using non-targeted therapies in targeted lung cancer populations
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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-PD-1/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
4
September 2011 January 2012
EML4-ALK Translocations in NSCLC
EML4-ALK frequency:
~4% (64/1709)
Primarily lung adenocarcinoma
EML4-ALK frequency:
~4% (64/1709)
Primarily lung adenocarcinoma
Soda et al., Nature 448: 561-566, 2007 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)
161Lee et al., Lung Cancer 2013, 79(1); 2Hanna et al., JCO 2004
Pemetrexed may have significant benefit for ALK+ pts
17Berge 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
PF
S p
rob
abili
ty
Erlotinib (n=86) Chemotherapy (n=87)
HR=0.37 (0.25–0.54)Log-rank p<0.0001
Time (months)
0 3 6 9 12 15 18 21 24 27 30 33
Data cut-off: 26 Jan 2011
1.0
0.8
0.6
0.4
0.2
09.75.2
Slide courtesy of Tony Mok, ASCO discussant. Rosell R, et al. J Clin Oncol. 2011;29(suppl): abstr# 7503.
EGFR Mutation+ NSCLC and Erlotinib
Day 0 4 months
25 months
Chemotherapy in unselected pts
21Schiller et al., N Engl J Med 2002;346:92-8.)
Chemotherapy may be more effective in EGFR mutants than in wt patients
Study Response RateIPASS 71% vs. 47%OPTIMAL 83% vs. 36%NEJ 002 74% vs. 31%WJTOG 3405 62% vs. 31%EURTAC 58% vs. 15%
22Chemo in BOLD
Pooled analysis of clinical outcome for EGFR TKI treated ‐patients with EGFR mutation positive NSCLC‐
Journal of Cellular and Molecular Medicine6 AUG 2014 DOI: 10.1111/jcmm.12278http://onlinelibrary.wiley.com/doi/10.1111/jcmm.12278/full#jcmm12278-fig-0002
24
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
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
27Wu et al., Lancet Oncol 2013; 14: 777–86
Median PFS 16.8 v 6.9 months
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
29Herbst et al., Lancet 2011 May 28;377(9780):1846-54
Study design
Presented By Terufumi Kato at 2014 ASCO Annual Meeting
- Phase 2 trial
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 non-trivial 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 NSCLCResponse 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
38Akbay et al., Can Disc 2013, 3, 1355; D’Incecco et al., ELCC 2914
PDL-1
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
39Rizvi et al., ASCO Proc 2014, Abst,
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!