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!

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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!