Nivolumab: Esperienze Italiane
… nel carcinoma polmonare avanzato
Diego Signorelli
U.O. Oncologia Toracica
Fondazione IRCCS – Istituto Nazionale dei Tumori
Disclosures
• Consultancy role and speaker’s fee
• AstraZeneca
• Bristol-Myers Squibb
• Boheringer Ingelheim
Expanded Access Program
therapeutic use of an investigational medical product when no other valid therapeutic options are available for patients
Nivolumab was made available upon physician request through the EAP
– From April 2015 to September 2015, 371 pts have been treated with nivolumab for SQ NSCLC indication
– From June 2015 to April 2016, 1588 pts have been treated with nivolumab for non-SQ NSCLC indication
Eligible patients:
– age ≥18 years
– progression after at least 1 prior systemic treatment in the advanced or metastatic setting – ECOG PS ≤2
– asymptomatic and controlled CNS metastases were allowed – patients with active autoimmune disease were excluded
Schedule and dose
– Nivolumab 3 mg/kg was administered intravenously every 2 weeks for up to 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent.
– Treatment beyond RECIST v1.1- defined progression was allowed in the absence of rapid disease progression in patients who were deriving investigator-assessed clinical benefit while also tolerating treatment
Non Squamous NSCLC Real Life Data
• 1588 patients received ≥1 dose of nivolumab in the EAP at 153 sites in Italy
• Patients received a median of 7 doses (range: 1–55) of nivolumab, with a median follow-up of 8.1 months (range: 1.0–27.4)
• 371 patients participated in the EAP in 96 centres in Italy and received ≥1 dose of nivolumab
• Patients were treated and monitored for a median of 7.1 months (range 0.1 -16.4 months) and received a median of 6 doses (range 1-22 months)
Squamous NSCLC Real Life Data
Squamous and
Non Squamous NSCLC
NIVOLUMAB REAL-LIFE DATA
Squamous NSCLC Real Life Data
Baseline and Demographic characteristics
Italian EAP N = 371
CheckMate 017 N = 135
CheckMate 063 N = 117 Gender, n (%)
Male Female
298 (80) 73 (20)
111 (82) 24 (18)
85 (73) 32 (27) Age, years (median, range)
Patients ≥75 years, n (%)
68 (31–91) 70 (19)
62 (39-85) 11 (8)
65 (57-71) 16 (14) Smoking status, n (%)
Smoker Ex-smoker Never smoker Unknown
83 (22) 225 (61)
31 (08) 32 (9)
121 (90) 10 (7)
4 (3)
108 (92) NR NR ECOG PS, n (%)
0 1 2
134 (36) 215 (58) 22 (6)
106 (78.5) 2 (1.5)
--
26 (22) 91 (78)
-- Metastasis site, n (%)
Brain Liver Bone
37 (10) 64 (17) 120 (32)
9 (6.7) NA NA
2 (2) NA NA Number of prior therapies, n (%)
1 2 3
≥4
162 (44) 120 (32) 68 (18)
21 (6)
134 (99.3) 1 (0.7)
-- --
0 41(35) 52 (44) 24 (21) ECOG PS = Eastern Cooperative Oncology Group performance status; NR = not reported; NA = not assessed
Crinò L et al, WCLC 2016; Brahmer J et al, NEJM 2015; Rizvi NA et al, Lancet Oncol 2015
Squamous NSCLC Real Life Data
Efficacy
Italian EAP CheckMate 017 CheckMate 063*
N (%) First Tumor
Assessment
Best Response
Objective Response Rate (ORR) 51 (14) 67 (18) 27 (20) 17 (15)
Disease Control rate (DCR) 151 (41) 175 (47) 65 (48) 53 (45)
Overall Response
Complete response 1 (<1) 4 (1) 1 (1) 2 (2)
Partial response 50 (13) 63 (17) 26 (19) 15 (13)
Stable disease 100 (27) 108 (29) 39 (29) 35 (30)
Progressive disease 212 (57) 189 (51) 56 (41) 53 (45)
Could not be determined 8 (2) 7 (2) 13 (10) 12 (10)
*2 years minimum FU; Crinò L et al, WCLC 2016; Brahmer J et al, NEJM 2015; Rizvi NA et al, Lancet Oncol 2015
Squamous NSCLC Real Life Data
Kaplan Meier – estimate of OS
CheckMate 017
Felip E et al, ESMO 2017; Crinò L et al, WCLC 2016
Italian EAP
mOS was 7.9 months (95% CI: 6.29.6) 1-year OS rate: 39%
CI = confidence interval; HR = hazard ratio
1-year OS rate: 42% vs 24%
Squamous NSCLC Real Life Data
Safety
• Treatment-related AEs grade 3–4 occurred in 21 (6%) patients
• Treatment-related AEs grade 3–4 occurred in 11 (8 %) patients
Nivolumab N = 371
Any Grade
Grade 3-4
Treatment-related AEs, n (%) 29 6
Treatment-related AEs leading to
discontinuation, % 7
Treatment-related deaths, n 0
Nivolumab N = 135
Docetaxel N = 129 Any
Grade
Grade 3-4
Any Grade
Grade 3-4
Treatment-related AEs, % 61 8 87 56
Treatment-related AEs leading to discontinuation,
%
6 4 10 6
Treatment-related deaths,
n 0 2
Borghaei H et al, ASCO 2016; Crinò L et al, WCLC 2016
Italian EAP
CheckMate 017
Non Squamous NSCLC Real Life Data
Baseline and Demographic characteristics
Checkmate 057 (292 pts)
Italian EAP (1588 pts)
Median age, years (range)
≥75 years, % 61 (37, 84)
7
66 (27,89) 15
Male, % 52 65
Smoking status, %
Current/former smoker
Never smoker 79
20
71 19 ECOG PS,a%
0 12
29
71 41
517
Number of prior systemic regimens, % 1
23
≥4
88
12 24
3521 19
EGFR-positive mutation status, % 15 6
ALK-positive translocation status, % 4 -
Borghaei H et al, NEJM 2015; Grossi F et al, WCLC 2017; Garassino MR, ESMO 2017
Non Squamous NSCLC Real Life Data
Efficacy
Checkmate 057 Italian EAP Nivolumab
(n = 292) Docetaxel
(n = 290) 1588
ORR(95% CI) 19%
(15, 24) 12%
(9, 17) 18%
Odds Ratio (95% CI) 1.72 (1.1, 2.6) P-value 0.0246
Best overall response, % Complete response
Partial response Stable disease
Progressive disease Early death
Unable to determine
118 2544 11-
<1 1242 29- 16
<1 1826 438 4
Borghaei H et al, NEJM 2015; Grossi F et al, WCLC 2017
Italian EAP Checkmate 057
Non Squamous NSCLC Real Life Data
Kaplan–Meier estimate of OS
Median follow up: 8.1 months 1 year OS rate: 48%
1 year OS rate: 51% vs 39%
Felip E et al, ESMO 2017, Grossi F et al, WCLC 2017
Italian EAP Checkmate 057
Non Squamous NSCLC Real Life Data
Disposition and Safety II
Nivolumab Docetaxel
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Treatment-related AEs, % 69 10 88 54
Treatment-related SAEs, % 7 5 20 18
Treatment-related AEs
leading to discontinuation, % 5 4 15 7
Treatment-related deaths, % 0 <1
Disposition 1588 pts
Total of pts who discontinued, n (%) 1300 (82%)
REASON FOR DISCONTINUATION, n (%):
Treatment-related AEs PD/Death
Other/UNK
65 (5) 1084 (83)
115 (9)
Borghaei H et al, NEJM 2015, Grossi F et al, WCLC 2017
Squamous and
Non Squamous NSCLC:
subgroups Analysis from Italian EAP
NIVOLUMAB REAL-LIFE DATA
Squamous and
Non Squamous NSCLC:
subgroups Analysis from Italian EAP
NIVOLUMAB REAL-LIFE DATA
CNS metastases
OAK: patients with brain metastases
OS
Time to development of new brain lesions
Lukas RV, et al. ELCC 2017
Cortinovis et al, WCLC 2016
Squamous NSCLC Real Life Data
Efficacy in pts with CNS metastases
The DCR was 49% among patients with CNS metastases, with CR in 1 patient, PR in 6 patients, and SD in 11 patients;
The DCR in all patients was 47%.
Response
CNS metastases (n = 37) All patients (N = 371) First tumor
assessment
Best response
First tumor assessment
Best response
ORR, n (%) 7 (19) 7 (19) 51 (14) 67 (18)
DCR, n (%) 18 (49) 18 (49) 151 (41) 175 (47)
Overall response, n (%)
CR 0 1 (3) 1 (<1) 4 (1)
PR 7 (19) 6 (16) 50 (14) 63 (17)
SD 11 (30) 11 (30) 100 (27) 108 (29)
PD 19 (51) 19 (51) 212 (57) 189 (51)
Not determined 0 0 8 (2) 7 (2)
Squamous NSCLC Real Life Data
Efficacy in pts with CNS metastases
OS rate at 12 months was 35% for patients with CNS metastases and 39% for all patients
Median OS was 5.8 months (95% CI: 1.8, 9.8) for patients with CNS metastases and 7.9 months (95% CI: 6.2, 9.6) for all patients
Cortinovis et al, WCLC 2016
Crinò L et al, WCLC 2017
Non Squamous NSCLC Real Life Data
Efficacy of nivolumab in pts with CNS metastases
• 409 (26%) patients had asymptomatic and controlled CNS metastases
• median of 7 doses (range: 1–54) of nivolumab; median follow-up of 6.4 months (range: 0.1–27.2);
• 117 (29%) patients were receiving steroid therapy at baseline.
DCR was 40% including 4 CR (1%), 64 PR (16%) and 96 SD (23%)
The OS rate at 1 year was 43% for patients with CNS metastases and 48% for all patients
Median OS was 8.6 months (95% CI: 6.4, 10.8) for patients with CNS metastases and 11.3 months (95% CI: 10.2, 12.4) for all patients
Non Squamous NSCLC Real Life Data
Efficacy of nivolumab in pts with CNS metastases
Crinò et al, WCLC 2017
Squamous and
Non Squamous NSCLC:
subgroups Analysis from Italian EAP
NIVOLUMAB REAL-LIFE DATA
Treatment beyond progression
OAK:
OS post-PD in the atezolizumab arm by post-PD treatment
Gandara R, et al. ASCO 2017. Abstract #9001
Non Squamous NSCLC Real Life Data
Efficacy of nivolumab in patients treated beyond progression, II
Cortesi E et al, WCLC 2017
• Of the 276 patients treated beyond PD, 57 (21%) achieved a
subsequent tumor burden
reduction or a stabilization in tumor lesion
• Of the 198 patients who showed no initial response to nivolumab (ie, best response was PD), 36 (18%) achieved at least disease
estabilization with continued nivolumab treatment
Checkmate 057
• 71 (24%) patients were treated beyond progression
• 16 (5%) had a non-conventional benefit
Borghaei H et al, NEJM 2015
Squamous NSCLC Real Life Data
Treatment beyond progression
Italian EAP
• 66 (18%) patients were treated beyond
progression
• 23 (6%) patients treated beyond progression
obtained a subsequent benefit (6 had a PR and 17 had SD)
Checkmate 017
• 28 (21%) patients were treated beyond
progression
• 9 (7%) patients treated beyond progression demonstrated a non- conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial PD followed by tumor reduction, or no further progression for ≥ 2 tumor
assessments). Reckamp K et al, WCLC 2015; Crinò L et al, ASCO 2016
Squamous and
Non Squamous NSCLC:
subgroups Analysis from Italian EAP
NIVOLUMAB REAL-LIFE DATA
Elderly patients
27
N Unstratified HR (95% CI)
Overall 272 0.59 (0.44, 0.78)
Prior paclitaxel vs other prior treatment
Prior paclitaxel 92 0.51 (0.31, 0.83)
Another agent 180 0.63 (0.45, 0.90)
Region
US/Canada 86 0.59 (0.36, 0.98)
Europe 155 0.50 (0.34, 0.72)
Rest of world 31 1.50 (0.65, 3.60)
Age
<65 years 152 0.52 (0.35, 0.75)
65 and <75 years 91 0.56 (0.34, 0.91)
75 years 29 1.90 (0.76, 4.50)
ECOG PS
0 64 0.48 (0.24, 0.99)
1 206 0.54 (0.39, 0.74)
Time from completion of most recent regimen to randomization
<3 months 123 0.56 (0.37, 0.85)
3–6 months 75 0.54 (0.31, 0.95)
>6 months 72 0.64 (0.37, 1.13)
CNS metastases
No 255 0.60 (0.45, 0.80)
Smoking status
Current/former smoker 250 0.59 (0.44, 0.80)
0 1 2
Reckamp K et al, WCLC 2015
Nivolumab Docetaxel
Squamous NSCLC
Checkmate 017: OS in predefined subgroups
CheckMate 171
Treatment until PDa or unacceptable
toxicity Study population (N = 809)
• Advanced/metastatic squamous NSCLC
• ≥1 prior platinum-containing systemic therapy
• No untreated CNS metastases
Predefined subgroup
• ECOG PS 2
Nivolumab 3 mg/kg IV Q2W
Primary endpoint: incidence of grade 3–4 select TRAEs
Popat S, ESMO 2017.
Overall survival
All patients (N = 809)
≥70 years (n = 279)
ECOG PS 2 (n = 98) Median OS, months (95% CI) 9.9 (8.7, 13.1) 11.2 (7.6, NA) 5.4 (3.9, 8.3) 3-month OS rate, % (95% CI) 81 (78, 83) 78 (73, 83) 65 (54, 74) 6-month OS rate, % (95% CI) 67 (63, 70) 66 (59, 71) 46 (34, 57)
All patients (N = 809)
≥70 years (n = 279)
ECOG PS 2 (n = 98) Any grade,
n (%)
Grade 3–4, n (%)
Any grade, n (%)
Grade 3–4, n (%)
Any grade, n (%)
Grade 3–4, n (%)
TRAEs 403 (50) 95 (12) 155 (56) 38 (14) 45 (46) 6 (6)
Serious TRAEs 60 (7) 41 (5) 19 (7) 13 (5) 4 (4) 2 (2)
TRAEs leading to
discontinuation 45 (6) 31 (4) 16 (6) 12 (4) 5 (5) 4 (4)
Safety summary
Popat S, ESMO 2017.
c c
Grossi et al. , EJC 2018.
Grossi et al. , EJC 2018.
Squamous and
Non Squamous NSCLC:
subgroups Analysis from Italian EAP
NIVOLUMAB REAL-LIFE DATA
Never smokers (EGFR +)
34
Non Squamous NSCLC Real Life Data
Efficacy of nivolumab in Never-Smokers and EGFR-Positive pts
• 305 (19%) patients were never-smokers
– Never-smokers received a median of 7 doses (range: 1–38) of nivolumab, with a median follow-up of 7.0 months (range: 0.1–20.3) – DCR was 42%
• 102 (6%) patients, in the full cohort, had a
tumor that was positive for an EGFR mutation;
EGFR status was evaluable for 1,395 patients – median of 6 doses (range: 1–40) of nivolumab,
with a median follow-up of 5.5 months (range:
0.1–20.9) – DCR was 30%
• 51 (17%) of 305 never-smokers had a tumor that was positive for an EGFR mutation; EGFR status was evaluable for 287 patients
– DCR was 22%
Garassino MC et al, ESMO 2017
Garassino MC et al, JTO 2018 36
Conclusions
• These reports represent the largest real-world analysis to date with nivolumab in previously treated patients with advanced SQ and non-SQ NSCLC
• Survival and response observed with nivolumab in the Italian cohorts of these EAPs were similar to those observed in the nivolumab arms of the CheckMate 017 and 057 studies
• The safety profile of nivolumab seemed to be consistent with that reported in the CheckMate 017 and 057 trials
• These results support the use of immunotherapy in particular settings (i.e: stable and asymptomatic CNS metastases, beyond progression, elderly patients)
Grazie per l’attenzione
38
