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Conversationsin OncologySunday, 13 November 2016Kerry HotelPudong, Shanghai, China

2

Antiangiogenic Therapy: Clinical Benefit for Second-Line NSCLC Professor Myung-Ju Ahn

Presenter

Presentation Notes

Thank you chairman for kind introduction. It is my great honor to be here, I would like to thank organizing committee for giving me an opportunity to give a talk today. I would like to talk about the role of antiangiogenic therapy as second-line therapy in the treatment of NSCLC.

3

• Consultant or advisory role: Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Novartis

• Honoraria: Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Novartis

• Research funding: AstraZeneca

Disclosures

4

• Review the role of angiogenesis in NSCLC

• Discuss current approaches in the development of antiangiogenic agents for the treatment of NSCLC

• Discuss future perspectives on the use of antiangiogenic agents in NSCLC

Outline

5

Angiogenesis: A Hallmark of Cancer

Hanahan D and Weinberg RA. Cell. 2011;144:646.

Resistingcell death

Degradingcellular

energetics

Sustainingproliferativesignalling

Inducingangiogenesis

Evadinggrowth

suppressors

Avoidingimmune

destruction

Enablingreplicativeimmortality

Tumour-promoting

inflammation

Activatinginvasion andmetastasis

Genomeinstabilitymutation Antiangiogenic therapy

Regression of existing tumour vasculature

Inhibition of new vessel growth No bone marrow suppression No cumulative toxicities

Improved efficacy in combination with a

well-established safety profile

6

How does anti-angiogenic therapy work?

Jain RK. J Clin Oncol. 2013;31:2205-18.

7

FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor.1. Bergers G and Hanahan D. Nat Rev Cancer. 2008;8:592; 2. Bottsford-Miller et al. J Clin Oncol. 2012;30:4026; 3. Cooper et al. Onco Targets Ther. 2016;9:1953; 4. Hilberg et al. Cancer Res.2008;68:4774.

VEGFR Inhibition1–3 Triple Angiokinase Inhibition4

VEGFR2

Ramucirumab

Inhibition of Tumour Angiogenesis

1. Effective inhibition of tumour angiogenesis

2. Normalisation of brittle and permeable blood vessels

3. Suppression of tumour escape mechanisms

8

Historical Development of Antiangiogenic Agents

Ang = angiopoietin; FGFR = fibroblast growth factor receptor; mAb = monoclonal antibody; MMPIs = matrix metalloproteinase inhibitors; PDGFR = platelet-derived growth factor receptor; TKI = tyrosine kinase inhibitor; VEGFR = vascular endothelial growth factor receptor.

First generation

1990s

• Thalidomide• Interferon-α• Tecogalan• Minocycline• Suramin• TNP-470• MMPIs

FAILED

Second generation

2000s

• Bevacizumab (now integrated in standard care)

• Endogenous antiangiogenics: endostatin, angiostatin

• TKIs (VEGFR ± PDGFR)

LARGELY DISAPPOINTING

IN NSCLC

Third generation

2010s

• Angiokinase inhibitors that target multiple pathways (eg, VEGFR, FGFR, PDGFR)

- Nintedanib efficacy confirmed in phase III trial

• New targets (eg, Ang1/2 inhibitors)

• VEGFR2 mAb: ramucirumab

PROMISING or ESTABLISHED IN

NSCLC

9

• Monotherapy

• Combination (usually based on synergistic interaction in preclinical models) – Chemotherapy– Targeted agent– Immunotherapy (eg, PD1 blockade)

Current Antiangiogenic Approaches in NSCLCSynergistic Interaction Between Bevacizumab and Chemo1

1. Ferrara N. Oncology. 2005;69(suppl 3);11; 2. Martinelli E et al. Clin Cancer Res. 2010;16:4990.

Synergistic Interaction Between Sorafenib and Erlotinib2

CI values between 0.02 and 0.5 suggest a significant synergistic interaction

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First-Line TreatmentBevacizumab (+ Erlotinib in EGFR+)

11

1st-line

First-Line Treatment of Metastatic NSCLC:ESMO Guidelines

EGFR-mutation negative/unknown

EGFR-mutation positive

Nonsquamous cell carcinoma

ALK-rearranged

Squamous cell carcinoma

ALK TKICisplatin + 3rd-gen CT

+/-Bevacizumab

EGFR TKI+/ Bevacizumab

Cisplatin + 3rd-gen CT

ESMO = European Society for Medical Oncology; CT = chemotherapy; ALK = anaplastic lymphoma kinase. Modified from Reck et al. Ann Oncol. 2014;25(suppl 3):iii27 and Besse et al. Ann Oncol. 2014;25:1475.Modified from Novello et al Ann Oncol 2016;27(supple 5)

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Treatment of Advanced NSCLC After First-Line Chemotherapy

Median OS <1 year No significant improvement in survival reported in this setting in nearly a decade!

NSCLC = non–small cell lung cancer. 1. Shepherd et al. J Clin Oncol. 2000;18:2095; 2. Hanna et al. J Clin Oncol. 2004;22:1589; 3. Shepherd et al. N Engl J Med. 2005;353:123; 4. Reck M et al. Lancet Oncol. 2014;15:143; 5. Garon EB et al. Lancet. 2014;384:665. Nintedanib is approved in the European Union (EU) under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration conditions differ internationally, please refer to locally approved prescribing information. Nintedanib is not approved in other indications.

Docetaxel approved by

EMA1

Pemetrexed approved by

EMA2

Erlotinib approved by

EMA3

Nintedanib plus docetaxel

approved by EMA

(LUME-Lung 1)4

Ramucirumab plus docetaxel approved by

FDA(REVEL)5

20152004 2006 2008 2010 2012 20141998 2000 2002 2016

Pembrolizumab

Nivolumab

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Phase 3 Studies With Antiangiogenic Agents in Second-Line Treatment of Advanced NSCLC

Nintedanib is approved in the European Union (EU) under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration conditions differ internationally. Please refer to locally approved prescribing information. Nintedanib is not approved in other indications.FGFR = fibroblast growth factor receptor; FLT3 = Fms-like tyrosine kinase 3; IV = intravenous; NSCLC = non–small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.1. Garon EB et al. Lancet. 2014;384:665; 2. Reck M et al. Lancet Oncol. 2014;15:143; 3. Hanna NH et al. J Clin Oncol. 2013;31(suppl). Abstract 8034 and poster.

Trial Mechanism of action Patients Regimens Primaryendpoint(s)

Secondaryendpoint(s)

REVEL1 IV monoclonal antibody targeting VEGFR-2

Stage IV NSCLC; any histology

(squamous 26%)

Ramucirumab + docetaxel

OS PFSORRPlacebo +

docetaxel

Trial Mechanism of action Patients Regimens Primaryendpoint(s)

Secondaryendpoint(s)

LUME-Lung 12Oral triple angiokinase

inhibitor targetingVEGFR 1–3, FGFR 1–

3, PDGFR α/β, RET and FLT3

Stage IIIB/IVNSCLC; any histology

(squamous 42%)

Nintedanib + docetaxel PFS

(central review)

OSPFS

(investigator)ORR

Placebo + docetaxel

LUME-Lung 23 Stage IIIB/IV NSCLC; nonsquamous histology

Nintedanib + pemetrexedPFS

(central review)

OSPFS

(investigator)ORRPlacebo + pemetrexed

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• Ramucirumab is a fully human IgG1, high-affinity (50 pM) neutralising monoclonal antibody specific for the human VEGFR-2 receptor

Ramicirumab: Fully Human IgG With High Affinity to VEGFR-2

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REVEL: Study Design

Bev = bevacizumab; ECOG PS = Eastern Cooperative Oncology Group performance status; ORR = objective response rate; PFS = progression-free survival; ROW = rest of world.

• Stage IV NSCLC after one platinum-based chemo +/-maintenance

• Prior Bev allowed• All histologies • PS 0 or 1

Treatment until disease progression

or unacceptable

toxicity

Ramucirumab 10 mg/kg +

Docetaxel 75 mg/m2 q3wN=628

Placebo +

Docetaxel 75 mg/m2 q3wN=625

RANDOMISE

1:1

Stratification factors:• ECOG PS 0 vs 1• Gender • Prior maintenance• East-Asia vs ROW

Primary endpoint: overall survival

Secondary endpoints:PFS, ORR, safety, patient-reported outcomes

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REVEL: Overall Survival (ITT Analysis)

Median OSRAM+DOC 10.5 (9.5-11.2)PL+DOC 9.1 (8.4-10.0)HR: 0.857 (0.75-0.98); p = 0.023

Garon EB et al. Lancet. 2014;384:655.

All patients (primary endpoint)1.00.90.80.70.60.50.40.30.20.1

00 3 6 9 12 15 18 21 24 27 30 33 36

Ove

rall

Surv

ival

Months

628 527 415 329 231 156 103 70 45 23 11 2 0Ramucirumab625 501 386 306 197 129 86 56 36 23 9 0 0Placebo

Number at risk

Non-squamous histology (73%)1.0

0.9

0.8

0.70.6

0.5

0.4

0.30.2

0.1

00 3 6 9 12 15 18 21 24 27 30 33 36

Ove

rall

Surv

ival

Months


Number at risk

Squamous histology (26%)

Ove

rall

Surv

ival

1.0

0.9

0.8

0.70.6

0.5

0.4

0.30.2

0.1

00 3 6 9 12 15 18 21 24 27 30 33 36

Months


Number at risk



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REVEL: Progression-Free SurvivalITT Population, Investigator Assessment

Median (95% CI) Censoring Rate

RAM+DOC vs PL+DOC:

4.5 (4.2-5.4) 11.1%3.0 (2.8-3.9) 6.7%

Stratified HR (95% CI) = 0.762 (0.677-0.859)Stratified log-rank P<0.0001

RAM+DOCPL+DOC

Prog

ress

ion-

Free

Sur

viva

l (%

)

RAM+DOCPL+DOCCensored

0 3 6 9 12 15 18 21 24 27 30 33 36

Survival Time (months)RAM+DOCPL+DOC

Number at risk383301

204172

12095

5937

3817

119

74

33

32

00

00

628625

00

0

20

40

60

80

100

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REVEL: OS by Subgroups

OS = overall survival.Garon EB et al. Lancet. 2014;384:655.

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Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm

Difference between arms for term was ≥5% higher in the RAM+DOC arm.Presented by Maurice Perol at 2014 ASCO Annual Meeting.

Preferred and Consolidateda TermRAM+DOC

(N=627)PL+DOC(N=618)

Grade 1-2, % Grade 3-4, % Grade 1-2, % Grade 3-4, %Neutropaeniaa 6.2 48.8 6.1 39.8Febrile neutropaenia 0 15.9 0 10.0Thrombocytopaenia 10.5 2.9 4.5 0.6Fatiguea 40.7 14.0 39.5 10.5Decreased appetite 26.8 2.2 23.6 1.3Nausea 25.8 1.1 26.1 1.5Stomatitis 19.0 4.3 11.3 1.6Mucosal inflammation 13.2 2.9 6.5 0.5Diarrhoea 27.1 4.6 24.6 3.1Neuropathya 20.4 2.7 18.8 1.6Oedema peripheral 16.3 0 8.3 0.3Lacrimation increased 13.2 0.2 4.5 0

• No grade 5 toxicity was observed for the events presented on this slide

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Nintedanib: A Triple-Angiokinase Inhibitor

• Oral angiokinase inhibitor targeting:– VEGFR 1–3– FGFR 1–3– PDGFR α/β

Presenter

Presentation Notes

Nintedanib is a potent, oral, triple angiokinase inhibitor Angiogenesis is an essential process for enabling tumour growth beyond a minimal size and for metastasis to other organs. As such, targeting angiogenesis is a valid approach for the treatment of cancer Nintedanib simultaneously blocks the three key receptors that regulate the formation and maintenance of new blood vessels, thereby preventing angiogenesis and tumour progression Critical regulators of angiogenesis inhibited by nintedanib include: VEGFRs: expressed in endothelial cells FGFRs: expressed in endothelial cells and smooth muscle cells PDGFRs: expressed in pericytes and smooth muscle cells The metabolic characteristics of nintedanib are predominantly independent of cytochrome P450-catalyzed metabolic pathways. As such, nintedanib does not change the pharmacokinetics of co-medication

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Nintedanib Clinical Development in Lung Cancer

NSCLC = non–small cell lung cancer.

Advanced NSCLC After First-Line Chemotherapy

LUME-Lung 1Phase III

NSCLC (all histologies)

LUME-Lung 2Phase III

Nonsquamous NSCLC

Presenter

Presentation Notes

The clinical development programme for nintedanib includes: LUME-Lung clinical trial programme Two LUME-Lung Phase III clinical trials investigated the efficacy and safety of nintedanib when administered concurrently with either docetaxel (LUME-Lung 1) or pemetrexed (LUME-Lung 2) in patients with stage IIIB/IV or recurrent NSCLC after first-line therapy. Patients with squamous histology were excluded from the LUME-Lung 2 study. Results of both trials have been reported LUM-Colon The ongoing Phase III LUME-Colon 1 trial is assessing the efficacy and safety of nintedanib plus best supportive care versus placebo in colorectal cancer patients refractory to standard therapies Nintedanib is also being investigated in other indications The Phase III LUME-OVAR 1 trial, also known as AGO-OVAR12 is investigating the efficacy and safety of first-line nintedanib versus placebo in combination with carboplatin and paclitaxel chemotherapy followed by nintedanib maintenance in women with advanced ovarian cancer A Phase II study in renal cell carcinoma evaluated whether first-line treatment with nintedanib had similar efficacy to sunitinib Two Phase I/II studies have been conducted in patients with advanced liver cancer, comparing nintedanib with sorafenib A phase II trial in patients with unresectable malignant pleural mesothelioma is evaluating the safety and efficacy of nintedanib + chemotherapy followed by nintedanib maintenance versus placebo Non-cancer indications Nintedanib is now approved as monotherapy in the US and European Union for the treatment of patients with idiopathic pulmonary fibrosis (IPF). Two replicate Phase III trials (INPULSIS-1 and INPULSIS-2) evaluated the efficacy and safety of nintedanib versus placebo in IPF patients. Results have been reported

22

LUME-Lung 1: Randomised Controlled Phase III Study

*UICC/AJCC = Union Internationale Contre le Cancer/American Joint Committee on Cancers (6th or 7th edition). BID = twice daily; po = by mouth; IV = intravenous; NSCLC = non–small cell lung cancer; PD = progressive disease; PFS = progression-free survival; OS = overall survival; ITT = intent-to-treat; ECOG PS = Eastern Cooperative Oncology Group performance status.Reck M et al. Lancet Oncol. 2014;15:143.

Stratification: ECOG PS (0 vs 1)Prior bevacizumab (yes vs no)Histology (squamous vs nonsquamous)Brain metastases (yes vs no)

Regions: Europe/Asia/South AfricaAccrual: 23 Dec 2008 to 9 Feb 2011

Primary Endpoint: PFS by independent central reviewKey Secondary Endpoint: OS, prespecified hierarchical analyses of patients with adenocarcinoma who progressed in <9

months after start of first-line therapy, all patients with adenocarcinoma, and ITT population

Nintedanib 200 mg BID po, days 2–21+ docetaxel 75 mg/m2 IV, day 1,

21-day cycles (n=655)

Placebo BID po, days 2–21,+ docetaxel 75 mg/m2 IV, day 1,

21-day cycles (n=659)

N=1314

RANDOMISE

1:1

PD

PD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

Stage IIIB/IV*or recurrent

NSCLC patients after first-line chemotherapy

(all histologies)

Presenter

Presentation Notes

The LUME-Lung 1 trial was a global randomised controlled Phase III trial Patients with Stage IIIB/IV or recurrent NSCLC (all histologies) who had failed prior first-line chemotherapy were recruited to the study In total, 1773 patients were recruited and 1314 patients were subsequently randomised to treatment: Nintedanib + docetaxel: nintedanib 200 mg twice daily orally + docetaxel 75 mg/m2 by intravenous infusion on Day 1 Placebo + docetaxel: oral placebo + docetaxel 75 mg/m2 by intravenous infusion on Day 1. Oral placebo tablet was given in order to maintain blinding of the trial patients and the treating physicians to treatment The number of docetaxel cycles was not restricted, and patients were able to continue monotherapy with either nintedanib/placebo or docetaxel after they had received 4 cycles of combination therapy; patients could receive any treatment until progression (combination therapy or either of the agents as monotherapy) The primary endpoint and key secondary endpoints are shown Additional notes: Docetaxel was administered every 3 weeks until unacceptable AEs or disease progression Nintedanib 100 mg or placebo capsules (×2) were taken each morning and evening after a meal (Boehringer Ingelheim, data on file) Prior to randomisation, patients were stratified by ECOG PS (0 vs 1), previous bevacizumab treatment (yes vs no), histology (squamous vs non-squamous), and presence of brain metastases (yes vs no) The study was conducted at 211 centres in 27 countries (23 European countries, plus China, South Korea, India and South Africa) Patients were enrolled into the study between 23 December 2008 and 9 February 2011

23

• Key inclusion criteria– Histologically or cytologically confirmed, locally advanced and/or metastatic, stage IIIB–IV* or

recurrent NSCLC – All NSCLC histologies– ECOG PS 0 or 1– Failure after first-line chemotherapy

• Key exclusion criteria– Prior docetaxel or VEGF/VEGFR inhibitors (other than bevacizumab)– Active brain metastases or leptomeningeal disease– Cavitary or necrotic tumours

Major Eligibility Criteria

*UICC/AJCC = Union Internationale Contre le Cancer/American Joint Committee on Cancers (6th or 7th edition). ECOG PS = Eastern Cooperative Oncology Group performance status; NSCLC = non–small cell lung cancer; VEGFR = vascular endothelial growth factor receptor.Reck M et al. Lancet Oncol. 2014;15:143.

Presenter

Presentation Notes

Patients with Stage IIIB/IV or recurrent NSCLC (all histologies) and an ECOG PS of 0 or 1 were recruited to the study Patients had to have experienced relapse or failure of one prior first-line chemotherapy but could not have received more than one prior regimen for advanced and/or metastatic or recurrent NSCLC Patients could not have received any prior treatment with a VEGF/VEGFR inhibitor (except bevacizumab) or docetaxel Patients also had to have at least one measurable non-irradiated target lesion but could not have active brain metastases or leptomeningeal disease, or have a cavitary or necrotic tumour Additional notes: EGFR status was not specified in the eligibility criteria Prior use of EGFR inhibitors was indirectly ruled out by allowing enrolment of patients only after one prior line of chemotherapy

24

LUME-Lung 1 Statistical Methodology

Primary endpoint

Key Secondary Endpoint

Independently assessed PFS ITT/all histologies

OSAdenocarcinoma

Time since start of first-line therapy <9 months

OSAll adenocarcinoma

OSITT/all histologies

Significant finding

Significant finding

• An exploratory analysis of LUME-Lung 2 data showed evidence for enhanced survival benefit in early progressing adenocarcinoma tumours1,2

• To confirm this finding in LUME-Lung 1, prespecified stepwise testing was incorporated in the secondary endpoint OS analysis. This stepwise approach was applied to control the type I error rate3

Significant finding

OS = overall survival; PFS = progression-free survival; ITT = intention-to-treat.1. Hanna N et al. J Clin Oncol. 2013;31(suppl). Abstract 8034; 2. Kaiser R et al. Eur J Cancer. 2013;49(suppl 2). Abstract 3479, Poster P388; 3. Reck M et al. Lancet Oncol. 2014;15:143.

Presenter

Presentation Notes

The statistical analysis of the LUME-Lung 1 primary and key secondary endpoints used a hierarchical analysis in order to reduce the error rate and maintain power for the important OS endpoint The OS analysis for the group of patients with adenocarcinoma was introduced prior to database lock for the final OS analysis to validate findings from the independent study, LUME-Lung 2 The testing for OS was performed in a prespecified hierarchical order: in patients with adenocarcinoma who progressed during or shortly after first-line therapy, followed by all patients with adenocarcinoma, and then all patients Testing of each endpoint was permitted only if the previous endpoint was significant As such, the study had an 80% power to show a significant improvement in OS, with an HR of 0.8475 (9 vs 10.6 months), based on 1151 deaths Additional notes: The study had 90% power to show a significant improvement in PFS with an HR of 0.7843 (4 vs 5.1 months) based on 713 centrally assessed progression events

25

Primary Endpoint PFS by Independent Central Review, All Patients

LUME-Lung 1 Met Its Primary Endpoint With Significant Improvement in Progression-Free Survival in All Patients

565 295 155 57 19 4 3 1 0569 250 116 43 21 2 1 0 0

NintedanibPlacebo

No. at risk

100

80

60

40

20Prob

abili

ty o

f PFS

(%)

0Time (months)

02 4 6 8 10 12 14 16 18

CI = confidence interval; HR = hazard ratio; PFS = progression-free survival.Reck M et al. Lancet Oncol. 2014;15:143.

Nintedanib + Docetaxel

Placebo + Docetaxel

Median PFS (months) 3.4 2.7

HR = 0.79 (95% CI: 0.68–0.92); P=0.0019

Presenter

Presentation Notes

LUME-Lung 1 met the primary endpoint (PFS): Nintedanib + docetaxel demonstrated a significant prolongation of centrally reviewed PFS when compared with placebo + docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy Patients in the nintedanib + docetaxel arm demonstrated prolonged median PFS (3.4 months) compared with the placebo + docetaxel arm (2.7 months; HR=0.79; 95% CI: 0.68–0.92; p=0.0019) This analysis was conducted at the time of the primary analysis (cut-off date 2 Nov 2010) Additional notes: PFS was assessed by independent central review, analysed by intention to treat after 714 events in the total population (all patients) PFS was assessed by central independent review using modified RECIST criteria at baseline (within 4 weeks of randomisation) and every 6 weeks after the first administration of docetaxel PFS was also evaluated by investigator-assessment but independent central review was used for the primary efficacy endpoint as it represents the most robust and unbiased assessment method

26

Asian vs Non-Asian Patients: PFS (LUME-Lung 1)

Reck M et al. Lancet Oncol. 2014;15:143.

27

Significant Improvement in Median Overall Survival in Patients With Adenocarcinoma

Key Secondary Endpoint, Prespecified Hierarchical Analysis

322 263 203 163 131 96 72 46 25336 269 184 139 101 73 55 33 15

NintedanibPlacebo

No. at risk107


Placebo + Docetaxel

Median OS (months) 12.6 10.3

HR 0.83 (95% CI: 0.70–0.99); P=0.0359

100

80

60

40

20

Prob

abili

ty o

f Sur

viva

l (%

)

0Time (months)

04 8 12 16 20 24 28 32 36

52.7%

44.7%25.7%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

19.1%


Presenter

Presentation Notes

In patients with adenocarcinoma, nintedanib + docetaxel demonstrated a significant prolongation of OS when compared with placebo + docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy Patients in the nintedanib + docetaxel arm demonstrated prolonged median OS (12.6 months) compared with the placebo + docetaxel arm (10.3 months; HR=0.83, 95% CI, 0.70–0.99; p=0.0359) The improvement in OS of 2.3 months with the addition of nintedanib to docetaxel alone extended OS time by more than 1 year The Kaplan–Meier survival curves separated at 6 months, with continued separation throughout the 36-month study observation period 1- and 2-year OS rates were higher with nintedanib + docetaxel 1-year survival Nintedanib + docetaxel 52.7% (95% CI 46.8–57.9) Placebo + docetaxel 44.7% (38.9–49.8) 2-year survival Nintedanib + docetaxel 25.7% (95% CI 20.5–30.2) Placebo + docetaxel 19.1% (14.4–23.2)

28

Asian vs Non-Asian Patients: OS (LUME-Lung 1)

Reck M et al. Lancet Oncol. 2014;15:143.

Presenter

Presentation Notes

Small number of patients in the Asian population Nintedanib is the only drug that shows significant benefit for patiens who have PD as their best response to 1st line chemotherapy and is according to the ESMO guidelines the only drug recommended for patients who progress within the first 9 months since the start of first line chemotherapy.

29

206 167 119 92 73 51 35 16 9199 154 91 62 42 25 17 12 5

NintedanibPlacebo

No. at risk31

100

80

60

40

20

Prob

abili

ty o

f sur

viva

l (%

)

0Time (months)

04 8 12 16 20 24 28 32 36

Overall Survival in Patients With Adenocarcinoma Who Progressed in <9 Months After Start of First-Line Therapy

Key Secondary Endpoint, Prespecified Hierarchical Analysis


Placebo + Docetaxel


HR = 0.75 (95% CI: 0.60–0.92); P=0.0073

46.8%

34.3% 20.7%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

10.4%


Presenter

Presentation Notes

In patients with adenocarcinoma and time since start of therapy <9 months, nintedanib + docetaxel demonstrated a significant prolongation in OS when compared with placebo + docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy Patients in the nintedanib + docetaxel arm demonstrated prolonged median OS (10.9 months) compared with the placebo + docetaxel arm (7.9 months; HR=0.75 (95% CI: 0.60–0.92); p=0.0073) 1- and 2-year OS rates were higher with nintedanib + docetaxel than with placebo + docetaxel 1-year survival (46.8% vs 34.3%) (Boehringer Ingelheim data on file) 2-year survival (20.7% vs 10.4%) (Boehringer Ingelheim data on file) This analysis provided external validation of time since start of first-line therapy as a clinical biomarker, and established time since first-line therapy of <9 months as a highly significant predictive marker of extended OS with nintedanib plus docetaxel in patients with adenocarcinomas The finding that the combination of nintedanib and docetaxel is especially beneficial in patients with adenocarcinoma with time since start of first-line therapy <9 months is also interesting as these patients have a poor prognosis and represent a population with a high unmet medical need

30

100

80

60

40

20

Prob

abili

ty o

f Sur

viva

l(%

)

0Time (months)

04 8 12 16 20 24 28 32 36

Overall Survival in Patients With Adenocarcinoma and No Response to First-Line Chemotherapy

CI = confidence interval; HR = hazard ratio; OS = overall survival; PD = progressive disease.Mellemgaard A et al. Eur J Cancer. 2013;49(suppl 2). Abstract 3409 and oral presentation.

53 44 27 22 18 13 10 7 464 51 24 14 11 7 3 2 2

NintedanibPlacebo

No. at risk21

Adenocarcinoma and PD as Best Response to First-Line Chemotherapy


Placebo + Docetaxel


HR = 0.62 (95% CI: 0.41–0.94); P=0.0246

43.0%

24.6%21.5%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

5.3%

Presenter

Presentation Notes

In patients with adenocarcinoma and PD as the best response to first-line therapy, nintedanib + docetaxel demonstrated a significant prolongation OS when compared with placebo + docetaxel in patients Patients in the nintedanib + docetaxel arm demonstrated prolonged median OS (9.8 months) compared with the placebo + docetaxel arm (6.3 months; HR=0.62 (95% CI: 0.41–0.94); p=0.0246) The Kaplan–Meier survival curves separated at 4 months, with continued separation throughout the 36-month study observation period 1- and 2-year OS rates were higher with nintedanib + docetaxel than with placebo + docetaxel 1-year survival (43.0% vs 24.6%) 2-year survival (21.5% vs 5.3%) This was an exploratory analysis in a subset of patients with adenocarcinoma who were most refractory to first-line treatment

31

Nintedanib + Docetaxel Safety Profile: All Grades Adverse Events

Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. *Group term. Highlighted events are AEs for which the frequency for nintedanib was >20% greater than with placebo.AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; WBC = white blood cell.Reck M et al. Lancet Oncol. 2014;15:143; Boehringer Ingelheim data on file.

All Grade AEs in ≥10% of Patients With Adenocarcinoma

4341

38

31 3028 28

2319 19 18 17 17

14 13 12 11 117

25

41

9

29

7

18

28

1612

1720

1611

1519

14

8

1412

0

10

20

30

40

50

Patie

nts

(%)

Nintedanib + docetaxel

Placebo + docetaxel

Presenter

Presentation Notes

Nintedanib + docetaxel had a manageable safety profile In patients with adenocarcinoma histology, the most commonly reported non-haematological AEs were GI events and liver enzyme elevations The most frequently observed non-haematological AEs that occurred in more than 20% of patients in the nintedanib + docetaxel arm than the placebo + docetaxel arm highlighted on the slide, and were: diarrhoea, liver enzyme elevations (ALT and AST increase) Nausea, vomiting, decreased appetite and mucositis were also common, and occurred in >5% more patients in the nintedanib + docetaxel arm vs the placebo + docetaxel arm The rate of haematological AEs was not increased by the addition of nintedanib to docetaxel Additional notes: These commonly reported AEs were manageable Diarrhoea was manageable with appropriate treatment or dose reduction, and only 0.9% of the patients in the nintedanib arm discontinued treatment because of diarrhoea Elevations in ALT and AST were reversible, and only 2.2% of the patients treated with nintedanib + docetaxel discontinued because of liver-related reasons Nausea was of low severity and manageable with the use of corticoids and prophylactic anti-emetic treatment, and <1% of the patients discontinued because of nausea Boehringer Ingelheim data on file: Rates of peripheral neuropathies and mucositis

32

The Majority of Grade ≥3 AEs Occurred at Similar Rates Between Treatment Arms

Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. *Reported as AEs of ‘all grades’ occurring in at least 10% of the patients in either treatment arm. Highlighted events are AEs for which the frequency for nintedanib was greater than twice the frequency with placebo.AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; WBC = white blood cell.Reck M et al. Lancet Oncol. 2014;15:143; Boehringer Ingelheim data on file.

36

20

12 12

6 5 5 4 3 1 1 1 1 1 1 1 0.3 0

35

18

14

14

6 41 1 2 1 0.3 2 1 1 0.3 0 0.3

0

10

20

30

40

50

Patie

nts

(%)

Nintedanib + docetaxelPlacebo + docetaxel

Grade ≥3 AEs in Patients With Adenocarcinoma*

Presenter

Presentation Notes

In patients with adenocarcinoma histology, the most frequently observed AEs of grade ≥3 that occurred in more than twice as many patients in the nintedanib + docetaxel arm than the placebo + docetaxel arm were liver enzyme elevations (ALT and AST increase) and asthenia; grade ≥3 diarrhoea was also more common with nintedanib + docetaxel than with placebo + docetaxel The rate of haematological grade ≥3 AEs was not increased by the addition of nintedanib to docetaxel Boehringer Ingelheim data on file: Rate of asthenia�

33

Adverse Events Commonly Associated With VEGF/VEGFR Inhibitors

ATE = arterial thromboembolism; GI = gastrointestinal; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VTE = venous thromboembolism.Reck M et al. J Clin Oncol. 2014;32(5 suppl). Abstract 8100 and poster; Boehringer Ingelheim data on file.

11

0.3

5

3

1

3

11

0.3

5

12

1

0

5

10

15

Patie

nts

(%)


Adverse Events of Special Interest in Patients With Adenocarcinoma

10.3

3

1 1 0.32

0.3

3

1 1 0.30

5

10

15

Patie

nts

(%)


All grades (%) Grade ≥3 (%)

Presenter

Presentation Notes

The addition of nintedanib to docetaxel was associated with a low frequency of VEGF/VEGFR inhibitor-associated AEs Adverse events commonly associated with VEGF/VEGFR inhibitor antiangiogenic agents include hypertension, bleeding, GI perforation, and arterial and venous thromboembolism The reported rates of these events occurred with similar frequencies in both treatment arms, and few patients experienced these events at grade ≥3 Hypertension was reported by more patients in the nintedanib arm, but the rate at CTCAE grade ≥3 was similar to placebo Boehringer Ingelheim data on file: Grade ≥3 rates of GI perforations and hypertension �

34

Addition of Nintedanib to Docetaxel Did Not Further Compromise Patients’ Self-Reported Quality of Life

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire-core 30; EORTC QLQ-LC13; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and Lung Cancer-13; NS = non-significant; QoL = Quality-of-life.Novello S et al. Eur J Cancer. 2015;51:317.

EORTC QLQ-C30 and QLQ-LC13 Prespecified Symptoms of Interest

Difference in mean score

P ValueCough (QLQ-LC13) NSDyspnoea (QLQ-LC13) NS

Dyspnoea at rest NSDyspnoea after walking NSDyspnoea after climbing stairs NS

Short of breath (QLQ-C30) NSPain (QLQ-C30) NS

Have pain 0.0332Pain affecting daily activities NS

Pain in chest (QLQ-LC13) 0.0196Pain in arm and shoulder (QLQ-LC13) 0.0004Pain in other parts (QLQ-LC13) NS

Global health status/QOL NS

Favours nintedanib

-10 -5 0 5Favours placebo

Presenter

Presentation Notes

In patients with adenocarcinoma histology, longitudinal analysis of mean symptom scores for the prespecified symptoms of interest showed an overall trend towards improved cough, dyspnoea, and pain symptoms and subscores in patients with the addition of nintedanib to docetaxel In patients with adenocarcinoma histology, longitudinal analysis of mean global health status showed a trend towards improved global health status/QoL with the addition of nintedanib to docetaxel These analyses demonstrate that these improvements in PFS and OS observed with the addition of nintedanib to docetaxel were achieved without compromising patients’ self-reported QoL or global health status Additional notes: QoL was measured using the EORTC QLQ-C30 and the EORTC QLQ-LC13 Prespecified symptoms of interest included: Cough (Q1 on the QLQ-LC13) Dyspnoea (composite of Q3–5 on the QLQ-LC13) Pain (composite of Q9 and Q19 on the QLQ-C30) EORTC global health status was measured using the QLQ-C30 which incorporates one global health status/QoL scale

35

Treatment of Advanced Adenocarcinoma in Second Line

4.6**

9.2*9.0*

7.8*

12.6*

10.5

0

2

4

6

8

10

12

14Su

rviv

al T

ime,

mo

No significant OS benefit

2000 2004 2004 2005 2014

Nintedanib14

● ● ● ●

*NSCLC–adenocarcinoma; ** NSCLC–all histologies; BSC = best supportive care.1. Shepherd FA et al. J Clin Oncol. 2000;18:2095; 2. Hanna N et al. J Clin Oncol. 2004;22:1589; 3. Scagliotti G et al. Oncologist. 2009;14:253; 4. Shepherd FA et al. N Engl J Med. 2005;353:123; 5. Wojtowicz-Praga S und Leon L. Ann Oncol. 2012;23(suppl 9):abstr 1277P; 6. Scagliotti GV et al. J Clin Oncol. 2012;30:2070; 7. Herbst RS et al. Lancet Oncol. 2011;11:619; 8. de Boer RH et al. J Clin Oncol. 2011;29:1067; 9. Natale RB et al. J Clin Oncol. 2011;29:1059; 10. Ramlau R et al. J Clin Oncol. 2012;303640; 11. Lara PN et al. J Clin Oncol. 2011;29:2965; 12. Scagliotti GV et al. J Clin Oncol. 2012;30:2829; 13. Belani CP et al. BMC Cancer. 2014;14:290; 14. Reck M et al. Lancet Oncol. 2014;15:143; 15. Garon EB et al. Lancet. 2014;384:665.

●

Survival Advantages Since 2000

BSC1

Docetaxel2,3Pemetrexed2,3

Erlotinib4,5

Sunitinib6

Vandetanib7–9

Aflibercept10

Vadimezan11

Motesanib12

Axitinib13

NS NS NS NS NS

Ramucirumab15

Presenter

Presentation Notes

As I mentioned before, in the treatment of adenocarcinoma as second line, there has been no significant improvement of overall survival since 2000, even though so many different clinical trials of combination of chemotherapy with other anti-angiogenic agents Such as sunitinib, vandetanib, aflibercept, mosetanib, axitinib. But 2014, two agents, nintedanib and ramucirumab showed survival advantage

36

Cisplatin + 3rd-gen CT1st-Line

Second-Line Treatment of Metastatic NSCLC:ESMO Guidelines




ALK-rearranged


ALK TKIEGFR TKI

+/-bevacizumab

NivolumabPembrolizumab

(PDL1 >1%)Ramucirumab-

DocetaxelDocetaxel or

EGFR TKI

EGFR TKI

Platinum doublet

Priorchemotherapy

Prior platinum-based treatment

Crizotinib

Platinum doublet

Prior crizotinib

Docetaxel or pemetrexed or

erlotinibNivolumab

PembrolizumabRamuc+ docNintedanib+

doc


+/- bevacizumab

Modified from Reck et al. Ann Oncol. 2014;25(suppl 3):iii27 and Besse et al. Ann Oncol. 2014;25:1475.Modified from Novello et al Ann Oncol 2016;27(supple 5)

2nd-LinePrior

EGFR TKI

Presenter

Presentation Notes

According to ESMO guideline 2016, we have more than 6 treatment options as second line therapy in Squmous cell NSCLC. These include nivolumab, pembrolizumab, ramucirumab+ docetaxel, docetaxel alone and EGFR TKI.

37

• Numerous phase III studies with PD1/PDL1 inhibitors in first- and second-line setting

• Patients selected (PD-L1+) or not; various methodologies – predictive role awaiting more analyses by PDL1+

• Checkmate 057 study: 2L nivolumab vs docetaxel in non-SCC, EGFR, ALK wild-type NSCLC (N=582)2

– Nivolumab demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155), higher ORR (19.2% vs 12.4%; P=0.0235). PD-L1 expression associated with benefit from NIVO (OS HR 0.59 with PDL1 ≥1% vs 0.40 PDL1 ≥10%). Grade 3–5 drug-related AEs occurred in 10.5% of NIVO and 53.7% of DOC pts

• Checkmate 017: 2L Nivolumab vs docetaxel in SCC patients who failed 1L chemotherapy3

– Nivolumab demonstrated significantly improved OS (HR= 0.59; 95% CI, 0.44 to 0.79; P<0.001), response rate (20% vs 9%, p=0.008) and PFS (HR= 0.62; 95% CI, 0.47 to 0.81; P<0.001) regardless of PD-L1 expression level

• KEYNOTE 010, second-line pembrolizumab vs docetaxel in NSCLC4

– Pembrolizumab demonstrated superior OS (HR= 0.71, 0.61 for 2 mg/kg vs 10 mg/kg) and PFS in patients with TPS ≥50% of PD-L1 expression (Herbst et al. ESMO 2016. LBA48)

• OAK: 2L Atezolizumab vs docetaxel in NSCLC who failed 1,2L chemotherapy5

– Atezolizumab improved OS in all patients (HR=0.73, 13.8m vs 9.6m)

Evolving Evidence With Immunotherapy

1. www.clinicaltrials.gov. Accessed October 20, 2016; 2. Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; abstr LBA109); 3. Brahmer J et al. N Engl J Med. 2015;373:123-35 4.Garon EB. Lancet Oncol. 2016;17:259. 5 Barlesi et al. ESMO 2016

38

Evolving Evidence With Immunotherapy

Docetaxel Overall survival

0

2

4

6

8

10

12

14

16

18

Checkmate

057

Nivolulmab

Checkmate

017

Nivolulmab

OAK

Atezolizumab

Keymate010

PDL1>50% vs.

1~49%

LUME-lung-1

Nitedanib

+Docetaxel

REVEL

Ramucirumab

+Dacetaxel

12.2 months

9.2 months

13.8months

15.8months

10.5months

12.6months

10.5months

0

2

4

6

8

10

12

39

Treatment related adverse events in Checkmate 057

Brahmer J et al. N Engl J Med. 2015;373:123-35

• Given the survival improvement regardless of PD-L1 expression and less side effects related to immune-check point inhibitors, the positioning of nintedanib or ramucirumab combined with docetaxel as second line therapy might be challenge

40

Cisplatin + 3rd-gen CT1st-Line

Second-Line Treatment of Metastatic NSCLC:ESMO Guidelines




ALK-rearranged


ALK TKIEGFR TKI

+/-bevacizumab

NivolumabPembrolizumab

(PDL1 >1%)Ramucirumab-

DocetaxelDocetaxel or

EGFR TKI

EGFR TKI

Platinum doublet

Priorchemotherapy

Prior platinum-based treatment

Crizotinib

Platinum doublet

Prior crizotinib

Docetaxel or pemetrexed or

erlotinibNivolumab

Pembrolizumab(PDL1>1%)

Ramuc+ docNintedanib+

doc


+/- bevacizumab

Modified from Reck et al. Ann Oncol. 2014;25(suppl 3):iii27 and Besse et al. Ann Oncol. 2014;25:1475.Modified from Novello et al Ann Oncol 2016;27(supple 5)

2nd-LinePrior

EGFR TKI

Atezolizumab

Atezolizumab

Presenter

Presentation Notes

According to ESMO guideline 2016, we have more than 6 treatment options as second line therapy in Squmous cell NSCLC. These include nivolumab, pembrolizumab, ramucirumab+ docetaxel, docetaxel alone and EGFR TKI.

41

• Lack of direct comparison between immune-checkpoint inhibitors and antiangiogenic inhibitors

• To off all the treatment options available would be important to extend patient survival and outcomes

• Considerations for choice of best option for second line therapyPatient characteristics Drugs– Performance status - Efficacy and safety profile of drugs– Comorbidities– Disease burden– Cancer-related symptoms– Response and tolerability to first-line therapy

Positioning of antiangiogenic agents as second-line therapy in the era of immune checkpoint inhibitors

42

Positioning of antiangiogenic agents as second-line therapy in the era of immune checkpoint inhibitors

Checkmate 057 (non-squamous cell )

OAK

• Given that more patients progress within 4 months with I-O drug compared to docetaxel, those patients might benefit from chemotherapy +/- antiangiogenic drug

43

Positioning of antiangiogenic agents as second-line therapy in the era of immune checkpoint inhibitors(adenocarcinoma)

1st-LinePlatinum-based

treatment

2nd-Line

3rd-Line

Modified from Bronte et al Ther Adv Med Oncol 2016(3), 1880197

NSCLC-adenocarcinomaNon-oncogene addicted

Chemotherapy fit

Docetaxel+ nintedanib

Docetaxel+ramucirumab

Immunotherapy

Immunotherapy

Yes No

Others (EGFR TKI)

Non-elderlyPS 0-1Tolerable to first line therapyNo comorbiditiesProgress within 9 months

44

• VEGF not only promotes angiogenesis but acts as a key mediator of the immunosuppressive microenvironment

– Affects lymphocyte trafficking across endothelium to tumor

– Has systemic effect on immune-regulatory cell functionvia Treg, MDSCs, DC, etc

Synergistic Combination of Antiangiogenesis and Immunotherapy

Inhibition of Tumour Angiogenesis and Immune Checkpoints

iDC = immature dendritic cell; IDO = indoleamine 2, 3-dioxygenase; IL-10 = interleukin-10; iNOS = inducible nitric oxide synthase; MDSC = myeloid-derived suppressor cell; NK = natural killer; PD1 = programmed death 1; PD-L1 = programmed death ligand 1; PGE2 = prostaglandin E2; RNOS = reactive nitrogen oxide species; TAM = tumour-associated macrophage; TGFβ = transforming growth factor-β; Treg = regulatory T cell; VEGF = vascular endothelial growth factor.

Nintedanib

Vessel normalisation

N

T

CD4

Treg

CD8NK

TAM

MDSC

iDCAnti-PD1

Dendritic cell maturation

VEGFPromotion of Tregs

- Discourages T-cell infiltration- Inhibits T-cell function

45

• Simultaneous treatment with anti-PD-1 and anti-VEGFR2 mAbs inhibited tumour growth synergistically in vivo

Synergistic Combination of Antiangiogenesis and Immunotherapy

Yasuda S et al. Clin Exp Immunol. 2013;172:500.

46

Ongoing Phase I Trials of Combination of Antiangiogenic Agents and Immune Checkpoint Inhibitors in NSCLC

Manegold C et al. J Thorac Oncol. 2016. [Epub ahead of print]

Compounds ClinicalTrials gov Pt No Relevant regimens

BevacizumabNivolumabipilimumab

NCT01454102(Checkmate 012)

412 Cohort D: nivolumab + bevacizumab maintenance

Bevacizumabpembrolizumab

NCT02039674 308 Part I Cohort B: pembrolizumab + paclitaxel+ carboplatin + bevacizumab

Bevacizumabatezolizumab

NCT01633970 225 Cohort A: atezolizumab + bevacizumabCohort B: atezolizumab + bevacizumab + FOLFOX

Ramucirumabpembrolizumab

NCT02443324 92 Cohort 3: ramucirumab + pembrolizumab in NSCLC

Nintedanibpembrolizumab

NCT02856425 258 Nintedanib + pembrolizumab

Nintedanibnivolumab

In preparation 50 Nintedanib + nivolumab

47

• Currently available antiangiogenic therapies target VEGF/VEGFR and PDGFR signalling and therefore do not neutralise all relevant mechanisms involved in angiogenesis1,2

• Acquired resistance to VEGF-targeted therapy is a major challenge for treatment of advanced or metastatic tumours2,3

• Activation or upregulation of FGF/FGFR and PDGF/PDGFR signalling serves as a mechanism of resistance to VEGF/VEGFR-targeted therapy4-6

• The PDGF/PDGFR and FGF/FGFR pathways have been implicated in the development of resistance to antiangiogenesis through induction of epithelial-mesenchymal transition (EMT)7-9

Current Challenges: The Need for Greater/More Complete Blockade of the Angiogenesis Pathway?

1. Rogosin S et al. Clin Lung Cancer. 2012;13:326; 2. Clarke JM and Hurwitz HI. J Gastrointest Oncol. 2013;4:253; 3. Ellis LM and Hicklin DJ. Clin Cancer Res. 2008;14:6371; 4. Batchelor TT et al. Cancer Cell. 2007;11:83; 5. Casanovas O et al. Cancer Cell. 2005;8:299; 6. Erber R et al. FASEB J. 2004;18:338; 7. Eckert MA et al. Cancer Cell. 2011;19:372; 8. Jechlinger M et al. J Clin Invest. 206;116;1561; 9. Wu Q et al. Cancer Treat Rev. 2013;39:640.

Crosstalk Among Key Regulators of Angiogenesis

48

• There are no well-validated biomarkers that can help monitor efficacy, toxicity, or resistance to current antiangiogenic therapies1,2

Lack of Biomarkers

1. Ellis LM and Hicklin DJ. Clin Cancer Res. 2008;14:6371; 2. Jain RK et al. Nat Rev Clin Oncol. 2009;6:327.

49

• Currently in unselected NSCLC adenocarcinoma (non-SCC) populations– Bevacizumab improves OS when added to chemo first line– Antiangiogenic agents improve OS and PFS added to chemo second line; benefit greatest with

docetaxel in adenocarcinoma Nintedanib added to docetaxel chemotherapya is an effective option for second-line treatment of

NSCLC patients with adenocarcinoma (median OS, 12.6 vs 10.3 months; HR=0.83; P=0.0359) OS benefit with nintedanib in patients who progressed within the first 9 months since the start of 1st

line therapy and those who had PD as their best response. The earlier the progression on 1st line chemotherapy, the larger the benefits seen (lower HR).

• The role of immunotherapy as second-line therapy in PD-L1 “unselected” NSCLC population should be further explored

• In the future, rationale and opportunity exist to explore novel immunotherapy and antiangiogenic agent combinations without chemotherapy

Summary

aCurrently is not approved for the treatment of patients with NSCLC in South Korea.PD-L1 = programmed cell death ligand 1.

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