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Liver Neoplasms

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Liver Diseases

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Pembrolizumab

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Talimogene laherparepvec

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Combination treatment of Talimogene Laherparepvec and Pembrolizumab

Talimogene laherparepvec (T-VEC) administered by intralesional injection into liver tumors, with ultrasound/computed tomography (US/CT) guidance. Part 1: initial dose of T-VEC is 10\^6 plaque forming unit (PFU)/mL up to 4mL in Cohorts 1 \& 2, up to 8mL in Cohorts 3 \& 4 of the Group A \& Group B. The 1st cycle of T-VEC will be 21 (+3) days (from the 1st dose at 10\^6 PFU/mL to the 2nd dose at 10\^7 or 10\^8 PFU/mL). Subsequent cycles of T-VEC will be 21 (±3) days. Max. volume of T-VEC administered at any dose is 4mL (Cohorts 1, 2, 5, and 6) or 8mL (Cohorts 3 \& 4) for any individual lesion or for all lesions combined. Part 2: Initial dose of T-VEC is 10\^6 PFU/mL followed by subsequent T-VEC doses at a concentration of 10\^8 PFU/mL. T-VEC volume is up to 8mL based on the size of the inejected lesions. NOTE: as of Protocol Amendment 6 \[dated 26 October 2021\], intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study.

Talimogene Laherparepvec

Pembrolizumab is a non-Amgen Investigational product that is manufactured by Merck. Pembrolizumab will be labeled, packaged, and distributed by Amgen (or designee) using Amgen (or designee) clinical study drug distribution procedures. Pembrolizumab is supplied as pembrolizumab 100 mg/4 mL vials (25 mg/mL) solution for IV infusion. The trial treatment will consist of a total dose of 200mg administered intravenously every 3 weeks (day 1 of each cycle) for up to 35 cycles.

This is a phase 1b/2, multicenter, open-label, basket trial to evaluate the safety of talimogene laherparepvec injected intrahepatically into liver tumors alone and in combination with systemic intravenous (IV) administration of pembrolizumab, in subjects with non-hepatocellular carcinoma (HCC) liver metastases from breast adenocarcinoma (BC), colorectal adenocarcinoma (CRC), gastroesophageal cancer (GEC), melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (RCC) in Part 1 Group A, and subjects with HCC with and without viral hepatitis in Part 1 Group B (viral hepatitis is only applicable in combination setting), and to evaluate the efficacy and safety of intratumoral talimogene laherparepvec in combination with systemic pembrolizumab in subjects with advanced triple negative breast cancer (TNBC), hormone receptor positive breast cancer, CRC, cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC) in Part 2 Group A and subjects with HCC with and without viral hepatitis in Part 2 Group B. The objective of Part 1 is to evaluate the safety of intrahepatic injection of talimogene laherparepvec into liver tumors alone and in combination with systemically administered pembrolizumab for the non-HCC (Group A) and HCC (Group B) cohorts separately. Part 2 consists of 2-stage design to evaluate the efficacy and safety of talimogene laherparepvec in combination with systemic pembrolizumab. Efficacy and safety will be evaluated in each of the five non-HCC tumor types from Group A separately. Similarly, the efficacy and safety of the combination treatment will be determined for Group B HCC subjects. As of Protocol Amendment 6 (dated 26 October 2021), intrahepatic injections of talimogene laherparepvec and liver biopsies are no longer performed in this study. Enrollment for this study has stopped.

Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Tumors Alone and in Combination With Systemic Pembrolizumab MK-3475-611/Keynote-611

A Phase 1b/2, Multicenter, Open-label, Basket Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Liver Tumors Alone and in Combination With Systemic Pembrolizumab in Phase 1b and to Evaluate the Efficacy and Safety of Intratumoral Talimogene Laherparepvec in Combination With Systemic Pembrolizumab to Treat Subjects With Advanced Solid Tumors in Phase 2 (MASTERKEY-318)

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

All toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03:

* Grade 1: Mild
* Grade 2: Moderate
* Grade 3: Severe or medically significant but not immediately life threatening
* Grade 4: Life threatening consequences
* Grade 5: Death related to adverse event (AE)

The occurrence of specific pre-defined toxicities during the DLT evaluation period were considered a DLT if judged by the investigator to be related to talimogene laherparepvec and/or pembrolizumab.

All Grade 5 toxicities, intolerable toxicities that lead to permanent discontinuation of talimogene laherparepvec and/or pembrolizumab and Grade 3 or higher AEs related to talimogene laherparepvec and/or pembrolizumab that resulted in a study treatment delay by \> 2 weeks were considered DLTs.

ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) per modified irRC-RECIST.

* CR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.
* PR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation.

A TEAE was defined as an event that emerged during treatment, having been absent pretreatment, or worsened relative to the pretreatment state.

A treatment-related TEAE was defined as a TEAE that was suspected to be related to the study treatment.

Merck Sharp & Dohme LLC

Amgen

A TEAE was defined as an event that emerged during treatment, having been absent pretreatment, or worsened relative to the pretreatment state.

Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10\^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 1 \& 2 and up to a volume of 8 mL in Cohorts 3 \& 4 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10\^7 (Cohorts 1 \& 4) or 10\^8 PFU/mL (Cohorts 2 \& 3).

Part 1: Monotherapy Group A

Participants with hepatocellular carcinoma (HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10\^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 1 \& 2 and up to a volume of 8 mL in Cohorts 3 \& 4 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10\^7 (Cohorts 1 \& 4) or 10\^8 PFU/mL (Cohorts 2 \& 3).

Part 1: Monotherapy Group B

Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10\^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 5 \& 6 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10\^7 (Cohort 5) or 10\^8 PFU/mL (Cohorts 6).

Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

Part 1: Combination Therapy Group A

Participants with hepatocellular carcinoma (HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10\^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 5 \& 6 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10\^7 (Cohort 5) or 10\^8 PFU/mL (Cohorts 6).

Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

Part 1: Combination Therapy Group B

Participants with HRBC were administered talimogene laherparepvec by intralesional injection at the maximum tolerated concentration (MTC) and maximum tolerated volume (MTV) identified in Part 1 on Day 1 of each 21-day cycle.

Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

Part 2: Hormone Receptor Positive Breast Cancer (HRBC)

Participants with TNBC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

Part 2: Triple Negative Breast Cancer (TNBC)

Participants with CSCC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

Part 2: Cutaneous Squamous Cell Carcinoma (CSCC)

Participants with BCC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

Part 2: Basal Cell Carcinoma (BCC)

Participants with CRC were administered talimogene laherparepvec by intralesional injection at the MTC and MTV identified in Part 1 on Day 1 of each 21-day cycle.

Participants were also administered 200 mg of pembrolizumab on Day 1 of each 21-day cycle as an intravenous infusion.

Part 2: Colorectal Adenocarcinoma (CRC)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Safety Analysis Set: Part 1 - Included all participants who have received at least 1 dose of talimogene laherparepvec in monotherapy arms, and at least 1 dose of talimogene laherparepvec or at least 1 dose of pembrolizumab in combination arms. Part 2 - Included all participants who have received at least 1 dose of talimogene laherparepvec or at least 1 dose of pembrolizumab.

Study Director

Participants with non-hepatocellular carcinoma (non-HCC) were administered talimogene laherparepvec by intralesional injection at an initial concentration of 10\^6 plaque forming unit (PFU)/mL in a volume of up to 4mL in Cohorts 1 \& 2 and up to a volume of 8 mL in Cohorts 3 \& 4 on Day 1 of the first 21-day cycle. The concentration of talimogene laherparepvec doses in the second and subsequent 21-day cycles were 10\^7 (Cohorts 1 \& 4) or 10\^8 PFU/mL (Cohorts 2 \& 3)

DLT Analysis Set: Participants who had at least 1 dose of planned monotherapy or combination treatment and had the opportunity to be on treatment for at least 6 weeks from the initial dosing of study treatment \& received at least 1 additional dose of monotherapy or combination or experienced a DLT during the DLT-evaluation period.

Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)

Full Analysis Set (Part 2): Included all participants in Part 2 who received at least 1 dose of talimogene laherparepvec and at least 1 dose of pembrolizumab in combination.

Part 2 Only: Objective Response Rate (ORR)

TEAEs

Treatment-related TEAEs

Safety Analysis Set (Part 2): Included all participants in Part 2 who have received at least 1 dose of talimogene laherparepvec or at least 1 dose of pembrolizumab.

Spots Global Cancer Trial Database for cutaneous or subcutaneous lymph node