Nathan Pennell MD PhD September 6 2014 Objectives Discuss the role of chemotherapy in molecularly defined populations Discuss the addition of chemo andor bevacizumab Avastin to targeted therapy ID: 513694
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Using Non-targeted Therapies in Targeted Lung Cancer Populations
Nathan Pennell, M.D., Ph.D.
September 6, 2014Slide2
ObjectivesDiscuss the role of chemotherapy in molecularly defined populationsDiscuss the addition of chemo and/or bevacizumab (Avastin) to targeted therapyDo immune checkpoint inhibitors (anti-PD-1/PDL-1) have a role in treatment of molecularly defined populations?
2Slide3
Why would anyone use chemotherapy in an
EGFR mutant or ALK+ lung cancer patient?3Slide4
Case 1 – 24M with ALK+ NSCLCPresented in 2011 with extensive adenopathy and malignant effusionsStarted crizotinib with CR
4September 2011
January 2012Slide5
EML4-ALK Translocations in NSCLC
EML4-ALK frequency: ~4% (64/1709) Primarily lung adenocarcinoma
Soda et al., Nature 448: 561-566, 2007 Slide6
First line chemotherapy versus crizotinib in ALK+ NSCLC (Mok ASCO 2014)Slide7
Case 1 – 24M with ALK+ NSCLCPresented in 2011 with extensive adenopathy and malignant effusionsCrizotinib with CR 8 months until progressionCeritinib (on trial as LDK378) CR
6 months until progression7Slide8
What are the options?Third generation TKI?Clinical trial, i.e. HSP90?How about chemotherapy?
8Slide9
Chemotherapy vs. BSC: Meta-analysis summary
ChemoHazard RatioMST (m)
1-yr OS (%)Alkylating1.26
-1
- 6
Vinca/VP16
0.87
+1
+ 4
Cisplatin
0.73
+2
+10
BMJ 311: 899, 1995Slide10
Platinum doublet chemotherapy in nonsquamous patients
Scagliotti GV et al, JCO 2008;26(21):3543-51 Slide11
Case 1 – 24M with ALK+ NSCLCPresented in 2011 with extensive adenopathy and malignant effusionsCrizotinib with CR 8 months until progressionCeritinib (on trial as LDK378) CR
6 months until progressionStarted carboplatin, pemetrexed, and bevacizumab followed by pem/bev maintenance in late 2012…11Slide12
Maintenance pemetrexed and bevacizumab
December 2012March 2013Slide13
June 2014 – 18 months on chemo13Slide14
Case 2 – 36 year old woman with hip pain August 2008Scans showed destructive bone lesion in pelvisBiopsy showed lung adenocarcinomaStarted on carboplatin, paclitaxel, bevacizumab in late 2008Progressed in summer 2009, started pemetrexed
14Slide15
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 monthsNo ALK directed therapy yet!
June 2014Slide16
Pemetrexed may have significant benefit for ALK+ pts65 ALK+ patients response to chemotherapy retrospectively analyzed1ORR to pem 34% (9% in unselected NSCLC pts2)
161Lee et al., Lung Cancer 2013, 79(1); 2Hanna et al., JCO 2004Slide17
Pemetrexed may have significant benefit for ALK+ pts17
Berge et al., Clin Lung Cancer. Nov 2013; 14(6): 636–643. Slide18Slide19
Erlotinib vs. CT in Advanced NSCLC Patients With EGFR Mutations: Interim Results of the European Erlotinib Versus CT (EURTAC) Phase III Randomized Trial
PFS probabilityErlotinib (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
0
9.7
5.2
Slide courtesy of Tony Mok, ASCO discussant.
Rosell R, et al.
J Clin Oncol
. 2011;29
(
suppl): abstr# 7503.Slide20
EGFR Mutation+ NSCLC and Erlotinib
Day 0
4 months
25 monthsSlide21
Chemotherapy in unselected pts21
Schiller et al., N Engl J Med 2002;346:92-8.)Slide22
Chemotherapy may be more effective in EGFR mutants than in wt patients
StudyResponse RateIPASS71% vs. 47%OPTIMAL83% vs. 36%NEJ 00274% vs. 31%WJTOG 340562% vs. 31%EURTAC58% vs. 15%
22Chemo in BOLDSlide23
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-0002Slide24
Conclusion: Chemo is effective in EGFR mutant and ALK+ NSCLCChemotherapy is effective and should be considered in patients when TKIs fail
24JJ (CHOP calendar) http://mbvshl.blogspot.com/2013/02/round-9-looking-good-billy-ray-feeling.htmlSlide25
Can we improve on the effectiveness of TKIs up front by adding non-targeted agents?Chemotherapy?B
evacizumab?(anti-VEGF)25Slide26
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 patientsBut what about EGFR mutation+ patients?
26Slide27
FASTACT 2: Chemotherapy plus erlotinib versus chemotherapy27
Wu et al., Lancet Oncol 2013; 14: 777–86Median PFS 16.8 v 6.9 monthsSlide28
Chemotherapy plus TKI in EGFR mutation+ ptsPromising signs but need randomized trial of chemo plus TKI versus TKI aloneChinese study ongoing of carboplatin + pemetrexed (CP), CP + gefitinib, and gefitinib (NCT02148380)
28Slide29
Does adding bevacizumab to TKIs improve efficacy?BeTa phase 3 trial of erlotinib +/- bevNot significant but promising trend towards better survival
29
Herbst et al., Lancet 2011 May 28;377(9780):1846-54 Slide30
Study design
Presented By Terufumi Kato at 2014 ASCO Annual Meeting
- Phase 2 trialSlide31
Primary endpoint: PFS by independent review
Presented By Terufumi Kato at 2014 ASCO Annual MeetingSlide32
PFS by EGFR mutation type
Presented By Terufumi Kato at 2014 ASCO Annual MeetingSlide33
AEs (incidence >20%)
Presented By Terufumi Kato at 2014 ASCO Annual MeetingSlide34
Conclusions: Adding to TKIsChemotherapy plus EGFR TKI results in a promising PFS compared to chemoBev plus erlotinib also results in a promising PFS compared to TKI aloneAdding 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 alone34Slide35
Immunotherapy: i.e. Checkpoint inhibitors (anti-PD-1 and PDL-1)?35Slide36
Checkpoint Inhibitors in Development in NSCLCResponse rates consistently ~20%Slide37
Duration of Response and Overall Survival with Nivolumab in Pretreated Advanced NSCLC
Presented By Scott Gettinger at 2014 ASCO Annual MeetingSlide38
Checkpoint Inhibitors in EGFR mutant population?In mouse models of EGFR mutant NSCLC PDL-1 was high and anti-PD1 was quite effective1In 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-1Slide39
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,Slide40
Conclusions: ImmunotherapyToo early to say whether checkpoint inhibitors will play a more significant role in EGFR mutant and ALK+ NSCLC treatment, BUTNo reason to think they won’t be at least as effective as in unselected patients!
40Slide41
Take Home PointsWhile TKIs are the most effective treatment for genetically defined NSCLC pts, chemotherapy can be an effective alternativeAdding chemotherapy or bevacizumab to TKIs may make TKIs more effective, but the jury is still outImmunotherapy is enormously promising in all types of lung cancer!
41Slide42
Thank You!