Using Non-targeted Therapies in
Targeted Lung Cancer Populations
Nathan Pennell, M.D., Ph.D.
September 6, 2014
Objectives
• Discuss the role of chemotherapy in
molecularly defined populations
• Discuss the addition of chemo and/or
bevacizumab (Avastin) to targeted therapy
• Do immune checkpoint inhibitors (anti-PD1/PDL-1) have a role in treatment of
molecularly defined populations?
2
Why would anyone use
chemotherapy in an EGFR
mutant or ALK+ lung cancer
patient?
3
Case 1 – 24M with ALK+ NSCLC
• Presented in 2011 with extensive adenopathy
and malignant effusions
• Started crizotinib with CR
September 2011
January 2012
4
EML4-ALK Translocations in NSCLC
EML4-ALK
frequency:
~4% (64/1709)
Primarily lung
adenocarcinoma
Soda et al., Nature 448: 561-566, 2007
First line chemotherapy versus crizotinib in
ALK+ NSCLC (Mok ASCO 2014)
Case 1 – 24M with ALK+ NSCLC
• Presented in 2011 with extensive adenopathy
and malignant effusions
• Crizotinib with CR
• 8 months until progression
• Ceritinib (on trial as LDK378) CR
• 6 months until progression
7
What are the options?
• Third generation
TKI?
• Clinical trial, i.e.
HSP90?
• How about
chemotherapy?
8
Chemotherapy vs. BSC:
Meta-analysis summary
Chemo
Hazard Ratio
MST (m)
1-yr OS (%)
Alkylating
1.26
-1
-6
Vinca/VP16
0.87
+1
+4
Cisplatin
0.73
+2
+10
BMJ 311: 899, 1995
Platinum doublet chemotherapy
in nonsquamous patients
Scagliotti GV et al, JCO 2008;26(21):3543-51
Case 1 – 24M with ALK+ NSCLC
• Presented in 2011 with extensive adenopathy
and malignant effusions
• Crizotinib with CR
• 8 months until progression
• Ceritinib (on trial as LDK378) CR
• 6 months until progression
• Started carboplatin, pemetrexed, and
bevacizumab followed by pem/bev
maintenance in late 2012…
11
Maintenance pemetrexed and
bevacizumab
December 2012
March 2013
June 2014 – 18 months on chemo
13
Case 2 – 36 year old woman with
hip pain August 2008
• Scans showed
destructive bone lesion
in pelvis
• Biopsy showed lung
adenocarcinoma
• Started on carboplatin,
paclitaxel, bevacizumab
in late 2008
• Progressed in summer
2009, started
pemetrexed
14
Case 2 – Now 42 year old woman
without hip pain
• On intermittent
pemetrexed until 2012
(2.5 years) when test
showed she was ALK+
• 4 treatment breaks
ranging from 6-12
months
• No ALK directed therapy
yet!
June 2014
Pemetrexed may have significant
benefit for ALK+ pts
• 65 ALK+ patients response to chemotherapy
retrospectively analyzed1
• ORR to pem 34% (9% in unselected NSCLC pts2)
1Lee
et al., Lung Cancer 2013, 79(1); 2Hanna et al., JCO 2004
16
Pemetrexed may have significant
benefit for ALK+ pts
17
Berge et al., Clin Lung Cancer. Nov 2013; 14(6): 636–643.
Erlotinib vs. CT in Advanced NSCLC Patients With EGFR
Mutations: Interim Results of the European Erlotinib Versus CT
(EURTAC) Phase III Randomized Trial
1.0
Erlotinib (n=86)
Chemotherapy (n=87)
PFS probability
0.8
HR=0.37 (0.25–0.54)
0.6
Log-rank p<0.0001
0.4
0.2
0
0
3 5.2
6
9 9.7 12
15
18
21
24
27
Time (months)
Data cut-off: 26 Jan 2011
Slide courtesy of Tony Mok, ASCO discussant.
Rosell R, et al. J Clin Oncol. 2011;29(suppl): abstr# 7503.
30
33
EGFR Mutation+ NSCLC and
Erlotinib
Day 0
4 months
25 months
Chemotherapy in unselected pts
21
Schiller et al., N Engl J Med 2002;346:92-8.)
Chemotherapy may be more effective
in EGFR mutants than in wt patients
Study
IPASS
OPTIMAL
NEJ 002
WJTOG 3405
EURTAC
Response Rate
71% vs. 47%
83% vs. 36%
74% vs. 31%
62% vs. 31%
58% vs. 15%
Chemo in BOLD
22
Pooled analysis of clinical outcome for EGFR TKI‐treated
patients with EGFR mutation‐positive NSCLC
Journal of Cellular and Molecular Medicine
6 AUG 2014 DOI: 10.1111/jcmm.12278
http://onlinelibrary.wiley.com/doi/10.1111/jcmm.12278/full#jcmm12278-fig-0002
Conclusion: Chemo is effective in
EGFR mutant and ALK+ NSCLC
• Chemotherapy is
effective and
should be
considered in
patients when
TKIs fail
JJ (CHOP calendar) http://mbvshl.blogspot.com/2013/02/round-9-looking-good-billy-ray-feeling.html
24
Can we improve on the effectiveness of TKIs
up front by adding non-targeted agents?
Chemotherapy?
Bevacizumab?
(anti-VEGF)
25
EGFR TKIs + Chemotherapy = Not
better than chemo alone?
• 4 large phase 3 trials with gefitinib (INTACT
1/2) and erlotinib (TRIBUTE/TALENT)
• All showed no evidence that chemo + TKI was
better in unselected NSCLC patients
• But what about EGFR mutation+ patients?
26
FASTACT 2: Chemotherapy plus
erlotinib versus chemotherapy
Median PFS 16.8 v 6.9 months
Wu et al., Lancet Oncol 2013; 14: 777–86
27
Chemotherapy plus TKI in EGFR
mutation+ pts
• Promising signs but need
randomized trial of chemo plus TKI
versus TKI alone
• Chinese study ongoing of carboplatin
+ pemetrexed (CP), CP + gefitinib,
and gefitinib (NCT02148380)
28
Does adding bevacizumab to TKIs
improve efficacy?
• BeTa phase 3 trial of erlotinib +/- bev
• Not significant but promising trend towards
better survival
Herbst et al., Lancet 2011 May 28;377(9780):1846-54
29
- Phase 2 trial
Study design
Presented By Terufumi Kato at 2014 ASCO Annual Meeting
Primary endpoint: PFS by independent review
Presented By Terufumi Kato at 2014 ASCO Annual Meeting
PFS by EGFR mutation type
Presented By Terufumi Kato at 2014 ASCO Annual Meeting
AEs (incidence >20%)
Presented By Terufumi Kato at 2014 ASCO Annual Meeting
Conclusions: Adding to TKIs
• Chemotherapy plus EGFR TKI results in a
promising PFS compared to chemo
• Bev plus erlotinib also results in a promising
PFS compared to TKI alone
• Adding chemo or bev to the TKI adds a nontrivial amount of side effects and risk (and
cost)
• Evidence for improved survival needed before
it becomes SOC compared to TKI alone
34
Immunotherapy: i.e. Checkpoint
inhibitors (anti-PD-1 and PDL-1)?
35
Checkpoint Inhibitors in Development in NSCLC
Response rates consistently ~20%
Duration of Response and Overall Survival with Nivolumab in Pretreated Advanced NSCLC
Presented By Scott Gettinger at 2014 ASCO Annual Meeting
Checkpoint Inhibitors in EGFR
mutant population?
• In mouse models of
EGFR mutant NSCLC
PDL-1 was high and
anti-PD1 was quite
effective1
• In a cohort of 56 EGFR
mutant NSCLCs, 71%
were PDL-1 positive
(compared to about
50% in unselected
NSCLC)2
PDL-1
38
Akbay et al., Can Disc 2013, 3, 1355; D’Incecco et al., ELCC 2914
Checkpoint Inhibitors in EGFR
mutant population?
• In a small phase 2 trial, 20 pts with EGFR
mutant NSCLC with AR were treated with
nivolumab + erlotinib with ORR of 15%2
Rizvi et al., ASCO Proc 2014, Abst,
39
Conclusions: Immunotherapy
• Too early to say whether checkpoint inhibitors
will play a more significant role in EGFR
mutant and ALK+ NSCLC treatment, BUT
• No reason to think they won’t be at least as
effective as in unselected patients!
40
Take Home Points
• While TKIs are the most effective treatment
for genetically defined NSCLC pts,
chemotherapy can be an effective alternative
• Adding chemotherapy or bevacizumab to TKIs
may make TKIs more effective, but the jury is
still out
• Immunotherapy is enormously promising in all
types of lung cancer!
41
Thank You!