Dati di letteratura: dallo stadio IV in I e II linea allo stadio III

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Rita Chiari

La rivoluzione dell’Immunoterapia nel NSCLC

Dati di letteratura: dallo stadio IV in I e II linea allo stadio III

Dr. Rita Chiari

Oncologia Medica

Azienda Ospedaliero-Universitaria Perugia

rita.chiari@unipg.it

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• Cancer cells develop many mutations that can make them appear foreign to the immune system

• Specificity

• Memory

• Adaptivity

Key Attributes of the Immune

System

Rita Chiari

(3)

• CD8+ T cells can recognize, attack and kill these

“foreign” cancer cells

B7.1

P13K Other NFKB

Rita Chiari

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Adaptive Tumor Expression of PD-L1 Turns the Immune System OFF!

• Cancer cells can evade

immune attack by expressing PD-L1

P13K NFKB

Other

IFNg-mediated up-regulation of tumor PD-L1

Shp-2

Stat

B7.1

Rita Chiari

(5)

• Cancer cells can evade

immune attack by expressing PD-L1

P13K NFKB

Other

IFNg-mediated up-regulation of tumor PD-L1

Shp-2

Stat

B7.1

Clinically we want to block PD-1 or PD-L1 (the big X) to reactivate the immune system!

Rita Chiari

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Stromal PD-L1 modulation of T cells

Immune cell modulation of T cells PD-L1/PD-1-mediated inhibition of

tumor cell killing IFNg-mediated

upregulation of tumor PD- L1

Priming and activation of T cells

PD-L2-mediated inhibition of TH2 T cells

receptor

B7.1

Chen DS, Irving BA, Hodi FS. Clin Cancer Res. 2012;18:6580.

PD-L1 Plays an Important Role in Dampening the Anti-Tumor Immune Response

Complexity of the system!

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- 63 y/o ex-smoker (15 pack years, quitting in 1983)

- Stage IV Squamous NSCLC dx in Jan. 2009;

metastatic to hilum/

mediastinum, liver, adrenal, bone and later, myocardium - 3 prior chemotherapy

regimens

- Nivolumab initiated June 2010

P age: 1 5 of 5 9 P age: 1 5 of 5 9 I M : 1 5 SE : 1 0 2 I M : 1 5 SE : 1 0 2 C ompres s ed 8 :1 C ompres s ed 8 :1

P age: 1 4 of 1 2 2 P age: 1 4 of 1 2 2 I M : 1 4 SE : 2 I M : 1 4 SE : 2 C ompres s ed 8 :1 C ompres s ed 8 :1

P age: 5 4 of 5 9 P age: 5 4 of 5 9 I M : 5 4 SE : 1 0 2 I M : 5 4 SE : 1 0 2 C ompres s ed 8 :1 C ompres s ed 8 :1

P age: 5 3 of 1 2 2 P age: 5 3 of 1 2 2 I M : 5 3 SE : 2 I M : 5 3 SE : 2 C ompres s ed 8 :1 C ompres s ed 8 :1

P age: 4 5 of 5 9 P age: 4 5 of 5 9 I M : 4 5 SE : 1 0 2 I M : 4 5 SE : 1 0 2 C ompres s ed 8 :1 C ompres s ed 8 :1 c m

c m C ompres s ed 8 :1C ompres s ed 8 :1P age: 4 0 of 1 2 2P age: 4 0 of 1 2 2 I M : 4 0 SE : 2 I M : 4 0 SE : 2 c m

c m

P age: 3 3 of 5 9 P age: 3 3 of 5 9 I M : 3 3 SE : 1 0 2 I M : 3 3 SE : 1 0 2 C ompres s ed 8 :1 C ompres s ed 8 :1 c m

c m C ompres s ed 8 :1C ompres s ed 8 :1P age: 3 1 of 1 2 2P age: 3 1 of 1 2 2 I M : 3 1 SE : 2 I M : 3 1 SE : 2 c m c m

Pre- Nivolumab 2 Years on Nivolumab Last month, > 4 Years off Nivolumab

O grady, M aureen O grady, M aureen

P age: 1 7 of 5 8 P age: 1 7 of 5 8 I M : 1 7 SE : 2 I M : 1 7 SE : 2 C ompres s ed 8 :1 C ompres s ed 8 :1 O grady, M aureen

O grady, M aureen

P age: 1 3 2 of 2 1 7 P age: 1 3 2 of 2 1 7C ompres s ed 8 :1C ompres s ed 8 :1 I M : 1 3 2 SE : 4 I M : 1 3 2 SE : 4

It Really works!

Patient with Lung Cancer on Nivolumab since June 2010

Cure?

Rita Chiari

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Rita Chiari

CI = confidence interval; HR = hazard ratio

292 194 148 112 82 58 49 39 7 0

290 195 112 67 46 35 26 16 1 0

135 86 57 38 31 26 21 16 8 0

137 69 33 17 11 10 8 7 3 0

CheckMate 057 (non-SQ NSCLC) CheckMate 017 (SQ NSCLC)

No. of patients at risk Nivolumab

Docetaxel

No. of patients at risk Nivolumab

Docetaxel

0 6 12 18 24 30 36 42 48 54

Δ10%

Nivolumab (n = 135) Docetaxel (n = 137)

1-y OS = 42%

2-y OS = 23%

3-y OS = 16%

1-y OS = 24%

2-y OS = 8% 3-y OS = 6%

HR (95% CI): 0.62 (0.48, 0.80) 100

80

60

40

20

0

OS(%)

Months

Δ18%

Δ15%

0 6 12 18 24 30 36 42 48 54

Months 1-y OS = 51%

2-y OS = 29%

3-y OS = 18%

1-y OS = 39%

2-y OS = 16%

3-y OS = 9%

Nivolumab (n = 292) Docetaxel (n = 290)

HR (95% CI): 0.73 (0.62, 0.88) 100

80

60

40

20

0

OS(%)

Δ12%

Δ13%

Δ9%

Felip E, et al. ESMO 2017

ESMO 2017 update on CheckMate 017 and 057:

OS with 3 years minimum follow-up

16% 18%

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Rita Chiari

Immunotherapy: key messages in NSCLC

1. Monotherapy with ICIs is effective in second-line

– Evidence of OS benefit irrespective of PD-L1 expression

– Some clinical and biological characteristics could help in patient selection

2. In non-progressing patients immunotherapy should be continued >1 year

3. Immunotherapy effective both in 1^st and in 2^nd line but ORR, PFS &OS seem to favor 1^st line ICIs

4. The PACIFIC trial probably establishes a new standard of care in locally advanced NSCLC treated with concomitant CT+RT

5. Combination of immunotherapy and standard chemo seems better than chemo alone

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I HOPE that it will not end up as a matter of dosing schedules and costs!

Summary of efficacy data : 2L NSCLC

Rita Chiari

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Rita Chiari

Immunotherapy: key messages in NSCLC

3. Immunotherapy effective both in 1^st and in 2^nd line but ORR, PFS &OS seem to favor 1^st line ICIs

(12)

Rita Chiari

ESMO 2017 update on CheckMate 017 and 057:

3-year estimated OS rate overall and by PD-L1 expression

aKaplan-Meier estimates, with error bars indicating 95% CIs;^bOf the 3-year survivors treated with docetaxel (n = 34) in CheckMate 017 and CheckMate 057, 25 (74%) received subsequent immunotherapy, either during crossover to nivolumab or as post-study treatment;^cOf the 3-year survivors treated with docetaxel in CheckMate 017 who had <1%, ≥1%, or ≥50% PD-L1 expression levels, 2, 4, and 2 patients, respectively, received subsequent immunotherapy;^dOf the 3-year survivors treated with docetaxel in CheckMate 057 who had <1%, ≥1%, or ≥50% PD-L1 expression levels, 5, 8, and 4 patients, respectively, received subsequent immunotherapy;^eOverall population includes those with no quantifiable PD-L1 expression (CheckMate 017: nivolumab, n = 18 [3-y OS, 28%] and docetaxel, n = 29 [3-y OS, 3%];

CheckMate 057: nivolumab, n = 61 [3-y OS, 15%] and docetaxel, n = 66 [3-y OS, 10%])

CheckMate 017 (SQ NSCLC)

16 6 13 4 14 9 29 20

0 20 40

60 Nivolumab Docetaxel

OS(%)a

<1% ≥1%

Overall^e

137 54 52 63 56

All patients, n PD-L1 expression^c,d

≥50%

17 10

135

Hazard ratio (95% CI)

0.62 (0.48, 0.80)

0.60 (0.40, 0.90)

0.72 (0.49, 1.06)

0.68 (0.27, 1.66)

3-y survivors, n 21 8^b 7 2^c 9 5^c 5 2^c

CheckMate 057 (non-SQ NSCLC)

18 9 11 8 26 10 39 9

0 20 40

60 Nivolumab Docetaxel

<1% ≥1%

Overall^e

292 290 108 101 123 123

≥50%

66 46

0.73 (0.62, 0.88)

0.90 (0.68, 1.20)

0.56 (0.42, 0.74)

0.34 (0.22, 0.53)

49 26^b 11 8^d 29 12^d 23 4^d

OS(%)a

Felip E, et al. ESMO 2017

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Rita Chiari

Evidence of survival benefit in PD-L1 negative:

Nivolumab and atezolizumab data

mOS (mo)

Nivolumab Docetaxel

PD-L1 ≥1% 9.3 7.2

PD-L1 <1% 8.7 5.9

1% PD-L1 Expression level

Time (months)

24 21 18 15 12 9

6 3 0 100

90 80 70 60 50 40 30

10 0 20

OS(%)

24 21 18 15 12 9

6 3 0 100

90

80

70

60

50

40

30

10

0 20

Brahmer J, et al. NEJM 2015

Atezolizumab Docetaxel

Months

HR, 0.75^a

(95% CI, 0.59, 0.96) P = 0.0205^b

Median 8.9 mo (95% CI, 7.7, 11.5)

Median 12.6 mo (95% CI, 9.6, 15.2)

OverallSurvival(%)

Minimum follow up = 19 months

CheckMate 017

Nivolumab in squamous-cell carcinoma

OAK

Atezolizumab in all histologies

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Rita Chiari

Immunotherapy: key messages in NSCLC

1. Monotherapy with IOs is effective in second-line

3. Immunotherapy effective both in 1^st and in 2^nd line but ORR, PFS &OS seem to favor 1^st line IO

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Meta-analysis of trials with ICIs in patients with EGFR mutations

Lee CK et al, JTO 2017

Rita Chiari

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Rita Chiari

0 10 20 30 40 50 60 70 80 90 100

Patients with factor in OS subgroup (%) OS ≤3 months OS >3 months

<3 mo from last

TX

PD best resp.

No maint.

TX

>5 sites with lesions

Bone mets

Liver mets

Never Current/

former

0 1 <1% ≥1% ≥5% ≥10%

EGFR mut.-pos.

Prior therapy

Smoking status Baseline

disease site

PD-L1 expression^a ECOG

PS

• Post-hoc, exploratory multivariate analysis suggested that nivolumab-treated patients with poorer prognostic

features and/or aggressive disease when combined with lower or no tumor PD-L1 expression may be at higher risk of death within the first 3 months

– These included the following known prognostic factors: <3 months since last treatment, PD as best response to prior treatment, and ECOG PS = 1

Peters S, et al WCLC 2016

Which patients are not candidate for 2nd-line monotherapy with ICIs?

Combination of clinical factors and PD-L1 expression in Checkmate 057

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Rita Chiari

Immunotherapy: key messages in NSCLC

3. Immunotherapy effective both in 1^st and in 2^nd line but ORR, PFS &OS seem to favor 1^st line IO

(18)

Rita Chiari

CheckMate 153: Continuous versus 1-year nivolumab

• At database lock (May 15, 2017), minimum/median follow-up time post-randomization was 10.0/14.9 months Exploratory endpoints^d: safety/efficacy^ewith continuous vs 1-year treatment, efficacy, other (eg, biomarkers, PK)

Key eligibility criteria

• Advanced/ metastatic NSCLC

• ≥1 prior systemic therapy^a

• ECOG PS 0−2

• Treated CNS

metastases allowed Stop nivolumab

Continuous nivolumab Nivolumab

3 mg/kg IV Q2W Treatment for 1 year^b

R^c

Nivolumab retreatment allowed at PD

Spigel D, et al. ESMO 2017

Stop nivolumab Continuous nivolumab

1,245 patients treated^a

220 patients on treatment at

1 year

76had response or SD at randomization^c

87had response or SD at randomization^d R^b

Efficacy analyses

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Rita Chiari

CheckMate 153: Continuous versus 1-year nivolumab PFS from randomization

Spigel D, et al. ESMO 2017

Median, months (95% CI)

PFS rate, % 6-month 1-year

Continuous tx NR (NR) 80 65

1-year tx^b 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

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)

PFS(%)

0 20 40 60 80 100

0 3 6 9 12 15 18 21 24

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2nd line monotherapy with ICIs works for about 20% of pts:

So what about the other 80% ?

Stromal PD-L1 modulation of T cells

Immune cell modulation of T cells PD-L1/PD-1-mediated

inhibition of tumor cell killing IFNg-mediated

upregulation of tumor PD-L1

Priming and activation of T cells

PD-L2-mediated inhibition of TH₂ T cells

receptor B7.1

Chen DS, Irving BA, Hodi FS.

Clin Cancer Res. 2012;18:6580.

Potential for benefit in all cancers!

Multiple Factors Determine Sensitivity and Resistance in the Immune Microenvironment

Use complexity as a resource!!

• ICIs 1

^st

line

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Rita Chiari

Immunotherapy: key messages in NSCLC

3. Immunotherapy effective both in 1^st and in 2^nd line but ORR, PFS &

OS seem to favor 1^st line ICIs

(22)

Rita Chiari

KEYNOTE 024 trial

Crossover to

• Platinum-doublets= 87.5%

• Pembrolizumab= 81.4%

Key message: Immunotherapy first seems better

Reck M NEJM 2016

Brahmer JR, et al. ASCO 2017

PFS OS

Brahmer et al, ASCO 2017; Abstract 9000

Pembrolizumab (n=154)

Chemotherapy (n=151)

HR P Value

PFS 18.3 months 8.4 months 0.54 <.001

OS (updated) Not reached 14.5 months 0.63 .003

Key End Points

Primary: PFS (RECIST v1.1 per blinded, independent central review) Secondary: OS, ORR, safety

Exploratory: DOR

Key Eligibility Criteria

• Untreated stage IV NSCLC

• PD-L1 TPS ≥50%

• ECOG PS 0-1

• No activating EGFR mutation or ALK translocation

• No untreated brain metastases

• No active autoimmune disease requiring systemic therapy

Pembrolizumab 200 mg IV Q3W

(2 years) R (1:1)

N = 305

Platinum-Doublet Chemotherapy

(4-6 cycles)

KEYNOTE 024 study design

PD^a Pembrolizumab 200 mg Q3W

for 2 years

aTo be eligible for crossover, progressive disease (PD) had to be confirmed by blinded, independent central radiology review and all safety criteria had to be met.

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Rita Chiari

Longer OS for patients receiving atezolizumab early

during the course of their disease: BIRCH updated results

TC2/3 or IC 2/3 TC3 or IC 3

Peters S, et al. JCO 2017

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Rita Chiari

Immunotherapy: key messages in NSCLC

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Rita Chiari

Auperin et al J Clin Oncol 2010; 28:2181

Concomitant chemoradiation is the standard of care in locally

advanced, unresectable NSCLC: meta-analysis of survival

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Rita Chiari

PACIFIC Trial design

Ph. III, randomized, double-blind, placebo-controlled, multicenter, international study

Antonia et al. , NEJM 2017

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Rita Chiari

PFS by BIRC (Primary end-point; ITT)

Antonia et al. , NEJM 2017

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2nd line monotherapy with ICIs works for about 20% of pts:

So what about the other 80% ?

Multiple Factors Determine Sensitivity and Resistance in the Immune Microenvironment

Use complexity as a resource!!

COMBINATIONS

Hodge JW, Semin Oncol 2012; Drake CG, Ann Oncol 2012; Ménard C, Cancer Immunol Immunother 2008; Hannani D, Cancer J 2011; Ribas A, Curr Opin Immunol 2013

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Unmet medical need remains: combination therapies are likely to be required to improve patient outcomes

Rita Chiari

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Potential Immuno-Oncology (ICIs) combinations

Lu H, Front Immunol 2014; Melero I, Nat Rev Cancer 2015; Drake CG, Ann Oncol 2012; Vanneman M, Nat Rev Cancer 2012; Sznol M, Clin Cancer Res 2013; Formenti SC, J Natl Cancer Inst 2013; Kang J, J ImmunoTher Cancer. 2016

x

Rita Chiari

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Rita Chiari

Immunotherapy: key messages in NSCLC

6. Other Combinations are to be established

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Rita Chiari

First-line ICI plus CHT combo:

pembrolizumab plus chemo (KEYNOTE-021, cohort G)

Cohorts A–C are pembrolizumab + platinum doublet chemotherapy; Cohorts D and H are pembrolizumab + ipilimumab; Cohorts E and F are pembrolizumab + EGFR TKI

Langer, et al. Lancet Oncol 2016 17(11): 1497–508

• Stage IIIB/IV Non Sq NSCLC

• No systemic therapy for recurrent disease

• ECOG PS 0–1

(Cohort G: n=123)

Pemetrexed 500mg/m² i.v. q3w + carboplatin AUC 6 i.v. q3w + pembrolizumab 200mg i.v. q3w

Pemetrexed 500mg/m² i.v. q3w + carboplatin AUC 6 i.v. q3w

1 ^ORR 2 OS, PFS and DoR

Endpoints

Patients included irrespective of PD-L1 expression

Cross over allowed at PD

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Rita Chiari

KEYNOTE-021, cohort G: Updated results

RR

PFS by Independent Central Review

Borghaei et al. ESMO 2017

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Potential Immuno-Oncology (ICIs) combinations

Lu H, Front Immunol 2014; Melero I, Nat Rev Cancer 2015; Drake CG, Ann Oncol 2012; Vanneman M, Nat Rev Cancer 2012; Sznol M, Clin Cancer Res 2013; Formenti SC, J Natl Cancer Inst 2013; Kang J, J ImmunoTher Cancer. 2016

Rita Chiari

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Combining T-cell modulators

Mellman I, Nature 2011

Antigen presenting cell B7H3

VISTA

T cell

CTLA-4 (eg, Ipilimumab, Tremelimumab)

ICOS (eg, MEDI-540)

LAG3 (eg, IMP701, BMS-986016, GSK2831781)

GITR (eg, MK-4166, BMS-986156, GWN323, MEDI1873)

TIM3 (eg, MBG453)

OX40 (eg, GBR 830, BMS-986178, MEDI6469)

IDO1 (eg, epacadostat, indoximod)

Rita Chiari

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ICI-ICI combinations (Phase I)

(Nivolumab/Ipilimumab – Durvalumab/Tremelimumab)

23% 22% 29%

40%

0%

10%

20%

30%

40%

50%

60%

70%

All PDL-L1+ (>25%) PD-L1- (<25%) PD-L1- (0%)

Objective Response Rate (D10-20 q4/2w T1)

Durva + Treme

Hellmann MD, Lancet Oncol 2017; Antonia S, Lancet Oncol 2016

Rita Chiari

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Phase III first-line combination of anti-PDL1 and CTLA-4 inhibitors

Rita Chiari

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Phase I/II study of Epacadostat + Pembrolizumab

Gangadhar TC, Ann Oncol. 2016

Rita Chiari

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Rita Chiari

Take home messages

• Second-line metastatic NSCLC:

• Immunotherapy is the standard of care

• Nivolumab, pembrolizumab and atezolizumab are superior to docetaxel

• Evidence of survival superiority over docetaxel in PD-L1 negative for nivolumab in squamous-cell carcinoma and for atezolizumab in all histologies

• Clinical and biological characteristics could help in patient selection

• Continuing immunotherapy over 1 year in non progressing patients is recommended

• First-line metastatic NSCLC:

• Pembrolizumab standard of care in PD-L1 high expressing NSCLC

• Locally advanced unresectable NSCLC:

• Durvalumab improves DFS after concomitant chemoradiotherapy

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Rita Chiari

«Due cose contribuiscono ad

avanzare: andare più rapidamente degli altri o andare per la buona

strada»

Cartesio

Dati di letteratura: dallo stadio IV in I e II linea allo stadio III

La rivoluzione dell’Immunoterapia nel NSCLC