La terapia del NSCLC in fase precoce, mesotelioma e carcinoma a piccole cellule

(1)

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

(2)

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

(3)

Agenda

Treatment algorithm

(4)

AIOM Algoritmo NSCLC malattia non metastatica

Linee guida AIOM 2016

(5)

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 (after chemotherapy)

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

Gefitinib x 2 years CDDP/VNR 4 cycles

Disease free survival

China ICTAN

Chemotherapy

Chemotherapy followed by 6 or 12 months of icotinib

China 300 pts

Stage II-IIIA

Icotinib versus placebo x 2 years (after chemotherapy)

Dana Farber MGH

92 pts Stage I-III

Afatinib 3 months versus 2 years (after chemotherapy)

Adjuvant therapy: phase III trials in patients with EGFR mutation

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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

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CTONG 1104: DFS (Primary Endpoint)

*Secondary endpoint.

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

(8)

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

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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

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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%

Kelly K, JCO 2015

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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.

(12)

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

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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

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Durvalumab after Chemoradiotherapy in Stage III NSCLC: consort diagram

Antonia S, NEJM 2017

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Durvalumab after Chemoradiotherapy in Stage III NSCLC: PFS

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Durvalumab after CT/RT in stage III NSCLC: prognostic factors for PFS

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Durvalumab after Chemoradiotherapy in stage III NSCLC: antitumor activity

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Durvalumab after Chemoradiotherapy in stage III NSCLC: AEs of any cause

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Agenda

Treatment algorithm

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AIOM Algoritmo SCLC Ia linea

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AIOM Algoritmo SCLC IIa linea

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CheckMate 032 Nivolumab +/-

Ipilimumab in SCLC: study design

Hellmann M, ASCO 2017

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CheckMate 032 Nivolumab +/- Ipilimumab in SCLC: OS

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CheckMate 032 Nivolumab +/- Ipilimumab in SCLC: response

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CheckMate 032 Nivolumab +/- Ipilimumab in SCLC: 3-mos PFS & OS rates

(26)

Agenda

Treatment algorithm

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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

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Trimodality with extrapleural pneumonectomy and radiation

therapy for MPM

Krug LM, JCO 2009

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MAPS-1: ITT PFS and OS

Zalcman G, Lancet 2016

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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

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MAPS-2 trial (IFCT 1501):

drug related AEs

Zalcman G, ESMO 2017

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MAPS-2 trial (IFCT 1501): response after first 12 weeks

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MAPS-2: some major objective responses

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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)

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efficacy ITT median PFS

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efficacy ITT median OS

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conclusions

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Pembrolizumab as second or further line in relapsed MPM: a swiss registry

Mauti LA, ESMO 2017

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Baas P, ESMO 2017

Anti-PD-1/PD-L1 in MM

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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

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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?

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Grazie per l’attenzione!

francesco.grossi@hsanmartino.it