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

Summary of Subject Eligibility Criteria:

Key Inclusion Criteria:

Subjects must be age = 18 years at the time of informed consent. Subjects must have
histologically or cytologically confirmed disease.

Part 1 is restricted to BC, CRC, GEC, melanoma, NSCLC, or RCC with liver metastases or HCC.

Part 2 Group A is restricted to advanced hormone receptor positive BC, CRC, TNBC, CSCC, and
BCC with or without liver metastases.

- Part 2 Hormone receptor positive Breast Cancer Arm only: Histologically and/or
cytologically confirmed diagnosis of estrogen receptor (ER) positive and/or
progesterone receptor (PrR) positive breast cancer.

- Triple negative breast cancer: Histologically and/or cytologically confirmed diagnosis
of ER negative, PrR negative, human epidermal growth factor receptor 2 (HER2)-Neu
negative.

Part 2 Group B is restricted to HCC (fibrolamellar and mixed
hepatocellular/cholangiocarcinoma subtypes are not eligible).

For HCC subjects with a diagnosis of hepatitis B, they must be on antiviral therapy for at
least 4 weeks prior to enrollment and hepatitis B virus (HBV) viral load by real-time
polymerase chain reaction (qPCR) must be < 100 IU/mL. HCC subjects with past or ongoing
hepatitis C infection must have completed treatment for hepatitis C at least 1 month prior
to study enrollment and hepatitis C viral load must be undetectable; subjects with
hepatitis B and C must fulfill the eligibility criteria for hepatitis B and hepatitis C.
Subjects with unresectable locally recurrent TNBC are eligible.

Non-HCC subjects must have received at least 1 prior standard of care systemic anti-cancer
therapy for their locally advanced or metastatic disease. For the combination cohorts
(Cohorts 5 and 6 in Part 1) and Part 2, subjects with melanoma CSCC or NSCLC do not need to
have received prior therapy. In Part 1, subjects must have measurable liver tumors and
liver tumors that are suitable for injection. In Part 2, subjects must have measurable
disease and cutaneous, subcutaneous, lymph node, or liver tumors suitable for injection.
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,
enrollment for this study has stopped. Eastern Cooperative Oncology Group (ECOG)
performance status must be 0 or 1, and life expectancy should be approximately 5 months or
more. Adequate hematological, renal, hepatic, and coagulation function is required. Liver
function tests may be mildly abnormal but within the parameters. Child-Pugh score must be
A.

Key Exclusion Criteria:

Subjects must not be candidates for surgery or locoregional therapy with curative intent or
planned systemic anti-cancer therapy, with the exception of immunotherapy in the
combination cohorts (Cohorts 5 and 6 in Part 1 and all subjects in Part 2). Liver tumors
must not be estimated to invade approximately more than one-third of the liver. Liver
tumor-directed therapy, hepatic surgery or major surgery, antibody-based therapy, or
immunotherapy must not have been performed < 28 days, chemotherapy < 21 days, and targeted
small molecule therapy or hormonal therapy < 14 days prior to enrollment. Subjects must
either (1) have no central nervous system (CNS) metastasis, or carcinomatous meningitis, or
(2) if CNS metastasis is present, must have stable treated cerebral metastases. Subjects
must not have symptomatic auto-immune disease or be symptomatically immunosuppressed. They
must not have a history of solid organ transplantation. For non-HCC, there must not be
acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. For HCC with
prior hepatitis B and/or C infection, HBV and/or HCV viral load by qPCR must be
undetectable, and they must not have had recent treatment within 12 weeks for HBV or HCV
with certain antiviral medications in Part 1 Group B cohorts 1-5 and 6a, and Part 2 Group B
HCC without viral hepatitis. For all patients in Part 1 and for patients in Part 2 where
intrahepatic liver injection is planned (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, enrollment for this study has stopped), there should be no
macroscopic intravascular invasion of tumors into the main portal vein, hepatic vein, or
vena cava. Subjects must not: have active herpetic skin lesions or prior complications of
herpetic infection (eg, herpetic keratitis or encephalitis); require treatment with an
antiherpetic drug; have received live-virus vaccination within 30 days of planned treatment
start; have previous therapy with talimogene laherparepvec, oncolytic viruses, or tumor
vaccine. Subjects in the combination treatment cohort must not have: a history or evidence
of psychiatric, substance abuse, or any other clinically significant disorder; toxic
effects of the most recent prior chemotherapy not resolved to grade 1 or less (except
alopecia); or expected other cancer therapy while on study with the exception of local
radiation to the site of bone or other metastasis for palliative treatment. Male subjects
of reproductive potential in the combination treatment must be willing to use acceptable
methods of effective contraception during treatment and through 4 months after the last
dose of pembrolizumab.