On October 21, 2018 LSK BioPharma (or "LSKB"), a US-based biopharmaceutical firm and Jiangsu Hengrui Medicine, Co., Ltd. (SHA:600276, or "Hengrui"), one of the largest and most innovative fully-integrated biopharmaceutical companies based in China, reported that the companies have entered into a global clinical collaboration in patients with advanced hepatocellular carcinoma (HCC), evaluating the safety and efficacy of LSKB’s rivoceranib, also known as apatinib or Aitan (brand name) in China, a selective and potent VEGFR-2 inhibitor, in combination with Hengrui’s camrelizumab (SHR-1210), a humanized anti-PD-1 monoclonal antibody currently under NDA review in China for classic Hodgkin’s Lymphoma (cHL) (Press release, LSK BioPharma, OCT 21, 2018, View Source [SID1234530127]).

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Under the terms of the clinical collaboration agreement, Hengrui will be responsible for administering the clinical trial with all study costs outside of China shared equally among both parties. LSKB will retain full commercial rights for rivoceranib outside of China and Hengrui will retain full commercial rights for camrelizumab worldwide.

"At diagnosis, hepatocellular carcinoma typically has a dismal prognosis due to a lack of treatment options and the ineffectiveness of standard systemic therapies," said Dr. Sung Chul Kim, LSKB’s President, "we are enthusiastic to work with Hengrui for the potential to help more patients by combining rivoceranib with camrelizumab."

"We are pursuing camrelizumab in about 20 clinical trials in China. There is ample scientific evidence and preliminary clinical data supporting the synergistic effects of camrelizumab when used in combination with apatinib (rivoceranib)," said Dr. Lianshan Zhang, President of Global R&D of Hengrui. "We look forward to partnering with LSKB to build upon the existing preclinical and clinical data and further explore this combination therapy for patients with hepatocellular carcinoma, an area of high unmet medical needs."

"As one of the leading biopharmaceutical companies in China, we are committed to developing innovative medicines to address the urgent clinical needs. Through years of effort, Hengrui has built a robust oncology pipeline, which holds significant potential to benefit cancer patients. We are excited about this collaboration to accelerate the delivery of effective and durable treatment options for patients around the world," said Dr. Piaoyang Sun, Chairman of Hengrui.

Currently, Hengrui is conducting an open-label, single arm multicenter phase 2 study (NCT03463876) to evaluate the efficacy and safety of the combination of camrelizumab and apatinib in patients with advanced HCC in China, where Hengrui has received approval of apatinib monotherapy for advanced gastric cancer. At ASCO (Free ASCO Whitepaper) 2018, it was reported that the objective response rate (ORR) and disease control rate (DCR) were 50.0% and 85.7%, respectively, among 14 evaluated advanced HCC patients treated by camrelizumab in combination with apatinib in an open-label, phase 1 study in China (Xu et al., NCT02942329). In addition, camrelizumab and apatinib combination therapy is also being evaluated by Hengrui for multiple indications including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and gastric cancer (GC) in China.

It is hypothesized that the combination of rivoceranib and camrelizumab may enhance the immune system, aiding the fight against cancer. In addition to the known anti-angiogenic effects of rivoceranib, it may also enhance camrelizumab’s anti-tumor activity by normalizing tumor vasculature and reversing the tumor suppressive immune microenvironment.

About Rivoceranib (Apatinib)
Rivoceranib, also known as apatinib or Aitan (brand name) in China, is the first successful small-molecule angiogenesis inhibitor in gastric cancer. Rivoceranib acts by inhibiting angiogenesis, a critical process in cancer growth and proliferation. Specifically, rivoceranib selectively inhibits VEGFR-2 which mediates the primary pathway for tumor-mediated angiogenesis.

Hengrui, who owns the China rights to rivoceranib, received the approval from China National Medical Products Administration (NMPA, formerly known as CFDA) in 2014 to market the drug under the brand name Aitan in China for advanced gastric cancer. LSKB, which holds the global rights (ex-China), is currently conducting a global (12 countries including US, Japan, Korea, Italy, Germany, and Russia) phase 3 clinical trial of rivoceranib in advanced or metastatic gastric cancer patients. Rivoceranib (apatinib) is currently listed in 220 clinical studies on www.clinicaltrials.gov with over 20,000 patients enrolled or planned to be enrolled in numerous cancers including GC, colorectal cancer (CRC), HCC, NSCLC, esophageal cancer, thyroid cancer, mesothelioma, and neuroendocrine tumors. It has also shown potential to significantly improve outcomes in combination with chemotherapeutics and immunotherapy, as well as for maintenance therapy. LSKB has received notification designating rivoceranib as an orphan medicinal product for the treatment of gastric cancer from the European Commission in the European Union, the US FDA, as well as the MFDS in South Korea.

Rivoceranib was developed by Advenchen Laboratories in Southern California under the designation YN968D1. The compound was exclusively licensed to Hengrui in China (2005) and LSKB (2008) for rest of the world.

About Camrelizumab (SHR-1210)

Camrelizumab (SHR-1210) is an investigational humanized monoclonal antibody recognizing the programmed death-1 (PD-1) receptor. Camrelizumab functions as an immune checkpoint inhibitor by specifically blocking the interaction between PD-1 and PD-L1 and reversing the immunosuppressive signal of PD-1 on the T cell. Approximately 20 clinical trials on camrelizumab in multiple indications including lung cancer, liver cancer, gastric cancer, esophageal cancer, nasopharyngeal carcinoma, lymphoma, melanoma and other advanced solid tumors are being conducted in China and Australia as monotherapy or in combination with other therapeutic agents. A marketing application for camrelizumab for relapsed/refractory classic Hodgkin’s Lymphoma was submitted by Hengrui to China NMPA, which was accepted in April 2018, and is currently under review.

On October 21, 2018 Servier and Taiho Oncology, Inc. (U.S.), a subsidiary of Taiho Pharmaceutical Co., Ltd. (Japan), jointly announced today clinical data from the pivotal Phase III TAS-102 Gastric Study (TAGS) evaluating LONSURF (trifluridine/tipiracil, TAS-102) versus placebo and best supportive care in patients with heavily pre-treated metastatic gastric cancer who have progressed or are intolerant to previous lines of therapy (Press release, Servier, OCT 21, 2018, View Source [SID1234530014]). The study met its primary endpoint of prolonged overall survival (OS) and secondary endpoint measures of progression-free survival (PFS) consistently supported the OS results, as well as continuing to demonstrate the predictable safety and tolerability profile of trifluridine/tipiracil. Data from TAGS was presented by Dr. Hendrik-Tobias Arkenau, Executive Medical Director of the Sarah Cannon Research Institute UK and an investigator for TAGS, at the ESMO (Free ESMO Whitepaper) 2018 Congress in Munich, Germany during an oral session (Abstract #LBA25). The study results were simultaneously published in The Lancet Oncology.

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Based on the results, Servier filed a new application for an additional indication for gastric cancer to the European Medicines Agency (EMA) for LONSURF.

"Patients with metastatic gastric cancer currently have limited treatment options after first and second line therapies have failed," said Dr. Arkenau. "We are pleased to present new data that demonstrate the overall survival clinical benefit of trifluridine/tipiracil in metastatic gastric and gastroesophageal cancer."

In TAGS patients treated with trifluridine/tipiracil showed a clinically meaningful and statistically significant improvement in OS compared with placebo and a 31 percent risk reduction of death (HR 0.69 one sided p=0.00029), which translated into a prolonged median survival of 2.1 months (5.7 months for trifluridine/tipiracil versus 3.6 months for placebo). In addition, trifluridine/tipiracil demonstrated a statistically significant improvement in PFS and time to deterioration of ECOG performance status versus placebo, as well as a predictable and manageable safety profile consistent with that previously reported in patients with metastatic colorectal cancer.

"We’re very excited by the results of TAGS as they show trifluridine/tipiracil has the potential to make a difference to the lives of people living with metastatic gastric cancer who continue to struggle with this devastating disease," said Patrick Therasse, Head of Servier Research and Development Oncology Department.

Trifluridine/tipiracil is currently indicated in 61 countries, including those of the European Union, for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents.1

The abstract for the trifluridine/tipiracil presentation is available on the ESMO (Free ESMO Whitepaper) website and the manuscript is published online in The Lancet Oncology.

ENDS

About TAGS
TAGS (TAS-102 Gastric Study) is a Taiho-sponsored pivotal Phase III, multinational, randomized, double-blind study evaluating trifluridine/tipiracil, also known as TAS-102, plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic gastric cancer, including gastro esophageal junction cancer, refractory to standard treatments. The primary endpoint in the TAGS trial is overall survival (OS), and the main secondary endpoint measures include progression-free survival (PFS), and safety and tolerability, as well as quality of life.

TAGS enrolled 507 adult patients with metastatic gastric cancer who had previously received at least two prior regimens for advanced disease. The study was conducted in Japan, the United States, the European Union, Russia, Belarus, Israel, and Turkey.

For more information on TAGS, please visit www.ClinicalTrials.gov (View Source). The ClinicalTrials.gov Identifier is NCT02500043.

About Metastatic Gastric Cancer
Gastric cancer, also known as stomach cancer, is a disease in which malignant cells form in the lining of the stomach. It is the fifth most common cancer worldwide and the third most common cause of cancer-related death (after lung and liver cancer), with an estimated 723,000 deaths annually.2　

When cancer spreads it is called advanced cancer. Locally advanced cancer is when the cancer has grown outside the organ it started in but hasn’t spread to other parts of the body. When the cancer spreads to other parts of the body this is called metastatic cancer. In the last two decades, the proportion of patients with gastric cancer who present with metastases has risen to over 40%.3

Standard chemotherapy regimens for advanced gastric cancer include fluoropyrimidines, platinum derivatives, and taxanes (with ramucirumab), or irinotecan. The addition of trastuzumab to chemotherapy is standard of care for patients with HER2-neu-positive advanced gastric cancer. However, after failure of first- and second-line therapies, standard third-line treatments are limited.

About LONSURF (trifluridine and tipiracil, TAS-102)
LONSURF is an oral anticancer drug, comprising a combination of trifluridine (FTD) and tipiracil (TPI), whose dual mechanism of action is designed to maintain clinical activity. LONSURF is registered in Japan, USA, European Union, and in many other countries. In the European Union, LONSURF is indicated for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan- based chemotherapies, anti-VEGF agents, and anti-EGFR agents.1

LONSURF is recommended by the National Institute for Health and Care Excellence (NICE),4 NCCN5,6 and ESMO (Free ESMO Whitepaper) Guidelines7 for the treatment of adult patients with metastatic CRC.

In June 2015, Servier and Taiho Pharmaceutical entered into an exclusive license agreement for the co-development and commercialization of LONSURF.

As of October 2018, LONSURF has been approved as a treatment for mCRC in 61 countries and regions worldwide.

More than 60 Late Breaking Abstracts (LBA’s) are scheduled to be published at this year’s European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (E.S.M.O 2018). Below you will find the 10 published at the sessions on Saturday 20th October, the second day of the conference. For full analysis identifying new technologies, drugs, targets, start-ups etc. we recommend Commercial Interest at E.S.M.O Annual Meeting 2018: Analytical Tool.

• LBA1_PR – IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC)
• LBA2_PR – Overall survival (OS) with palbociclib plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2_) advanced breast cancer (ABC): Analyses from PALOMA-3
• LBA3_PR – Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the Phase 3 SOLAR-1 trial
• LBA11 – Defining the lethal subclone in metastatic lung cancer
• LBA22 – Negative hyper-selection of RAS wild-type (wt) metastatic colorectal cancer (mCRC) patients randomized to first-line FOLFOX plus panitumumab (Pan) followed by maintenance therapy with either 5FU/LV plus Pan or single-agent Pan: translational analyses of the VALENTINO study
• LBA23 – Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Metastatic Colorectal Cancer (mCRC)
• LBA31 – Molecular correlates differentiate response to atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun): results from a Phase III study (IMmotion151) in untreated metastatic renal cell carcinoma (mRCC)
• LBA32 – Nivolumab (N) Alone or in Combination With Ipilimumab (I) in Patients (pts) With Platinum-Pretreated Metastatic Urothelial Carcinoma (mUC), Including the Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Expansion From CheckMate 032
• LBA35 – TROPHIMMUN, a 2 cohort phase II trial of the anti-PD-L1 monoclonal antibody avelumab in chemo-resistant gestational trophoblastic neoplasia (GTN) patients: preliminary outcomes in cohort A.
• LBA36 – Association of PD-L1 Expression and Gene Expression Profiling With Clinical Response to Pembrolizumab in Patients With Advanced Recurrent Ovarian Cancer: Results From the Phase 2 KEYNOTE-100 Study

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On October 20, 2018 Novartis reported positive results from the global Phase III SOLAR-1 trial evaluating the investigational alpha-specific PI3K inhibitor BYL719 (alpelisib) in combination with fulvestrant (Press release, Novartis, OCT 20, 2018, View Source [SID1234529998]). The trial evaluated the efficacy and safety of alpelisib in postmenopausal women with PIK3CA mutated hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer that progressed on or after an aromatase inhibitor with or without a CDK4/6 inhibitor. These data will be presented today at the official press briefing at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress and as a late-breaker during the Presidential Symposium (Abstract LBA3_PR).

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In patients with PIK3CA mutated HR+/HER2- advanced breast cancer, BYL719 plus fulvestrant demonstrated a median progression-free survival (PFS) of 11 months (95% CI: 7.5-14.5 months) compared to 5.7 months (95% CI: 3.7-7.4 months) for fulvestrant alone. BYL719 plus fulvestrant reduced the risk of death or progression in those patients by an estimated 35% compared to fulvestrant alone (HR=0.65; 95% CI: 0.50-0.85; p<0.001). Overall response rate (ORR), indicating a reduction in tumor size of at least 30%, was more than doubled in patients with measurable disease who received BYL719 plus fulvestrant (36%) compared to those receiving fulvestrant alone (16%)[1].

"The results from SOLAR-1 are the most encouraging observed to date from a trial evaluating a PI3K inhibitor for patients with PIK3CA mutated HR+/HER2- advanced breast cancer," said Fabrice André, MD, PhD, research director and head of INSERM Unit U981, and professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France. "These data have the potential to allow physicians to address an unmet need in this patient population by using a biomarker-driven treatment to inform their sequencing decisions."

PFS treatment effect was consistent across all subgroups, and regardless of whether aromatase inhibitor treatment was given, with or without a CDK4/6 inhibitor. The significant PFS improvement demonstrated with BYL719 plus fulvestrant in patients with a PIK3CA mutation was not observed for patients without the mutation[1].

"We are excited about the meaningful results seen in SOLAR-1 and about the possibility to reimagine what potential treatment options could look like for patients living with PIK3CA mutated HR+/HER2- advanced breast cancer – some of who were previously treated with a CDK4/6 inhibitor," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We are actively engaging in discussions on these results with health authorities worldwide."

Most adverse events were mild to moderate in severity and generally manageable through dose modifications and medical management. The discontinuation rate of BYL719 plus fulvestrant due to adverse events was 5% compared to 1% for fulvestrant alone. The most common all-grade adverse events (>=30%) were hyperglycemia (64% vs 10%), diarrhea (58% vs. 16%), nausea (45% vs. 22%), decreased appetite (36% vs. 11%) and rash (36% vs. 6%). Of these, the most common grade 3/4 events (>=5%) were hyperglycemia (37% vs. <1%), rash (10% vs. <1%), and diarrhea (7% vs. <1%)[1].

The SOLAR-1 trial is ongoing to evaluate secondary endpoints, including overall survival. Further analysis from SOLAR-1 will be presented and discussed at future medical congresses.

About PI3K inhibition in advanced breast cancer
Studies have established the role of PI3K signaling in several processes for cancer progression, including cell metabolism, growth, survival and motility[3]. Activation of the PI3K pathway in breast cancer is associated with resistance to endocrine therapy, disease progression and poorer prognosis[4],[5].

Proteins in the PI3K pathway consist of four smaller parts called isoforms[6]. Approximately 40% of HR+ advanced breast cancer patients have genetic mutations that activate the alpha isoform, called PIK3CA mutations[2]. Mutations in the three other isoforms are typically not associated with advanced breast cancer[6].

Currently, there are no approved PI3K inhibitors for breast cancer.

About SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying investigational BYL719 in combination with fulvestrant for postmenopausal women with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor[1].

The trial randomized 572 patients. Patients were allocated based on tumor tissue assessment to either a PIK3CA-mutated cohort or a PIK3CA non-mutated cohort. Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with BYL719 (300mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment[1].

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with the PIK3CA mutation. Secondary endpoints include but are not limited to overall survival, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability[1].

About BYL719 (alpelisib)
BYL719 is an investigational, orally bioavailable, alpha-specific PI3K inhibitor. In breast cancer cell lines harboring PIK3CA mutations, BYL719 has been shown to potentially inhibit the PI3K pathway and have antiproliferative effects. In addition, cancer cell lines with PIK3CA mutations were more sensitive to BYL719 than those without the mutation across a broad range of different cancers[7].

On October 20, 2018 OncoMed Pharmaceuticals, Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer therapeutics, reported interim results from its ongoing Phase 1b trial investigating navicixizumab, OncoMed’s anti-DLL4/VEGF bispecific antibody, in combination with paclitaxel in patients with platinum-resistant ovarian cancer (Press release, OncoMed, OCT 20, 2018, View Source [SID1234530049]).

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The interim results were presented at the European Society for Medical Oncology in Munich. The patients had received a median of four prior therapies, all of whom had received prior paclitaxel and 69% had received prior bevacizumab. Twenty-two of the 26 patients (85%) treated with the novel regimen experienced clinical benefit. Notably 11 of the 26 patients (42%) achieved a partial response and the median progression-free survival was 5.4 months (95% CI: 3.5-8.0 months). Historical response rates for patients with heavily pretreated platinum-resistant ovarian cancer treated with chemotherapy are typically 15% or less.

"These are impressive results that warrant further evaluation in this historically difficult-to-treat patient population," said Kathleen Moore, M.D., Jim and Christy Everest Endowed Chair in Cancer Research, Clinical Research Director, University of Oklahoma Health Science Center and one of the lead investigators for the Phase 1b clinical trial. "When ovarian cancer stops responding to platinum-based therapy, our best option is chemotherapy plus bevacizumab, which may be effective, but often for only a short duration. Following this line of therapy, there are no approved, effective options for patients. Combination weekly paclitaxel and navicixizumab appears to provide durable responses among patients with multiple lines of prior therapy and/or prior exposure to bevacizumab, which represents a high unmet need."

The ongoing Phase 1b multicenter, open-label, dose-escalation and expansion trial is designed to assess the safety, preliminary efficacy, immunogenicity, pharmacokinetics and biomarker effects of navicixizumab plus paclitaxel. The trial has been expanded to enroll up to 60 patients with platinum-resistant ovarian cancer (including fallopian tube or primary peritoneal cancers) who have previously received bevacizumab and/or have failed at least two prior therapies.

Additional highlights from the poster were:

The median number of prior therapies was four. All patients had previously received paclitaxel and 69% had received bevacizumab.
The RECIST response rate was 42% and the RECIST response rate in the bevacizumab naïve and bevacizumab pretreated patients was 57% and 33%, respectively.
CA-125 is a widely utilized tumor marker for ovarian cancer that is used along with radiographic assessments to determine the efficacy outcome to treatment. Of the 23 patients evaluable for a GCIG CA-125, 14 (61%) had a response. Specifically, the CA-125 response rates in the bevacizumab naïve and bevacizumab pretreated patients were 100% and 47%, respectively.
The overall median progression free survival (PFS) was 5.4 months (95% CI: 3.5 — 8 months). The median PFS for the subset of bevacizumab pretreated patients was 3.7 months (95% CI: 3.3 months — not reached).
The most common related adverse events of any grade related to navicixizumab were hypertension (53%), fatigue (32%), diarrhea (24%) and headache (18%). Other related rare adverse events of special interest were one Grade 2 pulmonary hypertension, one Grade 1 related heart failure, one Grade 4 related gastrointestinal perforation and one Grade 4 thrombocytopenia. Three patients (12%) experienced infusion reactions that were associated with anti-drug antibodies which impacted drug exposure.
About Navicixizumab
OncoMed’s anti-DLL4/VEGF bispecific antibody, navicixizumab, is designed to inhibit the function of both DLL4 and VEGF and thereby induce potent anti-tumor responses while mitigating certain angiogenic-related toxicities. Navicixizumab was developed utilizing OncoMed’s BiMAb bispecific platform technology, which enables the design of bispecific antibodies comparable to traditional monoclonal antibodies but possessing dual target-binding specificity. In preclinical studies, navicixizumab demonstrated robust in vivo anti-tumor efficacy across a range of solid tumor xenografts, including colon, ovarian, lung and pancreatic cancers, among others. Further, in preclinical studies dual inhibition of DLL4 and VEGF appeared to exhibit synergistic anti-tumor activity at doses where blockade of either target alone elicited sub-optimal activity. In a Phase 1a study with single-agent navicixizumab published in Investigational New Drugs, 19 of 66 patients with various types of refractory solid tumors had tumor shrinkage following treatment with navicixizumab. Notably, 3 of the 12 (25%) ovarian cancer patients treated in the trial achieved a partial response with single-agent navicixizumab therapy