On June 3, 2017 Amgen (NASDAQ:AMGN) reported new data from the Phase 2 ‘264 study that demonstrated IMLYGIC (talimogene laherparepvec) in combination with the immune checkpoint inhibitor YERVOY (ipilimumab)* more than doubled objective response rate (ORR), defined as the proportion of patients with tumor size reduction, compared to YERVOY alone in patients with unresectable stage IIIB-IV melanoma, meeting the primary endpoint of the study (Press release, Amgen, JUN 3, 2017, View Source [SID1234519359]).

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The analysis showed that 38.8 percent of patients treated with IMLYGIC plus YERVOY achieved an objective response versus 18 percent of patients treated with YERVOY alone (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 YERVOY alone (13.3 percent versus 7 percent). The results were presented at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

"Metastatic melanoma continues to be one of the most difficult-to-treat and aggressive cancers," said Jason Chesney, M.D., ‘264 study investigator and acting director of the James Graham Brown Cancer Center, University of Louisville, Louisville, Ky. "The results from this study demonstrate the potential of combining the complementary mechanisms of action of an oncolytic viral immunotherapy and a checkpoint inhibitor to enhance anti-tumor effect in patients with advanced melanoma."

Responses were not limited to injected lesions. Among patients with visceral disease treated with IMLYGIC plus YERVOY, 35 percent had a reduction in size of visceral lesions by at least 50 percent. The rate was 14 percent in patients in the YERVOY arm. Patients in the IMLYGIC plus YERVOY arm experienced a median progression-free survival (PFS) of 8.2 months (median follow up 68 weeks) versus 6.4 months in the YERVOY arm. The effect was not statistically significant (HR=0.83, 95 percent CI; p=0.35); however, the PFS analysis was not event-driven and is still ongoing, with only approximately 50 percent of PFS events reported at this time.

"Patients with metastatic melanoma are in need of innovative, effective treatment options that can improve response rates and help prevent disease recurrence," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "These are the first randomized, controlled, Phase 2 data demonstrating clear efficacy and safety of an oncolytic virus with a checkpoint inhibitor. We are excited to be exploring IMLYGIC with PD-1 and PDL-1 checkpoint inhibitors as well."

The most common adverse events in the IMLYGIC plus YERVOY arm were fatigue (59 percent versus 42 percent, respectively), chills (53 percent versus 3 percent, respectively) and diarrhea (42 percent versus 35 percent, respectively). Evaluation of overall survival (OS) is ongoing and continues to be monitored. 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 YERVOY’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.

In addition, these results follow the presentation of new interim data from a Phase 2 biomarker study, which evaluated CD8+ T cell density in biopsies from patients with unresectable stage IIIB-IVM1c melanoma treated with IMLYGIC. These data were presented at the 13th Congress of the European Association of Dermato Oncology in Athens, Greece. The study demonstrated a significant four-fold mean increase in intratumoral CD8+ cell density in uninjected melanoma lesions among 32 matched biopsy pairs collected at baseline and after two doses of IMLYGIC. The response rate was consistent with other IMLYGIC monotherapy studies and the adverse events profile was consistent with the known safety profile of IMLYGIC.

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 YERVOY compared to YERVOY 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, disease control rate, PFS, OS and safety. The study randomized 198 patients, 98 in the IMLYGIC plus YERVOY arm and 100 in the YERVOY 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.1,2 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.3 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 (talimogene laherparepvec) 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.

On June 3, 2017 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of cancer metabolism and rare genetic diseases,reported updated data from the dose-escalation and expansion cohorts of the Phase 1 study evaluating single agent AG-120 (ivosidenib) in isocitrate dehydrogenase-1 (IDH1) mutant positive cholangiocarcinoma at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 2-6, 2017 in Chicago (Press release, Agios Pharmaceuticals, JUN 3, 2017, View Source [SID1234519357]).

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"The durable disease control signal seen with the Phase 1 data, combined with AG-120’s favorable safety profile, are encouraging for patients with advanced IDH1 mutant cholangiocarcinoma who have received multiple prior therapies," said Maeve Lowery, M.D., Memorial Sloan Kettering Cancer Center who presented the study results. "With no approved treatments and few effective options beyond the first line setting in this challenging disease, we look forward to continuing to characterize AG-120’s activity in the Phase 3 ClarIDHy study."

"Consistent with AG-120’s unique mechanism of action and in the context of this heavily pre-treated patient population, we believe durable stable disease is a meaningful measure of clinical benefit," said Chris Bowden, M.D., chief medical officer at Agios. "These data support further development of AG-120 in our ongoing Phase 3 registration-enabling ClarIDHy study, where we aim to confirm the early efficacy signal and evaluate the potential to impact tumor biology."

The ongoing Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, cholangiocarcinoma and chondrosarcomas with an IDH1 mutation. Enrollment is now complete for the dose-escalation and expansion cohorts. As of March 10, 2017, 73 patients with IDH1 mutant positive cholangiocarcinoma have been treated with single agent AG-120 in the dose escalation (n=24) and expansion cohorts (n=49). Thirteen patients remain on treatment. AG-120 was administered at the following dose levels and schedules in the dose-escalation cohort: 100 mg twice daily, and 300, 400, 500, 800 and 1200 mg once a day over a 28 day cycle length. In the dose expansion cohort, patients received 500 mg once a day, which was the selected dose for the ongoing Phase 3 ClarIDHy trial. Among the Phase 1 cholangiocarcinoma population, the median age is 60 (ranging from 32-81). Sixty-five patients had intrahepatic cholangiocarcinoma and eight had extrahepatic disease. The median number of prior systemic therapies was two (ranging from one to five) and 97% of patients received a prior gemcitabine-based chemotherapy regimen.

Safety Data


A safety analysis conducted for all 73 treated patients as of the data cut-off demonstrated that AG-120 was well-tolerated with a favorable safety profile in IDH1 mutant positive cholangiocarcinoma patients.

No dose limiting toxicities or treatment-related deaths have been observed.
The majority of adverse events (AEs) reported were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea and decreased appetite.
Four patients experienced drug-related AEs ≥ grade 3: two at the 500 mg dose level, fatigue (n=1) and blood alkaline phosphatase increases (n=1) and two at the 1200 mg dose level, fatigue (n=1) and blood phosphorous decreases (n=1).
One patient had a dose reduction for a grade 2 AE of worsening leg cramps that was considered to be possibly drug-related.
Efficacy Data

Efficacy data from all 73 treated patients as of the data cut-off showed:

Four patients (5%) experienced a confirmed partial response (one at 300 mg QD and three at 500 mg QD). A partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Forty-one patients (56%) experienced stable disease.
Landmark analyses of progression free survival at six (PFS6) and 12 months (PFS12) were 38.5% and 20.7% respectively. The median progression free survival (PFS) was 3.8 months (95% CI 3.6, 7.3).
AG-120 treatment inhibited plasma 2-hydroxyglutarate (2-HG) to within levels found in healthy volunteers, and also reduced 2-HG in tumor biopsies, with 2-HG levels in plasma and tumor biopsies showing a positive correlation.
Pathology review of on-study tumor biopsies were conducted in a patient achieving a partial response, which showed morphologic changes suggestive of cellular differentiation which is consistent with the proposed mechanism of action of AG-120.
ClarIDHy Phase 3 Trial

AG-120 (ivosidenib) is currently being evaluated in an ongoing, global, registration-enabling randomized Phase 3 trial known as ClarIDHy, enrolling 186 previously treated IDH1m positive cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting.

Patients will be randomized 2:1 to receive either single-agent AG-120 500 mg once daily or placebo with crossover to AG-120 permitted at the time of progression.
The primary endpoint of the trial is PFS with secondary endpoints including safety and tolerability, overall response rate, overall survival, duration of response, PK/PD and quality of life assessments.
Assuming a median PFS of 3 months for the control group, the study was designed with 96% power to detect a hazard ratio of 0.5 for PFS (AG-120 vs placebo), with a one-sided alpha of 0.025.
Thermo Fisher Scientific is providing next-generation sequencing to detect IDH1m for all tumor samples as inclusion criteria for enrollment in the study and will develop and commercialize the validated companion diagnostic.
About Cholangiocarcinoma

Cholangiocarcinoma (CC) is a rare cancer of the bile ducts within and outside of the liver. Cases that occur within the liver are known as intrahepatic cholangiocarcinoma (IHCC) and those that occur outside the liver are considered extrahepatic. Mutations in IDH1 occur in 13–15% of CC cases overall and in up to 25% of IHCC cases. Current treatment options for localized disease include surgery, radiation and/or other ablative treatments. There are no approved systemic therapies for cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed metastatic disease. Progression-free survival (PFS) in patients with advanced biliary cancer receiving second-line chemotherapy is 2–3 months.