III SESSIONE Highlights in Immunoncologia Il NSCLCmedia.aiom.it/userfiles/files/doc/AIOM-Servizi/slide/20171013ME_32... · cells, suggest that durvalumab may be an effective adjuvant

Alessandro Russo UOC Oncologia Medica, A.O. Papardo, Messina

(Dir. Prof. V. Adamo)

Borsa FSE Dottorato XXXII ciclo Università degli Studi di Messina

[email protected]

III SESSIONE

Highlights in Immunoncologia

Il NSCLC

Outline of my presentation

What’s new in LA-NSCLC?

First line ICIs: a new standard of care in selected

patients and novel combinations

New insights into ICIs use in pre-treated pts

Emerging Challenges:

Optimal timing & re-treatment;

Use in special populations: elderly and PS2

Hyperprogressive disease

Novel predictive biomarkers

Conclusions

Progresses in stage III NSCLC over the past 3 decades:

from palliative to curative-intent treatment in selected pts

0

5

10

15

20

25

30

RT alone [1] CHT + RT [1] ConcurrentCHT-RT [2]

CHT-RT 74Gyvs. 60Gy [3]

Cis-Pem + RTvs. Cis-VP16

+ RT [4]

CHT-RT ±Cetuximab [3]

CHT-RT ±Tecemotide

[5]

10

14

18 20,3

26,8 25 25,6

28,7

25 24 22,3

[1]; Auperin A, et al. Ann Oncol 2006 [2] Auperin A, et al. J Clin Oncol 2010; [3] Bradley JD, et al. Lancet Oncol 2015; [4] Senan S, et al. JCO 2016; [5] Butts C, et al. Lancet Oncol 2014

1980s 1990s 2000s 2010s

Palliative

+4% at 2 years.

Curative

Med

ian

Overa

ll S

urv

ival

(mo

nth

s)

No significant

improvements in mOS

over the last 10 years in

the RTOG0617, Proclaim

and START trials

Experimental arm Control arm

PACIFIC trial

Paz-Ares L, et al. ESMO 2017; Antonia SJ, et al. NEJM 2017

Efficacy results [1]

PFS by BICR (Primary Endpoint; ITT)

“...In conclusion, in the PACIFIC study, one of the coprimary end points was met at this planned interim analysis, and this

study showed a significant increase in progression-free survival and no new safety signals with durvalumab in patients with

stage III, unresectable NSCLC who had received chemoradiotherapy....”

“... These positive findings in an unselected patient population, irrespective of baseline expression of PD-L1 on tumor

cells, suggest that durvalumab may be an effective adjuvant therapy in patients with stage III disease after standard

treatment...”

Antonia SJ, et al. NEJM 2017; Paz-Ares L, et al. ESMO 2017


Efficacy results [2]

Incidence of new lesions by BICR

Time to Distant

Metastasis or Death by

BICR

Median follow-up: 14.5 mos

(range 0.2–29.9)

“...Uncertainty about the potential mechanisms driving the interaction between immunotherapy and chemoradiotherapy

warrants further investigation...”


Safety & Conclusions

SAFETY

SUMMARY











Conclusions

0

5

10

15

20

25

30

35

7,9 11,5 12,3 12,6 13,9

19,3 21,6

27,3

34,9

OS

(M

ON

TH

S)

Schiller et al. ECOG 4599 JMBD PARAMOUNT EURTAC IPASS LUX-LUNG 3 & 6

HISTOLOGY-SELECTED EGFR-MUTATED MAINTENANCE

SQUIRE

SqCC

Progresses in the 1st line treatment of

metastatic NSCLC over the past 2 decades

Non-SqCC

KEYNOTE-001*

*PD-L1 ≥50%, 1L Cohort

PD-L1 SELECTED

2002 2017

0

5

10

15

20

25

30

35

7,9 11,5 12,3 12,6 13,9

19,3 21,6

27,3

34,9

OS

(M

ON

TH

S)

Schiller et al. ECOG 4599 JMBD PARAMOUNT EURTAC IPASS LUX-LUNG 3 & 6

HISTOLOGY-SELECTED EGFR-MUTATED MAINTENANCE

SQUIRE

SqCC

Progresses in the 1st line treatment of

metastatic NSCLC over the past 2 decades

Non-SqCC

KEYNOTE-001*

*PD-L1 ≥50%, 1L Cohort

PD-L1 SELECTED

2002 2017

OS DATA OF THE KN-001 TRIAL:

TREATMENT-NAIVE COHORT

Leighl NB, et al. ASCO 2017

ORR: 40.6% (30.9-50.8)

CR: 2.0% and PR: 38.6%

SD: 42.6%

Median time to response: 2.1 mos (1.7-9.5)

No evidence of cumulative immune-

related toxicities

KEYNOTE-024: UPDATED DATA

PFS2 useful to:

Assess the impact of cross-

over on OS

Assess the effects of a therapy

on subsequent treatments

Death

Brahmer J, et al. ASCO 2017

KEYNOTE-024: UPDATED DATA

Brahmer J, et al. ASCO 2017

Pembrolizumab continued to show OS benefit over chemotherapy as 1st line therapy for

advanced NSCLC with PD-L1 TPS ≥50%:

Median OS for pembrolizumab was not reached with a median follow-up of 19 mos;

Despite an effective crossover rate of 60%, there remained a high degree of separation

of the OS curves

Peters S, et al. JCO 2017

*TC2/3 or IC2/3 = TC or IC ≥5% PD-L1–expressing cells, respectively.

**TC3 or IC3 = TC ≥50% or IC ≥10% PD-L1–expressing cells, respectively

TC3/IC3** TC2/3 or IC2/3* (ITT population)

Cohort 1: 1L; Cohort 2: 2L; Cohort 3: ≥3L

Chemo + IO in 1st line: KEYNOTE 021 cohort G

Langer CJ, et al. Lancet Oncol 2016; Borghaei H, et al. ESMO 2017

2016 2017

HR 0.54; p=0.0067

“...Significant improvements in ORR and PFS observed in

prior analyses were maintained...”

Median PFS 13.0 vs. 8.9 mos

HR 0.53; p=0.010

PFS data

Chemo + IO in 1st line: KEYNOTE 021 cohort G

HR 0.90 [95% CI 0.42–1.91]

2016 2017

HR 0.59; p=0.03

Langer CJ, et al. Lancet Oncol 2016; Borghaei H, et al. ESMO 2017

“...Incremental OS benefit, though not statistically significant, continued despite

high (~75%) crossover rate to anti–PD-1/PD-L1 therapy in the PC alone arm...”

OS data











Conclusions

The evolution of 2nd line treatment in NSCLC

in the Immunotherapy era

02468

101214

7,5 5,7

9

6,7

10,5 12,6 12,2

9,2 10,4

13,8

*non-SqCC pts only

**SqCC pts only

***PDL-1+ >1% (10mg/kg arm)

2000

2017

[1] Shepherd FA, et al. JCO 2000; [2] Fossella FV, et al. JCO 2000; [3] Hanna N, et al. JCO 2005; [4]Scagliotti GV, et al. Oncologist 2009; [5] Shepherd FA, et

al. NEJM 2005; [6] Garon EB, et al. Lancet 2014; [7] Reck M, et al. Lancet Oncol 2014; [8] Borghaei H, et al. NEJM 2015; [9] Brahmer J, et al. NEJM 2015; [10]

Herbst RS, et al. Lancet 2016; [11] Rittmeyer A, et al. Lancet 2017.

ME

DIA

N O

S (m

os)

Five-Year Follow-up From the CA209-003 Study

Brahmer J, et al. ACCR 2017

5-Year Estimates of OSa CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

4

Median OS (95% CI), mo

Overall (N = 129) 9.9 (7.8, 12.4)

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8

129 49 27 20 17 16 3 1 0

Years No. at Risk

OS

(%

)

1 y OS, 42%

2 y OS, 24% 3 y OS, 18% 5 y OS, 16%

aThere were 3 deaths between 3 and 5 years, all due to disease progression; 1 surviving patient was censored for OS prior to 5 years (OS: 58.2+ months) “...The estimated 5-yr OS rate with nivolumab was 16%...”

PD-L1 ≥1% (n = 38)

38 10 8 7 7 7 2 0 1

Years

100

0 1 2 3 4 5 6 7 8

5 y OS, 23%

20

40

60

80

0

5-Year Estimates of OS by PD-L1 Statusa CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

6

PD-L1 <1% (n = 30)

No. at Risk

OS

(%

)

0 1 2 3 4 5 6 7 8

Years

20

40

60

80

100

0

5 y OS, 20%

30 13 7 5 4 3 0 0 0

PD-L1 ≥50% (n = 13)

13 5 5 5 5 5 2 0 1

Years

100

0 1 2 3 4 5 6 7 8 0

5 y OS, 43%

20

40

60

80

aPD-L1 status was not evaluable in 61 (47%) of 129 patients; the estimated 5-y OS rate in patients with unknown PD-L1 status was 10%

Five-Year Follow-up From the CA209-003 Study

Brahmer J, et al. ACCR 2017

5-Year Estimates of OS by Histology CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

5

Non-squamous (n = 74)

74 28 14 10 9 8 0 0 0

Years

1 y OS, 42%

2 y OS, 24%

3 y OS, 17% 5 y OS, 15% 20

40

60

80

100

0 0 1 2 3 4 5 6 7 8

Squamous (n = 54)

No. at Risk

54 20 12 10 8 8 3 0 1

OS

(%

)

Years

1 y OS, 41%

2 y OS, 24%

3 y OS, 20% 5 y OS, 16% 20

40

60

80

100

0 0 1 2 3 4 5 6 7 8

Characteristic

All Treated Patients (N = 129)

5-Year Survivors (n = 16)

Median age, years (range) 65 (38, 85) 62 (44, 80)

≥65 years, n (%) 66 (51) 6 (38)

Male, n (%) 79 (61) 9 (56)

ECOG PS, n (%)a

0 1

27 (21) 100 (78)

4 (25) 12 (75)

No. of prior systemic regimens, n (%) 1−2

≥ 3

59 (46)

70 (54)

6 (38)

10 (62)

Smoking status, n (%) Former smoker Current smoker

Unknown

16 (12)b 92 (71)

21 (16)

3 (19)b 11 (69)

2 (12)

Tumor histology, n (%)c

Squamous Non-squamous

54 (42) 74 (57)

8 (50) 8 (50)

Characteristic

All Treated Patients (N = 129)

5-Year Survivors (n = 16)

EGFR status, n (%)

Not evaluable Evaluable

Mutant Wild-type

61 (47) 68 (53)

13 (19)d,e 55 (81)d

9 (56) 7 (44)

2 (29)d,e 5 (71)d

PD-L1 status, n (%) Not evaluable Evaluable

<1% ≥1%

≥50%

61 (47) 68 (53)

30 (44)d 38 (56)d

13 (19)d

6 (38) 10 (62)

3 (30)d

7 (70)d

5 (50)d

Select TRAEsf on nivolumab, n (%) Any grade

Grade 3−4

56 (43)

7 (5)

11 (69)

1 (6)

Long-term survivors had diverse baseline characteristics, including:

Squamous and non-squamous histology

≥1% and <1% PD-L1 tumor expression

1 to 4 prior lines of systemic therapy

The majority of long-term survivors had durable responses to

nivolumab, although some had SD or PD as best overall response

Felip E, et al. ESMO 2017

Three-Year Follow-up From CM-017/057 studies

Nivolumab continued to demonstrate long-term OS and PFS benefit in patients with advanced SQ and non-SQ

NSCLC

No new safety signals were identified and rates of TRAEs were similar to those seen at 2 years’ minimum follow-up

Atezolizumab beyond PD:

a subset analysis of the OAK trial

Gandara DR, et al. ASCO 2017











Conclusions

Spigel DR, et al. ESMO 2017

CheckMate 153:

Continuous vs 1-Year Nivolumab

Exploratory endpointsd: safety/efficacye with continuous vs 1-year treatment, efficacy, other (eg, biomarkers, PK)

Key eligibility criteria

• Advanced/ metastatic NSCLC

• ≥1 prior systemic therapya

• ECOG PS 0−2

• Treated CNS metastases allowed

Stop nivolumab

Continuous nivolumab

Nivolumab

3 mg/kg IV Q2W

Treatment for 1 yearb

Rc

Nivolumab retreatment allowed at PD

Stop nivolumab

Continuous nivolumab

1,245 patients treateda

220 patients on treatment at

1 year

76 had response or SD at randomizationc

87 had response or SD at randomizationd

Rb

Efficacy analyses

Median, months (95% CI)

PFS rate, %

6-month

1-year

Continuous tx

NR (NR) 80 65

1-year txb 10.3 (6.4, 15.2) 69 40

HR: 0.42 (95% CI: 0.25, 0.71)

No. at risk

1-year tx

Continuous tx

87 50 43 33 21 16 5 1 0

76 60 53 49 35 22 10 3 0

Time post-randomization (months)

PF

S (

%)

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24

Spigel DR, et al. ESMO 2017

Median, months

(95% CI)

OS rate, %

6-month

1-year

Continuous tx

NR (NR) 97 88

1-year txb 23.2 (23.2, NA) 95 81

HR: 0.63 (95% CI: 0.33, 1.20)


0

20

40

60

80

100

OS

(%

)

0 3 6 9 12 15 18 21 24 27

Median, months

(95% CI)

Continuous tx

NR (NR)

1-year txb,c 10.6 (4.8, NA)

HR: 0.45 (95% CI: 0.24, 0.85)

Median, months

(95% CI)

Continuous tx

NR (5.6, NA)

1-year txb 9.6 (4.5, 12.6)

HR: 0.44 (95% CI: 0.17, 1.09)

CR/PR SD

1-year tx 49 29 26 20 14 11 3 1 0

Continuous tx 53 45 41 39 28 17 7 2 0

No. at risk

0

20

40

60

80

100

PF

S (

%)

0 3 6 9 12 15 18 21 24


38 21 17 13 7 5 2 0 0

23 15 12 10 7 5 3 1 0

0

20

40

60

80

100

PF

S (

%)

0 3 6 9 12 15 18 21 24


PFS data OS data

Outcomes according to prior response

Re-treatment responses not so exciting

PFS advantage consistent across subgroups

(CR/PR vs. SD)

This is only an exploratory analysis: a randomized

trial should address this question

Re-Treatment after irAEs: a retrospective

analysis of the MSKCC

Santini FC, et al. ASCO 2017

In patients with irAEs that improve, retreatment

with anti–PD-L1 therapy resulted in recurrent

or new irAEs in 50% of patients

Among those who were retreated,

hospitalization and early onset of irAE were

associated with increased risk of recurrent/new

irAE

The majority of patients who developed

recurrent/new irAE were successfully managed,

but 2 deaths occurred (mortality rate 5%).

Limited responses occurred

following retreatment

Among those with CR/PR prior to

onset of first irAE, PFS and OS were

similar in the retreatment and

discontinuation cohorts

Description and severity of irAEs requiring delay/re-retreatment or discontinuation

Re-Treated Discontinued p-value

Grade of the 1st irAE

G1-2

G3-4

24 (63%)

14 (37%)

11 (34%)

21 (66%)

0.01

Type of irAE

Colitis

Pneumonitis

Musculoskeletal

Skin

Pancreas

Liver

CNS

Endocrine

Nephritis

Other

7 (18%)

6 (16%)

5 (13%)

5 (13%)

4 (11%)

3 (8%)

2 (5%)

2 (5%)

2 (5%)

2 (6%)

5 (16%)

8 (25%)

1 (3%)

7 (22%)

0 (0%)

5 (16%)

1 (3%)

1 (3%)

2 (6%)

2 (6%)

0.41

Hospitalization 8 (22%) 18 (56%) 0.003

irAE resolved to:

G 0-1

G≥2

37 (97%)

1 (3%)

22 (76%)

7 (24%)

0.007











Conclusions

NIVOLUMAB IN ECOG PS 2/ELDERLY PATIENTS:

THE CHECKMATE 171 TRIAL

Popat S, et al. ESMO 2017

“...Efficacy of nivolumab in patients aged ≥70 years were comparable to that

observed in the overall population (median OS: 11.2 mos); median OS in pts

with ECOG PS 2 was 5.4 mos...”

“...The tolerability of nivolumab in patients with ECOG PS 2 and elderly was

comparable to the overall population,..”

Use of Nivolumab in Elderly Patients With Advanced Non-Squamous

NSCLC:Results From the Italian Expanded Access Program (EAP)

Maria Rita Migliorino,1 Alain Gelibter,2 Francesco Grossi,3 Daniele Fagnani,4 Paola Bordi,5 Tindara Franchina,6 Daniele Turci,7

Luigi Di Lauro,8 Stefano Cascinu,9 Luana Calabrò,10 Matteo Brighenti,11 Natale Tedde,12 Alessandra Bearz,13 Sabrina Giusti,14

Enrico Vasile,15 Giammarco Surico,16 Giacomo Cartenì,17 Paolo Marchetti,18 Francesco Verderame,19 Barbara Melotti20

Migliorino MR, et al. ESMO 2017

Higher

proportion of

elderly than CM-

057 trial (15%

vs. 7%)

Efficacy similar to that

observed in the overall EAP

population (mOS 11.0 mos;

mPFS 3.0 mos) and the CM-

057 trial population (mOS

12.2 mos, mPFS 2.3 mos)











Conclusions

Hyperprogressive Disease (HPD): a new

pattern of PD

Ferrara R, et al. ESMO 2017; Champiat S, et al. Clin Cancer Res 2017; kato S, et al. Clin Cancer Res 2017

“...A novel aggressive pattern of hyperprogression exists in a fraction of patients treated with anti-PD-

1/PD-L1 (~9%). This observation raises some concerns about treating elderly patients (>65 years old) with anti-

PD-1/PD-L1 monotherapy and suggests further study of this phenomenon...” (Champiat S, et al. CCR 2017)

“... Here we report that specific genomic alterations may be associated with accelerated progression, i.e., the

presence of MDM2 family amplification or EGFR aberrations...” (Kato S, et al. CCR 2017)

Ferrara R, et al. ESMO 2017

In 36% of 242 advanced NSCLC pts IO

accelerated tumor growth, 40 pts (16%)

experienced HPD.

HPD correlated with >2 metastatic sites before

IO;

HPD is a negative prognostic factor (median OS

HPD pts <3.5months).











Conclusions

Impact of Tumor Mutation Burden on the Efficacy of First-

Line Nivolumab in the CheckMate 026: PFS and ORR

15

PFS by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

Nivolumab

Chemotherapy 47 30 26 21 16 12 4 1

60 42 22 15 9 7 4 1

111 54 30 15 9 7 2 1 1

94 65 37 23 15 12 5 0 0

Nivolumab n = 47 n = 60

9.7 (5.1, NR)

5.8 (4.2, 8.5)

Chemotherapy

Median PFS, months

(95% CI)

High TMB P

FS

(%

)

3 6 9 12 15 18 21

No. at Risk Months

100

90

80

70

60

50

40

30

20

10

0

0

Nivolumab

Chemotherapy

0 3 6 9 12

Months

15 18 21 24

Nivolumab

Chemotherapy

100

90

80

70

60

50

40

30

20

10

0

n = 111 n = 94

4.1 (2.8, 5.4)

6.9 (5.5, 8.6)

HR = 1.82 (95% CI: 1.30, 2.55)

Nivolumab Chemotherapy

(95% CI) Median PFS, months

Low/medium TMB

HR = 0.62 (95% CI: 0.38, 1.00)

16

ORR by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

47

23 28

33

0

10

20

30

40

50

60

70

80

90

100

High Low/medium

OR

R (

%)

TMB Subgroup

Nivolumab

Chemotherapy

111 94 47 60 n =

Peters S, et al. AACR 2017

17

OS by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

n = 111 n = 94

12.7 (9.9, 16.1)

13.2 (9.5, 15.2)

HR = 0.99 (95% CI: 0.71, 1.40)


(95% CI) Median OS, months

Low/medium TMB

55% received

nivolumab as crossover and/or

post-study treatment

1-y OS rate = 54% vs 53%

0 3 6 9 12

Months

15 18 21 24

100

90

80

70

60

50

40

30

20

10

0

111 99 82 69 59 47 28 11 3

94 87 71 60 50 38 21 6 2

27

Nivolumab

Chemotherapy

0

1

n = 47 n = 60

18.3 (11.4, NR)

18.8 (11.3, NR)

HR = 1.10 (95% CI: 0.64, 1.88)


(95% CI) Median OS, months

68% received

nivolumab as crossover and/or

post-study treatment

High TMB

0 3 6 9 12

Months

15 18 21 24

No. at Risk

Nivolumab

Chemotherapy

OS

(%

)

100

90

80

70

60

50

40

30

20

10

0 Nivolumab

Chemotherapy

47 41 35 33 30 24 13 4 0

60 56 48 45 36 34 19 9 1

1-y OS rate = 64% vs 60%

“...OS was similar between treatment arms; 68% of patients with high TMB in the

chemotherapy arm received nivolumab as crossover and/or post-study treatment...

Impact of Tumor Mutation Burden on the Efficacy of First-

Line Nivolumab in the CM-026: OS data


PFS by TMB Subgroup and PD-L1 Expression CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

32 24 13 12 7 5 2 1 28 18 9 3 2 2 2 0

53 35 23 13 10 8 3 0 41 30 14 10 5 4 2 0

No. at Risk High TMB, PD-L1 ≥50%

High TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 ≥50%

16 13 10 8 8 6 2 0 0 31 17 16 13 8 6 2 1 0

70 33 18 9 7 5 1 1 1 41 21 12 6 2 2 1 0 0

22

Months

100

75

50

25

0

6 18 9 3 0 12 15 21

Months

100

75

50

25

0

6 18 9 3

PF

S (

%)

0 12 15 24 21

High TMB, PD-L1 ≥50%


Low/medium TMB, PD-L1 1–49%




Low/medium TMB,

PD-L1 1–49%

High TMB, PD-L1 ≥50%

Nivolumab Arm Chemotherapy Arm

TMB level and tumor PD-L1 expression did not appear to be associated

PFS appeared to be longer in patients with high TMB regardless of PD-L1 status in the

nivolumab arm, albeit numbers were small

Patients with both high TMB and ≥50% PD-L1 expression had the greatest benefit from

nivolumab compared with those with one or neither of these factors

Impact of Tumor Mutation Burden and PDL1 on the

Efficacy of First-Line Nivolumab in the Check-Mate 026


bTMB (blood tumor mutation burden)

analysis of POPLAR trial: training set

Gandara D, et al. ESMO 2017; Fabrizio DA, et al. ESMO 2017

“...these exploratory analyses represent the first demonstration of a novel blood-based assay

measuring bTMB that may predict atezo clinical efficacy in 2L+ NSCLC...”

Gandara D, et al. ESMO 2017

bTMB (blood tumor mutation burden)

analysis of OAK trial: validation set











Conclusions

Conclusions and open questions

Is durvalumab a new standard of care in LA-NSCLC

after chemo-radiotherapy?

Immunotherapy in PD-L1+ ≥50% NSCLCs should be

better administered first;

Chemo + IO for whom? KN-189 trial will provide

definitive conclusions;

Continuing nivolumab over 1 year in non-progressing

patients is recommended;

Novel predictive biomarkers beyond PD-L1 IHC

expression are eagerly awaited.

Grazie!

III SESSIONE Highlights in Immunoncologia Il NSCLCmedia.aiom.it/userfiles/files/doc/AIOM-Servizi/slide/20171013ME_32... · cells, suggest that durvalumab may be an effective adjuvant

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