Uncategorized – Page 15718 – 1stOncology™: Cancer Intelligence Service

ASCO 2016: Pivotal Avelumab Study Shows Positive Results in Metastatic Merkel Cell Carcinoma

On June 6, 2016 Merck KGaA, Darmstadt, Germany, and Pfizer (NYSE: PFE) reported results from the first pivotal, international, multicenter, open-label, Phase II study of avelumab*, which showed a 31.8% objective response rate (ORR) (28 of 88 patients; 95.9% CI: 21.9–43.1%†), in the pre-planned primary analysis of the study, and a manageable safety profile in patients with metastatic Merkel cell carcinoma (MCC) who were treated with avelumab in second or subsequent lines of therapy (Press release, Pfizer, JUN 6, 2016, View Source [SID:1234513076]). Tumor responses were rapid, with 78.6% of patients (22 of 28) responding within 7 weeks of starting treatment, and durable, with 82.1% of patients (23 of 28) still responding at the time of analysis. No unexpected safety signals were reported. These data will be reported today during an oral presentation at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

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"To see a tumor response in almost a third of patients in this trial, and for the majority to keep responding after six months, represents a potential breakthrough for this challenging disease," said lead investigator Howard L. Kaufman, M.D., FACS, Rutgers Cancer Institute of New Jersey, USA. "Currently, the only treatment option available for advanced stages of this aggressive type of skin cancer is chemotherapy, where the response rates are not adequate or durable."

Metastatic MCC has a poor prognosis with less than 20% of patients surviving longer than five years.1 Although chemotherapy is considered a second-line treatment option for metastatic MCC, it is not a standard of care. Current guidelines recommend that these patients participate in clinical trials.2

"This is an important milestone for us as this is the largest data set of any anti-PD-L1 or anti-PD-1 reported to date in this patient population," said Luciano Rossetti, Executive Vice President, Global Head of Research & Development in the biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "The clinically meaningful tumor response rate for avelumab in metastatic Merkel cell carcinoma where chemotherapy has failed, reinforces our belief in the promise of this molecule, particularly considering the high unmet need in this disease."

In the trial, eight patients (9.1%) achieved complete responses and 20 patients (22.7%) achieved partial responses. The median duration of response has not been reached (95% CI: 8.3 months – not estimable; range, 2.8–17.5+ months). Tumor responses were seen in patients regardless of the status of certain biomarkers (PD-L1 and Merkel cell polyomavirus). The progression-free survival (PFS) rate at 6 months was 40% (95% CI: 29–50%, estimated by the Kaplan-Meier method). Early data also showed an overall survival (OS) rate at 6 months of 69% (95% CI: 58–78%) and a median OS of 11.3 months (7.5–14.0 months); however, these OS data are still maturing since minimum follow-up was 6 months for inclusion in this analysis. Treatment-related adverse events (AEs) occurred in 62 patients (70.5%); the most common were fatigue (23.9%) and infusion-related reactions (17.0%), all of which were Grade 1 or 2. Grade 3 treatment-related AEs were reported in four patients (4.5%). There were no Grade 4 treatment-related AEs or deaths.

"This has been an exciting ASCO (Free ASCO Whitepaper) for the strategic collaboration between the two companies, between the MCC data and the other encouraging responses observed across a broad range of tumors," said Chris Boshoff, M.D., PhD., Vice President and Head of Early Development, Translational and Immuno-Oncology at Pfizer Oncology. "The clinical benefits for avelumab as a monotherapy in notably hard-to-treat cancers may be amplified even further when combined with other therapies."

Avelumab has received multiple regulatory designations in MCC from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), including Orphan Drug (FDA and EMA), Fast Track and Breakthrough status (FDA). There are plans to submit marketing applications for avelumab to regulatory authorities based on these data.

About JAVELIN Merkel 200

JAVELIN Merkel 200 is an international, multicenter, open-label, Phase II study of avelumab conducted in 88 patients with metastatic MCC. Patients in this study were generally elderly (median age was 72.5 years, range 33–88 years) and pre-treated, with at least one line of chemotherapy (one [59.1%], two [29.5%] or three or more [11.4%] previous treatments). Patients received avelumab 10 mg/kg intravenously once every two weeks. The protocol-defined analysis set for efficacy and safety consisted of all patients who received at least one dose of study treatment. The cut-off date for the planned primary analysis was 6 months after start of study treatment of the last patient. The primary endpoint of the study was confirmed best overall response according to RECIST v1.1 and assessed by an independent review committee. Secondary endpoints were duration of response, PFS, OS, response status by RECIST at 6 and 12 months, safety and tolerability, pharmacokinetics, and immunogenicity of avelumab.

*Avelumab is the proposed nonproprietary name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.

†Multiplicity adjustment accounting for interim analysis to achieve overall 95% confidence level.

References

Lemos B, Storer B, Iyer J, et al. Pathologic Nodal Evaluation Improves Prognostic Accuracy in Merkel Cell Carcinoma: Analysis of 5,823 Cases as the Basis of the First Consensus Staging System for this Cancer. Journal of the American Academy of Dermatology. 2010;63:751-761.
NCCN Merkel Cell Carcinoma Guidelines Version I. 2016. Available from: www.nccn.org/professionals/physician_gls/PDF/mcc.pdf (link is external). Accessed April 2016.
About Avelumab

Avelumab (also known as MSB0010718C) is an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US

Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US, enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an investigational anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance Pfizer’s PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab as a monotherapy, as well as in combination regimens, and is striving to find new ways to treat cancer.

About Merck KGaA, Darmstadt, Germany

All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group Website. In case you are a resident of the USA or Canada please go to www.emdgroup.com/subscribe (link is external) to register again for your online subscription of this service as our newly introduced geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

Merck KGaA, Darmstadt, Germany, is a leading science and technology company in healthcare, life science and performance materials. Around 50,000 employees work to further develop technologies that improve and enhance life – from biopharmaceutical therapies to treat cancer or multiple sclerosis, cutting-edge systems for scientific research and production, to liquid crystals for smartphones and LCD televisions. In 2015, Merck KGaA, Darmstadt, Germany, generated sales of € 12.85 billion in 66 countries.

Founded in 1668, Merck KGaA, Darmstadt, Germany, is the world’s oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck KGaA, Darmstadt, Germany operates as EMD Serono, MilliporeSigma and EMD Performance Materials in the United States and Canada.

Kolltan Pharmaceuticals Presents Clinical Data for KTN3379 in an Oral Presentation at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting

On June 6, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of clinical data related to KTN3379, the Company’s most advanced product candidate for the potential treatment of various solid tumors (Press release, Kolltan Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513100]). These data were discussed in an oral presentation titled, "Safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity in a phase 1b study evaluating anti-ErbB3 antibody KTN3379 in adults with advanced tumors alone and with targeted therapies," at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting, which is taking place in Chicago, IL, June 3-7, 2016. KTN3379 is a novel antibody that blocks the activity of the ErbB3 (HER3) receptor by binding to a unique epitope and effectively locking the ErbB3 receptor in an inactive conformation. In addition, KTN3379 has been engineered to extend serum half-life. These features are believed to contribute to the favorable potency and pharmacology of KTN3379.

"The data presented today are very encouraging and demonstrate that anti-tumor activity was observed in certain extensively pretreated patients when KTN3379 was administered in combination with other targeted therapeutics. The evidence from the Phase 1b clinical trial and several preclinical studies supports the initiation of a Phase 2 clinical trial in HNSCC, and we believe KTN3379 has the potential to provide clinical benefit across multiple tumor types where ErbB3 plays a role in tumor progression and therapeutic resistance. There exists an unmet medical need in cancer patients that have exhausted many or all treatment options, and we plan to advance the clinical development of KTN3379 to address this need," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

Study KTN3379-CL-001 (NCT02014909) has two parts. In Part 1, which was the subject of an oral presentation by Dr. Patricia LoRusso at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, KTN3379 was administered to patients with advanced solid tumors as a single agent. In this part of the study, a maximum tolerated dose was not reached and KTN3379 demonstrated favorable tolerability and pharmacology profiles. In Part 2 of the study, the focus of today’s oral presentation, KTN3379 was evaluated in combination with four different targeted therapies. KTN3379 was administered at 15 and 20 mg/kg every three weeks in combination with cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4), or trastuzumab (N=10). Safety monitoring and RECIST-based tumor assessments were conducted. Pharmacokinetic parameters and immunogenicity were evaluated. In addition, archival tumor tissue was tested for mRNA expression of neuregulin (NRG) in baseline tumor samples. Sixty percent of the patients had received at least four prior treatment regimens. Enrollment in the vemurafenib patient cohort is currently being expanded.

Joseph Paul Eder, M.D., Professor of Medicine (Medical Oncology) at the Yale Cancer Center, commented, "The ErbB family of receptors has been among the most successful targets in the treatment of cancer, resulting in therapies that are standard of care across a number of tumor types. The scientific rationale supporting the development of this anti-ErbB3 antibody, including its differentiated features and potency, together with durable responses observed in patients with resistant tumors, warrants the further development of KTN3379 in combination with targeted therapies."

Ronald Peck, M.D., Chief Medical Officer and Senior Vice President, Clinical Development at Kolltan added, "The responses reported in this trial were impressive, in particular the durable complete response in a HNSCC patient receiving the combination of KTN3379 and cetuximab after disease progression on single agent cetuximab and the durable partial response in a non-small cell lung cancer (NSCLC) patient receiving KTN3379 plus vemurafenib after progressing on another BRAF inhibitor and other prior therapy. These results, as well as extensive preclinical data, support the planned Phase 2 clinical trial of KTN3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma and the ongoing expansion of the Phase 1b BRAF-mutant tumor cohort receiving KTN3379 in combination with vemurafenib."

The results were presented by Gerald Falchook, M.D., Director of Drug Development at Sarah Cannon Research Institute at HealthONE in Denver, Colorado. Following is a summary of the key results:

38 total patients were treated in four cohorts with KTN3379 in combination with the following targeted therapies: cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4), or trastuzumab (N=10);

The patient population enrolled in Part 2 of Study KTN3379-CL-001 was generally heavily pretreated, with approximately 97% of patients having received at least one prior treatment regimen and 60% of patients having received at least four prior treatment regimens;

The safety profile of the combination therapies was consistent with the safety profiles of the individual agents. The most common treatment related adverse events included diarrhea and rash, which were resolved with medical therapy or dose reduction;

Pharmacokinetic data demonstrated that all patients achieved serum concentrations of KTN3379 required for maximal anti-tumor activity in animal tumor models; and

Showed a consistent trend towards slower clearance and longer terminal half-life of KTN3379 compared to published data for other anti-ErbB3 antibodies

Anti-tumor activity was achieved in several patients with resistant tumors treated with KTN3379 in combination with cetuximab or vemurafenib

Cetuximab combination arm:

Anti-tumor activity was observed in certain of the nine patients with HNSCC treated with KTN3379 in combination with cetuximab including a patient with a durable complete response (CR) who had undergone extensive prior therapy including chemotherapy, radiation, and multiple surgeries; and

The patient with a CR had previously progressed five months after initiating single agent cetuximab. The patient’s CR with KTN3379 in combination with cetuximab persisted for 10.5 months after starting study therapy. The patient’s tumor was found to express the ErbB3 ligand, neuregulin.

Vemurafenib combination arm:
In four patients with BRAF-mutant cancers that were treated with KTN3379 in combination with vemurafenib, stable disease was reported in one patient with colorectal cancer and durable partial responses (PRs) were reported in two patients with NSCLC; and
Notably, one of the two NSCLC PRs was in a patient who underwent extensive prior therapy, which included combination chemotherapy, another BRAF-inhibitor (dabrafenib), and combination immunotherapy (an investigational regimen of an anti-CTLA4 and an anti-PDL-1). Previously, the patient had disease progression within two months of initiating dabrafenib. The patient’s PR persisted for 12 months after starting study therapy. The patient’s tumor was found to express neuregulin.

About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), a receptor tyrosine kinase (RTK) that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers, including head and neck, breast, lung, and gastric cancers, and melanoma. Kolltan is conducting multiple clinical trials evaluating KTN3379 in the treatment of solid tumors (NCT02014909, NCT02456701, and NCT02473731).

OncoCyte Presents Positive Bladder Cancer Diagnostic Data at the 2016 American Society of Clinical Oncology Annual Meeting

On June 06, 2016 OncoCyte Corporation (NYSE MKT:OCX), a developer of novel, non-invasive tests for the early detection of cancer, reported that it will be presenting data today from a bladder cancer study featured as a poster and also highlighted during a live panel discussion during the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois (Press release, BioTime, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175182 [SID:1234513033]).

The poster abstract, entitled Derivation of Gene Expression Classifiers for the Non-invasive Detection of Bladder Cancer in the Hematuria and Recurrence Surveillance Populations, describes OncoCyte’s recent results in the development of a urine-based test for bladder cancer. Dr. Matthew T. Olson, Department of Pathology at Johns Hopkins University School of Medicine, Baltimore, MD, will serve as the presenting author in the live panel discussion. He will be joined by Karen B. Chapman, Ph.D., OncoCyte’s Vice President of Research.

"We are very encouraged by the accuracy of our non-invasive test for the detection of high-grade and low-grade lesions in both the screening (hematuria) and recurrence cohorts. Of particular note, the test was 100 percent accurate in detecting high-grade lesions within the 241 patient group studied." said OncoCyte President & Chief Executive Officer William Annett. "There was also high accuracy in the detection of low-grade lesions, with 77 percent for screening and 75 percent for recurrence. The results warrant a larger study to validate these findings."

The detection of bladder cancer is typically accomplished with a combination of cystoscopy and urine cytology, each with inherent limitations. Urine cytology lacks the desired level of sensitivity, whereas cystoscopy is relatively invasive for routine screening and recurrence surveillance.

OncoCyte’s study developed four gene expression classifiers (GECs) optimized for the non-invasive detection of both high-grade and low-grade urothelial carcinoma in patients presenting with hematuria or for bladder cancer recurrence surveillance. This study included 241 patient urine samples taken at multiple centers. Individual patient results for high-grade and low-grade screening or high-grade and low-grade recurrence can be obtained from a patient’s single urine sample which utilizes two sequential algorithms.

OncoCyte’s approach of sequential GECs optimized for the detection of high-grade and low-grade malignancies provides information to distinguish between these different types of lesions and benign conditions in a non-invasive manner. Low-grade urothelial carcinoma is usually a non-aggressive cancer, whereas high-grade urothelial carcinoma is more aggressive, invasive and causes significantly more cancer-related mortality. The GEC optimized for the detection of high-grade urothelial carcinoma in patients presenting with hematuria performed with a cross-validated Receiver Operating Characteristic Area Under the Curve (ROC AUC) of 0.93, while the low-grade performed with an ROC AUC of 0.81. In the recurrence surveillance cohort, the detection of high-grade performed with an ROC AUC of 0.81 and low-grade with an ROC AUC of 0.64.

ROC AUCs

Low Grade High Grade
Screening (Hematuria) 0.81 0.93

Recurrence 0.64 0.81

"Currently, there is an unmet need for a non-invasive test for bladder cancer for patients requiring recurrence surveillance and for patients presenting with hematuria," added Karen B. Chapman, Ph.D., OncoCyte’s Vice President of Research, who led the study. "These results establish the feasibility of using a non-invasive, urine-based test to detect bladder cancer and also to distinguish between high-grade and low-grade cancers. A multicenter clinical trial will allow us to validate test performance on a larger independent test set of prospectively collected urine samples."

About Bladder Cancer

Bladder cancer has been projected to have the highest lifetime treatment costs per patient of all cancers. The high recurrence rate and ongoing invasive monitoring requirements drive the financial burden of this disease. The detection of bladder cancer in hematuria and recurrence patients is routinely accomplished with a combination of urine cytology and cystoscopy which is invasive, and lacks the desired level of sensitivity. Approximately 3 million patients present with hematuria every year in the U.S., of whom about 77,000 are diagnosed with bladder cancer. In addition there are about 587,000 patients in the U.S. living with bladder cancer, and they are candidates for recurrence testing.

Sunesis Announces Study Examining the Value of Complete Remission Prior to HCT in Patients with AML Presented at 2016 ASCO Annual Meeting

On June 06, 2016 Sunesis Pharmaceuticals, Inc. (NASDAQ:SNSS) reported the presentation of results from a study conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) at the Medical College of Wisconsin evaluating the value of achieving complete remission prior to allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML) (Press release, Sunesis, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175348 [SID:1234513056]). The study was funded jointly by Sunesis and CIBMTR. The results are being presented today, Monday, June 6th from 8:00 a.m. to 11:30 a.m. Central Time at the Hematologic Malignancies – Leukemia, Myelodyplastic Syndromes, and Allotransplant General Poster Session of the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, Illinois.

The poster presentation (Poster #25, Abstract 7033, Hall A), titled "Allogeneic transplantation for advanced acute myelogenous leukemia: The value of complete remission," will be available on the Sunesis website at www.sunesis.com, following the ASCO (Free ASCO Whitepaper) presentation.

For the study, researchers evaluated records from 4,382 patients with AML who had proceeded to allogeneic transplantation to understand comparative survival between those in complete remission following additional salvage therapy and those receiving prompt HCT without achieving complete remission or in first relapse following primary induction. Of the 4,382 patients, 1,440 had transplantation in primary induction failure (PIF), 1,256 were first relapse (Rel1), and 1,986 had achieved a second complete remission (CR2). Baseline characteristics were similar in the three disease status groups.

The results showed that more patients who had achieved CR2 had de novo AML, a longer duration of a first complete remission (CR1), and were more likely to report performance scores of 90 or 100. Adverse cytogenetics were more common in PIF patients and duration of CR1 was shorter in patients with Rel1 than in those with CR2. Mortality was higher for HCT in Rel1 compared to CR2 regardless of CR1 duration (RR 1.65, p < 0.0001). Similarly, mortality was higher for HCT in PIF compared to CR2 with CR1 duration < 6 (RR 1.26, p < 0.0001), 6-12 (RR 1.60, p < 0.0001) and > 12 months (RR 2.24, p < 0.0001). The probabilities of overall survival by disease status at 6 months are: CR2 73 (71-75)%; Rel1 53 (50-55)%; PIF 58 (56-61)%; and at 2 years, CR2 50 (48-52)%; REL1 27 (24-29)%; PIF 29 (27-32)%.

The data suggest that patients in remission fare better following HCT than those who receive transplant without having achieved CR, and that the ability to achieve remission is a powerful prognostic marker.

"These data point to the importance of achieving remission as an indicator of prognosis after HCT for patients with relapsed/refractory AML, and underscore the need for an effective salvage therapy," said Parvinder S. Hyare, Vice President, Global Oncology Operations and an author of the study. "We thank CIBMTR and their collaborators for this important research, and continue to work toward delivering new treatment options to high unmet need patients with AML around the world."

Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer

On June 6, 2016 Merck KGaA, Darmstadt, Germany, and Pfizer (NYSE: PFE) reported results from the first pivotal, international, multicenter, open-label, Phase II study of avelumab*, which showed a 31.8% objective response rate (ORR) (28 of 88 patients; 95.9% CI: 21.9–43.1%†), in the pre-planned primary analysis of the study, and a manageable safety profile in patients with metastatic Merkel cell carcinoma (MCC) who were treated with avelumab in second or subsequent lines of therapy (Press release, Pfizer, JUN 6, 2016, View Source [SID:1234513077]). Tumor responses were rapid, with 78.6% of patients (22 of 28) responding within 7 weeks of starting treatment, and durable, with 82.1% of patients (23 of 28) still responding at the time of analysis. No unexpected safety signals were reported. These data will be reported today during an oral presentation at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.