Nivolumab: Esperienze Italiane - AIOM · 2018-09-20 · Non Squamous NSCLC Real Life Data • 1588...

Nivolumab: Esperienze Italiane… nel carcinoma polmonare avanzato

Diego SignorelliU.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 NSCLCNIVOLUMAB REAL-LIFE DATA

Squamous NSCLC Real Life Data Baseline and Demographic characteristics

Italian EAPN = 371

CheckMate 017N = 135

CheckMate 063N = 117

Gender, n (%) MaleFemale

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 (%)

SmokerEx-smokerNever smokerUnknown

83 (22)225 (61)31 (08)32 (9)

121 (90)

10 (7)4 (3)

108 (92)

NRNR

ECOG PS, n (%) 012

134 (36)215 (58)

22 (6)

106 (78.5)2 (1.5)

--

26 (22)91 (78)

--

Metastasis site, n (%) BrainLiverBone

37 (10)64 (17)

120 (32)

9 (6.7)NANA

2 (2)NANA

Number of prior therapies, n (%)

123≥4

162 (44)120 (32)68 (18)21 (6)

134 (99.3)1 (0.7)

----

041(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 EAPmOS 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

AnyGrade

Grade 3-4

Treatment-related AEs, n (%) 29 6

Treatment-related AEs leading to discontinuation, %

7

Treatment-related deaths, n 0

NivolumabN = 135

DocetaxelN = 129

Any Grade

Grade 3-4

Any Grade

Grade 3-4

Treatment-related AEs, % 61 8 87 56


6 4 10 6

Treatment-related deaths, n

0 2

Borghaei H et al, ASCO 2016; Crinò L et al, WCLC 2016

Italian EAPCheckMate 017

Non Squamous NSCLC Real Life DataBaseline 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 smokerNever smoker

7920

7119

ECOG PS,a %012

2971

41517

Number of prior systemic regimens, % 123≥4

8812

24352119

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 DataEfficacy

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 responsePartial responseStable diseaseProgressive diseaseEarly deathUnable to determine

1182544-

11

<1124229-

16

<118264384

Borghaei H et al, NEJM 2015; Grossi F et al, WCLC 2017

Italian EAPCheckmate 057

Non Squamous NSCLC Real Life DataKaplan–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 EAPCheckmate 057

Non Squamous NSCLC Real Life DataDisposition and Safety II

Nivolumab Docetaxel

Any Grade

Grade3–4

Any Grade

Grade3–4

Treatment-related AEs, % 69 10 88 54

Treatment-related SAEs, % 7 5 20 18


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/DeathOther/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



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 metastasesand 39% for all patientsMedian 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



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 treatmentCheckmate 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



Elderly patients

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)

RegionUS/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 PS0 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 metastasesNo 255 0.60 (0.45, 0.80)

Smoking statusCurrent/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

discontinuation45 (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



Never smokers (EGFR +)

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

36Garassino MC et al, JTO 2018

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

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