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

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

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

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

FLAURA: Osimertinib as Front-Line Therapy for EGFR-Mutant NSCLC HR 0.46 and p <0.0001 Interim OS (Median not reached) HR: 0.63, p = 0.0068* * <0.0015 required for significance 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 Subsequent to this interview, these data were presented at ESMO 2017 Ramalingam SS et al. Proc ESMO 2017;Abstract LBA2_PR.

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

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

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

ALEX: Investigator-Assessed PFS and CNS Progression Median PFS = not reached Median PFS = 11.1 mo HR = 0.47 p < 0.001 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 Peters S et al. N Engl J Med 2017;377:829-38; Shaw AT et al. Proc ASCO 2017;Abstract LBA9008.

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

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

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

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

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

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

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

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 Mean scores for tumor cells Rimm et al, JAMA Onc 2017;3(8):1051-8.

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

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.

Patients with confirmatory response data available (n = 50) Integrated Analysis of Response in 3 Studies of Larotrectinib in 17 Cancer Types with TRK Fusions Patients with confirmatory response data available (n = 50) Objective response rate Partial response Complete response 76% 64% 12% Stable disease Progressive disease Similar response regardless of: Age Tumor type NTRK gene Fusion 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. Hyman DM et al. Proc ASCO 2017;Abstract LBA2501.

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 MET amplification 3% HER2 + T790M 4% Small cell+MET 1% Small cell 1% Small cell + T790M 2% MET+T790M 3% Yu HA et al. CCR 2013;19(8):2240-7.

Acquired resistance to 3rd generation EGFR inhibitors Radiation spine Carboplatin/pemetrexed/bavacizumab Erlotinib Radiation right lung Afatinib/cetuximab Carboplatin/pemetrexed/bevacizumab/erlotinib Gemcitabine/vinorelbine/erlotinib Docetaxel/erlotinib Cisplatin/nab paclitaxel/erlotinib AZD9291 Craniotomu/SRS Docetaxel (administered after biopsy 3) Yu HA et al. JAMA Oncol 2015;1(7):982-4.

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