HERMES SUMMER SCHOOL

18/05/2016

Session 6 – Thoracic Tumours

NSCLC – Management

Rudolf M. Huber

University of Munich

Thoracic Oncology Centre Munich

Conflict of interest disclosure I have the following, real or perceived direct or indirect conflicts of interest that

relate to this presentation:

Affiliation / financial interest Nature of conflict / commercial company name

Grants/research support (to myself, myinstitution or department):

Funding by German Ministry of Education and Research (BMBF), German Research Society (DFG), Wilhelm-Sander-Stiftung

Advisory boards, presentations: Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Clovis, Lilly, Novartis, Roche

Other support or other potentialconflict of interest:

Clinical trials with Amgen, Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Clovis, DaichiSankyio, MSD, Novartis, Pfizer, Pierre Fabre, Roche

IntroductionAIMS

• To describe the treatment principles and

modalities in NSCLC with emphasis on the

relevance of staging

• To understand the rationale of multimodality

treatment

• To analyse the differential indications of

treatment modalities in stage III disease

• To describe the relevance of patient factors and

histology / biology for systemic therapy

• To outline the development of molecular

targeted therapy and immunooncology

NON SMALL CELL LUNG CANCER (80% of lung cancer)

50–55%* 35–40%† 10%*

Adeno-Ca Squamous cell Ca Large cell Ca

Images used with permission:*Image from www.surgical-pathology.com; †Image from http://www.lmp.ualberta.ca/resources/pathoimages/PC-S.htm

Various

subtypes of

adenocarcinoma

Lungcancer

SIGNS AND SYMPTOMS

• Cough (40 – 75 %)

• Dyspnoea (30 – 40 %)

• Haemoptysis (15 – 35 %)

• Recurrent pneumonia (15 – 25 %)

• Dull thoracic pain (20 – 40 %)

• Loss of body weight (40 – 50 %)

... No symptoms, paraneoplasia, seizure

NSCLC – TREATMENT MODALITIES

• Internal Medicine

– local treatment (interventional pneumology)

– systemic therapy

• Surgery

• Radiotherapy

• Multimodality approaches

0

5

10

15

20

25

30

35

40

45

Stage I Stage II Stage III Stage IV

NSCLC STAGING AT PRESENTATION

Mod. from Mountain CF, Semin Surg Oncol. 2000

Primarily radical local treatment

± systemic therapy

Primarily systemic

therapy

± local interventions

30 resectable 70 unresectable

20

resectable10

technicallyresectable

40

metastasized

30

locally advanced disease

25-40 %

5-year-survival

Lung Cancer

100 patients with

NSCLC

15 % < 5 % < 5 %

Lungcancer DISTRIBUTION OF NSCLC

Performance Status

6247

Also relevant:

- Weight loss

- In part LDH ...

- Biology

PROGNOSTIC FACTORS

IN LUNG CANCER

Huber

Infections

Gastro-

enterology

Hematology

Nephrology

CrCl

ultrasound

PneumologyAge

Gender

BMI

Neurology

CNS

PNP

Cardio-

vascular

ORGAN SYSTEMS

Smoking and age cause damages to many organs

SURGERY OF LUNG CANCER

Pneumonectomy

Lobectomy

Segmentectomy

Parenchyma sparinganatomical resections

SURGERY OF LUNG CANCER

• Anatomical resection!

• Systematic lymphadenectomy

• Thoracotomy

– Anterolateral

– Posterolateral

– Sterniotomy

• Minimal-invasive surgery (VATS)

COURSE OF LUNG FUNCTION AFTER RESECTION

Values are presented as mean +/- SD. * p<0.05 compared with preoperative value. # p<0.05 compared with previous test.

Circles indicate lobectomy (n=62), triangles pneumon-ectomy group (n=20)

Nezu K ea. Chest 113 (1998)

COURSE OF LUNG FUNCTION AFTER RESECTION

Values are presented as mean +/- SD. * p<0.05 compared with preoperative value. # p<0.05 compared with previous test.

Circles indicate lobectomy (n=62), triangles pneumon-ectomy group (n=20)

Nezu K ea. Chest 113 (1998)

Lobectomy: permanent functional loss is

about 10 %, exercise capacity slightly

reduced.

Pneumectomy: permanent loss of about 33

% of lung function and of 20 % of exercise

capacity

LUNG CANCER: MORTALITY OF SURGICAL

RESECTION (EUROPE)

• Lobectomy 1.4 % - 2.7 %

• Pneumonectomy 5.7 % - 7.9 %

• Roxburg ea. (1991): Ann Thorac Surg 51: 800 – 803

• Damhuis ea. (1996): Eur Respir J 9: 7 – 10

• Licker ea. (1999): Eur J Cardio-Thorac Surg 15: 314 -

319

RADIOTHERAPY

• Can be curative, depending on the

dosage and the tumour volume

• Local control depending from the

applied dose

• At least 60 Gy in 30 fractions at 2 Gy,

better 66 Gy and more necessary for

radical treatment

• Loss of lung function – in contrast to

surgery delayed

RADIOTHERAPY

• Greatest limitation to definitive radio-

therapy, apart from acute esophagitis, is

radiotherapy-induced lung toxicity

• Limited by lung function, volume of

irradiated lung (especially with more than

20 Gy) and mean lung dose

• Palliative applications for metastases

• Stereotactic radiotherapy comparable to

surgery

NON SURGICAL RADICAL TREATMENTS

• Percutaneous thoracic radiotherapy

• Stereotactic radiotherapy

• Brachytherapy

• (simultaneous) Radiochemotherapy

• Chemotherapy (plus other local

therapy)

• Chemotherapy can also impair

pulmonary function

ENDOSCOPIC INTERVENTIONS

Situs NdYAG-Laser Dilatation Prothetics Brachytherapy

Exophytic

central *** 0 0 **

periphery * 0 0 *

compression /mural growth

central 0 ** ** ***

periphery 0 * * **

bronchial instability 0 0 *** 0

Stenosis by scar * *** ** 0

HDR-BRACHYTHERAPY – EFFICACY

Vergnon J-M, Huber RM, Moghissi K. Eur Respir J 2006; 28: 200–218

Tumour before first brachytherapy session and 3 weeks later(before the second session)

Huber

NSCLC: Stage at diagnosis, therapy and 5-year-survival

55%

20%

25%

Stage I–II

Surgery ± RT ± CT

24–61%

Stage IIIA/IIIB

RT ± CT ± surgery

5–13%

Stage IV

CT + supportive

measures

1%

RT = radiotherapy

CT = chemotherapy Mod. from Mountain C. Chest 1997;111:1710–17

recurrence in 50% of pts.

Almost always recurrence or

progression

EXPECTED OUTCOME AFTER SURGICAL RESECTION IN OPERABLE NSCLC

Surgical Stage

5-Yr Survival

(%)

Relapse (%)

Local Distant

IA T1N0M0 67 10 15

IB T2N0M0 57 10 30

IIA T1N1M0 55

IIB T2N1M0 39 12 40

T3N0M0 38

IIIA T3N1M0 25 15 60

T1-3N2M0 23

Pisters and Le Chevalier. J Clin Oncol. 2005;23:3270-3278

Local-

Regional

Relapse

Distant

Relapse

INOPERABLE STAGE III NSCLC

Recurrence Patterns after Chemoradiotherapy

Adapted from Furuse K et al. JCO 17:2692-2699, 1999

33%56%

4%

MULTIMODALITY TREATMENT

• Surgery

– Local control +++

– Metastases -

• Radiotherapy

– Local control ++

– Metastases -

• Chemotherapy

– Metastases ++

– Local control (+)

• But: Toxicity increased

Combination: local control and systemic efficacy

= increased toxicity

NSCLC – LOCALLY ADVANCED

Multimodality Treatment

• Inoperable stage

– Radiochemotherapy

• Operable stage

– Neoadjuvant concepts

– Adjuvant therapy of operable NSCLC

Huber

The absolute effect of chemo-therapy at 5 years was a decrease of 6.9% for lung cancer death and an increase of 1.4% for non–lung cancer death.

N = 4584

LUNG ADJUVANT CISPLATIN EVALUATION: A

POOLED ANALYSIS BY THE LACE COLLABORATIVE GROUP

Pignon J-P ea. JCO; 26:3552-3559 2008

Benefit of chemotherapy & stage

CT may be detrimental for stage IA

META

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. Entered

Hazard ratio(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051

Chemotherapy better | Control better0.5 1.0 1.5 2.0 2.5

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. Entered

Hazard ratio(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051

Chemotherapy better | Control better0.5 1.0 1.5 2.0 2.5

vinorelbine in combination with 320 - 400 mg/m² cisplatin probably preferable (HR 0.80)

Huber

LACE

Non-small cell lung cancer: Therapy options RT / CT

sequential RCT

concomitant RCT

Induction conc. RCT

Conc. RCTConsolidation

RT dose escalation orhyperfractionated?

HuberERS, 28.11. 2008

BROCAT study CTRT 99/97 Disease-free Survival

Huber RM ea. JCO 2006

Inoperable stage IIIA, mostly IIIB NSCLC

HuberVancouver, 19. 10. 2011

BROCAT study CTRT 99/97 Survival of patients with CR/PR after induction

Multivariate analysis:

independent factor

Huber RM ea. JCO 2006

Resectable / Non-

resectableLung Cancer

Radiation

Daily Fractions

Hyperfractio-nated

SurgeryRadiation and Chemotherapy

Sequential Concurrent Combined

Surgery and Chemotherapy

Local

control

Systemic

control

THERAPY OPTIONS IN LOCALLY ADVANCED

NON SMALL CELL LUNG CANCER

HuberAmsterdam, 26. 9. 2011

André F ea. JCO 18 (2000)

PROBLEM N2 – MEDIASTINUM

RESECTED N2 NSCLC

N2 Subgroups and survival

NSCLC: IIIA N2 – subsets

• IIIA1 incidental nodal metastases found on final surgical pathology

• IIIA2 single nodal metastasis, recognized intraoperatively

• IIIA3 Mediastinal nodal metastases, detected preoperatively by mediastinoscopy or PET

• IIIA4 „Bulky“, multi-station

Adapted from ACCP Guideline. Chest 2003

Huber

CHEMOTHERAPY IN ADDITION TO SUPPORTIVE CARE

IN ADVANCED NSCLCSimple (nonstratified) Kaplan-Meier curve for survival by

treatment

NSCLC Meta-Analyses Collaborative Group, J Clin Oncol; 26:4617-4625 2008

Survival

Hazard ratio 0,77 (95 % CI 0,71 – 0,83),p < 0.0001

Huber

Delbaldo C ea. JAMA. 2004;292:470-484

1 vs. 2Reduction of mortality by 17 %

2 vs. 3no reduction of mortality

Usually doublet : Platin + „new“ substance (Taxane, Gemcitabine, Vinorelbine)

NSCLC Stage IV1 vs. 2, 2 vs. 3 substances

Huber

COMBINATION THERAPY OF NSCLC

Schiller J ea. Proc. ASCO 2000

ECOG 1594 survival

Similar data for Cis/Vinorelbin in SWOG-trial

„TARGETED THERAPY“ AND BIOLOGICAL MARKERS IN THORACIC TUMOURS

• Individualisation

– Patient

– Histology

– Predictive / prognostic markers

• „targeted therapy“

• Immunooncology

CISPLATIN VS. CARBOPLATIN META-ANALYSIS: MORTALITY

Huber

Ardizzoni A ea. J Natl Cancer Inst 2007;99: 847 – 57

HR = 1.1295 % CI 1.01-1,23

Subgroup analysis

CIS/PEM VS. CIS/GEM IN FIRST-LINE OF

NSCLC – OVERALL SURVIVAL

G. V. Scagliotti et al., JCO 26 (2008), 3543-51

p= 0.03 p=0.05

Non squamous Squamous

Same signal in 2nd line and maintenance therapy

PROPERTIES OF A TUMOUR CELL

Hanahan D, Weinberg RA. Cell 100 (2000)

PROPERTIES OF A TUMOUR CELL

Hanahan D, Weinberg RA. Cell 144 (2011)

BIOLOGICAL TARGETS

Hanahan D, Weinberg RA. Cell 144 (2011)

ALK-, ROS1 inhibition: Crizotinib, Ceritinib

Gefitinib, Erlotinib, Afatinib, Osimertinib. Necitumumab

Multi-Tyrosinkinaseinhibitors, Antibodies

PD1/PDL1inhibition: Nivolumab

45

Cancer Immunotherapy

Chen DS, Mellman I. Immunity. 2013.

Cancer cells may express tumor-specific antigens due to the presence of mutations

These antigens may induce an immune response

Up-regulation of PD-L1 in the tumor microenvironment enables cancers to evade T-cell−mediated killing

Inhibition of the PD-L1/PD-1 and PD-L1/B7.1 interaction may restore antitumor T-cell activity

Lisbon, 15. 6. 2016 Huber

GERMAN S3-GUIDELINE 2010

NSCLC IV – First Line: Platinum-based combination

– Poor PS / comorbidity: Monotherapy or non-Platin-

based combination

– optionally Bevacizumab (non-squamous)

– Gefitinib with activating EGFR mutation

Second Line: monotherapy

– Docetaxel, Erlotinib, Pemetrexed (non-squamous)

Cisplatin

(Carboplatin)

Pemetrexed (non-squamous)

Gemcitabin

Docetaxel

Paclitaxel

Vinorelbin

SYSTEMIC THERAPY IN STAGE IV

• First Line : – Platinum-based combination (+/- Bevacizumab)

– Gefitinib monotherapy (EGFR mutation)

– Erlotinib / Afatinib monotherapy (EGFR mutation)

– Crizotinib monotherapy (EML4-ALK Fusion)

– Necitumumab with Gemcitabin/Cisplatin (squamous)

• Maintenance therapy (Pemetrexed)

SYSTEMIC THERAPY IN STAGE IV

• Second Line: monotherapy – Docetaxel +/- Nintedanib (Adeno) or Ramucirumab,

Erlotinib, Afatinib (squamous), Pemetrexed (non-squamous)

– Osimertinib monotherapy (EGFR T790M mutation)

– Ceritinib monotherapy (EML4-ALK Fusion)

– Immune check-point inhibitors: Nivolumab

• Third und further lines– Erlotinib, Afatinib (squamous), Met-, BRAF-, HER2-

Inhibition **

– Immune check-point inhibitors: Nivolumab

** not yet registered

Lung Cancer Mutation Consortium

Incidence of Single Driver Mutations

Mutation found in 54% (280/516) of

tumors completely tested (CI 50-59%)Kris, ASCO 2011

Individualised Therapy?

51

Individualised Therapy?

ROS-1

HER-2

B-RAF

RET

EGFR-TKIChemotherapy

Cisplatin … ?EGFR antibody?

Antiangiogenesis … ?

1921

20?

ALK

PD1/PDL1

WHAT ARE THE OBJECTIVES OF THE

TREATMENT LUNG CANCER ?

Improvement of

• survival

• symptom control

• quality of life

Interdisciplinary management and

multidisciplinary approach, especially

for stage III

Conclusion

Stage I: surgery

Stage II: surgery, adjuvant chemotherapy

Stage IIIA: surgery in combination with (neo-)adjuvant chemotherapy

Stage IIIB or inoperable IIIA: (simultaneous) radiochemotherapy

Stage IV: palliative systemic therapy

Local interventions

“You just cannot call it lung cancer anymore”