Is NSCLC Becoming a Chronic Disease?

Paul A. Bunn, Jr, MDDistinguished Professor and Dudley Chair

University of Colorado Cancer CenterAurora, Colorado, United States

Q1: Which of the following statements regarding EGFR-mutant or ALK-rearranged NSCLC is FALSE?

1. To determine EGFR and ALK status for initial treatment selection, primary tumors or metastatic lesions are equally suitable for molecular testing

2. Deletions in exon 19 and the point mutation of L858R constitute about 90% of all EGFR-activating mutations

3. ORR to first/second generation EGFR TKIs is 60%-70%, but most of the patients progress after 10-13 months of therapy

4. Afatinib compared to chemotherapy significantly improved survival in patients with tumors harboring exon 19 del or L858R mutation

5. The CNS is the most common site of progression in patients with ALK-rearranged NSCLC treated with crizotinib

NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase;ORR, overall response rate; TKI, tyrosine kinase inhibitor; CNS, central nervous system

Q2: Do you think that for patients diagnosed with metastatic lung adenocarcinoma, testing for EGFR mutations and ALKrearrangements should be performed as part of multiplex next-generation sequencing?

1. Yes2. No; based on currently approved treatment options we

should use recommended companion diagnostic assays

3. Uncertain

Is NSCLC Becoming a Chronic Disease?Timeline of Historical Milestones in NSCLC Management

Thomas A, et al. Nat Rev Clin Oncol. 2015 May 12 [Epub ahead of print].

Lindeman NI, et al. J Mol Diagn. 2013;15(4):415-453; Leighl NB et al. J Clin Oncol. 2014 Nov 10;32(32):3673-3679.

Testing for EGFR Mutations and ALKRearrangements Is Now Routine

2015 Treatment AlgorithmNonsquamous

DriverNonsquamous

No DriverSquamous LCNE

PS 0-3 PS 0-2 PS 0-2 PS 0-21st Line EGFR +

Gefitinib, Erlotinib, AfatinibPlatinum doublet (Pem,Taxane) ±Bevacizumab

Platinum doublet (Gem, Taxane) ±Necitumumab

Etop+ Platinum

ALK/ROS1+CrizotinibBRAF+ Debrafenib/TrametinibRET, MET, HER2, NTRAK+ specific TKI

Maintenance Continue TKI Bev, Pem, ErlotinibOr none

None? Doce, Gem, Erlotinib

None

2nd/3rd Line 2nd/3rd-generation TKI then chemotherapy

NivolumabDoce ± RamucirumabErlotinib

Nivolumab,Doce ± RamErlotinib

CAV, Irinotecan, Taxane, Gem

Determine Performance Status, Histology, and Presence of Driver Mutations

LCNE, Large cell neuroendocrine (LCNE) carcinomas; TKI, tyrosine kinase inhibitor; Pem, pemetrexed; Gem, gemcitabine; Etop, etoposide; Doce, docetaxel; Ram, ramucirumab

Approved in 2015 Not yet approved

Randomized Trials of EGFR TKI vs Chemotherapy in 1st-Line Therapy

Study ORR,TKI vs CT

PFS,mo

HR

EURTAC1 58% vs 15% 9.7 vs 5.2 0.37OPTIMAL2 83% vs 36% 13.7 vs 4.6 0.16NEJ 0023 74% vs 31% 10.8 vs 5.4 0.32WJTOG 34054 62% vs 32% 9.2 vs 6.3 0.49IPASS5 71% vs 47% 9.8 vs 6.4 0.48LUX LUNG 36 56% vs 23% 11.1 vs 6.9 0.58

LUX LUNG 67 67% vs 23% 11.0 vs 5.6 NR

There are no survival differences in any of the trials presumably because of crossover effects.1. Rosell R, et al. Lancet Oncol. 2012;13(3): 239-246; 2. Zhou C, et al. Lancet Oncol. 2011;12(8):735-742; 3. Maemondo M, et al. N Engl J Med. 2010;362(25):2380-2388; 4. Mitsudomi T, et al. Lancet Oncol. 2010;11(2):121-128; 5. Mok TS, et al. N Engl J Med. 2009;361(10):947-957; 6. Sequist LV, et al. J Clin Oncol. 2013;31(27):3327-3334; 7. Wu YL, et al. Lancet Oncol. 2014;15(2):213-222.

Erlotinib Gefitinib Afatinib

LUX-Lung 3 and 6 Exploratory Combined OS Analysis: Del19 and L858R

Yang JC, et al. Lancet Oncol. 2015;16(2): 141-151.

Del19

• Is afatinib better than gefitinib in patients with EGFR mutation?

Advanced NSCLC• Adenocarcinoma• EGFR mut+• First-line treatment• PS 0-1

RANDOMIZE

Afatinib 40 mg qd

Gefitinib 250 mg qd

1

1

N = 264 patients

Sample size increased

to 319

Second- or First-Generation TKI?LUX Lung 7 Randomized Phase IIb Study

National Institutes of Health. www.clinicaltrials.gov/ct2/show/NCT01466660. Accessed 10 August 2015.

Accrual completed!

RECIST Criteria for Progressiona Signal to Stop the EGFR TKI?

Mok T. Presented at: 11th Annual Targeted Therapies of the Treatment of Lung Cancer; February 23-26, 2011: Santa Monica, California.

Trials Treating Beyond RECIST ProgressionSu

rviv

al P

roba

bilit

y

Progression-Free Survival Time, Months

1.0

0

0.8

0.6

0.4

0.2

0.010 20 30

PFS1PFS2

11.0 months 14.1 months

Study N PFS1, months PFS2, months

Colorado 25 10 6.2MSKCC 18 19 10

Park K, et al. Ann Oncol. 2014;25(Suppl 4): Abstract 1223O.

Weickhardt AJ, et al. J Clin Oncol. 2012;30(suppl): Abstract 7526; Yu HA, et al. J Clin Oncol. 2012;30(suppl): Abstract 7527.

RADIANT Trial: DFS and OS for EGFR M+ Subset

DFS OS

Shepard F, et al. J Clin Oncol. 2015;33(suppl): Abstract 7539.

• ALK (anaplastic lymphoma kinase) is a receptor tyrosine kinase activated by chromosomal rearrangement in NSCLC, leading to constitutive kinase activation and oncogene addiction.

• ALK rearrangements are identified in 3%-7% of lung adenocarcinomas, commonly from younger never-smoking patients, identified by FISH, IHC, or Nex Gen sequencing (NGS). Crizotinib is a potent ALK inhibitor.

ALK Rearrangement in NSCLC

KinaseIC50 (nM)

mean* Selectivity

ratioc-MET 8 –ALK 40-60 5-8X

ROS1 60 7X

ALK EML4

ALK

EML4

EML4

ALK5 5

53

Camidge DR. Clin Cancer Res. 2010;16(22):5581-5590.

3 3

PROFILE 10011

(N = 143)

PROFILE10052

(N = 259)

PROFILE 10073

(N = 172)

PROFILE10144

(N = 172)Phase 1 2 3 3

Line of therapy Any line 2nd line and beyond

2nd line 1st line

ORR 61% 60% 65% 74%PFS, median (months)

9.7 8.1 7.7 10.9

Survival probability at 12 months

75% NA 70% NA

1. Camidge DR, et al. Lancet Oncol. 2012;13(10):1011-1019. 2. Kim D-W, et al. J Clin Oncol. 2012;30(15S): Abstract 7533. 3. Shaw AT, et al. N Engl J Med. 2013;368(25):2385-2394. 4. Mok T, et al. N Engl J Med , 2014; 371 (23):2167-2177

Crizotinib Studies in ALK-Positive NSCLC

Previously Untreatedfor Brain Metastasis

(n = 109)

Previously Treated for Brain Metastasis

(n = 166)

No Brain Metastasis Detected(n = 613)

n Outcome n Outcome n Outcome

Target lesions only 4 9% 8 13% 52 21%

Non-target lesions or new lesions (n = 43) (n = 54) (n = 201)

Intracranial (IC)/Brain 30 70% 39 72% 51 25%

Lung 3 7% 6 11% 25 12%

Bone 4 9% 8 15% 25 12%

Liver 2 5% 3 6% 47 23%

Other sites not included in this table

The Brain Is the Most Common Site of Relapse on Crizotinib

Costa DB, et al. J Torac Oncol. 2013;8(Suppl 2): Abstract MO07.02.

Status ORRPFS,

monthsDR,

monthsCNS Activity

RR

Ceritinib1

(LDK378)Novartis

Approved55%

(N = 163)6.9 7.4

Yes(50%)

Alectinib2

(CH5424802)Roche

Breakthrough therapy

designationPhase II/III

50%(N = 122)

8.9 11.2 Yes

(57%)

Brigatinib3

(AP26113)Ariad

Phase I/II71%

(N = 70)13.4 9.3

Yes(53%)

PF-064639224

Pfizer Phase I/II44%

(N = 34)Most >1 TKI

NR NRYes

(36%)

Next Generation ALK Inhibitors in Crizotinib Resistance

1. Kim D-W, et al. J Clin Oncol 2014;32(5S): Abstract 8003; 2. Ou S-H, et al. J Clin Oncol 2015;33(Suppl): Abstract 8008; 3. Camidge DR, et al. J Clin Oncol 2015;33(Suppl): Abstract 8062; 4. Shaw AT, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8018.

Crizotinib in ROS1-Rearranged NSCLC

Shaw AT, et al. N Engl J Med , 2014; 371 (21):1963-1971.

PFS

Crizotinib in MET-Positive NSCLC Low MET,

n = 2Intermediate MET, n = 6

High MET,n = 6

ORR, % (95% CI)b 0 (0–84) 17 (0–64) 67 (22–96)

Best response, n (%)Complete responsePartial responseStable diseaseObjective progression

000

2 (100)

01 (17)4 (67)1 (17)

1 (17)3 (50)1 (17)1 (17)

Median duration of response, weeks (range)c

– 16 73.6(24.1–128.0)

Duration of stable disease, n (%)d

0–<3 months3–<6 months

––

3 (75)1 (25)

01 (100)

ORR, objective response rate

aRECIST v1.0, based on investigator assessmentbComplete response + partial response; CI based on exact F distributioncDescriptive statistics are presented based on all respondersdAmong patients with stable disease as best overall response

Camidge DR, et al. J Clin Oncol. 2014;32(5S): Abstract 8001.

Early Results With Other Targeted TherapyDriver Alteration Therapy ORR mPFS, months

ALK (1st line) Alectinib 94%** 28**ROS1 (any line) Crizotinib 60% 19.2MET* (any line) Crizotinib 67% 17MET exon14 splice Crizotinib and Cabozantinib 4/5 NR

BRAF (2nd line) Dabrafenib 32% 5.5BRAF (2nd line) Dabrafenib + Trametinib 63% NRHER2 (any line) Dacomitinib 3/26 = 12% 3HER2 (2nd line) Neratinib + Torisel 1/6 NRRET Cabozantinib, Alectinib 2/3 NRRET Many NR NRTRK LOXO101, RXDX101 NA NA

*High MET expression; **First-line Japanese study

Kris MG, et al. JAMA. 2014;311(19):1998-2006.

Using Multiplexed Assays of Oncogenic Drivers in Lung Cancer to Select Targeted Drugs

Driver detected –Targeted Rx

Survival by Subgroup

Using Multiplexed Assays of Oncogenic Drivers in Lung Cancer to Select Targeted Drugs

Driver detected –No targeted Rx

No driver

Kris MG, et al. JAMA. 2014;311(19):1998-2006.

Brahmer J et al. N Engl J Med 2015;373(2):123-135.

Nivolumab vs Docetaxel in 2nd-Line SqCLC: Overall Survival

Q3: What treatment would you recommend for a 41yo otherwise healthy woman, never smoker, who is diagnosed with symptomatic EGFR mutation−positive (L858R) stage IV lung adenocarcinoma (FDG avidity in left upper lobe, left hilum, ipsilateral mediastinal lymph nodes, and left pleura)? Her PS is 0.

1. First-generation TKI ( eg, erlotinib, gefitinib)2. Second-generation TKI (eg, afatinib)3. Erlotinib + bevacizumab4. Chemotherapy→ erlotinib5. Clinical trial with third-generation TKI