Presentación de PowerPoint - Doctaforum...NSCLC ( Stage III) who have not progressed following definitive, platinum-based, concurrent chemoradiation N = 702 Arm 1 MEDI4376 10mg/kg

Santiago Ponce AixServicio Oncología Médica

Hospital Universitario “12 de Octubre”Madrid

Tratamiento Multidisciplinar de Estadios Localmente Avanzadosen Cáncer de Pulmón

Stage III: heterogenous disease

* Stage IIIA - IIIB

* Performance Status

* Number nodes stations

* Resectable/UnResectable

Stage III: heterogenous disease

Van Schil Eur J Cancer 2009

Stage III: heterogenous disease

Goldstraw JTO 2007. IASLC staging book 2009

Stage III: heterogenous disease

* Stage IIIA - IIIB

* Performance Status: weight loss / physiologic age / cardiopulmonary fitness

* Number nodes stations: volume of disease / volume to XRT

* Resectable/UnResectable

Stage III: heterogenous disease

De Ruysscher Ann Oncol 2009

Patients elegible for concurrent chemo-radiotherapy

Stage III: heterogenous disease

* Stage IIIA - IIIB

* Performance Status: weight loss / physiologic age / cardiopulmonary fitness

* Number nodes stations: volume of disease / volume to XRT

* Resectable/UnResectable

Stage III: heterogenous disease

Legras Ann Thorac Surg 2014

Different patterns of spread

Stage III: heterogenous disease

Optimal volume for chemo-radiotherapy

Extended Field RT(not recommended)

Involved Field RT(current standard)

Percentage volume of the whole lung irradiated by more than 20 Gy

V20 definition

Strong relationship betweenGrade II pneumonitis and V20(p=0.005)

V20 > 35% was associatedwith > Grade III esophagitis(p=0.032)

Stage III: heterogenous disease

* Stage IIIA - IIIB

* Performance Status

* Number nodes stations

* Resectable/UnResectable

N2: Resectable / UnResectable

Definition Resectable / UnResectable / Bulky Disease

Thoracic Surgeon Criteria

UnResectable / Bulky Disease Different Definitions:- Nodes > 2 cm, extra nodal affections, several nodes stations - SWOG: Node > 3 cm- EORTC: any N2 with non squamous; affections 4R or 5L/6L

Definition Resectable / UnResectable / Bulky Disease

Thoracic Surgeon Criteria

UnResectable / Bulky Disease Different Definitions:- Nodes > 2 cm, extra nodal affections, several nodes stations - SWOG: Node > 3 cm- EORTC: any N2 with non squamous; affections 4R or 5L/6L

N2: Resectable / UnResectable

Stage III: Milestones in the treatment

* Majority of old studies without PET-scan and brain evaluation

* Low statistical power of most of the trials

* Suboptimal radiotherapy techniques

* Majority of squamous cell carcinoma

* Selection of patients included in clinical trials of chemo-RT- not reflecting the patient in common clinical practice - a minority of patients are eligible for concurrent chemo-RT

Limitations

EIIIA N2 Resectable

EIIIA N2 Resectable

EIIIA N2 Resectable

Albain Lancet 2009

Intergroup 0139

EIIIA N2 Resectable

Albain Lancet 2009

Intergroup 0139

Median OS both arms: 23 m

EIIIA N2 Resectable

Albain Lancet 2009

Intergroup 0139OS Lobectomy vs CT/RT

EIIIA N2 UnResectable

von Meerbeeck JNCI 2007

EORTC 08941

EIIIA N2 UnResectable

von Meerbeeck JNCI 2007

EORTC 08941

EIIIA N2

Sorensen JCO 2013

Surgery for NSCLC T1-3N2M0 having pathologically verified N2:A prospective multinational phase III trial by the Nordic Thoracic Onc

EIIIA N2

Sorensen JCO 2013

Surgery for NSCLC T1-3N2M0 having pathologically verified N2:A prospective multinational phase III trial by the Nordic Thoracic Onc

Neo-adjuvant chemotherapy with or without preoperative irradiation in stage IIIA/N2 non-small cell lung cancer (NSCLC): A randomized phase III trial by the Swiss Group for ClinicalCancer Research (SAKK trial 16/00)

EIIIA N2

This is the first completed phase III tr ial to investigate the value of the addition of neoadjuvant radiotherapy toCT and surgery. RT did not improve EFS or survival, nor did it reduce the local failure rate. Never theless, theoverall survival rates of our neoadjuvant chemotherapy strategy confirm our previous repor t, and are among thebest results repor ted to date in a multicenter setting.

E IIIA UnResectable / E IIIB

Chemo-Radiotherapy: Sequential / Concurrent

Filman NEJM 1990; Sause Am J Clin Oncol 1992; Le Chevalier JNCI 1991; Chaake-koning NEJM 1992; NSCLC Collaborative Groups BMJ 1995; Auperin JCO 2010

Auperin JCO 2010

NSCLC Collaborative Group Meta Analysis Sequential vs Concomitant - OS

NSCLC Collaborative Group Meta Analysis Sequential vs Concomitant - Cumulative risk of Loco-Regional failure

Chemo-RT Stage III: RT alone vs Sequential vs Concurrent: Magnitude of Survival Benefit

Auperin Ann Oncol 2006 ; Auperin JCO 2010

Chemo-RT Stage III: RT alone vs Sequential vs Concurrent: Toxicity

Auperin Ann Oncol 2006 ; Auperin JCO 2010

ChemoRadiotherapy

Role of Chemotherapy

M Perol ELCC 2017

ChemoRadiotherapy

Chemo Combinations

ChemoRadiotherapy

Chemo CombinationsAre the new regimen better than the old generation regimen

Voces JCO 2012

ChemoRadiotherapy

Chemo CombinationsCarboplatin-Paclitaxel vs Cisplatin-Etoposide

Santana-Davila JCO 2014

PROCLAIM

Suresh Senan ASCO 2015

ChemoRadiotherapy

Chemo Combinations

PROCLAIM

Suresh Senan ASCO 2015

ChemoRadiotherapy

Chemo Combinations

PROCLAIM

Suresh Senan ASCO 2015

ChemoRadiotherapy

Chemo Combinations

ChemoRadiotherapy

Mostly frequently Chemo Combinations

Other Approaches To Improve ChemoRadiotherapy

Rationale to Increase duration of systemic treatment

Ph III CALGB 39801

Objetive: increased 40% median survival from 13 m to 18.2 mVokes JCO 2007

Other Approaches To Improve ChemoRadiotherapy

Chemo Induction

Vokes JCO 2007

Induction Chemo: Ph III CALGB 39801

Hanna JCO 2008

The Hoosier Oncology Group and US Oncology

Other Approaches To Improve ChemoRadiotherapy

Chemo Consolidation

Hanna JCO 2008

The Hoosier Oncology Group and US Oncology

Other Approaches To Improve ChemoRadiotherapy

Meta-analysis of Consolidation Therapy Trial (CCT)

Tsujino JTO 2013

Other Approaches To Improve ChemoRadiotherapy

Induction vs Consolidation Chemotherapy

Garrido Lung Cancer 2013; Belani JCO 2005; Fournel Eur J Cancer 2016; Van Houtte WCLC 2013;

OSPFS using

PI assessments according to RECIST 1.1*

Follo

w-u

p Pe

riod

Patients with unresectable NSCLC ( Stage III) who have not progressed following definitive,

platinum-based, concurrent

chemoradiation N = 702

Arm 1MEDI4376

10mg/kg Q2W for up to 12 months (MAX 26 doses)

MEDI4736 will commence treatment on Day 1 and continue on a Q2W schedule for a maximum of 12 months (26 doses) or until PD– IV administration

Arm 2Placebo (matching placebo for infusion

Q2W iv for up to 12 months(MAX 26 doses)

2:1

Re-treatment for patients who have experienced disease control atend of 12 months treatment but progressed during follow-upDay 1 Max 42 days after the

end of chemoradiation

PACIFIC

OSPFS using

PI assessments according to RECIST 1.1*

Follo

w-u

p Pe

riod

Patients with unresectable NSCLC ( Stage III) who have not progressed following definitive,

platinum-based, concurrent

chemoradiation N = 702

Arm 1MEDI4376

10mg/kg Q2W for up to 12 months (MAX 26 doses)

MEDI4736 will commence treatment on Day 1 and continue on a Q2W schedule for a maximum of 12 months (26 doses) or until PD– IV administration

Arm 2Placebo (matching placebo for infusion

Q2W iv for up to 12 months(MAX 26 doses)

2:1

Re-treatment for patients who have experienced disease control atend of 12 months treatment but progressed during follow-upDay 1 Max 42 days after the

end of chemoradiation

PACIFIC

PFS Benefit!!!!

A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy)conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lungcancer: Results on radiation dose in RTOG 0617.

Other Approaches To Improve ChemoRadiotherapy

XRT Dose

Conclusions

Over the past 50 years combined modality regimens for inoperable stageIII NSCLC have almost tripled the median survival of this disease

Recommendations

ASCO

Unresectable stage III NSCLC. A. In unresectable stage III disease,chemotherapy plus radiotherapy prolongs survival compared withradiation alone and is most appropriate for individuals with goodperformance status

ESMO

The preferred treatment of unresectable LA-NSCLC is definitiveconcurrent chemotherapy and radiotherapy with a dose no less thanthe biological equivalent of 60 Gy in 2.0 Gy fractions [I, A].

Vansteenkiste Ann Onco 20133; Pfister JCO 2004

Conclusions

Stage III remains a challenging and heterogeneous diseaseMany patients remain not elegible for concurrent chemo-RT

Treatments should be evaluated by a multidisciplinary team

Concurrent chemoradiotherapy is the standard of care for fitpatients with unresectable stage III NSCLC, but often not feasible in clinical practice

The difference between currently used chemotherapy regimens is likely to be small, if any

Available data do not support additional induction or consolidation chemotherapy beyondconcurrent chemo-RT

Hope from immunotherapy !

GRACIAS

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