1. Immunotherapy targeting PD-1 and PD-L1 has shown exciting promise in NSCLC, with several trials reporting benefit in patients who are positive for the PDL-1 marker, though 9-20% of PDL-1 negative tumors also responded. 2. Studies have found that resistance to EGFR and ALK tyrosine kinase inhibitors can develop through additional mutations, but new inhibitors targeting these resistance mutations like AZD9291 and ceritinib have shown efficacy in treating tumors after initial resistance. 3. Insights into lung cancer biology have come from sequencing tumor DNA from smokers and non-smokers, finding some tumors are heterogeneous with different mutations in different metastases, and that initial mutations may

1. My Top Four Lung Cancer Highlights 2014
Thomas John MBBS, PhD
Olivia Newton-John Cancer Centre
Melbourne, Australia
www.cancerGRACE.org
Dec. 23, 2014

2. 4: Insights into lung cancer biology
Figuring out how lung cancers develop in the first
place provides important insights that may enable
researchers to not only prevent this process but
also better target treatments.
In this pivotal study published in Science this year,
the DNA from lung tumors taken from smokers
and non-smokers were sequenced. In addition
the authors sequenced multiple sites of tumor
spread to compare mutation patterns between
the primary and subsequent metastases.
The results suggest some tumors are very heterogenous, with different mutations in
different metastatic sites.
The study also showed that initial mutations in smokers probably begin some 20 years
before a tumor is diagnosed, indicating a long latency between the initial tumor
causing event and subsequent diagnosable tumor.
de Bruin et al. Science 2014

3. 3: MET another oncogenic driver
Tumor Shrinkage Seen in Intermediate <br />and High MET Cohorts
Presented By D. Camidge at 2014 ASCO Annual Meeting
Although mutations have been the main
targetable drivers in lung cancer, this
study presented at ASCO 2014 showed
that true MET amplification also drives
NSCLC.
Impressively when MET amplified
tumors were treated with the drug
Xalkori (crizotinib), responses were seen
in most patients
It is important to note that MET amplification only occurs in around 3% of NSCLC.
In a series of 800 cases from the University of Colorado only 30 had true MET
amplification.
Xalkori has been used to treat ALK rearranged lung cancer and is safe and
relatively non-toxic.

4. 2: Targetability of resistance mutations
Presented by: Pasi A. Jänne
Response rate* in central T790M+
• ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC
• Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%)
20 mg 40 mg 80 mg 160 mg 240 mg
N (107) 10 29 34 28 6
ORR 50% 62% 68% 64% 83%
Best percentage change from baseline in target lesion: all evaluable T790M+ patients, Part B
*Includes confirmed responses and responses awaiting confirmation; # represents imputed values.
Population: all dosed central T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD or PD), N=107 (from 120
T790M+ patients, 13 patients with a current non-evaluable response are not included).
QD, once daily; central T790M+, T790M positive by central laboratory testing
Best percentage change from baseline in target lesion:
T790M+ evaluable patients, expansion cohorts only (N=107)
40 mg QD
80 mg QD
160 mg QD
240 mg QD
20 mg QD
40
20
-20
-40
-60
-80
-100
0
# #
D D
D D
D
D DD D
D D
D D
D D
D
D D
D D
D D
D
In both EGFR and ALK driven
tumors, resistance to tablet
tyrosine kinase inhibitors inevitably
develops. In most cases the
mechanism is the development of a
further mutation within the tumor.
Now several inhibitors targeting
resistance mutations have shown
significant promise.
The plots shown detail the EGFR
T790M inhibitor AZD 9291 (top)
and the ALK inhibitor Zykadia
(ceritinib; bottom).
Both of these drugs demonstrate
efficacy in both initial and
subsequent treatment of EGFR
mutated and ALK rearranged
NSCLC, indicating they work after
resistance develops to other
inhibitors.

5. 1: Immunotherapy
PDL-1 is used by tumor cells to evade the immune system. Once it is blocked,
immune cells are able to see and attack the tumor cells. Of note, PDL-1 is not a
static marker. It can be induced and may explain why between 9-20% of tumors that
are negative, still respond to the inhibitors.
PD-1 inhibitors are now being trialed in combination with TKIs, chemotherapy and
other immunotherapies.
The exciting responses appear durable and have minimal toxicity compared to
chemotherapy.
Response
Note bw 9-20% PD-L1 negative respond
Immune therapy has finally
shown exciting promise in
NSCLC through the
inhibition of PD-1 or PDL-1.
Several trials have now
reported benefit in
patients who are both
positive for the marker
PDL-1 (summarized in this
table).