RenovoRx Announces Initial Results in Pharmacokinetic (PK) Substudy: Data on RenovoGem™ Supports Potential for RenovoTAMP® Therapy Platform to Increase Local Gemcitabine (Chemotherapy) Delivery and Decrease Side Effects of Pancreatic Cancer Treatment

On January 18, 2023 RenovoRx, Inc. (Nasdaq: RNXT), a biopharmaceutical company focused on the localized treatment of solid tumors, reported initial results from a pharmacokinetic (PK) substudy within the phase III un-blinded randomized control TIGeR-PaC clinical trial to be presented at the 2023 ASCO (Free ASCO Whitepaper) Gastrointestinal (ASCO GI) Cancers Symposium this week (Press release, Renovorx, JAN 18, 2023, View Source [SID1234626362]). The TIGeR-PaC clinical trial is evaluating intra-arterial (IA) administration of gemcitabine (chemotherapy) using the proprietary RenovoRx Trans-Arterial Micro-Perfusion (RenovoTAMP) platform for targeted treatment of Locally Advanced Pancreatic Cancer (LAPC). The substudy provides clinical support that RenovoTAMP may increase local drug delivery and thus concentration at the tumor site while decreasing the debilitating side effects often associated with systemic intravenous (IV) delivery, which is the current standard of care.

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Three additional abstracts supporting the use of RenovoTAMP with gemcitabine for treatment of LAPC will also be presented at the ASCO (Free ASCO Whitepaper) GI on January 19-21, 2023 in San Francisco, California, and available online.

"Intra-arterial Gemcitabine vs IV Gemcitabine PK Substudy in Patients with Locally Advanced Pancreatic Cancer," presented by Amer H. Zureikat, MD, et al., evaluates RenovoTAMP for IA delivery of gemcitabine (chemotherapy) directly into tumors for higher local drug concentration and decreased systemic drug concentration and associated side effects. The PK substudy evaluates a sample of LAPC patients (N=13) participating in the TIGeR-PaC study and demonstrates that the cohort had an average greater than 50% reduction in systemic drug exposure with IA delivery of gemcitabine using RenovoTAMP when compared with IV administration. The substudy concludes that RenovoTAMP may increase local gemcitabine concentration, which may be beneficial in decreasing gemcitabine-related systemic side effects. Five TIGeR-PaC clinical sites participated in this substudy.

"The upcoming presentation of our TIGeR-PaC clinical trial substudy at ASCO (Free ASCO Whitepaper) GI highlights significant potential benefits for patients with LAPC," said Ramtin Agah, MD, Chief Medical Officer and Founder of RenovoRx. "Targeted local delivery of standard dose gemcitabine via the RenovoTAMP therapy platform may be associated with significantly less systemic drug exposure. The clinical implications may be decreased side effects and enhanced chemotherapy delivery. Ongoing studies are quantifying the resulting impact on improving patients’ quality of life and extending lifespan."

"This substudy data, and the additional three studies to be presented at ASCO (Free ASCO Whitepaper) GI, enhance the strong clinical momentum of our therapy platform as we prepare for our most significant milestone to date: the initial interim analysis for our randomized phase III TIGeR-PaC trial." said Shaun Bagai, CEO of RenovoRx.

Three additional clinical data abstracts presented by researchers at ASCO (Free ASCO Whitepaper) GI with data from the induction phase of the TIGeR-PaC study help to advance the science behind pancreatic cancer. In one abstract, Dr. Amer H. Zureikat, et al. investigates Mesenteric Venous Thrombosis (MVT), often identified on routine imaging studies performed with LAPC, and concludes that severe MVT is more prevalent in this patient population than previously reported. Anticoagulation is also underutilized in this cohort; however, chemotherapy may have a beneficial effect in downstaging MVT beyond anticoagulation. In a second abstract, Dr. Karyn A. Goodman, et al. performs an exploratory analysis to compare the toxicity and efficacy between patients receiving either stereotactic body radiation therapy (SBRT) or intensity-modulated radiation therapy (IMRT) during the induction phase (prior to randomization) of the TIGeR-PaC study. When compared to IMRT, SBRT demonstrates improved tolerability for treatment of patients with LAPC with comparable clinical efficacy. It was this finding that led to the modification of the TIGeR-PaC study design in 2021. Finally, a third abstract presented by Michael J. Pishvaian, et al. focuses on the TIGeR-PaC trial design and status.

The poster presentations for the four RenovoRx abstracts to be presented at the ASCO (Free ASCO Whitepaper) GI Symposium will be available on RenovoRx’s website once available: View Source

Pyramid Biosciences to Present at the B. Riley Securities Third Annual Oncology Conference

On January 18, 2023 Pyramid Biosciences, Inc., a privately-held, clinical-stage biotechnology company focused on developing new and highly differentiated precision therapies for cancer and other serious diseases, has reported its participation this week in the B. Riley Securities 3rd Annual Oncology Conference (Press release, Pyramid Biosciences, JAN 18, 2023, View Source [SID1234626361]). Its Chief Executive Officer, Dr. Brian Lestini, will present on Thursday, January 19, 2023, at 2 PM ET.

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The conference will feature more than 30 SMiD cap healthcare companies focused on the development and commercialization of new medicines and key enabling technologies, cutting across multiple next-generation therapeutic modalities. Highlights include panel discussions with academic and industry key opinion leaders at the forefront of translational and clinical research. Topics span novel immunotherapy, cell therapy, and targeted oncology approaches, as well as imaging and radiation oncology initiatives aimed at driving meaningful improvements to current standard of care for cancer patients.

Teon Therapeutics Announces Clinical Trial Collaboration With Merck to Evaluate TT-816, a Novel Oral Immune Response Modifier, in Combination with KEYTRUDA® (pembrolizumab)

On January 18, 2023 Teon Therapeutics (Teon), a clinical-stage biopharmaceutical company targeting metabolic signaling pathways and pioneering the development of G-Protein Coupled Receptor (GPCR) immuno-oncology therapies in difficult-to-treat cancers, reported that it has entered into the clinical trial collaboration agreement with Merck (known as MSD outside the United States and Canada), a leader in immuno-oncology (IO) (Press release, Teon Therapeutics, JAN 18, 2023, View Source [SID1234626360]). The agreement is for the combination arm of Teon’s ongoing, two-armed, open-label, dose escalation and expansion clinical study and will evaluate Teon’s oral, immune response modifier, TT-816, in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), for patients with advanced solid tumors. The study will include patients with many difficult-to-treat cancers with high unmet medical need who have not responded to the standard-of-care and may have limited treatment options.

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"We are fortunate to have the opportunity to collaborate with Merck for this Phase 1/2 trial. The collaboration of the combination arm of our TT-816 clinical trial represents an important advancement in our comprehensive development program and further supports our mission to invent new hope for patients by potentially providing meaningful treatments to those with few remaining alternatives," said Serge Messerlian, Chief Executive Officer of Teon Therapeutics. "In addition to its great potential as a monotherapy, by blocking both the PD-1 and CB2 pathways, we believe that TT-816 in combination with KEYTRUDA may have an additive benefit in ‘hot’ tumors and synergistic effect in ‘cold’ tumors that may result in improved outcomes for more patients. Results of our preclinical studies indicate that TT-816 has unique mechanisms of action that enhance both T cell and NK cell antitumor immunity, prevent broad-based T cell exhaustion, synergize antitumor effects with current immune checkpoint inhibitor therapies, and directly promote T cell infiltration into solid tumors."

"New treatment options are desperately needed in oncology care as today, most patients see their cancer return on current immunotherapy treatment. TT-816 in combination with KEYTRUDA could potentially offer a clinically meaningful new option that can overcome tumor resistance mechanisms in many patients with difficult-to-treat cancers," said Anthony W. Tolcher, M.D., FRCPC, FACP, principal investigator and CEO, founder of NEXT Oncology.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About Teon’s Multicenter TT-816 Phase 1/2 Clinical Trial

This clinical trial is an open-label, Phase 1/2, first-in-human (FIH), multiple ascending dose and dose-expansion study of TT-816 orally administered as monotherapy and in combination with KEYTRUDA, Merck’s anti-PD-1 therapy. An estimated 200 patients will be enrolled. Phase 1 will evaluate safety, tolerability, pharmacokinetics, preliminary clinical activity and establish a recommended dose of TT-816 to be used as a monotherapy and in a combination therapy for Phase 2. Phase 2 will continue to evaluate safety and define the preliminary efficacy of these regimens in the setting of advanced solid tumors with high unmet medical needs including Non-Small Cell Lung Cancer (NSCLC), Ovarian Cancer and Renal Cell Carcinoma (RCC).

Additional information about the trial can be found on clinicaltrials.gov using the study identifier (NCT05525455).

About TT-816

TT-816 is a first-in-class, oral cannabinoid CB2 receptor antagonist acting as a novel immune response modifier for the treatment of a broad range of solid tumors and is highly selective for the CB2 receptor versus the CB1 receptor. By inhibiting the actions of the CB2 receptors on immune cells in many difficult-to-treat cancers, including lung, renal, and ovarian, TT-816 has the potential to enhance T cell and NK cell activity and directly promote T cell infiltration into solid tumors.

Preclinical results indicate that TT-816 enhances both the effect of NK cell tumor killing and T cell activation in vitro, increases both tumor infiltrating T cells and NK cells in vivo and prevents broad-based T cell exhaustion. TT-816 dose-dependently inhibits tumor growth in animal models, has an additive effect with anti-PD-1 in the ‘hot’ tumor model and acts synergistically with anti-PD-1 in the ‘cold’ tumor model where the anti-PD-1 alone had no effect.

About the CB2 receptor

The cannabinoid CB2 receptor belongs to the G protein-coupled receptor (GPCR) family. The cannabinoid CB2 receptor, selectively inhibited by TT-816, is a peripheral receptor found predominantly in the immune system and regulates inflammation and the immune response. Elevated CB2 receptor expression is associated with worse overall survival and aggressiveness of cancer. Research has shown that CB2 receptor activation does not have any psychoactive properties unlike CB1 receptors which are located primarily in the brain.

Lunit Highlights the Effectiveness of AI in Predicting Cancer Treatment Outcomes – Findings to be Presented at ASCO GI 2023

On January 18, 2023 Lunit (KRX:328130.KQ) reported that it will deliver two poster presentations at the upcoming 2023 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI), to be held in San Francisco, CA, and online from Jan. 19 – 21 (Press release, Lunit, JAN 18, 2023, View Source;findings-to-be-presented-at-asco-gi-2023-301724599.html [SID1234626358]).

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As a leading provider of state-of-the-art cancer diagnostic technology, Lunit has focused on developing novel AI biomarkers for application in immunotherapy. Since 2019, the company has released groundbreaking findings based on its AI-powered tissue analysis platform, Lunit SCOPE, demonstrating the software’s predictive value in identifying patients eligible for immunotherapy.

This year, Lunit’s presentations at ASCO (Free ASCO Whitepaper) GI 2023 will highlight the effectiveness of Lunit SCOPE IO as a biomarker to predict liver and colon cancer treatment outcomes.

Lunit SCOPE IO assesses a patient’s cancer tissue slide image by analyzing the distribution of tumor-infiltrating lymphocytes (TILs)—one of the representative immunocytes that fight cancer cells. Based on the spatial distribution of TILs and cancer cells in the tumor microenvironment, Lunit SCOPE IO identifies the sample as one of three immune phenotypes: inflamed, immune-excluded, or immune-desert.

One of the studies to be presented investigates the correlation between AI-powered immune phenotype and real-world outcomes in liver cancer.

Anti-PD-(L)1 monotherapy or combination with bevacizumab or ipilimumab are approved treatment options for hepatocellular carcinoma (HCC; liver cancer). However, not all patients benefit from immunotherapy regimens, raising a need for biomarkers to predict treatment outcomes. Lunit SCOPE IO was used to assess the correlation between the AI solution’s immune phenotype and actual outcomes from two separate immunotherapy regimens across 177 HCC patient cases.

Findings showed progression-free survival (PFS) of the nivolumab or nivolumab plus ipilimumab (Niv+/-Ipi) regimen to be significantly longer in patients with high inflamed scores—the proportion of area with a high intra-tumoral TIL infiltration. Thus, results showed that the inflamed score, as evaluated by Lunit SCOPE IO, can be used as a biomarker to predict outcomes of Niv+/-Ipi treatment.

Lunit will also present findings from a study assessing the clinical significance of Lunit SCOPE IO for the prediction of prognosis in stage II-III colon cancer patients treated with surgery and adjuvant chemotherapy.

Across 289 patients included in the study, TIL quantification evaluated by Lunit SCOPE IO showed clinically meaningful correlations with microsatellite instability status, stage of cancer progression, and the occurrence of perineural invasion—factors known to be associated with the prognosis of colon cancer. Furthermore, patients with low TIL quantification were more likely to exhibit recurrence.

"TIL quantification is important in the prediction of prognosis in colon cancer, but assessment usually requires additional tissue processing and interpretational efforts," explained Chan-Young Ock, Chief Medical Officer of Lunit’s Oncology Group. "This study shows that AI-powered TIL analysis using only an H&E-stained whole-slide image can provide prognostic information in stage II-III colon cancer patients in a practical manner."

"Our presentations at this year’s ASCO (Free ASCO Whitepaper) GI continue to demonstrate the credibility of Lunit SCOPE IO as a practical biomarker as we expand the range of our research across all cancer types," said Brandon Suh, CEO of Lunit. "We will expand our research and commercial access programs for Lunit SCOPE throughout this year to provide optimized treatment to cancer patients around the world."

Eisai Aims to Advance Gastrointestinal Cancer Treatment with Research Across Multiple Tumor Types at ASCO GI 2023

On January 18, 2023 Eisai reported the presentation of research across various types of gastrointestinal cancers during the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (#GI23), which is taking place in-person in San Francisco, California and virtually from January 19-21 (Press release, Eisai, JAN 18, 2023, View Source [SID1234626357]).

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Notable data include an update from the dose-escalation part of a Phase 1 Study evaluating E7386, a CREB-binding protein (CBP) / β-catenin interaction inhibitor, in patients with advanced solid tumors including colorectal cancer (NCT03833700; Abstract: #106). Based on these additional analyses, further investigation of safety, preliminary efficacy, pharmacokinetics and biomarker analyses of E7386 is ongoing using two dose levels in the expansion part.

Research from the LEAP (LEnvatinib And Pembrolizumab) clinical program includes a poster presentation featuring a health-related quality of life analysis from the Phase 3 LEAP-002 trial investigating the lenvatinib (LENVIMA) plus pembrolizumab (KEYTRUDA) combination versus lenvatinib plus placebo as a first-line treatment for patients with unresectable hepatocellular carcinoma (NCT03713593; Abstract: #506). Additional presentations on Eisai’s oncology pipeline showcase Eisai’s investigational compound, E7389-LF, a new liposomal formulation of eribulin, in combination with nivolumab in patients with solid tumors. Efficacy and safety were evaluated in expansion cohorts, including an esophageal cancer cohort (NCT04078295; Abstract: #337) and a gastric cancer cohort (NCT04078295; Abstract: #339).

"We are eager to share new data at the annual symposium where specialists in gastrointestinal cancers gather from all over the world, including findings from a Phase 1 study evaluating the novel investigational anticancer agent, E7386, in advanced solid tumors including colorectal cancer," said Dr. Takashi Owa, Chief Scientific Officer, Senior Vice President, Eisai Co., Ltd. "Our findings across colorectal, esophageal, gastric and liver cancer illustrate Eisai’s commitment to further oncology research for people living with gastrointestinal cancers, who account for over one quarter of the global cancer incidence."

In March 2018, Eisai and Merck (known as MSD outside the United States and Canada), through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of lenvatinib, both as monotherapy and in combination with Merck’s anti-PD-1 therapy pembrolizumab. To date, more than 10 trials have been initiated under the LEAP clinical program, which is evaluating the combination across multiple tumor types.

This release discusses investigational compounds and investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational compounds or investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

The full list of Eisai presentations is included below. The majority of abstracts are currently available on the ASCO (Free ASCO Whitepaper) website. The late-breaking abstracts will be released at the time of presentation during the symposium.

Cancer Type

Study/

Compound

Abstract Title

Abstract Type & Details

Pipeline

Solid Tumors

E7386

A phase 1 study of E7386, a CREB-binding protein (CBP)/β-catenin interaction inhibitor, in patients (pts) with advanced solid tumors including colorectal cancer: updated dose-escalation part

Poster Presentation

Abstract #106

January 21, 2023

6:30-7:55 AM PST /

9:30-10:55 AM ET

E7389-LF

Gastric cancer (GC) cohort of a phase 2 trial of E7389-LF (liposomal formulation of eribulin) in combination with nivolumab

Poster Presentation

Abstract #339

January 19, 2023

12:00-1:30 PM PST /

3:00-4:30 PM ET

E7389-LF

The esophageal cancer cohort of a phase 2 trial of E7389–LF (liposomal formulation of eribulin) + nivolumab

Poster Presentation

Abstract #337

January 19, 2023

12:00-1:30 PM PST /

3:00-4:30 PM ET

LEAP clinical program

Gastrointestinal Cancers

LEAP-015

First-line lenvatinib plus pembrolizumab plus chemotherapy versus chemotherapy in advanced/metastatic gastroesophageal adenocarcinoma: (LEAP-015): Safety run-in results

(Encore presentation)

Poster Presentation

Abstract #411

January 19, 2023

12:00-1:30 PM PST /

3:00-4:30 PM ET

LEAP-002

Health-related quality of life (HRQoL) impact of lenvatinib (len) plus pembrolizumab (pembro) versus len plus placebo (pbo) as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC): Phase 3 LEAP-002 study

Poster Presentation

Abstract #506

January 20, 2023

12:00-1:30 PM PST /

3:00-4:30 PM ET

Real World Evidence

Gastrointestinal Cancer

Real-world data

Prevalence of historical medical conditions or comorbidities with potential role in clinical decision making related to suitability of immuno-oncologic plus IV antiangiogenic therapy in newly diagnosed first-line unresectable hepatocellular carcinoma in the United States

Poster Presentation

Abstract #511

January 20, 2023

12:00-1:30 PM PST /

3:00-4:30 PM ET

About E7386
E7386 is a selective inhibitor of the interaction between the cAMP response element-binding protein (CREB) binding protein (CBP) / β-catenin and a modulator of the Wnt / β-catenin signaling pathway. E7386 is thought to block the protein-protein interaction between a transcriptional co-activator, CBP and β-catenin, resulting in the inhibition of Wnt / β-catenin pathway-dependent gene expression. Since E7386 acts on the CBP / β-catenin transcription complex located at the most downstream of the Wnt signaling, it is expected to inhibit not only ligand-dependent activation but also activation caused by gene mutations in Wnt signaling factors such as adenomatous polyposis coli (APC) and β-catenin. E7386 is created through collaboration research between Eisai and PRISM BioLab Co., Ltd. (Headquarters: Kanagawa)

About E7389-LF
E7389-LF is a new formulation designed for more efficient delivery of the halichondrin-class microtubule dynamics inhibitor, HALAVEN (eribulin mesylate), into cancer cells by liposome envelopment. A phase I clinical study is currently being conducted on select solid tumors in Japan. Additionally, a phase Ib/II clinical trial on the combination therapy of E7389-LF and nivolumab targeting select solid tumors is currently being conducted in Japan in collaboration with Ono Pharmaceutical Co., Ltd.

About LENVIMA (lenvatinib) Capsules
LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC)
In combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
LENVIMA, discovered and developed by Eisai, is a multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation. The combination of LENVIMA and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone. In syngeneic mouse tumor models, the combination of lenvatinib with an anti-PD-1 monoclonal antibody decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity compared to either treatment alone.

Important Safety Information
Warnings and Precautions
Hypertension. In DTC (differentiated thyroid cancer), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis, and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.

Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

Embryo-Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + pembrolizumab-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). The most common serious adverse reactions (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

In EC, the most common adverse reactions (≥20%) observed in LENVIMA and pembrolizumab–treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar–plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).

Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end-stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC and severe hepatic impairment.

LENVIMA (lenvatinib) is available as 10 mg and 4 mg capsules.

Please see Prescribing Information for LENVIMA (lenvatinib) at View Source

About HALAVEN (eribulin mesylate) Injection
HALAVEN (eribulin mesylate) is a microtubule dynamics inhibitor indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Discovered and developed by Eisai, eribulin is a synthetic analog of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai. First in the halichondrin class, eribulin is a microtubule dynamics inhibitor. Eribulin is believed to work primarily via a tubulin-based mechanism that causes prolonged and irreversible mitotic blockage, ultimately leading to apoptotic cell death. Additionally, in preclinical studies of human breast cancer, eribulin demonstrated complex effects on the tumor biology of surviving cancer cells, including increases in vascular perfusion resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype, promoting the epithelial phenotype, opposing the mesenchymal phenotype. Eribulin has also been shown to decrease the migration and invasiveness of human breast cancer cells.

Important Safety Information
Warnings and Precautions
Neutropenia: Severe neutropenia (ANC <500/mm3) lasting >1 week occurred in 12% of patients with mBC and liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 5% of patients with mBC and 2 patients (0.4%) died from complications. Patients with mBC with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels. Monitor complete blood cell counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting >7 days.

Peripheral Neuropathy: Grade 3 peripheral neuropathy occurred in 8% of patients with mBC (Grade 4=0.4%) and 22% developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Neuropathy lasting >1 year occurred in 5% of patients with mBC. Grade 3 peripheral neuropathy occurred in 3.1% of patients with liposarcoma and leiomyosarcoma receiving HALAVEN and neuropathy lasting more than 60 days occurred in 58% (38/65) of patients who had neuropathy at the last treatment visit. Patients should be monitored for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

Embryo-Fetal Toxicity: HALAVEN can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose.

QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome.

Adverse Reactions
In patients with mBC receiving HALAVEN, the most common adverse reactions (≥25%) were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%). Febrile neutropenia (4%) and neutropenia (2%) were the most common serious adverse reactions. The most common adverse reaction resulting in discontinuation was peripheral neuropathy (5%).