La terapia del NSCLC in fase precoce, mesotelioma e...

La terapia del NSCLC in

fase precoce,

mesotelioma e

carcinoma

a piccole cellule

Francesco Grossi

U.O.S. Tumori Polmonari

Ospedale Policlinico San Martino

Genova

Agenda

Early stages and locally advanced NSCLC

Treatment algorithm

News from targeted therapies and immunotherapy

Small-cell Lung Cancer

Treatment algorithm

News from immunotherapy

Malignant Mesothelioma

Treatment algorithm


AIOM Algoritmo NSCLC malattia non

metastatica

Linee guida AIOM 2016

N Design Primary Endpoint

ALCHEMIST 410 pts

Stage IB(>4cm-IIIA)

Erlotinib versus placebo x 2 years

(after chemotherapy)

Overall Survival

ADAURA 700 pts

Stage IB-IIIA

AZD9291 versus placebo x 3 years


Disease Free survival

Japan

WJOG6401L

230 pts

Stage II-IIIA

Gefitinib x 2 years

CDDP/VNR 4 cycles

Disease free survival at 5 years

China

CTONG1104

220 pts

Stage II-IIIA

Gefitinib x 2 years

CDDP/VNR 4 cycles

Disease free survival

China

ICTAN

477 pts

Stage II-IIIA

Chemotherapy

Chemotherapy followed by 6

or 12 months of icotinib


China 300 pts

Stage II-IIIA

Icotinib versus placebo x 2 years



Dana Farber

MGH

92 pts

Stage I-III

Afatinib 3 months versus 2 years



Adjuvant therapy: phase III trials

in patients with EGFR mutation

CTONG 1104: Study Design

Randomized, phase III trial

Pts 18-74 yrs of age with

completely resected

pathologic stage II-IIIA (N1-

N2) NSCLC and centrally

confirmed EGFR activating

mutation (exon 19 del or

exon 21 L858R);

ECOG PS 0-1

(N = 222)

Gefitinib 250 mg/day

for up to 2 yrs

(n = 111)

Vinorelbine 25 mg/m2 on Days 1, 8 +

Cisplatin 75 mg/m2 on Day 1

every 3 wks for up to 4 cycles

(n = 111)

Stratified by EGFR mutation, N stage

Primary endpoint: DFS

Secondary endpoints: 3-yr DFS, 5-yr DFS, OS, 5-yr OS, safety, HRQoL, exploratory biomarker analyses

Follow-up

every 12 wks

until PD,

unacceptable

toxicity, death,

or study

withdrawal

Wu YL, ASCO 2017

CTONG 1104: DFS (Primary Endpoint)

*Secondary endpoint.

Wu YL, ASCO 2017

Gefitinib

(n = 111)

Vinorelbine/

Cisplatin

(n = 111)

HR for

Recurrence

(95% CI)

P Value

Median DFS, mos

3-yr DFS rate,*

%

28.7

34

18.0

27

0.60 (0.42-0.87)

.005

CTONG 1104: AEs

AEs in ≥ 10%

of Pts, %

Gefitinib

(n = 106)

Vinorelbine/

Cisplatin

(n = 87)

All

Grades

Grade

≥ 3

All

Grades

Grade

≥ 3

Any 57.5 12.3 80.5 48.3

Neutropenia 2.8 0 52.9 34.5

Anemia 1.9 0.9 50.6 5.7

Leukopenia 3.8 0 47.1 16.1

Myelosuppress

ion 0 0 13.8 3.4

Nausea 2.8 0 43.7 6.9

Vomiting 4.7 0 41.4 9.2

Anorexia 1.9 0 23.0 0

AEs in ≥

10% of Pts,

%

Gefitinib

(n = 106)

Vinorelbine/

Cisplatin

(n = 87)

All

Grades

Grade

≥ 3

All

Grades

Grade

≥ 3

Rash 40.6 0.9 0 0

Elevated ALT 27.4 1.9 3.4 0

Elevated AST 11.3 1.9 1.1 0

Diarrhea 26.4 0.9 4.6 0

Cough 10.4 0 17.2 0

Fatigue 3.8 0 11.5 0

Fever 0.9 0 10.3 1.1

Wu YL, ASCO 2017

CTONG 1104: HRQoL

Pts With Clinically

Relevant

Improvement, %

Gefitinib Vinorelbine +

Cisplatin OR (95% CI) P Value

Total FACT-L 53.2 34.9 0.48 (0.25-0.91) .025

LCSS 71.3 46.0

0.34 (0.18-

0.67) .002

TOI 40.2 24.2

0.47 (0.23-

0.97) .041

Wu YL, ASCO 2017

CTONG 1104 vs RADIANT

EGFR activating

mutations occurs

more frequently

in Asian than

Caucasian

patients (47 vs

19)

Chinese patients

with resected

adenocarcinoma

have an EGFR

mutation positive

rate of 55%

Wu YL, ASCO 2017

Kelly K, JCO 2015

Adjuvant Gefitinib

12 weeks of chemotherapy were compared with 2 years of

gefitinib. Two years is a big commitment for patients.

The cost of gefitinib is also much higher than the cost of

chemotherapy, so we have to consider the financial

burden.

Whether this becomes a treatment option depends on

demonstrating an overall survival advantage.

The reasons for the excess deaths in the gefitinib arm

were not clear from the presentation. The number of

deaths is relatively similar in the two arms. One possibility

is an imbalance of increased comorbidities in the gefitinib

arm.

Will immune checkpoint inhibition be effective in the setting of

minimal residual disease in which a nonexistent or immature

tumor microenvironment may exists?

What influence, if any, does surgical resection and adjuvant

chemotherapy have on immune cells?

Who will benefit?

Those with PD-L1 tumor expression

Will benefit been seen across all stages of resectable disease?

Adjuvant immunotherapy

Phase III currently ongoing randomized

trials testing immune checkpoint

inhibitors in early lung cancer PEARLS is an international, triple-blinded, placebo-controlled randomized

phase III trial. Adjuvant pembrolizumab 200 mg every 3 weeks for a

maximum of 18 doses versus placebo in pathological stage IB (T ≥ 4 cm)-

IIIA, after completion of radical surgery with or without standard AC. A total

of 1380 eligible patients will be randomized with DFS as primary end-point

ANVIL is a phase III trial evaluating nivolumab 3 mg/kg every 2 weeks for

a maximum of 12 doses versus placebo in pathological stage IB (T ≥ 4 cm)-

IIIA with DFS and OS as primary end-points after

BR31 and NCT02486718 are phase III trial testing, respectively,

durvalumab 10 mg/kg every 2 weeks and atezolizumab 1200 mg every 3

weeks for 16 cycles, in the same setting of patients and stages, having as

primary end-point DFS in PDL-1-positive patients in BR31 trial and DFS in

overall population in NCT02486718.

Buffoni L, Curr Treat Options in Oncol 2016

Durvalumab after Chemoradiotherapy

in Stage III NSCLC: consort diagram

Antonia S, NEJM 2017


in Stage III NSCLC: PFS


Durvalumab after CT/RT in stage III

NSCLC: prognostic factors for PFS



in stage III NSCLC: antitumor activity



in stage III NSCLC: AEs of any cause


Agenda


Treatment algorithm



Treatment algorithm



Treatment algorithm


AIOM Algoritmo SCLC Ia linea


AIOM Algoritmo SCLC IIa linea


CheckMate 032 Nivolumab +/-

Ipilimumab in SCLC: study design

Hellmann M, ASCO 2017


Ipilimumab in SCLC: OS



Ipilimumab in SCLC: response


CheckMate 032 Nivolumab +/- Ipilimumab

in SCLC: 3-mos PFS & OS rates


Agenda


Treatment algorithm



Treatment algorithm



Treatment algorithm


Study Treatment Median OS in 2-Drug

Arm, Mos

International Cisplatin ± pemetrexed 12

EORTC/NCIC Cisplatin ± raltitrexed 11

Malignant Pleural Mesothelioma:

Phase III Trials

Before 2003: many phase II trials (no level I/II evidence)

– Cisplatin and antifolates were most active single agents

– Cisplatin/gemcitabine was “consensus best”

• After 2003: randomized phase II and III trials (level I/II evidence)

Vogelzang N, JCO; van Meerbeeck JP, JCO 2005

Trimodality with extrapleural

pneumonectomy and radiation

therapy for MPM

Krug LM, JCO 2009

MAPS-1: ITT PFS and OS

Zalcman G, Lancet 2016

PrimaryEndpoint = Disease control rate (DCR) at 12 weeks in the first 2x 54 accrued

eligible patients in each arm separately: 57 pts to be included assuming 5%

ineligibility

MAPS-2 trial (IFCT 1501)

Zalcman G, ESMO 2017; Scherpereel A, ASCO 2017

MAPS-2 trial (IFCT 1501):

drug related AEs

Zalcman G, ESMO 2017

MAPS-2 trial (IFCT 1501): response

after first 12 weeks


MAPS-2: some major objective

responses


PD-L1 expression (>1%) is associated to response,

High PD-L1 (>25%) is associated to RO and DC in the 99 patients with available PD-L1 IHC (both arms together)



efficacy ITT median PFS



efficacy ITT median OS



conclusions


Pembrolizumab as second or further line

in relapsed MPM: a swiss registry

Mauti LA, ESMO 2017

Baas P, ESMO 2017

Anti-PD-1/PD-L1 in MM

Conclusions

No real difference between nivo and pembro

Historic controls fit in the current results

ORR is correlated with PD-L1 expression

CTLA4 + PD-L1 blockers have the best OS

Toxicity is limited and manageable

Phase3 studies are ongoing before we consider it all

standard of care in 1st line

Take home messages

Early stage/locally advanced NSCLC: standard chemotherapy YES

Targeted therapies YES/NO? YES?

Antiangiogenetics NO

Immunotherapy YES/NO? YES for locally advanced post CT/RT

Small-cell Lung Cancer: standard chemotherapy YES

Targeted therapies NO

Antiangiogenetics YES/NO?

Immunotherapy YES/NO?

Malignant Mesothelioma: standard chemotherapy YES

Targeted therapies NO

Antiangiogenetics YES

Immunotherapy YES/NO? YES?

Grazie per l’attenzione!

[email protected]

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