Patient case: 48-year-old female with melanoma; genetic feature: tumor cells with >50% membranous PD-L1 expression

Clinical trial: Talimogene Laherparepvec and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

Summary: This phase II trial studies how well talimogene laherparepvec and pembrolizumab work in treating patients with stage III-IV melanoma. Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving talimogene laherparepvec and pembrolizumab may work better in treating patients with melanoma by shrinking the tumor.

Detailed description: PRIMARY OBJECTIVES:
  I. To evaluate the durable response rate of treatment with talimogene laherparepvec (T-VEC) in combination with pembrolizumab following progression on prior anti-PD-1 or anti-PD-L1 therapy alone or in combination with other agents different from T-VEC.
  SECONDARY OBJECTIVES:
  I. To estimate the objective response rate (confirmed and unconfirmed, complete and partial responses) in the injected lesions.
  II. To estimate the objective response rate (ORR) in the non-visceral, non-injected lesions.
  III. To estimate the objective response rate (ORR) in the visceral lesions (Cohort A).
  IV. To estimate the overall objective response rate (ORR). V. To estimate the median progression-free survival (PFS). VI. To estimate the median overall survival (OS). VII. To evaluate the toxicity of the regimen.
  TERTIARY OBJECTIVES:
  I. To evaluate whether adding T-VEC to PD1 blockade can increase T-cell infiltration into tumors and whether change in T-cell infiltration is associated with response.
  II. To evaluate whether adding T-VEC to PD1 blockade can increase T-cell receptor (TCR) clonality in tumors and in peripheral blood and whether increased TCR clonality is associated with response.
  III. To evaluate whether intra-tumoral injection of T-VEC is associated with the tumor immune microenvironment.
  IV. To evaluate whether tumor mutational load and mutations in the IFN pathway is associated with response to T-VEC plus pembrolizumab therapy in the anti-PD1/L1 therapy refractory melanoma patients.
  OUTLINE:
  Patients receive talimogene laherparepvec intralesionally (IL) and pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up every 6 months for up to 2 years and then annually for a total of 5 years.

Eligibility: Inclusion Criteria:
  -  Patients must have pathologically confirmed Stage IV or unresectable Stage III melanoma
  -  Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; non-measurable disease must be assessed within 42 days prior to registration; all disease must be assessed and documented on the baseline tumor assessment form (RECIST 1.1)
  -  Cohort A: Patients must have at least one measurable visceral lesion (per RECIST 1.1); a visceral lesion is any solid organ except for skin, lymph node, and musculoskeletal tissue; at least one of these visceral lesions must be measurable per RECIST 1.1
  -  Cohort B: Patients must not have any visceral lesions
  -  Patients must, in the opinion of the treating physician, be candidates for intralesional administration into cutaneous, subcutaneous, or nodal lesions; patients must have at least 2 injectable lesions
  -  Patients may have brain metastases if all lesions have been treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy with no evidence of progression and have not required steroids for at least 14 days prior to registration
  -  Patient must have had prior treatment with anti-PD-1 or anti-PD-L1 agents and have documented disease progression on these agents prior to registration; anti-PD1/L1 based therapy must be the immediate previous line of treatment prior to registration
  -  Patients must not have had surgery, chemotherapy, biologic therapy, hormonal therapy, or radiation therapy within 14 days prior to registration; patients must not have had an investigational agent or monoclonal antibodies, except anti-PD1/L1 antibodies, within 28 days prior to registration; patients must have recovered from all side effects from prior therapies prior to registration
  -  Patients must not have received prior treatment with T-VEC or other oncolytic virus agents
  -  Patients must not have received any infectious disease vaccination within 7 days prior to registration
  -  Patients must not be planning to receive other biologic therapy, radiation therapy, hormonal therapy, chemotherapy, surgery, or other therapy while on this protocol; palliative radiation therapy or surgery can be considered for symptomatic non-target lesions after discussions with the study team
  -  Patients must have Zubrod performance status =< 2
  -  Absolute neutrophil count (ANC) >= 1,500/mcL
  -  Hemoglobin >= 8 g/dL
  -  Platelets >= 100,000/mcL
  -  Total bilirubin =< 2.0 x institutional upper limit of normal (IULN) except patients with documented Gilbert's syndrome
  -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both < 3.0 x IULN
  -  Serum creatinine < 2.0 x IULN within 28 days prior to registration
  -  International normalized ratio (INR) or prothrombin time (PT) =< 2.0 x IULN if not using anticoagulants within 28 days prior to registration; if using anticoagulants, then the value must be within therapeutic range according to the condition for which the patient is being treated within 28 days prior to registration
  -  Activated partial thromboplastin time (aPTT) =< 2.0 x IULN if not using anticoagulants within 28 days prior to registration; if using anticoagulants, then the value must be within therapeutic range according to the condition for which the patient is being treated within 28 days prior to registration
  -  Patients must have lactate dehydrogenase (LDH) obtained prior to registration
  -  Patients must have complete physical examination and medical history obtained within 28 days prior to registration
  -  Patients must not require use of systemic corticosteroid within 14 days prior to registration or during protocol treatment; patients with preexisting severe autoimmune disease requiring systemic corticosteroids or ongoing immunosuppression are not eligible
  -  Patients must not have known history of hepatitis B, hepatitis C, human immunodeficiency virus (HIV)
  -  Patients must not have history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  -  Patients must not have an active infection requiring systemic therapy
  -  Patients must not have active herpetic skin lesions or prior complications of herpetic infection (e.g., herpetic keratitis or encephalitis) which requires intermittent or chronic treatment with an anti-herpetic drug other than intermittent topical use
  -  Patients must not have organ allografts
  -  Patients must not have an uncontrolled intercurrent illness including, but not limited to, nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy, or psychiatric illness/social situations which would limit compliance with study requirements
  -  No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for two years
  -  Patients must not be pregnant or nursing; women of reproductive potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 120 days after last study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  -  Patients must be willing to submit blood and tissue specimens for translational medicine
  -  Patients must be offered the opportunity to participate in specimen banking for future research
  -  Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  -  As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Relevance to patient case: not relevant