A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Combination with TSR-042 (Anti-PD-1) in Patients with Colorectal Cancer and Post-PD-1 NSCLC and Melanoma

Diwakar Davar,1 Peter Boasberg,2 Zeynep Eroglu,3 Gerald Falchook,4 Justin Gainor,5 Erika Hamilton,6 J. Randolph Hecht,7 Jason Luke,8 Michael Pishvaian,9 Antoni Ribas,7 Judy Wang,10 Kristen McEachern,11 Angela Waszak,11 Sharon Lu,11 Yong Li,11 Ying Wang,11 Patricia LoRusso12

1University of Pittsburgh Department of Medicine, University of Pittsburgh, Pittsburgh, PA; 2The Angeles Clinic and Research Institute, Los Angeles, CA; 3Department of Cutaneous Oncology at Moffitt Cancer Center, Moffitt Cancer Center, Tampa, FL; 4Sarah Cannon Research Institute at HealthONE, Sarah Cannon Research Institute, Nashville, TN; 5Massachusetts General Hospital, Boston, MA; 6Sarah Cannon Research Institute at Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN; 7Ronald Reagan UCLA Medical Center, Los Angeles, CA; 8The University of Chicago Medicine, Chicago, IL; 9MedStar Georgetown University Hospital, Washington, DC;

10Sarah Cannon Research Institute, Florida Cancer Specialists and Research Institute, Sarasota, FL; 11TESARO, Inc., Waltham, MA, USA; 12Yale Cancer Center, New Haven, CT

BACKGROUND• T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is a key immune checkpoint and a next-

generation cancer immunotherapy target (Figure 1).

Figure 1. TIM-3 Biology Has Been Implicated in T-Cell Exhaustion and Immune Suppression Mediated by Regulatory T Cells and Myeloid Cells

CD4/8+ T-Cell Exhaustion Diversity of Immune Profiles in NSCLC Dendritic Cells

• TIM-3 is a marker of progressively exhausted CD8+ T cells and negatively regulates their activation

• Blocking TIM-3 results in increased proliferation and cytokine production by these cells

• TIM-3 is highly expressed on CD8+ T cells from freshly isolated NSCLC tumors

• High levels of expression correlated with increased levels of PD-1 expression

• TIM-3 is expressed on tumor-associated DCs and may negatively regulate DC/T cell activation

• Expression on macrophages can influence MDSC activity in TME

PD-1 PD-1 TIM-3

RAGE

TLR2/4

Dead tumor cells Live tumor cells

HMGB1 Nucleic acidsNaïveT cell

APC

ActivatedT cell Exhausted

T cell

PD-1+PD-1+ TIM-3+ TADCTIM-3

0

50

150 >70% PD-1+

30%–69% PD-1+

% C

D8+

T c

ells

APC=antigen-presenting cell; CD=cluster of differentiation; DC=dendritic cell; HMGB1=high mobility group protein 1; MDSC=myeloid-derived suppressor cells; PD-1=programmed cell death receptor 1; RAGE=receptor for advanced glycation end products; TADC=tumor-associated dendritic cells; TIM-3=T-cell immunoglobulin and mucin-domain containing-3; TLR-2/4=toll-like receptor-2/4; TME=tumor microenvironment; Treg=regulatory T cell. Adapted from Anderson AC. Cancer Immunol Res. 2014;2:393-398.Travers et al. AACR 2017.

• In preclinical models, combination treatment with anti-PD-1 and anti-TIM-3 antibodies produces antitumor activity that surpasses that of monotherapy approaches (Presented at SITC 2017, Weiss).

• TSR-022 is a humanized anti-TIM-3 IgG4 monoclonal antibody that binds to TIM-3 with high affinity and has potent in vitro and in vivo activity.

METHODS• AMBER is a phase 1 dose escalation study enrolling 2 cohorts of patients who have progressed on a prior

ant-PD-1 treatment: non-small cell lung cancer (NSCLC; Figure 2) and melanoma.

Figure 2. AMBER Study Schema

= Complete= Enrolling

Escalated to 10 mg/kg without DLT. Several patients with stable disease

One PR in patient with leiomyosarcoma at high dose (10 mg/kg)

Part 1a All ComersMonotherapy

Dose Escalation (SITC 2017)

Part 1c All ComersCombination

Dose Escalation N=54

Part 2† NSCLCPatients Expansion

CohortsN=39 (ongoing)

+ TSR-042*

+ TSR-042*

BiomarkerAnalyses• PD-L1• TIM-3• NS IO360• TMB

TSR-022 100 mg

TSR-022 300 mg

TSR-022 900 mg

TSR-022 100 mg

TSR-022 300 mg

TSR-022 900 mg

*The TSR-042 dose was 500 mg. †Additional key inclusion criteria for part 2: measurable disease by RECIST, prior anti-PD-(L)1 treatment, and patient must have tumor biopsy available.

RESULTS

Table 1. Baseline Characteristics of Patients in the Part 1 Combination Dose Escalation

Baseline Characteristics Total (N=54)

Age, median (range), yrs 65 (34-85)Sex, n (%)

Male 37 (68.5)Female 17 (31.5)

ECOG performance status score, n (%)0 29 (53.7)1 25 (46.3)

Tumor type, n (%)Mesothelioma 12 (22.2)NSCLC* 11 (20.4)Melanoma† 10 (18.5)Leimyosarcoma 4 (7.4)All others 17 (31.5)

Lines of prior therapy, n (%)1 13 (24.1)2 15 (27.8)≥3 19 (35.2)

*2 (18%) patients PD-(L)1 pretreated, all others PD-(L)1 naïve.†All patients PD-(L)1 naïve.

Table 2. Treatment-Related TEAEs observed in ≥5% of PatientsTSR-022 (100 mg)

+ TSR-042* (N=13)

TSR-022 (300 mg) + TSR-042*

(N=19)

TSR-022 (900 mg) + TSR-042*

(N=22)Total

(N=54)

AE preferred term

All Grade (%)

Grade 3 (%)

All Grade (%)

Grade 3 (%)

All Grade (%)

Grade 3 (%)

All Grade (%)

Grade 3 (%)

Fatigue 2 (15.4) 0 2 (10.5) 0 4 (18.2) 0 8 (14.8) 0 Rash 1 (7.7) 1 (7.7) 3 (15.8) 0 2 (9.1) 0 6 (11.1) 1 (1.9) Hypothyroidism 1 (7.7) 0 1 (5.3) 0 2 (9.1) 1 (4.5)** 4 (7.4) 1 (1.9)** Chills 1 (7.7) 0 1 (5.3) 0 1 (4.5) 0 3 (5.6) 0 Nausea 1 (7.7) 0 1 (5.3) 0 1 (4.5) 0 3 (5.6) 0 Pruritus 0 0 2 (10.5) 0 1 (4.5) 0 3 (5.6) 0

*The TSR-042 dose was 500 mg.**Grade 4 hypothyroidism seen in 1 patient.AE=adverse event; TEAE=treatment-emergent adverse event

• No dose-limiting toxicities were observed (Table 2).

• Several patients at both 100 mg and 300 mg TSR-022 dose levels demonstrated response (Figure 3). An early sign of clinical activity was observed at a low TSR-022 dose level in a NSCLC patient who had progressed after nivolumab (Figure 4).

Figure 3. Combination Dose Escalation: Clinical Activity*

Time from Baseline Scan (Weeks)0 5 10 15 20 25 30 35 40

Tum

or S

ize

Rel

ativ

e to

Bas

elin

e

110100

908070605040302010

0-10-20-30-40-50-60-70-80-90

-100-110

120 Dose Level 100 mg 300 mg

*The TSR-042 dose was 500 mg.

• TSR-022 PK is dose proportional from 100 mg to 900 mg, with a terminal half-life of about 10 days based on first dose data (Figure 5).

• 900 mg dose required for effective exposure throughout dose interval (Figure 5).

Figure 5. TSR-022 PK Profile

Time (day)

Con

cent

ratio

n (µ

g/m

L)

0 5 10 15 20

1

10

100

1000 100 mg TSR-022 + 500 mg TSR-042 (N=12-14)300 mg TSR-022 + 500 mg TSR-042 (N=9-11)900 mg TSR-022 + 500 mg TSR-042 (N=5-9)

% pts > EC90 (MLR) at Ctrough

Results from the Expansion Cohorts

Table 3. Baseline Characteristics of Patients in the Post-anti-PD-(L)1 NSCLC Expansion Cohort

Baseline Characteristics TSR-022 + TSR-042(N=39)

Age, yrsMedian (range) 66 (35 - 86)

Sex, n (%)Male 22 (56.4)Female 17 (43.6)

ECOG performance status score, n (%)0 9 (23.1)1 30 (76.9)

PD-L1 status, n (%)TPS ≥1% 16 (41.0)TPS <1% 8 (20.5)Unknown 15 (38.5)

Lines of prior therapy, n (%)1 2 (5.1)2 10 (25.6)3 9 (23.1)≥4 18 (46.2)

Prior anti-PD-(L)1 antibody*, n (%)Pembrolizumab 14 (35.9)Nivolumab 23 (60.0)Atezolizumab 5 (12.8)Others 2 (5.1)

ECOG PS=Eastern Cooperative Oncology Group; PD-L1=programmed cell death ligand 1; TPS=tumor proportion score.*None of the patients had maximal treatment on prior PD-1 (eg, 2 years)

Table 4. Summary of AEs in AMBER

Category, n (%)

TSR-022 (100 mg) + TSR-042*

(N=41)

TSR-022 (300 mg) + TSR-042*

(N=110)

TSR-022 (900 mg) + TSR-042*

(N=22) Total

(N=173)

Patient with TEAE 38 (92.7) 97 (88.2) 19 (86.4) 154 (89.0)Patient with grade ≥3 AE 18 (43.9) 47 (42.7) 6 (27.3) 71 (41.0)Patient with drug-related AE 20 (48.8) 59 (53.6) 13 (59.1) 92 (53.2)Patient with drug-related grade ≥3 AE

4 (9.8) 9 (8.2) 0 13 (7.5)

Study drug discontinued due to drug-related AE

0 1 (0.9) 0 1 (0.6)

Drug-related AE leading to death 0 0 0 0 *Includes AEs observed in ≥4 patients in the overall cohort. The TSR-042 dose was 500 mg. AE=adverse event; TEAE=treatment-emergent adverse event.

Table 5. Treatment-Related TEAEs with ≥5% Incidence in all Post-Anti-PD-(L)1 Patients, Regardless of Tumor Type*

TSR-022 (100 mg) + TSR-042*

(N=41)

TSR-022 (300 mg) + TSR-042*

(N=110)

TSR-022 (900 mg) + TSR-042*

(N=22) Total

(N=173)

AE preferred term

All Grade (%)

Grade 3-4 (%)

All Grade (%)

Grade 3-4 (%)

All Grade (%)

Grade 3-4 (%)

All Grade (%)

Grade 3-4 (%)

Fatigue 9 (22.0) 1 (2.4) 18 (16.4) 0 4 (18.2) 0 31 (17.9) 1 (0.6)Nausea 3 (7.3) 0 9 (8.2) 0 0 0 12 (6.9) 0Pruritus 3 (7.3) 0 8 (7.3) 0 1 (4.5) 0 12 (6.9) 0Rash maculo-papular 2 (4.9) 0 7 (6.4) 2 (1.8) 1 (4.5) 0 10 (5.8) 2 (1.2)Rash 4 (9.8) 1 (2.4) 3 (2.7) 0 2 (9.1) 0 9 (5.2) 1 (0.6)Decreased appetite 1 (2.4) 0 8 (7.3) 0 0 0 9 (5.2) 0Hypothyroidism 1 (2.4) 0 3 (2.7) 0 2 (9.1) 0 6 (3.5) 0Dyspnea 0 0 0 0 2 (9.1) 0 2 (1.2) 0Musculoskeletal chest pain

0 0 0 0 2 (9.1) 0 2 (1.2) 0

*Includes treatment-related AEs observed in ≥2 patients in the overall cohort. Grade 4 lipase increased seen in 1 patient. There were 2 (5%) patients with related irAEs: hypothyroidism and pancreatitis. The TSR-042 dose was 500 mg. irAE=immune-related adverse event.

• TSR-022 in combination with TSR-042 demonstrated clinical activity in post-PD(L)-1 NSCLC; a dose response trend was observed (Figures 6 and 7).

Figure 6. Percentage Change in Sum of Target Lesion Dimensions in Patients with Post-Anti-PD-(L)1 NSCLC

PD

NL

PDPD

NL

PD PD

NL

PDPD

NL

SD

SD SD

NL

SD PD

NL

PD

NL

SD

SD SD

PR SDPR

PR

PD

NL

PD

NL

PD

NL

PD

NL

PD

NL

PD

NL

SDPD

NL: New lesion

NL

SD SD

PR-70

-50

-30

-10

10

30

50

70

Per

cent

Cha

nge

-70

-50

-30

-10

10

30

50

70

Per

cent

Cha

nge

30% decrease

NL: New lesion

30% decrease

TSR-022 100 mg+ TSR-042 500 mg

TSR-022 300 mg+ TSR-042 500 mg

• 1 confirmed PR• 3 SD

• 3 confirmed PR • 8 SD

One patient with scan was not evaluable and hence not included in figure. PD=progressive disease; PR=partial response; SD=stable disease.

Figure 7. Percentage Change in Sum of Target Lesion Dimensions over Time in Patients Post-Anti-PD-(L)1 with NSCLC

-80-70-60-50-40-30-20-10

01020304050607080

TSR-022 100 mg+ TSR-042 500 mg

TSR-022 300 mg+ TSR-042 500 mg

Tum

or S

ize

Rel

ativ

e to

Bas

elin

e

-80-70-60-50-40-30-20-10

01020304050607080

Tum

or S

ize

Rel

ativ

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Bas

elin

e

0 5 10 15 20 25 30 35 40

Time from Baseline Scan (Weeks)0 5 10 15 20 25 30 35

Time from Baseline Scan (Weeks)Ongoing NL: New lesion

NL

NL

NL

NL NLNL

NL

NL

NL

NL

NLNL

NL

NL

• A dose response trend also observed in post-PD(L)-1 melanoma (Figure 8).

Figure 8. Percentage Change in Sum of Target Lesion Dimensions over Time in Patients with Post-Anti-PD-(L)1 Melanoma

TSR-022 100 mg+ TSR-042 500 mg

TSR-022 300 mg+ TSR-042 500 mg

-70-60-50-40-30-20-10

0102030405060708090

100110120130140

Tum

or S

ize

Rel

ativ

e to

Bas

elin

e

-40-30-20-10

0102030405060708090

100110120130140

Tum

or S

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Rel

ativ

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Bas

elin

e

0 5 10 15 20 25 30 35Time from Baseline Scan (Weeks)

0 5 10 15 20 25 30 35 40 45

Time from Baseline Scan (Weeks)Ongoing NL: New lesion

NLNL

NLNL

NLNL

NL

NL

NLNL

NLNL

NL

NLNLNLNL

NL

NL

NLNL

NLNL

NLNL

NL

• Objective responses observed were all in PD-L1 positive (TPS ≥1%) patients in the NSCLC cohort, indicating the potential for biomarker enrichment (Figure 9).

• Twelve patients had at least 1 scan. – Four had a confirmed PR (3 by RECIST and 1 by irRECIST; 3 ongoing).

▪ One in the 100 mg cohort ▪ Three in the 300 mg cohort

Figure 9. Best Response in PD-L1 Positive (TPS ≥1%) Patients*

Per

cent

age

Cha

nge

in T

arge

t Les

ions

(Bes

t Res

pons

e)

Dose level100 mg300 mg

30%decrease

* Confirmed response

*

**

*-80

-60

-40

-20

0

20

40

60

*The TSR-042 dose was 500 mg.

Figure 10. Ongoing Durable Partial Response in PD-1 Refractory Patient

• 69-year-old patient with metastatic NSCLC• Treated with nivolumab for 2.5 months• Treated with TSR-022 300 mg + TSR-042 500 mg Q3WPretreatment

After 6 cycles, ongoing PR by RECIST version 1.1

Hepatic dome tumor (22×21 mm) Periportal LN tumor (32×20 mm) R hepatic lobe tumor (36×23 mm)

R hepatic lobe tumor (17×16 mm)

×

Hepatic dome tumor (11×7 mm) Periportal LN tumor (32×20 mm)

LN=lymph node.

CONCLUSIONS• TSR-022 is a potent and selective anti-TIM-3 antibody that is being developed in combination with the

anti-PD-1 antibody TSR-042.• Treatment with TSR-022 in combination with TSR-042 was well tolerated.• TSR-022 in combination with TSR-042 demonstrated clinical activity in patients who have progressed on

prior anti-PD(L)-1 treatment.• Objective responses observed were in PD-L1 positive (TPS ≥1%) patients, indicating the potential for

biomarker enrichment.• A dose response trend was observed, with greater evidence of antitumor activity in the population receiving

the 300 mg dose compared with the 100 mg dose.• TSR-022 PK was dose proportional with the 900 mg dose required for effective exposure throughout dose

interval in most patients. Enrollment at the 900 mg dose level is ongoing in the NSCLC cohort.

Society for Immunotherapy of Cancer 33rd Annual Meeting | November 7-11, 2018 | Washington, DC, USA Medical writing, funded by TESARO, Inc. (Waltham, MA) and coordinated by Teodor G. Paunescu, PhD, (TESARO, Inc.) was provided by Nicole Renner, PhD, and Dena McWain of Ashfield Healthcare Communications (Middletown, CT).

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Figure 4. Response to TSR-022 in a NSCLC Patient with Prior PD on Nivolumab

Feb 23, 2017 Apr 20, 2017