La terapia del NSCLC in fase precoce, mesotelioma e...
Transcript of 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
News from immunotherapy
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
News from immunotherapy
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
(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
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
Disease free survival
China 300 pts
Stage II-IIIA
Icotinib versus placebo x 2 years
(after chemotherapy)
Disease free survival
Dana Farber
MGH
92 pts
Stage I-III
Afatinib 3 months versus 2 years
(after chemotherapy)
Disease free survival
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
Durvalumab after Chemoradiotherapy
in Stage III NSCLC: PFS
Antonia S, NEJM 2017
Durvalumab after CT/RT in stage III
NSCLC: prognostic factors for PFS
Antonia S, NEJM 2017
Durvalumab after Chemoradiotherapy
in stage III NSCLC: antitumor activity
Antonia S, NEJM 2017
Durvalumab after Chemoradiotherapy
in stage III NSCLC: AEs of any cause
Antonia S, NEJM 2017
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
News from immunotherapy
AIOM Algoritmo SCLC Ia linea
Linee guida AIOM 2016
AIOM Algoritmo SCLC IIa linea
Linee guida AIOM 2016
CheckMate 032 Nivolumab +/-
Ipilimumab in SCLC: study design
Hellmann M, ASCO 2017
CheckMate 032 Nivolumab +/-
Ipilimumab in SCLC: OS
Hellmann M, ASCO 2017
CheckMate 032 Nivolumab +/-
Ipilimumab in SCLC: response
Hellmann M, ASCO 2017
CheckMate 032 Nivolumab +/- Ipilimumab
in SCLC: 3-mos PFS & OS rates
Hellmann M, ASCO 2017
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
News from immunotherapy
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
Zalcman G, ESMO 2017; Scherpereel A, ASCO 2017
MAPS-2: some major objective
responses
Zalcman G, ESMO 2017
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)
Zalcman G, ESMO 2017
MAPS-2 trial (IFCT 1501):
efficacy ITT median PFS
Zalcman G, ESMO 2017; Scherpereel A, ASCO 2017
MAPS-2 trial (IFCT 1501):
efficacy ITT median OS
Zalcman G, ESMO 2017
MAPS-2 trial (IFCT 1501):
conclusions
Zalcman G, ESMO 2017
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!