Combining Intralesional Therapies & Checkpoint Inhibitors

Sanjiv Agarwala, MDTemple University

St Luke’s Cancer CenterBethlehem, Pennsylvania

Overview

• Current clinical trials

• Why this may represent the future

Overview

• Current clinical trials

• Why this may represent the future

Oncolytic Immunotherapy Combinations

• Many ongoing clinical trials– Phase Ib/II ipilimumab ± talimogene laherparepvec (T-VEC)1,2

– Phase Ib/III pembrolizumab ± T-VEC3

– Phase Ib ipilimumab + CVA214

– Phase II ipilimumab + HF105

– Phase II pembrolizumab + IL-12 electroporation6

– Phase Ib pembrolizumab ± CVA217

– Phase Ib/II pembrolizumab ± PV-107

1. Puzanov I, et al. J Clin Oncol. 2015;33(suppl): Abstract 9063. 2. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT01740297. Accessed November 2, 2018. 3. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02263508. Accessed November 2, 2018. 4. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02307149. Accessed November 2, 2018. 5. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02272855. Accessed November 2, 2018. 6. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02493361. Accessed November 2, 2018. 7. PI: Sanjiv Agarwala.

T-VEC + Ipilimumab Phase Ib Trial

SCREENING

ENROLLMENT

END

OF

TREATMENT

SAFETY

F-UP

Stage IIIB/C–IV M1c melanoma not suitable for surgical resection, no

prior systemic treatment (except adjuvant treatment)

T-VEC up to 4 mL106 PFU/mL week 1 day 1,

108 PFU/mL week 4 day 1 & then q2w+

Ipilimumab 3 mg/kgq3w x 4 starting week 6 day 1

N = 19

Screening 28 days prior to enrollment

T-VEC dosing until CR, all injectable tumors disappeared, PD per irRC, or intolerance for

treatment, whichever comes first

30 (+7) days after last dose of T-VEC or

60 (+7) days after last dose of ipilimumab

Up to 24 months after end of

randomization

SURVIVAL

F-UP

• Primary endpoint: Incidence of dose-limiting toxicities• Secondary endpoints: ORR, safety; all AEs, grade ≥3 AEs, serious AEs, events requiring discontinuation of study drug,

events with local effects on tumors (pain, inflammation, and ulceration)AE, adverse event; CR, complete response; ORR, overall response rate; irRC, immune-related response criteria; PD, progressive diseasePuzanob I, et al. J Clin Oncol. 2014;32(5S): Abstract 9029.

T-VEC + Ipilimumab Phase Ib Trial (20110264)Best Overall Response (BOR)

The waterfall plot shows best reductions in tumor burden at a single time point. For the irRC response table, CR, PR, and PD needed to be confirmed by consecutive assessments no less than 4 weeks apart to be considered confirmed with the following exception: if PD was the last tumor assessment, it was considered as confirmed.*≤ -98%, but > -100% , †Unconfirmed CR

N = 18

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-100-50

02550

100

200

300

Stage IV M1c (n = 5)Stage IV M1b (n = 5)Stage IV M1a (n = 4)Stage IIIc (n = 3)Stage IIIb (n = 1)

500

600Best irRC Confirmed Response Per irRC

n (%)ORR 9 (50)

CR 4 (22)Partial response (PR) 5 (28)

Stable disease (SD) 4 (22)PD 5 (28)

Disease control rate (DCR; CR + PR + SD) 13 (72)

* * †

Puzanov I, et al. J Clin Oncol. 2016;34(22):2619-2626.

Week 1

T-VEC + Ipilimumab Phase II Randomized Trial

Primary endpoint ORRirRC

Secondary endpoints PFS, OS, DRR, BOR, DCR, DoR, TTR, resection rate

Ipilimumab 3 mg/kg IV q3w x 4

Week 6

Ipilimumab 3 mg/kg IV q3w x 4

R

Unresectable Stage IIIB-IV Melanoma• Injectable• ≤1 line of systemic therapy for BRAF

wildtype, or ≤2 lines of systemic therapy including BRAFi regimen for BRAF mutated

• ECOG PS 0 or 1• No evidence of active CNS metastases

T-VEC intralesional106 PFU/mL, after 3 weeks 108 PFU/mL q2w

1:1

N = 100

N = 100

• T-VEC dosing until CR, all injectable tumors disappear, PD per irRC, or intolerance, whichever is first• Safety follow-up occurs 30 (+7) days after last dose of T-VEC or 60 (+7) days after last dose of

ipilimumab, whichever is later

CNS, central nervous system; DoR, duration of response; DRR, durable response rate; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; PFS, progression-free survival; PS, performance status; TTR, time to responseChesney J, et al. J Clin Oncol. 2018;36(17):1658-1667.

Randomized Phase II Trial T-VEC + Ipilimumab vs Ipilimumab: Results

T-VEC + Ipilimumab(n = 98)

Ipilimumab(n = 100)

ORR 39% 18%Odds ratio (95% CI) for ORR 2.9 (1.5 – 5.5) P = .002

CR 13% 7%

PR 26% 11%

SD 19% 24%

PD 32% 33%

Unevaluable/not done 10% 25%

DCR 58% 42%

Stage IIIB – IVM1a 44% 19% (P = .007)

Stage IVM1b/c 33% 16% (P = .09)

CI, confidence intervalChesney J, et al. J Clin Oncol. 2018;36(17):1658-1667.

Improved PFS with T-VEC+ ipilimumab

PFS,

%

Randomized Phase II Trial T-VEC + IpilimumabResults – PFS

Chesney J, et al. J Clin Oncol. 2018;36(17):1658-1667.

Events, n (%)

Median Months (95% CI)

T-VEC + ipilimumab (n = 98) 52 (53) 8.2 (4.2 – 21.5)Ipilimumab (n = 100) 51 (51) 6.4 (3.2 – 16.5)Hazard ratio (95% CI) 0.83 (0.56 – 1.23)Unstratified log-rank P value .35

PFS,

%

Study Month

Treatment until whichever occurs first:• PD per irRC• Intolerance• All injectable tumors disappeared (T-VEC only)• 2 years

SAFETY

FOLLOW-UP

30 (+7)days after

end of treatment

• Unresectable stageIII or IV melanoma

• Treatment naive• Injectable lesions• No clinically active

brain metastases• No active herpetic

skin lesions or prior complications from herpetic infection

N = 21

Wk 6DLTWindow

Pembrolizumab 200 mg IV q2w

Wk 0

T-VEC intralesional•Up to 4 mL per treatment •1st dose 106 PFU/mL •Then 108 PFU/mL q2w

T-VEC intralesional

Wk -5 Wk -2

T-VEC + Pembrolizumab Phase 1b Trial

DLT, dose-limiting toxicityRibas A, et al. Cell. 2017;170(6):1109-1119.

Phase Ib Trial T-VEC + Pembrolizumab Best Change in Tumor Burden

Response rateConfirmed: 62%

Ribas A, et al. Cell. 2017;170(6):1109-1119.

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MASTERKEY-265 Phase III Study DesignN = 660

1:1

N = 330

N = 330

• Unresectable stageIII or IV melanoma

• Treatment naive• Injectable lesions• No clinically active

brain metastases• No active herpetic

skin lesions or prior complications from herpetic infection

T-VEC intralesional• Up to 4 mL per treatment • 1st dose 106 PFU/mL • Then 108 PFU/mL q2w x 4, then q3w

Pembrolizumab 200 mg IV q3wT-VEC intralesional

Pembrolizumab 200 mg IV q3wT-VEC placebo intralesional

SAFETY

FOLLOW-UP

30 (+7)days after

end of treatment

Treatment until whichever occurs first:• CR• PD per irRC-RECIST• Intolerance• All injectable tumors disappeared (T-VEC/placebo only)• 2 years

R

National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02263508. Accessed November 2, 2018.

Treatment Phase(PV-10 and pembrolizumab q3w)

Cycle 1 Cycle 2 Cycle 3Screening Cycle 4 Cycle 5

Response Follow-Up(Pembrolizumab q3w)

RECIST Assessment(q12w)

•Patients receive up to 5 cycles of PV-10 and pembrolizumab (q3w)

•Patients continue to receive treatment until PD (q3w)

•Patients remain on active portion of study for up to 24 months

SurvivalCycle 6 Cycle 7 Cycle …

PV-10 + Pembrolizumab• Phase Ib

PI: Sanjiv Agarwala.

Preliminary Efficacy Results

Agarwala S, et al. Pigment Cell Melanoma Res. 2018;31(1):126 [abstract].

• Most subjects had robust response in their target lesions

• These included injected cutaneous/subcutaneous lesions and noninjected nodal/visceral lesions

• Response of target lesions coincided with combination regimen

• Subjects received a median of 5 cycles of PV-10 (mean 3.8, range 1 – 5)

HF10 + Ipilimumab Phase II Trial in Unresectable Stage IIIB-IV Melanoma

• Multicenter trial

• Primary objective: Best overall response rate (BORR) at 24 weeks (irRC)

• Secondary objective: Safety, tolerability, ORR, PFS, DRR, 1-year OS, correlative studies

Andtbacka, RHA et al. ASCO 2017 Abstract 166420 (and poster presentation)

3 weeks 3 weeks 3 weeks 3 weeks - - - - - - - - - - 1 year

Ipilimumab 3 mg/kg IV q3wk x 4 irRC/mWHO 12, 18, 24, 26, 48 wks

HF10 1 x 107 TCID50/mL IT q1wk x 4 wks, then q3wk up to 45 wks

Andtbacka RH, et al. J Clin Oncol. 2017;35(suppl):Abstract 9510.

BOR (N = 44) 24 Weeks, n (%) 48 Weeks, n (%)Overall response (irCR + irPR) 18 (41%) 20 (46%)

Clinical benefit (irCR +irPR + irSD) 30 (68%) 30 (68%)

Complete response (irCR) 8 (18%) 8 (18%)

Partial response (irPR) 10 (23%) 12 (27%)

Stable disease (irSD) 12 (27%) 10 (23%)

Unconfirmed progressive disease (irPD) 11 (25%) 11 (25%)

Confirmed irPD 3 (7%) 3 (7%)

HF10 + Ipilimumab Phase II trialBORR

Andtbacka RH, et al. J Clin Oncol. 2017;35(suppl):Abstract 9510.

HF10 + Ipilimumab Phase II Trial in Unresectable Stage IIIB-IV Melanoma

Maximum Change In Index Lesions

Andtbacka RH, et al. Presented at International Meeting on Replicating Oncolytic Virus Therapeutics; October 1-4, 2016: Vancouver, British Columbia, Canada. Abstract and Presentation. Andtbacka RH, et al. J Clin Oncol. 2017;35(suppl):Abstract 9510.

BOR 24 Weeks

StageIIIB/C- IVM1a,

n (%)

Stage IVM1b-M1c,

n (%)Number of patients (N = 44) 34 (77%) 10 (23%)Overall response (irCR + irPR) 16 (47%) 2 (20%)

Clinical benefit (irCR + irPR + irSD) 24 (70%) 6 (60%)

irCR 7 (21%) 1 (10%)irPR 9 (26%) 1 (10%)irSD 8 (23%) 4 (40%)Unconfirmed irPD 7 (21%) 3 (30%)Confirmed irPD 3 (9%) 1 (10%)

HF10 + Ipilimumab Phase II TrialBORR

Stage IIIB/C-IVM1a vs Stage IVM1b-M1cSpider PlotBest Overall Response at 24 weeks

StageStage IIIB+IIIC+IVM1a Stage IVM1b+M1c

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[+] Percentage change from baseline in tumor lesion size exceeds +100%. Spider plot truncated for the patient at this point.[#] Unconfirmed CR based on investigator decision.EOS – end of study includes those patients who went off-study before week 24 or day 169.

Coxsackievirus A21 + Ipilimumab(VLA-013, MITCI Phase II Trial)

Curti B, et al. Presented at the Society for Immunotherapy of Cancer; November 11-13, 2016: National Harbor, Maryland. Abstract 140.

Response38% 60%

Grade 3/4 AE 1 of 18 (6%)

IL-12 (TAVO) OMS-I102 Trial Design

IT - TAVO-EP IT - TAVO-EP IT - TAVO-EP

…

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5

P = Pembrolizumab treatment

P P P P P

• 3 week treatment cycles with pembrolizumab administered as a 30-minute IV infusion at day 1 of every cycle (flat dose of 200 mg)

• Patients treated with IT-TAVO-EP on days 1, 5, and 8 of every 6 weeks • Patients were selected using CTLA4hiPD1hi TIL phenotype

OMS-I102: Demographics OMS-I102 Tavo + Pembro Combination

Age, yearsN / mean (SD) 23 / 65.5 (12.2)Median, min, max 67, 39, 91Sex - male / female 13 (56.5%) / 10 (43.5%)Stage at enrollmentStage IIIb and IIIc 14 (60.9%)Stage IV M1a and M1b 4 (17.4%)Stage M 1c 5 (21.7%)Prior checkpoint inhibitorsaPD-1 10aCTLA-4 7BRAFMutant 7 (30.4%)Unknown, not tested 16 (69.6%)

Algazi A, et al. Presented at 9th World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Abstract FC05-3.

PISCES TRIAL: IL-12 Electroporation + PembrolizumabAnti-PD-1 IL-12 Stage III/IV Combination Electroporation Study

• Single-arm phase II/III study, Simon 2 stage minimax design- 4 responders out of 23 in the first stage additional 25 patients

• Primary outcome: BORR based on RECIST v1.1• Secondary outcomes: DOR, PFS, and OS• Eligible patients: Anti–PD-1 nonresponders with stage III/IV melanoma

- Received 4+ doses of anti–PD-1- Progressive disease according to RECIST v1.1- Documented disease progression ≤24 weeks of the last dose of anti–PD-1

= Pembrolizumab treatmentP

Overview

• Current clinical trials

• Why this may represent the future

Can Oncolytic Therapies…

• Make “cold” tumors “hot”?

• Reverse resistance to checkpoint inhibitor (CPI) therapy?

Making Tumors “Hot”

PD-1/PD-L1 monotherapy

GenerateT-cells:

+ Anti–CTLA-4+ Intralesional oncolytic therapy+ TLR agonists+ IDO or macrophage inhibitors+ Targeted therapies

Bring T-cells into tumors:

VaccinesTCR engineered ACTCAR engineered ACT

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Weeks Since Treatment Initiation Months Since Treatment Initiation

PFS for PD-1 Responders Only

PFS for PD-1 All Nonresponder Population With Significant Unmet Medical Need

Topalian et al. J Clin Oncol. 2017;32(10);1020-1030

Anatomy of Anti–PD-1 Failures in Melanoma

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Anti–PD-1 Failure Populations

Refractory PD<12 weeks

Relapse PD>12 weeks

Acquired Resistance PD>24 weeks

Predicting Which Patients Are Unlikely to Respond to Pembrolizumab Alone

Patients with <20% CTLA-4hiPD-1hi CD8+ Tumor Infiltrating Lymphocytes did not respond to anti–PD-1 therapy

Daud AI, et al. J Clin Invest. 2016;126(9):3447-3452.

The picture can't be displayed.

Daud AI, et al. J Clin Oncol. 2016;34(34):4102-4109.

Total and Activated CD8 T-Cells* Increase After T-VEC and Combination Treatment

*Activated CD8 T cells are defined as HLA-DR+CD3+CD4- cells

• Total and activated CD8 T cells in the peripheral blood increased from baseline after T-VEC administration at weeks 4 and 6 and further increased at weeks 9 and 15 after combination T-VEC and ipilimumab

102

103

1 4 6 9 15Scheduled visit, week

Abso

lute

Cou

nt, c

ells

/μL

Total CD8

n = 17 n = 17 n = 17 n = 16 n = 10

P = .04 P<.001 P<.001 P<.001101

102

103

1 4 6 9 15Scheduled Visit, week

Abso

lute

Cou

nt, c

ells

/μL

Activated CD8a

n = 17 n = 17 n = 17 n = 16 n = 10

P = .004 P<.001 P<.001 P<.001

P = .02

P = .002

Data points are overlaid on the box plots. Each box plot shows the range between 25th percentile (q1) and 75th percentile (q3) as a yellow box, with a pink line showing the 50th percentile. The whiskers on each box are q3 ± 1.5* (q3 – q1). A red plus sign indicates outlier data within a subset. P values below each post week 1 subset indicate significant changes from baseline level on week 1, and those above week 9 subset indicate significant changes from week 6 to week 9.

Puzanov I, et al J Clin Oncol. 2016;34(22):2619-2626.

Phase IB Trial T-VEC + Pembrolizumab(Masterkey – 265)

• T-VEC increases CD8+ TILs

• Further increased with pembro

Ribas A, et al. Cell. 2017:170(6):1109-1119

• Female: Stage IIIC with melanoma to legs

• Prior treatment with ipilimumab and pembrolizumab

Pt 04-015 Day 0 (Pretreatment) Day 8 (Post-CVA21)

Andtbacka RH, et al. Presented at 9th International Conference on Oncolytic Virus Therapeutics; June 13-16, 2015: Boston, Massachusetts. Abstract and Presentation.

After 3 intratumoralinjections of

CVA21

IT-TAVO: Significant Increase of Proliferating “Partially Exhausted” CD8+ T Cells With Combination Therapy

IT-Tavo-EP IT-Tavo-EP + Pembro

Algazi A, et al. Presented at: 9th World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Abstract FC05-3.

P<.005

Summary & Conclusions

• The future of intralesional agents probably lies in combination therapy

• Several clinical trials are ongoing and maturing• Combination therapy may

– Provide synergy with increased RR and clinical benefit– May represent a way to overcome resistance to CPI therapy