinski MA, et al. ASCO 2018. Abstract 9002.
Socinski MA, et al. ASCO 2018. Abstract 9002.
OS in the ITT‐WT (Arm B vs Arm C)
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OS in Key Subgroups(Arm B vs Arm C)
Socinski MA, et al. ASCO 2018. Abstract 9002.
Socinski MA, et al. ASCO 2018. Abstract 9002.
Safety Summary
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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 an emerging choice for first‐line EGFR TKI therapy
• Push single agent immunotherapy off until after 2 lines of chemo
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National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: non–small‐cell lung cancer. Version5.2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July 2018.
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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.
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Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for First‐Line Treatment of Metastatic NonsquamousNSCLC. N Engl J Med. 2018;378(24):2288‐2301.
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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.
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