On October 5, 2017 Amgen (NASDAQ:AMGN) reported that the Journal of Clinical Oncology has published positive results from the IMLYGIC (talimogene laherparepvec) Phase 2 ‘264 study (Press release, Amgen, OCT 5, 2017, View Source [SID1234520797]). The study met its primary endpoint of objective response rate (ORR), demonstrating that IMLYGIC in combination with YERVOY (ipilimumab) more than doubled ORR, defined as the proportion of patients with tumor size reduction, compared to ipilimumab alone in patients with unresectable stage IIIB-IV melanoma (39 percent versus 18 percent; odds ratio=2.9, 95 percent CI: 1.5, 5.5; p=0.002). Patients in the combination arm also experienced nearly double the complete response rate compared to ipilimumab alone (13 percent versus 7 percent).

“Advanced melanoma is highly aggressive and can require multiple treatment approaches over the course of the disease,” said Jason Chesney, M.D., lead author of the ‘264 study and director of the James Graham Brown Cancer Center, University of Louisville, Louisville, Ky. “Results from the study found that administration of IMLYGIC in combination with ipilimumab led to greater efficacy versus ipilimumab alone in both uninjected and visceral lesions. These data show that this combination of a checkpoint inhibitor plus IMLYGIC demonstrated a synergistic clinical effect and enhanced anti-tumor immune response in patients with metastatic melanoma.”

IMLYGIC is designed to rupture cancer cells causing the release of tumor-derived antigens, which along with granulocyte-macrophage colony-stimulating factor (GM-CSF), may help to initiate an anti-tumor immune response. However, the exact mechanism of action is unknown. This may be complementary to ipilimumab’s mechanism of action, as the blockade of cytotoxic T-lymphocyte-associated antigen-4 has been shown to augment activation and proliferation of tumor infiltrating T-effector cells.

Melanoma is one of the most dangerous types of skin cancers, especially when it spreads to other parts of the body.1 The study showed that responses occurred in both injected and uninjected lesions, including visceral lesions, demonstrating a systemic anti-tumor response. Thirty-one (32 percent) and 22 (22 percent) of the patients were shown to have visceral disease at baseline in the combination and ipilimumab arms, respectively. Of these patients, 16 (52 percent) in the combination arm and five (23 percent) in the ipilimumab arm were observed to have a decrease in visceral lesion tumor burden. Patients in the combination arm also experienced a median progression-free survival (PFS) of 8.2 months (median follow up 68 weeks) versus 6.4 months in the ipilimumab arm. The effect was not statistically significant (HR=0.83, 95 percent CI: 0.56, 1.23; p=0.35); however, the PFS analysis was not event-driven and is still ongoing. Evaluation of overall survival (OS) is ongoing and continues to be monitored.

The most common adverse events in the IMLYGIC plus ipilimumab arm compared to the ipilimumab alone arm were fatigue (59 percent versus 42 percent, respectively), chills (53 percent versus 3 percent, respectively), diarrhea (42 percent versus 35 percent, respectively), pruritus (40 percent versus 36 percent, respectively), rash (39 percent versus 28 percent, respectively) and nausea (38 percent versus 24 percent, respectively).

“IMLYGIC is the first and only approved oncolytic viral therapy in the U.S. and Europe, reinforcing Amgen’s leadership and commitment to developing innovative therapies for difficult-to-treat cancers,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “The data published today in the Journal of Clinical Oncology supports the scientific hypothesis behind the combination of IMLYGIC with an immune checkpoint inhibitor. We are excited about the promise of our diverse immuno-oncology pipeline that looks at combinations that may be effective in stimulating an immune attack on cancer cells.”

In the study, response rate was also higher in the combination arm across subsets of the disease. ORR for patients with stage IIIB/IIIC/IVM1a disease was 44 percent in the combination arm and 19 percent in the ipilimumab arm (overall response [OR]=3.3, 95 percent CI: 1.4, 7.8; p=0.007). In patients with stage IVM1b/IVM1c disease, ORR was 33 percent and 16 percent, respectively (OR=2.6, 95 percent CI: 0.9, 7.0; p=0.09). Among BRAF wild-type patients, ORR was 42 percent in the combination arm versus 10 percent in the ipilimumab arm (OR=6.5, 95 percent CI: 2.4, 17.4; p<0.0001). In patients with BRAF-mutant tumors, which comprised a minority of each arm at 35 (36 percent) and 34 (34 percent) for the combination and ipilimumab arms respectively, ORR was 34 percent in the combination arm versus 32 percent in the ipilimumab arm (OR=1.1, 95 percent CI: 0.4, 3.0; p=1.0). The disease control rate (DCR) was 58 percent in the combination arm and 42 percent in the ipilimumab arm (OR=1.9, 95 percent CI: 1.1, 3.4; p=0.033). DCR in all subgroups, with the exception of patients with BRAF mutations, favored the combination arm. About the '264 Study The '264 study is a Phase 1b/2, multicenter, open-label trial evaluating the safety and efficacy of IMLYGIC in combination with ipilimumab compared to ipilimumab alone in patients with unresectable stage IIIB-IV melanoma. The primary endpoint of the Phase 2 portion of study is ORR. Secondary endpoints include duration of response, DCR, PFS, OS and safety. The study randomized 198 patients, 98 in the IMLYGIC plus ipilimumab arm and 100 in the ipilimumab arm. About Metastatic Melanoma Melanoma remains a significant public health concern across the globe. Unlike some other cancers, melanoma incidence rates have doubled in the past 40 years, with 132,000 cases occurring worldwide each year.2,3 Melanoma is more dangerous than other skin cancers, especially when it spreads to other parts of the body, which is referred to as metastatic disease.1 The overall five-year risk of relapse after surgery increases as disease stage advances, from 48 percent for stage IIIA to 85 percent for stage IIIC.4 Risk of recurrence is even higher for patients in stage IV undergoing surgery, with 91 percent experiencing relapse.5 Despite new options, additional treatments are needed – particularly for patients with metastatic disease. About IMLYGIC (talimogene laherparepvec) IMLYGIC is a genetically modified herpes simplex type 1 virus that is injected directly into tumors. IMLYGIC replicates inside tumor cells and produces GM-CSF, an immunostimulatory protein. IMLYGIC then causes the cell to rupture and die in a process called lysis. The rupture of the cancer cells causes the release of tumor-derived antigens, which together with virally derived GM-CSF may help to promote an anti-tumor immune response. However, the exact mechanism of action is unknown. IMLYGIC is the first oncolytic viral therapy approved by the U.S. Food and Drug Administration (FDA) based on therapeutic benefit demonstrated in a pivotal study. IMLYGIC is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. IMLYGIC has not been shown to improve OS or have an effect on visceral metastases. Important U.S. Safety Information Contraindications Do not administer IMLYGIC to immunocompromised patients, including those with a history of primary or acquired immunodeficient states, leukemia, lymphoma, AIDS or other clinical manifestations of infection with human immunodeficiency viruses, and those on immunosuppressive therapy, due to the risk of life‐threatening disseminated herpetic infection. Do not administer IMLYGIC to pregnant patients. Warnings and Precautions Accidental exposure to IMLYGIC may lead to transmission of IMLYGIC and herpetic infection, including during preparation and administration. Health care providers, close contacts, pregnant women, and newborns should avoid direct contact with injected lesions, dressings, or body fluids of treated patients. The affected area in exposed individuals should be cleaned thoroughly with soap and water and/or a disinfectant. Caregivers should wear protective gloves when assisting patients in applying or changing occlusive dressings and observe safety precautions for disposal of used dressings, gloves, and cleaning materials. Exposed individuals should clean the affected area thoroughly with soap and water and/or a disinfectant. To prevent possible inadvertent transfer of IMLYGIC to other areas of the body, patients should be advised to avoid touching or scratching injection sites or occlusive dressings. Herpetic infections: Herpetic infections (including cold sores and herpetic keratitis) have been reported in IMLYGIC‐treated patients. Disseminated herpetic infection may also occur in immunocompromised patients. Patients who develop suspicious herpes-like lesions should follow standard hygienic practices to prevent viral transmission. Patients or close contacts with suspected signs or symptoms of a herpetic infection should contact their health care provider to evaluate the lesions. Suspected herpetic lesions should be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442). Patients or close contacts have the option of follow-up testing for further characterization of the infection. IMLYGIC is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the effectiveness of IMLYGIC. Consider the risks and benefits of IMLYGIC treatment before administering antiviral agents to manage herpetic infection. Injection Site Complications: Necrosis or ulceration of tumor tissue may occur during IMLYGIC treatment. Cellulitis and systemic bacterial infection have been reported in clinical studies. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds. Impaired healing at the injection site has been reported. IMLYGIC may increase the risk of impaired healing in patients with underlying risk factors (e.g., previous radiation at the injection site or lesions in poorly vascularized areas). If there is persistent infection or delayed healing of the injection site, consider the risks and benefits of continuing treatment. Immune-Mediated events including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported in patients treated with IMLYGIC. Consider the risks and benefits of IMLYGIC before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events. Plasmacytoma at the Injection Site: Plasmacytoma in proximity to the injection site has been reported in a patient with smoldering multiple myeloma after IMLYGIC administration in a clinical study. Consider the risks and benefits of IMLYGIC in patients with multiple myeloma or in whom plasmacytoma develops during treatment. Obstructive Airway Disorder: Obstructive airway disorder has been reported following IMLYGIC treatment. Use caution when injecting lesions close to major airways. Adverse Reactions The most commonly reported adverse drug reactions (≥ 25%) in IMLYGIC-treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. Pyrexia, chills, and influenza-like illness can occur at any time during IMLYGIC treatment, but were more frequent during the first 3 months of treatment. The most common Grade 3 or higher adverse reaction was cellulitis. Please see full Prescribing Information and Medication Guide for IMLYGIC.