On January 5, 2016 Cellectar Biosciences, Inc. (NASDAQ:CLRB), an oncology-focused biotechnology company reported data from the first cohort of patients enrolled in its orphan drug-designated Phase 1 study of CLR 131 in patients with relapsed or refractory multiple myeloma (Filing, 8-K, Cellectar Biosciences, JAN 5, 2016, View Source [SID:1234508665]). Schedule your 30 min Free 1stOncology Demo! Based on safety and efficacy data from the first cohort, the trial’s Data Monitoring Committee approved enrollment of the second cohort of patients with a 50 percent escalation in dose level of CLR 131.
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The primary objective of the multi-center, open label, Phase 1 dose escalation study is to characterize the safety and tolerability of CLR 131 in patients with relapsed or refractory multiple myeloma. Secondary objectives include establishment of the recommended Phase 2 dose, both with and without dexamethasone, as well as an assessment of therapeutic activity.
Prior to their participation in this study, patients in the first cohort had received a minimum of three systemic regimens and up to 12 lines of therapy.
"Judging by the results of the first cohort, I believe there is significant potential for CLR 131 as a safe and tolerable treatment modality for relapsed or refractory multiple myeloma," stated Sikander Ailawadhi, MD, senior associate consultant, Division of Hematology/Oncology, Department of Medicine, The Mayo Clinic, Jacksonville, Florida, and the site’s lead investigator. "I believe initiating the second cohort of the trial will provide additional useful information, both in terms of establishing an appropriate treatment dose, as well as further understanding the compound’s potential in this indication."
Data from the first cohort of patients in the Phase 1 study demonstrated safety and tolerability with a favorable adverse event profile. Additionally, stable disease was achieved in four of five treated patients with two of these patients maintaining stable disease throughout the 85-day study monitoring period.
"Importantly, these data collectively demonstrate safety and tolerability in heavily pre-treated multiple myeloma patients as well as provide promising signals of activity," said Jim Caruso, president and CEO of Cellectar Biosciences. "These early outcomes and feedback from the investigators are encouraging and we look forward to further evaluating CLR 131 in the second cohort to determine optimal dose and regimen. More globally, these results provide us with further confirmation on the utility of our PDC delivery platform, which we believe is instrumental to these outcomes."
The company is developing CLR 131, its lead radiotherapeutic phospholipid drug conjugate (PDC), for the treatment of multiple myeloma through the targeted delivery of iodine-131 to myelomatous cells.
Year: 2016
OncoMed Achieves $72.5 Million in Milestone Payments From Celgene; Announces Year-End Cash Balance
On January 05, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED) reported the achievement of two milestones from Celgene Corporation and pre-announced its 2015 year-end pro-forma cash balance and key anticipated events for 2016 (Press release, OncoMed, JAN 5, 2016, View Source [SID:1234508664]). Schedule your 30 min Free 1stOncology Demo! OncoMed achieved the $70 million safety milestone from Celgene based on an analysis of available Phase 1b and blinded interim Phase 2 clinical trial safety data associated with the demcizumab (anti-DLL4, OMP-21M18) program. The data from the pancreatic, non-small cell lung and ovarian cancer clinical trials showed no demcizumab-related Grade 3 or higher cardio-pulmonary toxicities among 155 patients treated with truncated dosing. Of those, 68 patients have received at least two cycles of demcizumab at the Phase 2 dose or higher and have been followed for at least 100 days. OncoMed also achieved a $2.5 million milestone for clinical candidate designation of an undisclosed preclinical immuno-oncology program, "IO#2". This is OncoMed’s second immuno-oncology program to reach clinical candidate designation, and both programs are advancing in IND-enabling studies.
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Including the Celgene milestones, OncoMed ended 2015 with approximately $227.2 million in pro-forma cash, representing approximately 1.5 years of cash, without taking into account future potential milestone payments from partners, and exceeding its 2015 guidance predicting a year-end cash balance of greater than $120 million. Full-year operating expenses for 2015 are anticipated to be approximately $110 million, in accordance with previous guidance. OncoMed plans to provide full-year 2016 guidance during its 2015 fourth quarter earnings call in the first quarter of 2016.
"The achievement of the demcizumab $70 million safety milestone is based on extensive Phase 1b and blinded Phase 2 data, and positions OncoMed to rapidly enroll its Phase 2 randomized YOSEMITE and DENALI clinical trials, as well as the Phase 1b demcizumab plus pembrolizumab (anti-PD1) trial, and also to explore the potential of demcizumab in ovarian cancer," said Paul J. Hastings, OncoMed’s Chairman and Chief Executive Officer. "We enter 2016 in a strong cash position to support all seven internally discovered programs through clinical trials, including four randomized Phase 2 clinical studies, and to advance two immuno-oncology candidates toward IND filings while maintaining ongoing discovery efforts. Over the course of this year, we anticipate completing and reporting on our first randomized Phase 2 clinical trial, the tarextumab ALPINE study in pancreatic cancer, presenting additional data from our ongoing clinical- and discovery-stage programs, filing at least one new IND and achieving additional milestones related to our collaborations."
2016: Anticipated Key Financial Milestones and Pipeline Progress by Program
Demcizumab (anti-DLL4, OMP-21M18)
Present updated Phase 1b survival data for demcizumab in combination with Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in previously untreated pancreatic cancer at the Gastrointestinal Cancer Symposium (ASCO GI) being held January 21-23, 2016 in San Francisco, CA. OncoMed’s presentation, titled "A Phase 1b study of the anti-cancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) +/- nab-paclitaxel in patients with pancreatic cancer (Abstract 341)," will be presented by Dr. Manuel Hidalgo during Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract on Friday, January 22, 2016.
Initiate Phase 1b clinical trial of demcizumab plus anti-PD1 pembrolizumab in the first quarter of 2016.
Update survival data from the demcizumab Phase 1b non-small cell lung cancer (NSCLC) clinical trial.
At the ASCO (Free ASCO Whitepaper) meeting in June 2015, OncoMed reported Phase 1b clinical trial data in NSCLC for 23 advanced-stage patients who received continuous dosing of demcizumab plus standard-of-care chemotherapy. These data showed that 43 percent (10 of 23) of patients were alive past two years, demonstrating prolonged survival in this subset of patients. A recent update of continuous dosing data revealed one additional death with 39 percent (9 of 23) of patients alive past 2 years.
In August, 2015, OncoMed updated survival data for 23 patients who received truncated doses of demcizumab plus chemotherapy and were showing a similar trend toward improved survival. At that time, fifty-two percent (12 of 23) of patients who received truncated doses of demcizumab plus carboplatin and pemetrexed remained alive from 8-30 months after initial dosing. A recent update of these data has revealed four additional deaths. Currently, 35 percent (8 of 23) of patients remain alive between 12 and 34 months after the initiation of treatment and median overall survival is 11.6 months. Although these data represent a Phase 1b clinical trial in small numbers of patients, they suggest that a subset of patients treated with the demcizumab truncated dosing regimen in NSCLC continues to derive long-term benefit. These data continue to support and enable the current randomized Phase 2 "DENALI" trial.
Complete enrollment in the randomized Phase 2 "YOSEMITE" clinical trial of demcizumab in combination with Abraxane and gemcitabine in patients with first-line pancreatic cancer by year end. Data from this study are expected to be available by early 2017.
Continue enrollment in the Phase 2 "DENALI" clinical trial of demcizumab plus carboplatin and pemetrexed in first-line non-squamous NSCLC.
Report results from the ovarian cancer Phase 1b trial of demcizumab plus paclitaxel.
The next potential financial milestone for demcizumab is an opt-in payment from Celgene that may occur through the end of either of the Phase 2 pancreatic cancer or NSCLC trials. Following option exercise, OncoMed and Celgene will co-develop and co-commercialize demcizumab in the U.S., sharing profits 50/50, while Celgene would lead development and commercialization outside the U.S.
Tarextumab (anti-Notch 2/3, OMP-59R5)
Present updated survival data from the Phase 1b clinical trial of tarextumab plus chemotherapy in small cell lung cancer at the time of the IASLC 16th Annual Targeted Therapies of Lung Cancer Meeting being held February 17-21, 2016.
Report top-line results from the Phase 2 "ALPINE" clinical trial of tarextumab in combination with Abraxane plus gemcitabine in advanced pancreatic cancer during the second half of 2016.
GlaxoSmithKline (GSK) may exercise the option for tarextumab through the end of either of the randomized Phase 2 clinical trials in pancreatic or small cell lung cancers. If GSK elects to exercise its option, OncoMed is eligible to receive a $25 million payment, and GSK would lead and fully fund further development and commercialization.
Wnt programs — Vantictumab (anti-Fzd7, OMP-18R5) and Ipafricept (Fzd8-Fc, OMP-54F28)
Advance vantictumab and ipafricept through multiple ongoing Phase 1b clinical studies.
Bayer can elect to exercise its options on vantictumab and ipafricept at any point through completion of Phase 1b trials. OncoMed and Bayer amended their agreement November 2015 to enroll up to 24 additional subjects in the ongoing Phase 1b clinical trials of vantictumab in breast cancer and ipafricept in ovarian cancer. Bayer has agreed to reimburse OncoMed for all out-of-pocket expenses to support this additional patient enrollment. OncoMed anticipates presenting opt-in packages to Bayer for both vantictumab and ipafricept in late 2016/early 2017.
Brontictuzumab (anti-Notch1, OMP-52M51)
Initiate Phase 1b clinical trial of brontictuzumab combined with FOLFIRI in colorectal cancer patients including an expansion cohort of biomarker-selected subjects based on promising data presented in November 2015 at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).
GSK may currently elect to opt in brontictuzumab at the end of Phase 1a, for a fee of $18.75 million or at the conclusion of Phase 2 for a fee of $25 million. GSK and OncoMed have agreed to share out-of-pocket costs on the Phase 1b clinical trial described above, and are currently discussing a potential extension of GSK’s Phase 1a option through the end of Phase 1b.
Anti-DLL4/VEGF bispecific (OMP-305B83)
Aim to present data from the Phase 1a dose-escalation clinical trial of anti-DLL4/VEGF bispecific. Presentation of data will be contingent on the number of dose cohorts needed to identify a Phase 2 single-agent dose and abstract acceptance at a scientific conference.
Through the conclusion of the Phase 1a and 1b clinical trials, Celgene may exercise its option to co-develop and co-commercialize anti-DLL4/VEGF bispecific.
Anti-RSPO3 (OMP-121R10)
Initiate enrollment of Phase 1a biomarker-selected expansion cohort
Aim to present Phase 1a data at an upcoming medical meeting in the second half of 2016, contingent upon dose-escalation and abstract acceptance.
Initiate enrollment of Phase 1b component in the first-in-human trial of anti-RSPO3 in combination with FOLFIRI chemotherapy in subjects with colorectal cancer including biomarker-positive subjects.
As with the anti-DLL4/VEGF bispecific, Celgene may exercise its option to co-develop and co-commercialize anti-RSPO3 through the conclusion of the Phase 1 clinical trial.
Immuno-oncology Pipeline
Advance either the immuno-oncology product candidate that is part of OncoMed’s collaboration with Celgene (IO#2) or OncoMed’s wholly owned GITRL-Fc program to an Investigational New Drug (IND) application filing by the end of 2016. Both programs are currently advancing in IND-enabling preclinical studies.
OncoMed estimates that over the course of the next two-to-three years (2016, 2017 and 2018), the company may be eligible to receive more than $168 million in potential opt-in payments from its collaboration with Celgene, $60 million in potential opt-in and milestone payments from Bayer and $43 million in potential opt-in payments from GSK. Overall, in future years, OncoMed is eligible for more than $5 billion in total potential milestone and option payments from its partners under its collaboration agreements with Celgene, Bayer, and GSK. To date, OncoMed has received over $450 million from its existing partners.
Aduro Biotech Expands Patent Portfolio With Key Newly Issued Composition and Methods Patents
On January 05, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that two patents have been issued by the U.S. Patent and Trademark Office covering composition and methods related to its LADD and GVAX immunotherapy technologies (Press release, Aduro BioTech, JAN 5, 2016, View Source [SID:1234508662]). Schedule your 30 min Free 1stOncology Demo! Patent 9,198,960 claims methods for enhancing an immune response to mesothelin by administering first a "prime" dose of an inactivated tumor cell containing a nucleic acid that encodes granulocyte macrophage-colony stimulation factor (GM-CSF) followed by a "boost" dose of an immunotherapy comprising an attenuated Listeria that encodes an expressible, immunologically active portion of mesothelin. The patent also specifically claims the method for Aduro’s live attenuated double deleted (LADD) platform containing deletions of the actA and inlB genes within Listeria. The nominal expiration date for this patent is July 17, 2027, subject to any extensions that may be available. Aduro has demonstrated in a randomized 93-patient Phase 2a clinical trial in metastatic pancreatic cancer that the claimed prime-boost approach utilizing its LADD and GVAX immunotherapies resulted in significant improvement in overall survival when compared to GVAX alone. The company is currently evaluating this regimen against single agent chemotherapy in the randomized Phase 2b ECLIPSE trial and also in combination with the PD-1 immune checkpoint blocker, nivolumab in the randomized Phase 2b STELLAR trial.
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Patent 9,200,057, which is jointly owned with Providence Health & Services, claims compositions containing a bacterium or virus which comprises a nucleic acid encoding at least three copies of an EGFRvIII polypeptide, a tumor-specific neo-antigen, which facilitates both antigen expression levels and immunogenicity. Aduro is collaborating with Providence on an investigator-sponsored trial of its LADD immunotherapy containing EGFRvIII and NY-ESO-1, ADU-623 for which Aduro has exclusive rights, to evaluate treatment of high-grade glioma, a form of brain cancer. The EGFRvIII tumor-associated antigen is also being utilized by Aduro for other exclusively-owned LADD-based vaccine strains directed to additional cancer types. The nominal expiration date for this patent is November 17, 2031, subject to any extensions that may be available.
"These two patents are important expansions of our patent estate, encompassing claims associated with our therapeutic approaches and extending patent coverage into 2031," said Thomas Dubensky, Jr., chief scientific officer of Aduro. "These newly issued patents are illustrative of our objective to maintain a leadership position and we look forward to continued advancements, including key data announcements from randomized studies this year."
About LADD
LADD is Aduro’s proprietary platform of live-attenuated double-deleted Listeria monocytogenes strains that have been engineered to induce a potent innate immune response and to express tumor-associated antigens to induce tumor-specific T cell-mediated immunity. The LADD technology has been applied to several novel compounds in clinical and preclinical testing including CRS-207 (pancreatic cancer, mesothelioma and ovarian/fallopian/peritoneal cancer (collaboration with Incyte Corporation to be tested in combination with epacadostat)), ADU-623 (brain cancer), ADU-214 (lung cancer, licensed to Janssen Biotech, Inc.) and ADU-741 (prostate cancer, licensed to Janssen Biotech, Inc.).
About GVAX
GVAX a family of immunotherapies derived from human cancer cell lines that are genetically modified to express granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune system-stimulating cytokine. GVAX Pancreas, the company’s lead approach in this platform, is derived from human pancreatic cancer cell lines and is designed to activate specific T cell immunity to pancreatic cancer antigens, including mesothelin.
CTI BioPharma And Baxalta Complete Submission Of New Drug Application For Pacritinib For Unmet Medical Need In Myelofibrosis
On January 5, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) and Baxalta Incorporated (Baxalta) (NYSE: BXLT) reported the completion of the rolling submission of the New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for pacritinib, an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R (Press release, CTI BioPharma, JAN 5, 2016, View Source [SID:1234508660]). Schedule your 30 min Free 1stOncology Demo! CTI BioPharma and Baxalta are requesting U.S. marketing approval of pacritinib for the treatment of patients with intermediate and high-risk myelofibrosis with low platelet counts of less than 50,000 per microliter (<50,000/μL) – a specific patient population for which there is an existing unmet medical need. The Companies are seeking accelerated approval and have requested a Priority Review of the application.
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Pacritinib is an investigational treatment being developed for patients with myelofibrosis regardless of their platelet counts. If approved, pacritinib would be the first JAK2 inhibitor indicated for the treatment of patients with myelofibrosis and baseline platelet counts of less <50,000/μL.
"We are pleased to have completed the rolling submission and look forward to working with the FDA during the review process with the goal of bringing this important treatment to people living with myelofibrosis, including those with low platelet counts," said James Bianco, M.D., president and chief executive officer of CTI BioPharma.
Myelofibrosis is a rare, but serious and life-threatening chronic leukemia that disrupts the normal production of blood cells and results in scarring of the bone marrow, limiting the ability to produce new blood cells and prompting the spleen and other organs to take over this function. The disease often leads to an enlarged spleen and lower than normal counts of blood cells – including red blood cells and platelets, which are essential for blood clotting.
"Pacritinib has the potential to change the treatment paradigm for people with intermediate and high-risk myelofibrosis, particularly those patients with cytopenias," said David Meek, executive vice president, president of Oncology at Baxalta. "Together with CTI BioPharma, we are continuing to develop this potential new treatment for more people in need around the world."
About the Pacritinib NDA
The NDA includes data from the PERSIST-1 Phase 3 trial – as well as data from Phase 1 and 2 studies of pacritinib. Submission of an NDA after a single Phase 3 trial under accelerated approval, instead of waiting to complete two Phase 3 trials, could potentially reduce time to market by up to 14 months. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high-risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment emergent thrombocytopenia on another JAK2 therapy; or patients who are intolerant to or whose symptoms are not well controlled (or sub-optimally managed) on another JAK2 therapy.
CTI BioPharma and Baxalta are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Baxalta will jointly commercialize pacritinib in the U.S. while Baxalta has exclusive commercialization rights for all indications outside the U.S.
About Myelofibrosis and Myeloproliferative Neoplasms
Myelofibrosis is one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of hematological blood cancers. The three main types of MPNs are myelofibrosis, polycethemia vera and essential thrombocythemia.1
Myelofibrosis is a serious and life-threatening chronic bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue, and pain.
The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S., of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis2 and is a progressive disease with approximately 20 percent of patients eventually developing AML.3 The median survival for high-risk myelofibrosis patients is less than one and a half years, while the median survival for patients with myelofibrosis overall is approximately six years.4
Exelixis Announces Positive Results From Subgroup Analyses of the METEOR Phase 3 Pivotal Trial of Cabozantinib in Advanced Renal Cell Carcinoma to be Presented at ASCO 2016 Genitourinary Cancers Symposium
On January 4, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported the presentation of positive data from subgroup analyses of METEOR, the phase 3 pivotal trial comparing cabozantinib to everolimus in 658 patients with renal cell carcinoma (RCC) who have experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI) (Press release, Exelixis, JAN 4, 2016, View Source;p=RssLanding&cat=news&id=2126057 [SID:1234508661]). Cabozantinib treatment resulted in benefits in progression-free survival (PFS), the trial’s primary endpoint, and objective response rate (ORR), a secondary endpoint, across various prespecified and post-hoc analysis subgroups. Importantly, observed benefits were independent of the location and number of organ metastases, tumor burden, the type, duration and number of prior VEGF receptor TKI therapies, and prior PD-1/PD-L1 therapy.
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Bernard Escudier, M.D., chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy (Villejuif, France) and an investigator on the METEOR trial, summarized the results during a press briefing in advance of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Genitourinary Cancers Symposium (ASCO GU), which is being held January 7-9, 2016 in San Francisco. Dr. Escudier will formally present the data (Abstract #499) at ASCO (Free ASCO Whitepaper) GU during an oral presentation session starting at 2:45 p.m. PT on Saturday, January 9, 2016.
"In the METEOR trial, cabozantinib was previously associated with statistically significant improvements in progression-free survival and objective response rate as compared to everolimus, a standard of care in the second-line renal cell carcinoma treatment setting," said Dr. Escudier. "This latest data set demonstrates that these benefits are favorable across a variety of prespecified and post-hoc subgroups, including patients who have received prior therapy with immune checkpoint inhibitors. In addition, cabozantinib was active in patients with low and high tumor burden, including patients with both bone and visceral metastases. Collectively, the data from METEOR suggest that cabozantinib could become an important addition to the renal cell carcinoma treatment landscape if approved."
As previously announced, the METEOR trial met its primary endpoint of demonstrating a statistically significant increase in PFS for cabozantinib as compared to everolimus, as determined by an independent radiology committee. Per the trial protocol, the primary analysis was conducted among the first 375 patients randomized to ensure sufficient follow up and a PFS profile that would not be primarily weighted toward early events. The median PFS for this population was 7.4 months for the cabozantinib arm versus 3.8 months for the everolimus arm, corresponding to a 42% reduction in the rate of disease progression or death for cabozantinib as compared to everolimus (hazard ratio [HR]=0.58, 95% confidence interval [CI] 0.45-0.75, p<0.001). These data were later presented at the European Cancer Congress (ECC) in September 2015 and concurrently published in The New England Journal of Medicine.
The ASCO (Free ASCO Whitepaper) GU presentation will be the first to include PFS data from the METEOR trial’s entire 658-patient study population. As assessed by independent radiology committee, the median PFS across all enrolled patients was 7.4 months for the cabozantinib arm versus 3.9 months for the everolimus arm, corresponding to a 48% reduction in the rate of disease progression or death for cabozantinib as compared to everolimus (HR = 0.52, 95% CI 0.43-0.64, p<0.001).
Updated ORR results from the full 658-patient study population will also be presented at ASCO (Free ASCO Whitepaper) GU for the first time. As assessed by independent radiology committee, the ORR across all 658 patients was 17% for cabozantinib and 3% for everolimus. The median duration of response for cabozantinib was not reached (95% CI 7.2 months; not reached), as compared to 7.4 months (95% CI 1.9 months; not reached) for everolimus. As previously reported at the ECC in September 2015, the ORR for the first 375 patients enrolled was 21% for cabozantinib and 5% for everolimus.
Cabozantinib’s effects on PFS and ORR were favorable across patient subgroups including: ECOG performance status; commonly applied RCC risk criteria developed by Motzer et al.; organ involvement, including bone and overall tumor burden; extent and type of prior VEGF receptor TKI therapy; and prior PD-1/PD-L1 therapy. For patients without prior PD-1/PD-L1 therapy, median PFS was 7.4 months for cabozantinib and 3.9 months for everolimus (HR = 0.54, 95% CI 0.44-0.66). For patients who had received prior PD-1/PD-L1 therapy, the median PFS for cabozantinib was not reached, and the median PFS for everolimus was 4.1 months (HR = 0.22, 95% CI 0.07-0.65).
"These new METEOR subgroup analyses further underscore the potential for cabozantinib to significantly impact the treatment of renal cell carcinoma, an aggressive cancer for which patients and physicians need new options," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "These data were included in our New Drug Application with the U.S. Food and Drug Administration, filed last month, and we intend to include them in our upcoming European Union Marketing Authorization Application, which we expect to submit shortly. Additionally, in 2016 we await the final analysis for METEOR’s overall survival secondary endpoint."
As previously reported, data pertaining to overall survival (OS) in the entire study population of 658 patients, a secondary endpoint of the trial, were immature at the data cutoff. A pre-specified interim analysis triggered by the primary analysis for PFS showed a strong trend in OS favoring cabozantinib (HR=0.67, 95% CI 0.51-0.89, p=0.005). At the time of the interim analysis, the p-value of 0.0019 to achieve statistical significance was not reached, and the trial will continue to the final analysis of OS anticipated in 2016.
Safety data from the trial were consistent with what was previously presented and published.
Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of Exelixis’ New Drug Application with the U.S. Food and Drug Administration for advanced RCC.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3
Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two small-molecule therapies and an immune checkpoint inhibitor have been approved for the treatment of patients with advanced RCC who have received prior systemic therapy. The currently approved small-molecule agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.
The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7
About Cabozantinib
Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.
Cabozantinib, marketed under the brand name COMETRIQ, is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).
The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.
Important Safety Information, including Boxed WARNINGS
WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE
Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.
COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.
Wound complications have been reported with COMETRIQ.
COMETRIQ treatment results in an increase in hypertension.
Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.
The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.
Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.
Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman.
Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.
Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf
Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.