Quando e come inserire l’immunoterapia nella strategia terapeutica

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Quando e come inserire l’immunoterapia nella strategia terapeutica

Sara Lonardi

Regione del Veneto

SS Neoplasie Gastroenteriche UOC Oncologia Medica 1

Dipartimento di Oncologia Clinica e Sperimentale Istituto Oncologico Veneto – IRCCS, Padova

Convegno AIOM Nazionale

Presente e futuro dell’Immuno-Oncologia

Milano, 17 novembre 2017

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Gastric cancer

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DIAGNOSIS of

ADVANCED DIDEASE

CHEMO

10% never treated 75%

15%

100%

40% 20%

CHEMO + trastuzumab

1

^st

line 2

^nd

line 3

^rd

line

SUPPORTIVE CARE

CHEMO

+/- RAM

^CHEMO

M O D I F I E D F R O M L I N E E G U I D A A I O M , U P D A T E O C T O B E R 2 0 1 6

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Cunningham D, NEJM 2008 Al Batran SE, JCO 2008

First line doublets: cisplatin/oxaliplatin and 5FU/cape

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First line doublets: mFOLFOX6

Yoon HH, Ann Oncol 2016

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Van Cutsem E, JCO 2006

First line triplets: docetaxel, cis/oxaliplatin, 5FU/cape

Van Cutsem E, Ann Oncol 2015

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Al Batran SE, Jama Onc 2017 Al Batran SE, Ann Oncol 2008

First line triplets: FLOT

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Bang YJ, Lancet 2017

First line target therapy: trastuzumab and cisplatin+FPs

(9)

COUGAR-02

Second lines: irinotecan or docetaxel

(10)

7.4 9.6

Wilke H, Lancet Oncol 2014

Second lines: ramucirumab and paclitaxel

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1° line RR 40-60%

1° line Median PFS 5-7 m 1° line Median OS 10-12 m

2° line RR 20-30%

2° line Median PFS 3-4 m

2° line Median OS 5-9 m

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First line anti-PD-1: KEYNOTE-059

Weinberg et al. ESMO ‘17

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First line anti-PD-1: KEYNOTE-059

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KEYNOTE-059 cohort 2: response

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KEYNOTE-059 cohort 3: response

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KEYNOTE-059 cohort 2: PFS and OS

Wainberg et al. ESMO ‘17

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KEYNOTE-059 cohort 3: PFS and OS

(18)

Key Eligibility Criteria

• Advanced or Metastatic GC/GEJ

• No prior systemic treatment

• ECOG PS 0–1

• Tissue available for PDL1 testing

• F/U visits

• Survival F/U

Treatment Follow-Up

Screening

R A N D O M I Z A T I O N

PD, unacceptable toxicity, withdrawal IC

1:1 (N=930)

• PDL1 status (≥1% vs. <1%)

• Region (Asia vs US vs ROW)

• ECOG PS (0 vs 1)

Nivo 1 mg/kg + Ipi 3 mg/kg

Q3W x 4 (N=465)

Investigator’s choice (N=465)

OR

Nivo Mono 240 mg Q2W

XELOX (Oxaliplatin + Capecitabine) Q3W

FOLFOX (Oxaliplatin + Leucovorin + Fluorouracil) Q2W

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Purpose

To compare OS in patients with gastric or gastroesophageal junction cancer treated with nivolumab plus ipilimumab or with

chemotherapy SOC (oxaliplatin plus fluoropyrimidine)

Primary Endpoint^a

• OS in patients with PD-L1+ tumors Secondary Endpoints^a

• OS in all randomized patients

• PFS in patients with PD-L1+ tumors and all randomized patients

• Time to symptom deterioration (GaCS questionnaire) in patients with PD-L1+

tumors and all randomized patients Study Specific Eligibility Criteria

• Inoperable, advanced or metastatic gastric cancer or gastroesophageal junction cancer

• No neoadjuvant or adjuvant chemotherapy or radiotherapy within last 6 months

• Tumor tissue available from within last 6 months

• No untreated CNS metastases

aAssessed approximately 35 months after first patient randomized

CNS=central nervous system; GaCS=Gastric Cancer Subscale; OS=overall survival; PD-L1=programmed death ligand 1; PFS=progression-free survival; SOC=standard of care.

ClinicalTrials.gov. NCT02872116

CheckMate 649: first line nivo randomized trial

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KEYNOTE-059

Weinberg et al. ESMO ‘17

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Second line anti-PD-1: KEYNOTE-059

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KEYNOTE-059 cohort 1: PFS and OS by PD-L1 expression

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Le DT, et al. Presentation at the ASCO Gastrointestinal Cancers Symposium. 2016;

ClinicalTrials.gov. NCT01928394;

Janjigian, et al. Poster at the American Society of Clinical Oncology (ASCO) Annual Meeting. 2016

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Overall Survival

CA209-032 update: Overall survival

Janjigian et al. ASCO Annual Meeting’17

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Yoon-Koo Kang et al. Lancet 2017

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Attraction-2 Study: Overall Survival

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Attraction-2 Study: Progression-Free Survival

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Patients with advanced GC

refractory to platin-5-FU

(N=720)

Pembrolizumab 200 mg q 3 weeks

Paclitaxel

80 mg/mq weekly

Primary endpoint: OS in PDL-1 +

Secondary endpoints: ORR, safety, OS, PK, biomarker

R 1:1

unblinded

Phase III second line randomized trial of pembro vs paclitaxel

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1° line RR 26-60%

1° line median PFS 3-6 m 1° line median OS 14-20 m

Later lines RR 10%

Later lines median PFS 3-5 m Later lines median OS 5-8 m

Anti-PD-1 outcomes

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FDA website (accessed on Nov 15, 2017) Wainberg ZA et al. ESMO 2017 (abstr. LBA_28PR)

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ATTRACTION-2: OS by PD-L1 expression

Boku et al. ESMO ’17

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Hypermutated phenotype Elevated PD-L1/2 expression CHROMOSOMAL

INSTABILITY (CIN)

GENOMICALLY STABLE

(GS) EPSTEIN-

BARR VIRUS

TYPE (EBV)

MICRO- SATELLITE INSTABILITY SUBGROUP

(MSI)

immune checkpoint agents

molecularly targeted

agents

Aberration in specific genes

(e.g. RHO) Aberration in

specific genes (e.g. EGFR, HER2, VEGF)

molecularly targeted

agents

chemotherapeutic agents

B O N O T T O M , E T A L . E X P E R T R E V C L I N P H A R M A C O L . S U B M I T T E D

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Confirmatory Results

Le et al, Science 2017

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Confirmatory Results

Le et al, Science 2017

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Confirmatory Results

Le et al, Science 2017

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A new era

www.fda.org accessed on May 23rd, 2017,

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Colorectal cancer

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RAS and BRAF wt

RAS or BRAF mut

First line strategy deeply influences the whole story..

The right treatment to the right patient with the aim of:

1) a chance of cure, if possible..

2) longer and better survival

3) maintanance of good PS to get subsequent lines of therapy

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UNFIT for combo and/or

elderly patients FIT for combo PATIENT - age and fitness

MONOCHEMO TRIPLET

DOUBLET

Chemo-intensity choice

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MEDIAN F-UP 48.1 mos (74% events) FOLFIRI + bev: N = 256 / Died = 200 FOLFOXIRI + bev: N = 252 / Died = 174

FOLFIRI + bev, median OS : 25.8 mos FOLFOXIRI + bev, median OS : 29.8 mos

HR: 0.80 [0.65-0.98]

p=0.030

Cremolini et al, Lancet Oncol 2015

TriBe: updated OS data

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✓ Bevacizumab  majority of pts

✓ Aflibercept  only with FOLFIRI;

✓ Ramucirumab  only with FOLFIRI;

✓ anti-EGFRs  only RAS and BRAF wt;

mainly if shrinkage is needed

Second line options summary

(41)

 Anti-EGFR (pani, cet +/- irinotecan)

In RAS wt pts not previously treated with anti-EGFR

 Chemo Rechallenge

No prospective evidences

Carefully consider previous benefit and toxicity

Treatment options in later lines

 Small molecules: Regorafenib

 Chemotherapy: Trifluridine/tipiracil (TAS-102)

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A new piece on the puzzle!

50%

RAS mutations

BRAF mutation

RAS/BRAF wild-type

40% ^10%

HER-2 3%

Rearrangem

MSI

5%

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dMMR/MSI-H per Local Laboratory

(N = 74)

dMMR/MSI-H per Central Laboratory

(n = 53)

Investigator BICR Investigator BICR ORR, n (%)

95% CI

23 (31.1) 20.8, 42.9

20 (27.0) 17.4, 38.6

19 (35.8) 23.1, 50.2

17 (32.1) 19.9, 46.3

Best overall response, n (%) CR

PR SD PD

Unable to determine

0 23 (31.1) 29 (39.2) 18 (24.3) 4 (5.4)

2 (2.7) 18 (24.3) 28 (37.8) 20 (27.0) 6 (11.1)

0 19 (35.8) 21 (39.6) 10 (18.9) 3 (5.7)

1 (1.9) 16 (30.2) 21 (39.6) 12 (22.6) 3 (5.7) Disease control for ≥ 12 weeks, n (%)^a 51 (68.9) 46 (62.2) 39 (73.6) 37 (69.8)

Overman et al, Lancet Oncol 2017

Response in patients receiving Nivolumab monotherapy

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PFS per Investigator

Median [95% CI], months 12-month rate [95% CI], %

9.6 [4.3, NE]

48.4 [33.6, 61.7]

PFS per BICR

12-month rate [95% CI], % 45.6 [32.2, 58.1]

0 3 6 9 12 15 18 21 24

Months

74 48 22 14 12 10 7 3 0

No. at risk 0 10 20 30 40 50 60 70 80 90 100

Probability of PFS (%)a

Nivolumab PFS in MSI-H

Overman et al, Lancet Oncol 2017

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Median OS [95% CI], months 12-month OS rate [95% CI], %

NR [17.1, NE]

73.8 [59.8, 83.5]

3 6 9 12 15 18 21 24 27

74 64 54 24 21 21 14 10 3 0

0 10 20 30 40 50 60 70 80 90 100

Probability of Survival (%)a

Months No. at risk

0

Nivolumab OS in MSI-H

Overman et al, Lancet Oncol 2017

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Efficacy in Patients With dMMR/MSI-H Metastatic CRC per Investigator Assessments

dMMR/MSI-H (N = 84)^a

Investigator ORR, n (%)

[95% CI]

46 (54.8) [43.5, 65.7]

Best overall response, n (%) CR

PR SD PD

Not determined Not reported

2 (2.4) 44 (52.4) 26 (31.0) 9 (10.7)

2 (2.4) 1 (1.2)

Disease control for ≥ 12 weeks, n (%)^b 66 (78.6)

Median TTR, months (range) 2.8 (1.1–14.0)

Median DOR, months, [95% CI] NR [0.0+, 15.9+]

DOR, duration of response; NR, not reached; PD, progressive disease; SD, stable disease; TTR, time to response.

aPatients from monotherapy stage 1 and 2 combined. ^b Patients with CR, PR, or SD for ≥ 12 weeks.

Nivolumab and ipilimumab activity in MSI-H

Andre et al, ASCO Annual Meeting 2017

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• Median TTR was 2.8 (1.1–14.0) months

• Median DOR: not reached; 85% (39/84) responses ongoing (Figure 2B)

*Ongoing response include responders who had neither progressed nor initiated subsequent therapy at the time of analysis and excludes responders censored prior to 8 weeks of the clinical data cutoff date if a patient is still in the first 24 weeks follow-up period, otherwise, the window is 14 weeks

Best Change in Target Lesion Size Change Tumor Burden Over Time

Nivolumab and ipilimumab activity in MSI-H

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• Medians for PFS and OS had not yet been reached

• The 6-month rates of PFS and OS were 77.4% and 89.1%, respectively

Nivolumab + Ipilimumab (N=84)

6 mo PFS rate, % [95% CI]

77.4 (66.5, 85.1)

Median PFS, mo [95% CI]

NA (11.47, NE)

No. events 21/84

Nivolumab + Ipilimumab (N=84)

OS rate, % [95%

CI]

6 mo 89.1 (80.2, 94.2 9 mo 87.6 (78.1, 93.1) Median PFS,

mo [95% CI]

NA (NE, NE)

No. events 15/84

Nivolumab and ipilimumab efficacy in MSI-H

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Nivolumab and ipilimumab safety

dMMR/MSI-H (N = 84)

Patients, n (%) Any Grade Grade 3/4

Any TRAEs 57 (68) 24 (29)

Serious TRAEs 15 (18) 14 (17)

Discontinuation due to TRAEs^a 11 (13) 8 (9)

TRAEs reported in ≥ 10% of patients

Diarrhea 20 (24) 1 (1)

Fatigue 14 (17) 1 (1)

Aspartate aminotransferase increase 14 (17) 8 (9)

Pyrexia 13 (16) 0

Pruritus 13 (16) 2 (2)

Alanine aminotransferase increase 12 (14) 7 (8)

Nausea 12 (14) 0

Hyperthyroidism 11 (13) 0

Hypothyroidism 11 (13) 0

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Response according to PD-L1, KRAS/BRAF and Lynch sdr

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TCGA Nature 2012 Giannakis et al, Cell Reports 2016 4% POLE-mutant

“Ultramutated”

Microsatellite stable

TCGA colorectal cancers Recurrent heterozygous

missense mutations in exonuclease domain (P286R, V411L, S459F)

POLE proofreading domain mutations

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Extremely rare, extremely sensitive

Gong et al. JNCCN ‘17

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How to warm a ‘’cold’’ tumor?

- New combinations to increase immune response activation (eg. antiPD-L1 and MEKinhib)

- Locoregional treatments to release high burden of new epitopes (eg. RFA/TACE plus antiPD1)

- Iatrogenic switch to an instable tumor under

chemotherapy pressure (eg alkylating agents before

antiPD1 treatment, association between chemo and IO)

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• in MSI-H patients clinical responses were observed with NIVO and NIVO+IPI across all biomarker groups assessed

– PD-L1 tumor expression, BRAFor KRAS mutations, and clinical history of Lynch syndrome did not exhibit clear correlation with clinical responses when

reviewed as single biomarkers or combined

• Additional analyses are ongoing to evaluate the predictive value of other biomarkers of interest in addition to dMMR/MSI-H status for response to treatment with immune-checkpoint inhibitors

Conclusions (1)

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Conclusions (2)

• data on first line treatment are pending

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Conclusions (3)

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