Low TPS High TPS TPS = PD-L1 tumor proportion score Low TPS = 10%; high TPS = 60% - PowerPoint Presentation

Low TPS High TPS TPS = PD-L1 tumor proportion score Low TPS = 10%; high TPS = 60% No targetable mutation Low TPS High TPS EGFR mutation ALK rearrangement ROS1 rearrangement Low TPS High TPS BRAF V600E mutation MET exon 14 mutation RET rearrangement HER2 mutation The New Taxonomy of Metastatic Non-Small Cell Lung Cancer Low TPS High TPS T790M mutation-positive T790M mutation-negative T790M mutation-positive T790M mutation-negative Low TPS High TPS Low TPS High TPS Low TPS High TPS Low TPS High TPS Low TPS High TPS Nonsquamous Squamous (no targetable mutation)  Targeted treatment Chemotherapy ± biologic Chemotherapy + checkpoint inhibitor Checkpoint inhibitor The New Taxonomy of Metastatic NSCLC and Physician Treatment Based on Pathologic and Molecular Characteristics Love N et al. Proc IASLC 2017;Abstract 75. 

Subtypes of NSCLC can be defined by genotypes MSK-IMPACT data Courtesy of Gregory J Riely, MD, PhD

Low TPS High TPS TPS = PD-L1 tumor proportion score Low TPS = 10%; high TPS = 60% No targetable mutation Low TPS High TPS EGFR mutation ALK rearrangement ROS1 rearrangement Low TPS High TPS BRAF V600E mutation MET exon 14 mutation RET rearrangement HER2 mutation The New Taxonomy of Metastatic Non-Small Cell Lung Cancer Low TPS High TPS T790M mutation-positive T790M mutation-negative T790M mutation-positive T790M mutation-negative Low TPS High TPS Low TPS High TPS Low TPS High TPS Low TPS High TPS Low TPS High TPS Nonsquamous Squamous (no targetable mutation)  Targeted treatment Chemotherapy ± biologic Chemotherapy + checkpoint inhibitor Checkpoint inhibitor The New Taxonomy of Metastatic NSCLC and Physician Treatment Based on Pathologic and Molecular Characteristics Love N et al. Proc IASLC 2017;Abstract 75. 

First-Line Treatment of Patients with Metastatic, Squamous NSCLCSurvey of clinical investigators (n = 25) Love N et al. Proc IASLC 2017;Abstract 75.  Carboplatin/nab paclitaxel

First-Line Treatment for Metastatic, Nonsquamous NSCLC and No Identified Targetable MutationSurvey of clinical investigators (n = 25) Love N et al. Proc IASLC 2017;Abstract 75. 

First-Line Treatment for Metastatic, Nonsquamous NSCLC and EGFR Exon 19 DeletionSurvey of clinical investigators (n = 25) Love N et al. Proc IASLC 2017;Abstract 75. 

FLAURA: Osimertinib as Front-Line Therapy for EGFR-Mutant NSCLCRamalingam SS et al. Proc ESMO 2017;Abstract LBA2_PR. Median PFS Osimertinib SoC HR p CNS mets (n = 53, 63 ) 15.2 mo 9.6 mo 0.47 0.0009 No CNS mets (n = 226, 214 ) 19.1 mo 10.9 mo 0.46 <0.0001 Interim OS (Median not reached) HR: 0.63, p = 0.0068* * <0.0015 required for significance Subsequent to this interview, these data were presented at ESMO 2017 HR 0.46 and p < 0.0001

Approach to Patients with Metastatic, EGFR Mutation-Positive Nonsquamous NSCLC After Disease Progression on ErlotinibSurvey of clinical investigators (n = 25) Love N et al. Proc IASLC 2017;Abstract 75.  Approach to T790M mutation testing

Treatment of Patients with Metastatic, EGFR Mutation-Positive Nonsquamous NSCLC After Disease Progression on Erlotinib Survey of clinical investigators (n = 25)Love N et al. Proc IASLC 2017;Abstract 75.  Systemic therapy recommendation: T790M mutation-positiveSystemic therapy recommendation: T790M mutation-negative

First-Line Treatment of Patients with Metastatic, Nonsquamous NSCLC and Targetable Alterations Survey of clinical investigators (n = 25) Love N et al. Proc IASLC 2017;Abstract 75.  ALK translocation ROS1 rearrangement

ALEX: Investigator-Assessed PFS and CNS ProgressionPeters S et al. N Engl J Med 2017;377:829-38; Shaw AT et al. Proc ASCO 2017;Abstract LBA9008. Alectinib (n = 152) Crizotinib (n = 151) HR p 12-month event-free survival rate 68.4% 48.7% 0.47 <0.001 12-month cum. incidence of CNS progression 9.4% 41.4% 0.16 < 0.0001 Median PFS = not reached Median PFS = 11.1 mo HR = 0.47 p < 0.001

First-Line Treatment of Patients with Metastatic, Nonsquamous NSCLC and BRAF V600E MutationsSurvey of clinical investigators (n = 25) Love N et al. Proc IASLC 2017;Abstract 75.  BRAF V600E mutation Chemotherapy + anti-PD-1/PD-L1 antibody

First-Line Treatment of Patients with Metastatic, Nonsquamous NSCLC and Targetable Alterations Survey of clinical investigators (n = 25) Love N et al. Proc IASLC 2017;Abstract 75.  ALK translocation ROS1 rearrangement BRAF V600E mutation MET exon 14 alteration TPS 10% TPS 60% Chemotherapy + anti-PD-1/PD-L1 antibody

PD-L1 Expression in MET Exon 14-Altered NSCLC (N = 54) and Response to Immunotherapy (N = 15) Sabari JK et al. Proc ASCO 2017;Abstract 8512. PD-L1 expression (N = 54) PD-L1 expression 0% 1%-49% ≥50% No. of patients 19 (35%) 10 (19%) 25 (46%)

First-Line Treatment of Patients with Metastatic, Nonsquamous NSCLC and RET Rearrangements or HER2 Mutations Survey of clinical investigators (n = 25)Love N et al. Proc IASLC 2017;Abstract 75.  RET rearrangement HER2 mutations TPS 10% TPS 60%

Response to T-DM1 and Prior Therapies for HER2-Mutant NSCLC Li BT et al. Proc ASCO 2017;Abstract 8510.ORR: 8/18 (44%) 6 of 8 responders were heavily pretreated, including prior HER2 targeted therapyMedian PFS: 4 months

Response and Survival to T-DM1 in HER2- Overexpressing NSCLC Stinchcombe T et al. Proc ASCO 2017;Abstract 8509. Median duration of response: 7.3 months IHC 2+ (n = 29) IHC 3+ (n = 20) All (N = 49) Median PFS 2.6 mo 2.7 mo 2.6 mo Median OS 12.2 mo 12.1 mo 12.2 mo * Indicates positive HER2 amplification; U indicates unknown HER2 amplification; a ll other patients’ ISH status is negative IHC 3+ ORR = 20% IHC 2+ ORR = 0%

PD-L1 as a biomarker: Old biopsy or new? 72% no change in PD-L1 pre- vs post-TKI Synchronous Metachronous Kowanetz  M et al . Proc WCLC 2015;Abstract ORAL13.03 . Gainor JF et al . CCR 2016;22(18):4585-93. PD-L1 expression may be more stable than expected

PD-L1 as a biomarker: Archival vs fresh?Archival tissue is reasonable to use for PD-L1 testing; fresh biopsy not routinely necessary Herbst RS et al. Proc ASCO 2016;Abstract 3030.

PD-L1 as a biomarker: Which assay?Rimm et al, JAMA Onc 2017 Courtesy of Gregory J Riely, MD, PhD

PD-L1 staining can be different with different antibodies Rimm et al, JAMA Onc 2017;3(8):1051-8.

There is general concordance of PD-L1 testing… with one exception Rimm et al, JAMA Onc 2017;3(8):1051-8 . Mean scores for tumor cells

There is general concordance of PD-L1 testing… with one exception Rimm et al, JAMA Onc 2017;3(8):1051-8 .Tumor cells positive at cut points

Courtesy of Gregory J Riely , MD, PhD

Proliferation of targetable molecular subsets lung adenocarcinoma Jordan E et al. Cancer Discovery 2017;7(6):596-609.

MET Exon 14 Alterations Drilon et al. Clin Cancer Res 2016;22 (12): 2832-4; Kong-Beltran M et al. Cancer Res 2006;66(1): 283-9; Ma et al. Cancer Res 2003;63 (19):6272-81 ; Frampton GM et al. Cancer Discov 2015;5 (8):850-9 .

Drilon A et al. Lancet Oncol 2016;17(12):1653-60.

Integrated Analysis of Response in 3 Studies of Larotrectinib in 17 Cancer Types with TRK FusionsHyman DM et al. Proc ASCO 2017;Abstract LBA2501. Similar response regardless of:AgeTumor type NTRK geneFusion partner* Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; # Pathologic CR Note: One patient not shown here. Patient experienced clinical progression and no post-baseline tumor measurements were recorded. Patients with confirmatory response data available (n = 50) Objective response rate Partial response Complete response 76% 64% 12% Stable disease 12% Progressive disease 12%

Analysis of the first 860 lung adenocarcinomas studied by MSK-IMPACT Jordan EJ et al, Cancer Discov 2017 ;7(6):596-609 .

Mechanisms of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors Yu HA et al. CCR 2013;19(8 ):2240-7. Small cell+ MET1% Small cell 1% Small cell + T790M 2% MET +T790M 3% MET amplification3% HER2 + T790M4%

Yu HA et al. JAMA Oncol 2015;1(7):982-4. Acquired resistance to 3rd generation EGFR inhibitors Afatinib / cetuximab Carboplatin/pemetrexed/bevacizumab/ erlotinib Gemcitabine/ vinorelbine/erlotinib Docetaxel/erlotinib Cisplatin/ nab paclitaxel/erlotinib AZD9291Craniotomu /SRS Docetaxel (administered after biopsy 3) ErlotinibRadiation right lung Radiation spineCarboplatin/ pemetrexed/bavacizumab

Yu HA et al. JAMA Oncol 2015;1(7):982-4. C797S