1. 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. 

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

3. 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. 

4. 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. 

5. 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. 

6. 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. 

7. 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 = *
* < 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.

8. 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. 

9. 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. 

10. 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. 

11. 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.

12. 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. 

13. 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. 

14. 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.

15. 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. 

16. 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.

17. 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.

18. 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):

19. 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.

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

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

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

23. 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):

24. Courtesy of Gregory J Riely, MD, PhD

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

26. 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): ; Frampton GM et al. Cancer Discov 2015;5(8):850-9.

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

28. 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.

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

30. 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):

31. 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.

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