Neoplasie del colon

(1)

Highlights in

immunoncologia

Neoplasie del Colon

Fabio Raiti

UOC Oncologia Medica Umberto I Siracusa

(2)

FDA approvals timeline (solid tumor)

Aug 2017

Nivolumab (dMMR/MSI-H only) Pembrolizumab (dMMR/MSI-H only)

(3)

MSI-H and Cancer

(4)

Baseline PD-L1 Expression and CD8 TCell Infiltration

Dung Le, ASCO 2017

(5)

Le DT, el al. N Engl J Med. 2015 May 14;372(20):2509-20

(6)

• KEYNOTE-016 (n = 58) CRC MSI +/- non CRC MSI+ II ongoing (2021)

• KEYNOTE-164 (n = 61) CRC II ongoing (2019)

• KEYNOTE-012 (n = 6) solid tumor I ongoing (2018)

• KEYNOTE-028 (n = 5) solid tumor I ongoing (2018)

• KEYNOTE-158 (n = 19) solid tumor II ongoing (2023)

Pts ORR CRs PRs

149 39,6 11(7,4%) 48 (32,2%)

(7)

KEYNOTE-164 and KEYNOTE-158: Study Design

Diaz L., ASCO 2017, Abstract 3071

ORR was 26.2% (95% CI, 15.8%-39.1%) for MSI-H CRC ORR was 42.9% (21.8%-66.0%) for MSI-H non-CRC

DCR was 50.8% (n = 31; 37.7%-63.9%) for MSI-H CRC

DCR was 66.7% (n = 14; 38.4%-83.7%) for MSI-H non-CRC.

Primary end point:

ORR (RECIST v1.1, central review

Secondary end point:

DOR, PFS, OS, and safety

(8)

Basaline Characteristics

MSI-HCRC N=61

MSHI-H Non CRC N=77

Age, years,median (range) 53 (21-84) 64 (24-87)

> 65 years 17 (28) 34 (44)

Men 36 (59%) 42 (55%)

ECOG PS 1 32 (52%) 39 (51%)

M1 stage 61 (100%) 65 (84%)

KRAS/BRAF/NRAS mutant 26%/15%/5% Not assessed Tumor size,mm, median

(range)

99 (11-408) 78 (14-316)

Prior (neo)adjuvant 23 (38%) 20 (26%)

≥ 2 prior therapies 55 (90%) 40 (52%)

(9)

Treatment Related AEs With Incidence >10%

Event,n (%) MSI-H CRC N=61

MSI-H CRC N=77

Events ≥ 10% Any Grade Grade 3-5 Any Grade Grade 3-5

Arthalgia 10 (16) 0 2 (3) 0

Nausea 9 (15) 0 6 (8) 0

Diarrhea 8 (13) 0 7 (9) 1 (1)

Asthenia 7 (12) 1 (2) 7 (9) 1 (1)

Pruritus 7 (12) 0 7 (9) 0

Fatigue 6 (10) 2 (3) 8 (10) 0

(10)

Checkmate 142: study design

Primary endpoint: ORR per investigator assessment

Secondary endpoint: ORR per blinded independent central review (BICR) Other endpoints: PFS, OS, biomarkers, safety and tolerability

A Phase 2 Clinical Trial of Nivolumab, or Nivolumab Combinations in Recurrent and Metastatic

Microsatellite High (MSI-H) and Non-MSI-H Colon Cancer

(11)

dMMR/MSI-H per Local Laboratory

(N = 74) dMMR/MSI-H (N = 84)

Age

Median (range), years

< 65 years, n (%)

52.5 (26–79)

57 (21–81)

61 (73)

Male, n (%) 44 (59.5) 48 (57)

Race, n (%) White Black Asian Other

65 (87.8) -- 7 (9.5) 2 (2.7)

77 (92)

2 (2) 3 (4) 2 (2) ECOG performance status, n (%)

0 1

32 (43.2) 42 (56.8)

31 (37) 53 (63) Disease stage at initial diagnosis, n (%)

I–II III IV

41 (55.4) [I-III]

33 (44.6)

9 (11) 33 (39) 42 (50)

Baseline patient demographics and disease characteristics

(12)

12 dMMR/MSI-H per Local Laboratory

(N = 74) dMMR/MSI-H (N = 84)

Clinical history of Lynch syndrome, n (%) Yes

No

Unknown

23 (31.1) 26 (35.1) 25 (33.8)

27 (32) 25 (30) 32 (38) Mutation status, n (%)

BRAF/KRAS wild type BRAF mutated

KRAS mutated

28 (37.8) 12 (16.2) 26 (35.1)

22 (26) 21 (25) 30 (36) Tumor PD-L1 expression quantifiable at baseline, n (%)

≥ 1%

< 1%

n = 66 21 (28.4) 45 (60.8)

16 (24) 50 (76) Prior lines of therapy, n (%)

0 1 2 3

≥ 4

1 (1.4) 11 (14.9) 22 (29.7) 40 (54.1) [≥3]

1 (1) 17 (20) 31 (37) 23 (27) 12 (14)

Prior radiotherapy, n (%) 27 (36.5) 17 (20)

Baseline patient demographics and disease characteristics

(13)

Efficacy

dMMR/MSI-H per Local Laboratory

(N = 74) dMMR/MSI-H (N = 84)

ORR, n (%) [95% CI]

23 (31.1) 20.8, 42.9

46 (55) [43.5, 65.7]

Best overall response, n (%) CR

PR SD PD

Not determined/reported

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

2 (2) 44 (52) 26 (31) 9 (11)

3 (4) Disease control for ≥ 12 weeks,^a n (%)

[95% CI]

51 (68.9)

66 (79) [68.3, 86.8]

Continuing treatment 40 (54.1) 51 (61)

Discontinued treatment 34 (45.9) 33 (39)

Disease progression 27 (36.5) 15 (18)

Treatment-related toxicity 4 (5.4) 11 (13)

DOR, duration of response; NE, not estimable; NR, not reached; TTR, time to response. ^aDefined as patients with complete response, partial response, or stable disease for ≥ 12 weeks.

(14)

PFS and OS Nivo 12 mo results data from ASCO 17

PFS and OS Combo 9 mo results data from ESMO 17

(15)

Safety

Patients, n (%)

dMMR/MSI-H per Local

Laboratory (N = 74) dMMR/MSI-H (N = 84)

Any Grade Grade 3 or 4 Any Grade Grade 3 or 4

Any TRAE 51 (68,9) 15 (20,3) 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 16 (21,6) 1 (1,4) 20 (24) 1 (1)

Fatigue 17 (23) 1 (1,4) 14 (17) 1 (1)

Aspartate

aminotransferase increase

14 (17) 8 (9)

Pyrexia 13 (16) 0

Pruritus 10 (13,5) 0 13 (16) 2 (2)

Alanine

aminotransferase increase

12 (14) 7 (8)

Nausea 12 (14) 0

Hyperthyroidism 11 (13) 0

Hypothyroidism 11 (13) 0

Lipase increased 9 (12,2) 6 (8,1)

Rash 8 (10,8) 0

(16)

Future Directions

(17)

KEYNOTE 177 first line mCRC MSI-H

Pembrolizumab 200 mg IV Q3W

Protocol specified follow-up

PD

Optional

Pembrolizumab 200 mg iv

Protocol specified follow-up

PD

Patients 270

Primary objectve:PFS Patients

•Treatment naive

•ECOG PS 0-1

• Stage IV CRC

•MMR deficient or MSI-H

•No active brain

metastases Investigator’s choice of one of the following:

•mFOLFOX6

• mFOLFOX6+ bevacizumab

•mFOLFOX6+cetuximab

•FOLFIRI

•FOLFIRI+bevacizumab

•FOLFIRI+ cetuximab

(18)

↑Adhesion molecules (ICAM-1) and death

receptors (FAS)

↑Peptide pools

Adapted from Semin Oncol; 39, Hodge JW, et al. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. 323-339. Copyright 2012, with permission from Elsevier.

Immunogenic Cell Death and Modulation

Dendritic cell

↓T_reg cells

↓MDS C

↓M2 Macrophages

↑TAA Cross- presentation

CD8 T- cells

↑Effector immune

infiltrate Release of tumor antigens

(cascade) Translocat

ion of calreticuli

n

↑TAA

↑Upregulation of MHC-I

↑Adhesion molecules/

death receptors

↑APM CD8 T-cells (Homeostatic peripheral expansion)

Chemotherapy

Small molecule inhibitors Radiation

↓T_reg cells

↓MDS C

↑CD8 T-cells

↑T-cell function Chemokine

release

↑Vascular normalization

↑T-cell infiltration

↑Activation of apoptosis

↑Blockage of cell cycle

↑Uploading of antigen processing

machinery Upregulation of

MHC-I CD8 T-

cell

(19)

For personal useonly

Immunotherapy + chemotherapy: rationale for combination

Graphical Elaboration from text data

1. Zitvogel L, et al. Nat Rev Immunol 2008; 8(1): 59-73; 2. Chen DS, Mellman I. Immunity 2013; 39(1): 1-10. 3. Giaccone G, et al. European Cancer Conference 2015; abstract P247; 4. Liu SV, et al. ASCO 2015: abstract 8030 Available at http://meetinglibrary.asco.org/content/108559?media=vm Last Access June ‘16

Tumor Lymph node

Blood vessel

Release of cancer cell antigens (cancer cell death) 1

Cancer antigen presentation (dendritic cells/APCs) 2

Priming and activation (APCs and T cells)

3 Infiltration of T cells

into tumors

(CTLs, endothelial cells) 5

Recognition of cancer cells by T cells (CTLs, cancer cells) 6

Killing of cancer cells (immune and cancer cells) 7

Trafficking of T cells to tumors (CTLs) 4

Chemotherapy immunotherapy

(20)

Atezolizumab + chemotherapy: Phase Ib study

a Atezolizumab dosing based on cohort.

b FOLFOX: Oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m². Study: GP28328.

Graphical Elaboration from text data ClinicalTrials.gov: NCT01633970 currently recruiting (last verified June 2016).

Primary endpoint

• Safety: AEs, DLTs

Additional endpoints

• PK

• Clinical activity:

best overall response, ORR, DOR, PFS

• Arms A and B:

incurable/ metastatic advanced solid tumors

• Arms C-E: untreated advanced/metastatic NSCLC

• Arm F: TNBC that has been treated with systemic cytotoxic therapy

• Tumor specimen available

• ECOG PS 0-1 N = 205

Atezolizumab + Paclitaxel

200 mg/m

²

IV q3w

+ Carboplatin

AUC6 IC q3w

Atezolizumab + Pemetrexed

500 mg/m

²

IV q3w

+ Carboplatin

AUC6 IC q3w

Atezolizumab + Nab-paclitaxel

100 mg/m

²

IV qw

+ Carboplatin

AUC6 IV q3w

Atezolizumab

^a

+ Bevacizumab

15 mg/kg IV q3w

Atezolizumab

IV q2w

+ Bevacizumab

10 mg/kg IV q2w

+ FOLFOX

^b

q2w

Atezolizumab + Bevacizumab

+ FOLFOX

Dose confirmation Dose expansion

Arm A:

Solid tumors

Arm A:

Solid tumors, RCC, CRC

Arms C-E: 1L NSCLC

Arm F: 2L TNBC Arm B:

Oxaliplatin-naive CRC Arm B:

Oxaliplatin-naive solid tumors and CRC

Atezolizumab + Nab-paclitaxel

125 mg/m

²

IV qw

(21)

Atezolizumab + bev ± chemo: Phase Ib results CRC (advanced)

a One patient in Arm A was classifi ed as missing or unevaluable.

Investigator-assessed unconfirmed responses per RECIST v1.1 | Efficacy-evaluable patients dosed by June 29, 2014, who had ≥ 1 scan.

ClinicalTrials.gov: NCT01633970.

1.Adapted from Bendell J, et al. ASCO GI 2015: abstract 704 Available at http://meetinglibrary.asco.org/content/105168?media=vm Last Update June

‘16

• Atezolizumab combination therapy with bevacizumab and bevacizumab with or without FOLFOX was well tolerated, without exacerbation of

bevacizumab or chemotherapy- associated AEs

• RECIST responses of up to 54 weeks were observed in patients with CRC

Safety

Clinical activity

(22)

Atezolizumab + cobimetinib: rationale for combination

Graphical Elaboration from text data

1. Liu J, et al. Blood 2007;110(1): 296-304; 2. Yamamoto R, et al. Cancer Sci 2009; 100(11): 2093-2100. 3. Irving BA. et al. Soc Immunother Cancer 2013; 1(suppl 1): P79 4. Chen DS, Mellman I. Immunity 2013; 39(1): 1-10.

Tumor Lymph node

Blood vessel

Release of cancer cell antigens (cancer cell death) 1

Cancer antigen presentation (dendritic cells/APCs) 2

Priming and activation (APCs and T cells)

3 Infiltration of T cells

into tumors

(CTLs, endothelial cells) 5

Recognition of cancer cells by T cells (CTLs, cancer cells) 6

Killing of cancer cells (immune and cancer cells) 7

Trafficking of T cells to tumors (CTLs) 4

MEK inhibitors such as

cobimetinib Immunotherapy

(23)

*Confirmed per RECIST v1.1

Cobimetinib + Atezolizumab efficacy: change in tumour burden

Change in tumor burden

Change in tumor burden over time

Confirmed Responses per RECIST v 1.1

KRASmt CRC Cohort

(n=20)

All patients with CRC

(n=23) ORR, n n(%)

(95%

4 (20%) (6%, 44%)

4 (17%) (5%, 39%)

PR , n (%) 4 (20%) 4 (17%)

SD, n(%) 4 (20%) 5 (22%)

PD, n(%) 10 (50%) 12 (52%)

Missing or unevaluable, n (%) 2 (10%) 2 (9%)

KRASmt CRC Cohort (n=20)

All patients with CRC (n=23) Median PFS (95% CI), months 2.3 (1.8, 9.5) 2.3 (1.8, 9.5) Median PFS (95% CI), months NE (6.5, NE) NE (6.5, NE) 1 year OS (95% CI), % 65% (42%, 88%) 61% (39%, 84%)

1. Ebert PJ, et al. Immunity. 2016;44:609-621. 2. Bendell J, et al. ASCO 2016. Abstract 3502.

(24)

Grazie

(25)

(26)

(27)

(28)