Novità nel trattamento del tumore polmonare
Francesco Grossi
UOC Oncologia Medica
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Milano Convegno Regionale AIOM Liguria
Genova, 21 Settembre 2019
Agenda
Immunotherapy in advanced and locally
advanced NSCLC and SCLC: focus on standard of care and future combinations
Beyond EGFR, ALK and ROS-1: the new targets BRAF, MET, RET, NTRK
NADIM: study design and results
Provencio M, WCLC 2019
NADIM: PFS and OS (ITT)
Provencio M, WCLC 2019
Summary of neoadjuvant I/O trials
Lee JM, ASCO 2019
PACIFIC: durvalumab after concomitant CT/RT in stage III NSCLC
Paz Ares L, ESMO 2017
PACIFIC: updated PFS and OS
Antonia S, NEJM 2018
IMpower133: atezolizumab+CBDCA+
etoposide in 1L ES-SCLC
a Only patients with treated brain metastases were eligible. ECOG PS, Eastern Cooperative Oncology Group Performance Status; IV, intravenous; PCI, prophylactic cranial irradiation;
PD, progressive disease; PFS, progression-free survival; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors.
Horn L, NEJM 2018
IMpower133 - atezolizumab+CBDCA+
etoposide in 1L ES-SCLC: OS
Horn L, NEJM 2018
CASPIAN: study design
Paz-Ares L, WCLC 2019
CASPIAN: OS (primary endpoint)
Paz-Ares L, WCLC 2019
CA209-003: 5-Year Overall Survival
Gettinger S, JCO 2018
5-year OS for pts with advanced NSCLC treated with pembrolizumab
Garon EB, ASCO 2019
15.9%
5-year pooled OS: Nivolumab vs Docetaxel (CheckMate 057 and 017)
Gettinger S, WCLC 2019
KEYNOTE-024: studies design
Reck M, NEJM 2016
KEYNOTE-024: updated OS (2 and 3-year)
Reck M, JCO 2019
Reck M, WCLC 2019
First-line Pembrolizumab and a PD-L1 TPS of 50-74% vs 75-100%
Aguilar EJ, WCLC 2018
KEYNOTE-189: study design
Key Eligibility Criteria
• Untreated stage IV nonsquamous NSCLC
• No sensitizing EGFR or ALK alteration
• ECOG PS 0 or 1
• Provision of a sample for PD-L1 assessment
• No symptomatic brain metastases
• No pneumonitis requiring systemic steroids
Pembrolizumab 200 mg + Pemetrexed 500 mg/m2 +
Carboplatin AUC 5 OR Cisplatin 75 mg/m2
Q3W for 4 cycles
Placebo (normal saline) + Pemetrexed 500 mg/m2 +
Carboplatin AUC 5 OR Cisplatin 75 mg/m2
Q3W for 4 cycles R
(2:1)
N = 410
N = 206
Pembrolizumab 200 mg Q3W for up to 31 cycles
+
Pemetrexed 500 mg/m2 Q3W
Placebo (normal saline) for up to 31 cycles
+
Pemetrexed 500 mg/m2 Q3W
Stratification Factors
• PD-L1 expression (TPSa <1% vs ≥1%)
• Platinum
(cisplatin vs carboplatin)
• Smoking history
(never vs former/current)
Pembrolizumab 200 mg Q3W for up to 35 cycles
PDb
aPercentage of tumor cells with membranous PD-L1 staining assessed using the PD-L1 IHC 22C3 pharmDx assay. bPatients could crossover during the induction or maintenance phases. To be eligible for crossover, PD must have been verified by blinded, independent central radiologic review and all safety criter ia had to be met.
Gandhi L, NEJM 2018
ASCO 2019 update: Overall Survival
Gadgeel SM, ASCO 2019
IMpower150: PFS and OS (arm B vs C)
Socinski M, NEJM 2018
KEYNOTE-407: study design and OS
Paz-Ares L, NEJM 2018
IMPOWER 131: OS (final results)
Cappuzzo F, WCLC 2019
Pooled Analysis of KN021G, KN189 and KN407: OS in patients with PD-L1<1%)
Data cutoff dates: KN021G, December 1, 2017; KN189, September 21, 2018; KN407, April 3, 2018.
Events, n HR (95% CI) Pembrolizumab +
Chemotherapy 112 0.56
(0.43‒0.73) Chemotherapy 110
Median (95% CI) OS 19.0 (15.2‒24.0) mo 11.0 (9.2‒13.5) mo
0 3 6 9 12 15 18 21 24 27 30 33
0 10 20 30 40 50 60 70 80 90 100
Time, months
OS, %
No. at risk Pembrolizumab +
chemotherapy Chemotherapy alone
221
243 186 153 117 92 79 49 29 13 2 0
165
185 127 83 56 34 26 16 7 5 4 1
66%
47%
52%
29%
Borghaei H, WCLC 2019
STK11 and KEAP-1 genomic alterations are associated with inferior clinical
outcomes with CT-I/O in ns-NSCLC
Skoulidis F, WCLC 2019
Overall Survival and prevalence of patients with POLE/POLD1 mutations
Wang F, Jama Oncol 2019
Agenda
Immunotherapy in advanced NSCLC: focus on standard of care and future combinations
Beyond EGFR, ALK and ROS-1: the new targets BRAF, MET, RET, NTRK
Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions
Janne PA, ASCO 2019
BRAF V600E mutation: responses with Dabrafenib +Trametinib
Planchard D, Lancet Oncology 2016
Efficacy of Larotrectinib in TRK fusion–
positive cancers in adults and children
Drilon A, NEJM 2018
Larotrectinib is active in TRK fusion lung cancer
Farago AF, WCLC 2019
Capmatinib in MET ex14-mutated
advanced NSCLC: phase II GEOMETRY trial (naive & pretrated)
Wolf J, ASCO 2019
Phase II study of tepotinib in NSCLC patients with METex14 mutations
Paik PK, ASCO 2019
BLU-667 demonstrates substantial antitumor activity in RET fusion+ advanced NSCLC
Gainor JF, ASCO 2019
LIBRETTO-001: Selpercatinib in RET- altered cancers
Drilon A, WCLC 2019
Efficacy of Selpercatinib
Drilon A, WCLC 2019
Phase 1, Multicenter, Open-label Study – Dose Escalation
AMG 510 First-in-Human Study Design
Key Eligibility
– Locally advanced or metastatic malignancy – Received prior
standard therapies – KRASG12Cmutation as assessed by molecular
testing of tumor biopsies – No active brain
metastases Cohort 1
180 mg
Cohort 2 360 mg
Cohort 3 720 mg
Cohort 4 960 mg
– 2–4 patients enrolled in each cohort
– Intra-patient dose escalation allowed – Additional patients may be added to any dose deemed safe
Safety Follow-up & Long-term Follow-upa
a30 (+7) days after end of treatment for safety follow-up; every 12 weeks for long-term follow-up. PK: pharmacokinetics; PFS: progression-free survival.
– Repeated oral daily dosing with 21-day cycles – Treatment until disease progression, intolerance, or consent withdrawal – Radiographic scan every 6 weeks
Primary endpoints: dose-limiting toxicities; safety
Key secondary endpoints: PK; objective response rate; duration of response; disease control rate; PFS; duration of stable disease
Screening / Enrollment
Dose Expansion
Expansion dose determined
Screening / Enrollment
Patients with KRASG12C mutant advanced tumors
N = ~20 (max 60)
Safety Follow-up & Long-term Follow-upa
4
AMG 510 a Novel KRASG12C inhibitor:
study design
Govindan R, WCLC 2019
960 mg 720 mg
360 mg 180 mg
Planned dose:
% Change From Baseline in Sum of Longest Diameter
Evaluable NSCLC Patients With Available Post-baseline Tumor Data, (N = 22)a
Best Tumor Response and Change in Tumor Burden From Baseline
Efficacy outcomes
All evaluable patients
N = 23
Evaluable patients treated with 960mg
N = 13 Best overall response
Partial response – n (%) Stable disease – n (%) Progressive disease – n (%)
11 (48) 11 (48) 1 (4)a
7 (54) 6 (46) 0 (0)
Objective response rate – % 48 54
Disease control rateb – % 96 100
aOne patient discontinued study due to PD prior to the 1st assessment, and the post-baseline tumor burden data are missing. bPR or SD at week 6. cPatient had complete response to the target lesions. Evaluable patients: patients who had the first 6-week scan or early PD; NSCLC: non-small cell lung cancer; PR: partial response; SD: stable disease; PD: progressive disease.
SD SD SD SD# SD#
SD# SD# SD# SD# SD# SD#
PR PR# PR# * PR# PR# PR* PR
PR# * PR# *
PR#
PR# * c
–100 –80 –60 –40 –20 0 20 40 60 80 100
10
# Study ongoing
* Confirmed response
Govindan R, WCLC 2019
AMG 510: best tumor response and change in tumor burden from baseline
Next Generation Sequencing (NGS) in NSCLC
