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

Take Home Messages

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