Talimogene Laherparepvec In Combination Research Articles

Phase Ib study of talimogene laherparepvec (T-VEC) injection into liver metastases (LMs) in combination with intravenous (IV) atezolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or colorectal cancer (CRC).

TPS725 Background: T-VEC is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immune responses. Atezolizumab is a monoclonal antibody checkpoint inhibitor (CPI) that targets PD-L1. The safety of intrahepatic administration of T-VEC has been demonstrated in a prior clinical trial (NCT02509507). A previous trial of T-VEC in combination with a CPI in advanced melanoma demonstrated improved responses compared to those with a CPI alone (Puzanov et al. JCO. 2016; 34:2619-26). We hypothesize that T-VEC combined with a CPI may also be effective in other tumor types. This phase 1b, multicenter study evaluates the safety of intrahepatic injection of T-VEC in combination with IV atezolizumab in pts with TNBC or CRC with LMs. Methods: The study will enroll up to 36 pts in two parallel cohorts (18 TNBC, 18 CRC) at sites in the USA, Europe, and Australia. The primary objective is to evaluate the incidence of dose-limiting toxicities (DLTs). Secondary objectives include objective response rate, lesion-level responses in injected and uninjected tumors, progression-free survival, and overall survival. Key eligibility criteria include age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG performance status 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable, injectable LM. T-VEC will be given by image-guided intralesional injection of up to 4 mL of 106 plaque forming units (PFU)/mL on day 1 and up to 4 mL of 108 PFU/mL every 21 days thereafter; atezolizumab 1,200 mg IV will be given on day 1 and every 21 days thereafter. The DLT-evaluation period is the first two cycles (1 cycle = 21 days). Interim safety analysis will occur after the first 4–6 pts have become DLT evaluable. Up to six cycles of T-VEC will be given with an additional 6 cycles allowed. After cycle three, nonhepatic lesions may be injected, subject to protocol-defined criteria. The study opened for enrollment in January 2018. (NCT03256344) Clinical trial information: NCT03256344.

Reversing resistance to PD-1 blockade by combination of talimogene laherparepvec (T-VEC) with pembrolizumab (pembro) in advanced melanoma patients following progression on a prior PD-1 inhibitor: SWOG S1607 (NCT#02965716).

TPS9603Background: A significant number of patients do not respond to PD-1/L1 blockade because there are no pre-existing tumor antigen-specific T-cells in their tumors ready to attack the cancer. W...

A phase II study of talimogene laherparepvec followed by talimogene laherparepvec + nivolumab in refractory T cell and NK cell lymphomas, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and other rare skin tumors (NCI #10057).

TPS219 Background: Talimogene laherparepvec, a modified herpes virus agent, induces a response in 65% of injected melanoma tumors. The combination of talimogene laherparepvec with ipilimumab or pembrolizumab appears promising in clinical trials of advanced melanoma. Talimogene laherparepvec-based therapy may be effective in other cancers of the skin and lymph nodes that are anatomically accessible for intratumoral injection. Methods: This phase II study will evaluate intratumoral talimogene laherparepvec monotherapy in 4 parallel disease cohorts: 1) Refractory T cell and NK cell lymphomas including cutaneous T cell lymphoma, 2) Merkel cell carcinoma 3) Cutaneous squamous cell carcinoma and 4) Other advanced/refractory non-melanoma skin cancers. Lymphoma patients must be refractory to or intolerant of all standard life-prolonging therapies. Skin cancer patients must be advanced/unresectable or refractory to one or more treatments including surgery, radiation therapy, or medical therapy. Prior PD-1-directed therapy is allowed. If an objective response is not achieved by Week 12, the PD-1 blocking antibody nivolumab will be added. The primary endpoint is the response rate with talimogene laherparepvec and secondary endpoints include response rate with the combination and overall survival. Using a two-stage design, if 1 or more response is observed in the first 9 patients in each parallel cohort, 8 additional patients will be accrued for a total sample size of 36 to 68 patients across the 4 disease cohorts. Tumor biopsies of injected lesions are mandatory at baseline and Week 6, and optional at Week 16 and the time of progression. Optional biopsies of non-injected lesions (when applicable) at Week 6 and 16 will be analyzed to identify biomarkers of systemic immunity. Tumor tissue and/or blood will be assayed for PD-L1 expression, RNA profiling, immune cell profiling, HVEM, NECTIN 1/2, IDO, tryptophan and L-kynurenine, mutational load, TIL TCR clonality, and prior exposure to herpes simplex type 1 virus and Merkel cell polyomavirus. Clinical trial information: NCT02978625.

Abstract IA24: New frontiers in oncolytic virus therapy

Abstract After decades of research, oncolytic viruses have finally demonstrated clinical efficacy against human tumors. Talimogene laherparepvec is a first-in-class, injectable oncolytic virus derived from herpes simplex virus (HSV) type 1. In talimogene laherparepvec, the HSV-1 is modified through deletion of two non-essential viral genes. Deletion of the neurovirulence factor genes (ICP34.5) leads to preferential replication of the virus in tumor cells as compared with normal cells, while deletion of the ICP47 gene is designed to reduce virus-mediated suppression of antigen presentation. In addition, insertion of a GM-CSF cassette induces local GM-CSF production and is intended to recruit and activate antigen-presenting cells, ultimately stimulating systemic tumor-specific T-cell responses. Directly administered into accessible lesions, talimogene laherparepvec is therefore designed to have a dual mechanism of action, namely tumor lysis of injected lesions and the induction of a systemic antitumor immune response. In a randomized, phase III trial comparing talimogene laherparepvec therapy with subcutaneously administered GM-CSF in patients with injectable melanoma that was not surgically resectable, the durable response rate (objective response lasting continuously ≥ 6 months) was 16.3% in patients receiving talimogene laherparepvec and 2.1% in those receiving GM-CSF (1). However, the mechanism by which talimogene laherparepvec may induce responses in uninjected, distant lesions has not been fully elucidated. To investigate this question, we conducted preclinical experiments using various syngeneic models in which both injected and uninjected tumors in a single mouse could be evaluated. These studies indicated that, as anticipated, a high proportion of lesions that were directly injected with OncoVexmGM-CSF, an HSV-1 modified similarly to talimogene laherparepvec except that murine GM-CSF is used in lieu of human GM-CSF, underwent complete regression. A proportion of distant, uninjected tumors also regressed, and these lesions demonstrated significant immune cell infiltrates, with efficacy dependent on the generation of systemic antitumor CD8-positive T cells. There was no evidence of viral replication in any distant tumors, consistent with findings from other preclinical models. Ongoing biomarker studies in clinical trials are intended to confirm and extend these findings, including investigation of potential markers of response or resistance to talimogene laherparepvec monotherapy. In addition to its use as a single agent, there is interest in combining talimogene laherparepvec with other immunotherapeutic agents. Preclinical experiments using tumor cell lines both susceptible and resistant to talimogene laherparepvec monotherapy suggest that the addition of either anti-CTLA-4 or anti-PD-1 antibodies significantly increases the proportion of mice that are “cured.” Preliminary data from early-phase clinical trials in advanced melanoma demonstrate that talimogene laherparepvec can be safely combined with ipilimumab or pembrolizumab, with evidence of antitumor effect, including complete responses. A randomized, double-blind phase III trial of talimogene laherparepvec in combination with either pembrolizumab or placebo in patients with advanced melanoma is actively recruiting patients and will provide significant insight into the effectiveness of this combination. Based on its mechanism of action, talimogene laherparepvec may have utility in tumor types beyond melanoma. An ongoing phase I trial is examining the safety of talimogene laherparepvec when injected into hepatic metastases of various solid tumors, and, once an acceptable safety profile has been demonstrated and a dose established, combination trials with checkpoint inhibitors are planned. One key question is whether tumors that are generally resistant to checkpoint inhibition can be rendered sensitive with the addition of talimogene laherparepvec.

What's new in melanoma? Combination!

Melanoma was again a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, in particular the use of combination treatment strategies involving immunotherapies and/or targeted agents. New data on targeted therapies confirmed previous findings, with combined BRAF inhibitor (vemurafenib) plus MEK inhibitor (cobimetinib) improving progression-free survival (PFS) compared to vemurafenib monotherapy in patients with BRAFV600 mutation-positive tumors (CoBRIM trial). Positive results were also seen with combined dabrafenib and trametinib in patients with BRAF V600E/K metastatic melanoma and encorafenib plus binimetinib in BRAFV600-mutant cutaneous melanoma. Even more interesting news centered on the use of combination immunotherapy, in particular the randomized, double-blind CheckMate 067 study in which median PFS with nivolumab plus ipilimumab was 11.5 months, compared to 2.9 months with ipilimumab alone (HR 0.42) and 6.9 months with nivolumab alone (HR 0.57). Of interest, in patients with ≥5% PD-L1 expression, median PFS was 14 months with the combination or with nivolumab alone compared with 3.9 months in the ipilimumab group, while in the PD-L1 negative cohort, the combination remained superior to both monotherapies. Given that combination therapy was accompanied by a high occurrence of side-effects, this raises the suggestion that combination therapy might be reserved for PD-L1 negative patients only, with PD-L1 positive patients achieving the same benefit from nivolumab monotherapy. However, overall survival data are awaited and the equivalence of single agent to the combination remains unconvincing. Interesting data were also reported on the combination of T-VEC (talimogene laherparepvec) with ipilimumab, and the anti-PD-1 agent MEDI4736 (durvolumab) combined with dabrafenib plus trametinib. Emerging data also suggested that predictive markers based on immunoprofiling and mismatch repair deficiency may be of clinical use. In conclusion, the use of combination approaches to treat patients with melanoma, as well as other cancers, is no longer a just a wish for the future but is today a clinical reality with a rapidly growing evidence-base. Moreover, the most exciting consideration is that this is far from the end of the story, but rather a fantastic introduction.