On December 10, 2014 Merck reported early study findings demonstrating an overall response rate of 18.5 percent with KEYTRUDA, the company’s anti-PD-1 therapy, as assessed by RECIST v1.1, central review (n=5/27), in PD-L1 positive, advanced triple-negative breast cancer – one of the most aggressive forms of breast cancer (Press release Merck & Co, DEC 10, 2014, View Source;0 [SID:1234501156]). At the time of analysis, the median duration of response had not been reached with three of five responders on therapy for 11 months or more (range, 15 to 40+ weeks). These early findings, from the ongoing Phase 1b KEYNOTE-012 study, were shared today for the first time as part of the official press program at the 2014 San Antonio Breast Cancer Symposium (SABCS) (ABSTRACT #S1-09) and will be presented in an oral session at 10:45 a.m. CST by Dr. Rita Nanda, the University of Chicago.

“Metastatic, triple-negative breast cancer is an aggressive and often difficult to treat disease,” said Dr. Rita Nanda, associate director, breast medical oncology, the University of Chicago and principal investigator for the KEYTRUDA triple-negative breast cancer Phase 1b study cohort. “The results presented at this year’s SABCS, while early, show encouraging anti-tumor activity in these patients, most of whom had received multiple prior chemotherapies.”

“This year, Merck has significantly advanced our immuno-oncology development program and new data for KEYTRUDA have been presented in seven different cancers, including these first findings in triple-negative breast cancer,” said Dr. Alise Reicin, vice president, global clinical development, oncology, Merck Research Laboratories. “These early data with KEYTRUDA show responses in patients with one of the most aggressive forms of breast cancer and further our understanding of the PD-1 pathway’s role in this disease. Our Phase 2 study planned for the first half of 2015 will be an important next step for our breast cancer clinical program.”

Early Findings Evaluating KEYTRUDA in Advanced Triple-Negative Breast Cancer

Data presented were from a cohort of the ongoing Phase 1b KEYNOTE-012 study which evaluated KEYTRUDA monotherapy at 10 mg/kg every two weeks in patients with advanced TNBC whose tumors were determined to be positive for PD-L1 expression (n=32). As measured by Merck’s proprietary PD-L1 immunohistochemistry (IHC) clinical trial assay, tumors were considered to be PD-L1 positive if staining was present in the stroma or in greater than or equal to one percent of tumor cells. In the study, 58 percent of patients screened had tumors determined to be positive for PD-L1 expression. Most patients enrolled in this study had received two or more prior chemotherapies for metastatic disease and 87.5 percent had received prior neo-adjuvant or adjuvant therapy.

Antitumor Activity with KEYTRUDA by Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1, Central Review*
Patients Evaluable for Response
(n=27)(a)
Overall Response Rate (ORR), n (%) 5 (18.5%)
Best Overall Response, n (%)
Complete Responseb 1 (3.7%)
Partial Responseb 4 (14.8%)
Stable Disease 7 (25.9%)
Progressive Disease 12 (44.4%)
No Assessmentc 3 (11.1%)

*Analysis cut-off as of: November 10, 2014.

a Includes patients with measurable disease at baseline who received ≥1 pembrolizumab dose and who had ≥1 post-baseline scan or discontinued therapy before the first scan due to progressive disease or a treatment-related AE. Five patients were excluded because they did not have any assessments per central review (n=2) or because they did not have measurable disease per central review at baseline (n=3).

b Confirmed responses only.

c “No assessment” signifies patients who discontinued therapy before the first post-baseline scan due to progressive disease or a treatment-related AE.

The median time to response was 18 weeks (range, 7-32 weeks). In the study, 33 percent of patients with KEYTRUDA achieved tumor shrinkage. At six months, the progression-free survival rate with KEYTRUDA was 23.3 percent.

Adverse events were consistent with previously reported safety data for KEYTRUDA. The most common treatment-related adverse events (occurring in greater than or equal to five percent of patients) included arthralgia (n=6), fatigue (n=6), myalgia (n=5), nausea (n=5), ALT increased (n=2), AST increased (n=2), diarrhea (n=2), erythema (n=2) and headache (n=2). Grade 3-5 treatment-related adverse events occurred in a total of five patients and included anemia, disseminated intravascular coagulation (DIC), headache, meningitis aseptic, decreased blood fibrinogen, and pyrexia. Two patients discontinued KEYTRUDA due to adverse events. One treatment-related death was reported in a patient with rapidly progressive disease and was due to DIC with thrombocytopenia and decreased blood fibrinogen.

On December 7, 2014 Agios Pharmaceuticals reported new data from the ongoing Phase 1 dose escalation study of AG-221 as a single agent in patients with IDH2-mutant positive advanced hematologic malignancies (Press release Agios Pharmaceuticals, DEC 7, 2014, View Source [SID:1234501095]). With additional patient enrollment and longer follow-up, the data continue to show a favorable safety profile as well as durable clinical activity for AG-221, with an overall response rate of 56 percent (25 of 45 evaluable patients) in advanced hematologic malignancies. Eytan Stein, M.D., lead investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center, will present the data in an oral presentation today at the 56th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held in San Francisco. AG-221 is a first-in-class, oral, selective, potent inhibitor of the mutant IDH2 (isocitrate dehydrogenase-2) enzyme being developed in collaboration with Celgene.

“The durable responses observed for AG-221 with minimal toxicity being reported are impressive in this advanced disease setting,” said Dr. Stein. “These findings build upon those presented throughout the year. In addition, they continue to provide evidence that AG-221 can inhibit the IDH2 mutant protein, stop production of the oncometabolite, 2-HG, and allow for cancer cells to become mature, functioning blood cells. This approach is different from traditional chemotherapy that attempts to non-selectively kill cancer cells. I believe AG-221’s unique mechanism targeting a specific mutation is the way of the future and represents a highly specific oral therapy that may transform the treatment of a devastating group of blood cancers.”

As of the data cut-off on October 1, 2014, the ongoing Phase 1 study of AG-221 had enrolled 73 patients, with a documented IDH2 mutation, in a broad range of advanced hematologic malignancies. Patients enrolled included those with relapsed or refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and untreated AML who decline intensive chemotherapy. At the time of the data cut-off, 45 patients were evaluable for an analysis of clinical activity. Twelve patients had initiated therapy too recently and were therefore not evaluable and 16 patients had discontinued without an evaluable day 28 assessment. The data showed that 25 out of 45 evaluable patients achieved investigator-assessed objective responses, including six complete remissions, nine complete remissions with various degrees of hematologic recovery and ten partial remissions. An estimated 90 percent of patients who responded had responses lasting for at least three months, with durations on AG-221 for as long as eight months and ongoing. For patients who achieved a complete remission, their cancer did not progress while on therapy. AG-221 was well tolerated and the overall safety profile observed was consistent with previously reported data. A maximum tolerated dose (MTD) had not been reached. These data form the basis for the planned initiation of a global registration program in 2015.

“We are making tremendous progress for patients with our AG-221 program, as the data from the Phase 1 study have consistently shown durable activity with a favorable safety profile in patients with several types of advanced hematologic malignancies, especially AML,” said Chris Bowden, M.D., chief medical officer of Agios. “While the data we are presenting today and those recently reported for AG-120, our IDH1-mutant inhibitor, are still early, we believe they validate our approach of targeting dysregulated metabolic enzymes. Along with our partner Celgene, we expect to begin a global registration program for AG-221 in 2015 in IDH2-mutant positive hematologic malignancies followed by a global registration program for AG-120 in IDH1-mutant positive hematologic malignancies by early 2016. We feel strongly that these investigational medicines with their unique mechanisms of action have the potential to profoundly impact treatment for individuals with IDH-mutant cancers, and we are pleased to share the results of the additional data for AG-221 with the medical community.”

About the Ongoing Phase 1 Trial for AG-221

The primary goals of the Phase 1 trial are to establish the safety profile, determine the maximum tolerated dose and assess the preliminary clinical activity of AG-221 as a single agent administered orally in 28-day cycles. The study is only enrolling patients who have an IDH2-mutant hematologic malignancy. Secondary objectives include characterization of the pharmacokinetics (PK) and pharmacodynamics (PD), including inhibition of 2-hydroxyglutarate (or 2HG). The trial uses an open-label, dose-escalating design. Data reported are from patients receiving AG-221 in 10 dose escalation cohorts administered from 60 mg to 300 mg total daily doses as of October 1, 2014. Dose escalation continues, as the maximum tolerated dose has not been reached. The median age of these patients is 67 (range 33-90).

Safety Data

A safety analysis was conducted for all 73 treated patients as of October 1, 2014.
The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, pyrexia, diarrhea and fatigue.
The majority of serious adverse events (SAE) were disease related; SAE’s possibly related to study drug were reported in 13 patients.
11 deaths were reported with nine unrelated to AG-221.
Two deaths were reported as possibly related to study drug: one in a patient with sepsis and hypoxia and one with atrial flutter.

Efficacy Data

25 out of 45 efficacy evaluable patients achieved investigator accessed objective responses for an overall response rate of 56 percent as of the October 1, 2014 data cut-off date.

Of the 25 patients who achieved an objective response, there were six complete remissions, four complete remissions with incomplete platelet recovery (CRp), four marrow complete remissions (mCR), one complete remission with incomplete hematologic recovery (CRi) and 10 partial remissions (PR).
Responses were durable, with duration on study drug as long as eight months and ongoing. An estimated 90 percent of responses are three months or longer, with four responders on AG-221 beyond six months of treatment.
Ten patients with stable disease remain on AG-221, with several patients on study as long as six months and ongoing
There have been no relapses in patients with a complete remission.
Five patients were removed from the study per the protocol following decision to undergo a potentially curative bone marrow transplant.
Treatment with AG-221 showed substantial reduction in the plasma levels of 2-HG to the level observed in healthy volunteers.

“Throughout 2014, we made significant progress across our company, in particular the achievement of proof-of-concept for two distinct IDH inhibitors, AG-221 and AG-120,” said David Schenkein, M.D., chief executive officer of Agios. “Over the coming year, we expect to expand the development programs into registration studies and in combination trials to explore the potential of broader use in patients who carry an IDH mutation. We also expect to present new data from multiple studies across our two lead IDH programs to help further define the potential of these investigational medicines to make a major impact on the treatment of cancer.”

Upcoming Milestones: Cancer Metabolism Program in Collaboration with Celgene

AG-221 (IDH2 mutant inhibitor): Multiple studies of AG-221 planned for 2015 support speed and breadth in development for patients with an IDH2 mutation

Phase 1 expansion cohorts: In 2015, Agios expects to present data from the expansion cohorts in the ongoing Phase 1 study from 100 patients with IDH2-mutant hematologic malignancies, including AML.
Global registration program: The company expects that a global registration program in hematologic malignances will start in 2015.
Frontline therapy approach: In 2015, Agios plans to initiate combination trials in patients with AML to evaluate the potential of AG-221 as a first line therapy for patients with hematologic malignancies.
Phase 1 solid tumor study: The company expects the Phase 1 trial in patients with advanced solid tumors whose cancers carry an IDH2 mutation to remain on track.

On December 5, 2014 Juno Therapeutics reported that it has entered into an agreement to obtain a license from Opus Bio, Inc. for a CAR-T cell product candidate targeting CD22, a protein expressed on most B cell leukemias and lymphomas (Press release Juno, DEC 5, 2014, View Source [SID:1234501086]). The CD22-targeted CAR T cell product candidate was developed by the National Cancer Institute (NCI) under cooperative research and development agreement (CRADA) with Opus Bio. The NCI has begun enrollment in a Phase I trial evaluating pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or non-Hodgkin’s lymphoma (NHL).

“This fully-human CD22 directed product candidate complements our existing CD19 directed portfolio, representing another important opportunity to investigate an immunotherapy addressing B cell malignancies,” said Juno CEO, Hans Bishop.

The NCI-sponsored trial is designed to enroll patients with CD22 positive cancers, with both CD19 positive and CD19 negative patients eligible for treatment.

CAR T cell therapy has the potential to address an important unmet need, according to Crystal Mackall, M.D., Chief, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health. There is still much to learn about these immunotherapies, but the early results are hopeful.

Financial terms were not disclosed. The license will not become effective until certain closing conditions are satisfied, including obtaining consent from the NCI.

About Juno’s Chimeric Antigen Receptor and High-affinity T Cell Receptor Platform
Juno is developing cell-based immunotherapies based on its chimeric antigen receptor, or CAR, and high-affinity T cell receptor, or TCR, platform to genetically engineer T cells to recognize and kill cancer cells. T cells are a type of white blood cell that identify and kill infected or abnormal cells, including cancer cells, in healthy individuals. Juno leverages its CAR and TCR platform to activate a patient’s own T cells so that they attack cancer cells. Through genetic engineering, a gene is inserted for a particular CAR or TCR construct into the T cell enabling it to better recognize cancer cells. The CAR technology directs T cells to recognize cancer cells based on the expression of specific proteins located on the cell surface, whereas the TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. CAR construct typically uses a single chain variable fragment, or scFv, to recognize a protein of interest. The modified T cells can be infused into the patient or frozen and stored for later infusion.