Second line therapy for nsclc

New Perspectives on Second-Line Therapy for NSCLC

Tony Mok, MD (Moderator)Professor, Department of Clinical Oncology,

Chinese University of Hong Kong;Honorary Consultant, Prince of Wales Hospital,

Hong Kong, China

Overview

• Discuss the current standards of care for second-line therapy in patients with advanced NSCLC

• Examine the unique and unmet needs of patients without targetable activating mutations

• Review emerging research findings on second-line therapy in NSCLC and their implications for clinical practice

NSCLC = non-small cell lung cancer

Luis Paz-Ares Rodríguez, MD, PhDChair, Department of Oncology,Seville University Hospital,Seville, Spain

Panelists

Martin Reck, MD, PhDHead, Department of Thoracic Oncology,Hospital Grosshansdorf, Grosshansdorf, Germany

Single-Driver Mutations in NSCLC

Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer. Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

NSCLC Without Targetable Mutations: An Unmet Need

Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer. Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

NSCLC Histology

Howlader N, et al (eds). SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, 2013.

Gene IncidenceKRAS 15% 25%

EGFR 10% 35%

ALK 3% 7%

MET 2% 4%

HER2 2% 4%

BRAF 1% 3%

PIK3CA 1% 3%

AKT1 1%

MAP2K1 1%

NRAS 1%

ROS1 1%

RET 1%

Single-Driver Mutations in NSCLC

Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer.Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

Outcomes With First-Line Doublet Therapy: ECOG 1594

Schiller JH, et al. New Engl J Med. 2002;346:92-98.

MonthsOS = overall survival; PFS = progression-free survival

Outcomes With First-Line Triplet Therapy: ECOG 4599

Sandler A, et al. New Engl J Med. 2006;355:2542-2550.

MonthsCI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio

Study Treatment ArmsMedian OS

(mos)1-Year

Survival

TAX 317[a]Docetaxel (N = 103) 7.0 37.0%

Best supportive care (N = 100) 4.6 12.0%

Hanna et al. 2004[b]Pemetrexed (N = 283) 8.3 29.7%

Docetaxel (N = 288) 7.9 29.7%

INTEREST[c]Gefitinib (N = 723) 7.6 32.0%

Docetaxel (N = 710) 8.0 34.0%

TITAN[d]

Erlotinib (N = 203) 5.3 26.0%

Chemotherapy (N = 221: 116 docetaxel, 105 pemetrexed) 5.5 24.0%

Second-Line Therapy: Options & Outcomes

a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.c. Kim ES, et al. Lancet. 2008;372:1809-1818.d. Ciuleanu T, et al. Lancet Oncol. 2012;13:300-308.

Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b]Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b]

40.2%

Adverse Event

Perc

ent R

epor

ting

Second-Line Therapy: Grade 3/4 Toxicities

a. Vamvakas L, et al. ASCO 2010.b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

Selecting Second-Line Therapy

Patient Factors

•PS•Age•Patient preference

Treatment History

•First-line regimen•Duration of response to first-line treatment

Tumor Characteristics

•Tumor burden•Histology•EGFR?•ALK?•KRAS?

Good PS + good response to first-line chemo Chemotherapy

Adenocarcinoma + targetable mutation/rearrangementTargeted therapy (erlotinib, gefitinib,crizotinib)

Wild-type or KRAS mutations Chemotherapy

PS = performance status

Second-Line Therapy: Outstanding Needs

• Options for patients with wild-type mutations (EGFR, etc)

• Predictive biomarkers

• New agents with efficacy in the second-line setting

Second-Line Therapy: Research To Date

All of these trials are against placebo only (no active comparator arm). Direct comparison is not possible. List contains examples and is not exhaustive.

In pre-treated patients, only 2 out of 15 trials to date have shown an improvement in OS

Study Treatment Median OS (mo)Tax 317 Docetaxel (D75/100) vs BSC 7.5 (D75) vs 4.6BR.21 Erlotinib vs placebo 6.7 vs 4.7JMEI Pemetrexed vs docetaxel

FAILED

Tax 320 Docetaxel (D75/100) vs ifosfamide or vinorelbine

ISEL Gefitinib vs placebo

ZODIAC Vandetanib + docetaxel vs docetaxel

ZEAL Vandetanib + pemetrexed vs pemetrexedZEST Vandetanib vs erlotinibVITAL Aflibercept + docetaxel vs docetaxel

BETA Bevacizumab + erlotinib vs erlotinib

TAILOR Docetaxel vs erlotinib, non-EGFR mutations

TITAN Docetaxel/pemetrexed vs erlotinib

Vinflunine Vinflunine vs docetaxel Topotecan Oral topotecan vs docetaxelSUN1087 Sunitinib + erlotinib vs erlotinib

DrugTarget

EGFR FGFR PDGFR VEGF VEGFRAxitinib β R-1, 2, 3Bevacizumab* BMS-690514 Brivanib R-1 R-2Cediranib α/β R-1, 2, 3Linifanib R-1, 2, 3MGCD265 Motesanib R-1, 2, 3

Nintedanib R-1, 2, 3 α/β R-1, 2, 3Pazopanib R-1, 3 α/β R-1, 2, 3Sorafenib β R-2, 3Sunitinib α/β R-1, 2, 3Vandetanib R-2, 3

Angiogenesis Inhibitors in NSCLC

* Currently approved for first-line therapy of NSCLC, in combination with a platinum and taxane

Ellis PM & Al-Saleh K. Critical Rev Onc/Hem. 2012;84:47-58.

Angiogenesis Inhibitors in NSCLC: Nintedanib• Investigational oral agent

• Can be combined with chemotherapy- Docetaxel[a]

- Pemetrexed[b]

- Paclitaxel/carboplatin[c]

- Gemcitabine/cisplatin[d]

a. Bousquet G, et al. Br J Cancer. 2011;105:1640-1645. b. Ellis PM, et al. Clin Cancer Res. 2010;16:2881-2889. c. Doebele RC, et al. Ann Oncol. 2012;23:2094-2102. d. http://clinicaltrials.gov/show/NCT01346540.

LUME-Lung 1: Trial Design

Reck M, et al. ASCO 2013.

Patients with NSCLC who have failed first-line chemotherapy

Oral nintedanib +Chemotherapy (docetaxel)

Placebo +Chemotherapy (docetaxel)

Primary endpoint: PFSKey secondary endpoint: OS

Results presented at ASCO 2013

Second-line treatment

Randomization

Number of docetaxel cycles not restrictedMonotherapy with nintedanib/placebo allowed after ≥ 4 cycles

LUME-Lung 1: Inclusion Criteria


Inclusion criteria:

•Male or female patients, aged ≥ 18 years

•Patients with IIIB/IV or recurrent NSCLC (all histologies)

•Progression after prior first-line chemotherapy

•ECOG score of 0 and 1

1314 patients: recruitment completed

100

80

60

40

20

0 0 2 4 6 8 10 12 14 16 18

LUME-Lung 1: PFS (All Patients)Pr

obab

ility

of s

urvi

val

with

out p

rogr

essi

on (%

)

Time (months)

Nintedanib + docetaxel(n = 655)

Placebo + docetaxel(n = 659)

Median, mo 3.4 2.7

HR (95% CI) 0.79 (0.68 to 0.92)

P .0019


100

80

60

40

20

0

0 4 8 12 16 20 24 28 32 36

Time (months)

Prob

abili

ty o

f sur

viva

l (%

)LUME-Lung 1: OS (All Patients)




Median, mo 10.1 9.1

HR (95% CI) 0.94 (0.83 to 1.05)

P .2720

100

80

60

40

20

00 4 8 12 16 20 24 28 32 36

52.7%

44.7% 25.7%

19.1%

LUME-Lung 1: OS (Adenocarcinoma Patients)Pr

obab

ility

of s

urvi

val (

%)

Time (months)




Median, mo 12.6 10.3

HR (95% CI) 0.83 (0.70 to 0.99)

P .0359

LUME-Lung 1: Adverse Events of Special Interest


Adverse Events, Grade ≥ 3 (incidence ≥ 1%)

Adverse Events, All Grades(incidence ≥ 15%)

Patie

nts

Repo

rting

(%)

Nintedanib + docetaxel

Placebo + docetaxel

LUME-Lung 1: Summary

• Met primary endpoint of delaying tumour growth following failure of first-line therapy

• Showed a significant survival benefit in patients with adenocarcinoma compared with an active comparator

• Well tolerated with manageable safety profile

Combination Therapy With Angiogenesis Inhibitors: First-Line vs Second-Line Outcomes

a. Sandler A, et al. New Engl J Med. 2006;355:2542-2550.b. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011.

OS

(mo)

LUME-Lung 1(Adenocarcinoma subset)

HR, 0.79;95% CI, 0.67 to 0.92

P = .003

HR, 0.83;P = .0359

[a] [b]

LUME-Lung 1: OS by Histology

Adenocarcinoma subset



Median, mo 10.1 9.1

HR (95% CI) 0.94 (0.83 to 1.05)

P .2720




Median, mo 12.6 10.3

HR (95% CI) 0.83 (0.70 to 0.99)

P .0359

All patients

Prob

abili

ty o

f sur

viva

l (%

)

100

80

60

40

20

00 4 8 12 16 20 24 28 32 36 0 4 8 12 16 20 24 28 32 36

• Benefit demonstrated regarding PFS

• OS benefit seen in patients with large tumors

• Role of FGFR amplification in squamous cell carcinoma requires further investigation

Nintedanib in Squamous Cell Carcinoma: Outstanding Issues

LUME-Lung 1: Toxicities Associated with VEGF/VEGFR Inhibitors

Adverse event

Nintedanib + docetaxel Placebo + docetaxel

All grades%

Grade ≥ 3%

All grades%

Grade ≥ 3%

Bleeding 14.1 2.3 11.6 1.8

Thromboembolism 5.1 2.1 4.6 3.1

Hypertension 3.5 0.2 0.9 0

VTE 2.8 1.2 1.5 1.1

ATE 0.6 0.5 1.4 0.6

GI perforation 0.5 0.2 0.5 0.5


ATE = arterial thromboembolism; GI = gastrointestinal; VTE = venous thromboembolism

• Combination vs monotherapy

Biomarkers to assist in patient selection

Role of clinical factors, histology, etc

Looking Forward: Research Needs

LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients


CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease

Angiogenesis Inhibitors in the Second-Line Setting: LUME-Lung 1 vs ZODIAC

a. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011.b. Herbst RS, et al. Lancet Oncol. 2010;11:619-626.

OS

(mo)

LUME-Lung 1[a]

HR, 0.9495% CI, 0.83 to 1.05

P = .2720

HR, 0.9197.52% CI, 0.78 to 1.07

P = .196

[b]

Angiogenesis Inhibitors in the Second-Line Setting: LUME-Lung 2

Entry Criteria•Stage IIB/IV or recurrent NSCLC•Non-squamous histology•Relapsed/failed one prior line of chemotherapy•Measurable lesion(s)•ECOG PS 0 or 1

Target enrollment: 1300Nintedanib + pemetrexed

(N = 353)Placebo + pemetrexed

(N = 360)

Disease Progression Disease Progression

• Study was halted after interim analysis suggested the primary endpoint of PFS would not be met

• Ongoing patients were unblinded and follow-up continued per protocol

Hanna NH, et al. ASCO 2013.

Randomization 1:1

LUME-Lung 2: Centrally-Reviewed PFS

Nintedanib + pemetrexed

(n = 353)

Placebo + pemetrexed

(n = 360)

Median PFS, mo 4.4 3.6

HR (95% CI) 0.83 (0.70 to 0.99)

Log-rank p value .0435

Hanna NH, et al. ASCO 2013.

Time from randomization (months)

Estim

ated

pati

ents

aliv

e an

d p

rogr

essi

on-f

ree

(%)

Docetaxel in the Second-Line Setting: Survival Trends

OS

(mo)

TAX 317[a] Hanna et al. 2004[b]

INTEREST[c]

a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597. c. Kim ES, et al. Lancet. 2008;372:1809-1818.d. Herbst RS, et al. Lancet Oncol. 2010;11:619-626.e. Reck M, et al. ASCO 2013.

LUME-Lung 1[e]

ZODIAC[d]

LUME-Lung 1: Patient Characteristics

CharacteristicNintedanib + docetaxel

(N = 655) Placebo + docetaxel

(N = 659)

Age < 65 years 69.5% 67.5%

Current/former smoker 74.8% 75.6%

Histology

Adenocarcinoma 49.2% 51.0%

Squamous cell carcinoma 42.1% 42.2%

Other 8.7% 6.7%

Prior therapy

Platinum 95.9% 96.5%

Bevacizumab 4.1% 3.5%


• Sequencing of therapy?

• Treatment beyond progression?

• Impact of maintenance therapy on subsequent treatment decisions?

Clinical Questions

LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients


• A majority of NSCLC patients do not have targetable mutations

• Second-line treatment options for these patients have historically been limited

• Combination therapy with the angiogenesis inhibitor bevacizumab has been successful in the first-line setting

• In the second-line setting, combination therapy with the angiogenesis inhibitor nintedanib has recently been shown to

Prolong PFS in patients with NSCLC, regardless of histology

Improve OS in patients with adenocarcinoma

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Second line therapy for nsclc