On September 10, 2020 University of California at Los Angeles reported that Despite the success of checkpoint inhibitors that remove the blockade that cancer cells impose on the immune system, the drugs only work in some patients (Press release, University of California at Los Angeles, SEP 10, 2020, View Source [SID1234565053]). A research team led by scientists at the University of California, Los Angeles figured that understanding how responders’ immune cells act differently from those of nonresponders could point to new ways to enhance the efficacy of immuno-oncology therapies.

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In a new study published in Cancer Cell, the UCLA team pinpointed two main drivers that help the immune system attack cancer in response to I-O treatment: T-cell infiltration of tumors and interferon-gamma signaling.

The researchers analyzed tumor biopsies from melanoma patients treated with Bristol Myers Squibb’s PD-1 inhibitor Opdivo, either on its own or in tandem with the company’s anti-CTLA-4 drug Yervoy, in the CheckMate-038 trial. They compared genomic data from the tumors collected before and during treatment in both patients who had a clinical response and those who didn’t respond.

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As previous researchers had reported, the UCLA scientists found that high levels of CD8 T cells traveling to tumors were associated with the clinical response to the checkpoint inhibitors.

So, they examined the expression of cancer cell-killing cytokines as a result of tumor antigen-specific T-cell activation. The team discovered that cytokine expression followed the pattern of interferon-gamma, which was found at high levels in biopsies of patients who had responded well to checkpoint inhibitors.

Further analysis of genes that are related to interferon-gamma exposure revealed that the main difference separating patients who had responded and those who resisted I-O therapy was an increase in antigen-presenting machinery.

"The cancer is blocking how the immune system attacks cancer cells by the immune checkpoints," Antoni Ribas, M.D., Ph.D., the study’s senior author, explained in a statement. "And whenever we’ve released them, then there’s an increased immune activation that depends on the strength of the T cells to produce [interferon gamma], resulting in the activation of over 600 genes that amplify the antitumor immune response."

RELATED: New insights into cancer cell escape mechanisms could boost immuno-oncology treatments

Numerous research efforts have focused on identifying methods to boost the efficacy of immuno-oncology treatments. These include combining the targeting of immune checkpoints. For example, Roche recently demonstrated that combining its PD-L1 blocker Tecentriq with experimental anti-TIGIT antibody tiragolumab shrank non-small lung cancer better than Tecentriq alone.

Researchers in China recently found that inhibiting AKT with Merck’s MK-2206 boosted T-cell infiltration in glioblastoma in mice. They argued that combining the drug with an anti-PD-1 medicine could improve the anti-tumor effect.

The UCLA-led team’s findings provide hope that combination therapies that "increase interferon signaling inside tumors to jump-start an anti-tumor immune response when it is not already pre-existing" may dial up the efficacy of immune checkpoint inhibitors so that they can help more patients, the scientists wrote in the study.

On September 10, 2020 Eisai reported that it will present two late breakers and 10 e-posters at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 from September 19-21, 2020 (Press release, Eisai, SEP 10, 2020, View Source [SID1234565041]).

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Notable data from ongoing LEAP clinical trials on the investigational lenvatinib plus pembrolizumab combination to be presented in advanced melanoma previously treated with a PD-1 or PD-L1 inhibitor (LEAP-004) (Abstract #LBA44), biliary tract cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, glioblastoma and ovarian cancer (LEAP-005) (Abstract #LBA41), metastatic NSCLC (LEAP-006) (Abstract 1313P), and renal cell carcinoma previously treated with PD-1/PD-L1 inhibitor (Study 111/KEYNOTE-146) (Abstract #710P).

In addition, there will be two Trial in Progress e-posters on LEAP trials currently recruiting patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (LEAP-010) (Abstract #973TiP) and intermediate-stage hepatocellular carcinoma not amenable to curative treatment (LEAP-012) (Abstract #1016TiP). To date, 19 trials have been initiated under the LEAP clinical program. For more information on the LEAP program, please visit clinicaltrials.gov.

There will also be a Trial in Progress e-poster on Study 230, evaluating ifosfamide and etoposide with or without lenvatinib in children, adolescents and young adults with relapsed or refractory osteosarcoma (Abstract #1668TiP). For more information on Study 230, please visit clinicaltrials.gov.

Eisai will also present results from its eribulin platform pipeline, comprised of safety and efficacy data from Study 114 evaluating the liposomal formulation of eribulin (E7389-LF) in various solid tumors (Abstracts #346P and #583P), and a real-world non-interventional study assessing treatment patterns and the clinical effectiveness of HALAVEN in patients with metastatic breast cancer, including triple-negative breast cancer subtype (Abstract #316P). For more information on Study 114, please visit clinicaltrials.gov.

"Our human health care (hhc) mission fuels our drive to serve patients, whether it’s iterative or innovative, pharmacotherapy or psycho-emotional-social resources and services," said Dr. Takashi Owa, Vice President, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. "From our combination clinical trials to Phase 1 results and real-world data in metastatic breast cancer, the research we will present at ESMO (Free ESMO Whitepaper) is evidence of our pursuit of breakthroughs that may impact the lives of patients living with unmet needs."

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 e-posters and presentations is included below. All e-posters will be available on demand via ESMO (Free ESMO Whitepaper)’s website starting Thursday, September 17.

Cancer Type(s)

Study/Trial

Abstract Name

Virtual Presentation
Details

Lenvatinib + pembrolizumab

Melanoma

LEAP-004

Lenvatinib (len) plus pembrolizumab (pembro) for advanced melanoma (MEL) that progressed on a PD-1 or PD-L1 inhibitor: initial results of LEAP-004

Proffered Paper (Late breaker)

Abstract #: LBA44

Ana Maria Arance Fernandez, MD

September 19

16:32-16:44 CEST

(10:32-10:44am EDT)

Channel 2

Solid Tumors (biliary tract cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, glioblastoma and ovarian cancer)

LEAP-005

LEAP-005: Phase 2 Study of Lenvatinib (Len) Plus Pembrolizumab (Pembro) in Patients (Pts) With Previously Treated Advanced Solid Tumors

Proffered Paper (Late breaker)

Abstract #: LBA41

Zarnie Lwin, MD

September 20

14:25-14:37 CEST

(8:25-8:37am EDT)

Channel 2

Non-Small Cell Lung Cancer

LEAP-006

Phase 3 LEAP-006 safety run-in (Part 1): 1L pembrolizumab (Pembro) + chemotherapy (Chemo) with lenvatinib (Len) for metastatic NSCLC

E-Poster

Abstract #: 1313P

Makoto Nishio, MD

Head and Neck Squamous Cell Carcinoma

LEAP-010

LEAP-010: Phase 3 study of first-line pembrolizumab with or without lenvatinib in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)

E-Poster

Trial in Progress

Abstract #: 973TiP

Lillian Siu, MD

Hepatocellular Carcinoma

LEAP-012

LEAP-012 trial in progress: Pembrolizumab plus lenvatinib and transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC) not amenable to curative treatment

E-Poster

Trial in Progress

Abstract #: 1016TiP

Josep M Llovet, MD

Renal Cell Carcinoma

Study 111/ KEYNOTE-146

Correlative serum biomarker analyses: Lenvatinib (LEN) plus pembrolizumab (PEMBRO) in a phase 1b/2 trial in advanced renal cell carcinoma (RCC)

E-Poster

Abstract #: 719P

Chung-Han Lee, MD, PhD

Study 111/ KEYNOTE-146

Phase 2 trial of lenvatinib (LEN) + pembrolizumab (PEMBRO) for progressive disease after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell (mcc) renal cell carcinoma (RCC): Results by independent imaging review and subgroup analyses

E-Poster

Abstract #: 710P

Chung-Han Lee, MD, PhD

Lenvatinib

Thyroid Cancer

HEOR/RWE

Assessment of the efficacy and safety of lenvatinib for the treatment of radioiodine-refractory differentiated thyroid cancer in real-life practice in Russia

E-Poster

Abstract #: 1923P

Ekaterina Borodavina, MD

Osteosarcoma

Study 230

A multicenter, open-label, randomized phase 2 study to compare the efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide and etoposide in children, adolescents and young adults with relapsed or refractory osteosarcoma (OLIE; ITCC-082)

E-Poster

Trial in Progress

Abstract #: 1668TiP

Nathalie Gaspar, MD

Eribulin

Breast Cancer

Study 114

Phase 1 study of the liposomal formulation of eribulin (E7389-LF): Results from the HER2-negative breast cancer expansion

E-Poster

Abstract #: 346P

Kenji Tamura, MD

HEOR/RWE

Real-world treatment patterns and clinical effectiveness outcomes of eribulin in metastatic breast cancer patients in community oncology centers in the United States

E-Poster

Abstract #: 316P

Sarah S. Mougalian, MD

Recurrent or Refractory Solid Tumors

Study 114

Effect of infusion rate, premedication, and prophylactic peg-filgrastim treatment on the safety of the liposomal formulation of eribulin (E7389-LF): Results from the expansion part of a phase 1 study

E-Poster

Abstract #: 583P

Satoru Iwasa, MD

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.

About LENVIMA (lenvatinib)

LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC)
In combination with everolimus, for the treatment of 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 that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy, and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial
Important Safety Information

Warnings and Precautions

Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, 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, 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. 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 1,327 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. Across clinical studies of 1,823 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.

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 (≥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 + pembrolizumab – treated patients were fatigue (65%), hypertension (65%), musculoskeletal pain (65%), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain (33%), headache (33%), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia (26%), dyspnea (24%), cough (21%) and rash (21%).

Adverse reactions led to dose reduction or interruption in 88% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (32%), hypertension (26%), diarrhea (18%), nausea (13%), palmar-plantar erythrodysesthesia (13%), vomiting (13%), decreased appetite (12%), musculoskeletal pain (11%), stomatitis (9%), abdominal pain (7%), hemorrhages (7%), renal impairment (6%), decreased weight (6%), rash (5%), headache (5%), increased lipase (5%) and proteinuria (5%).

Fatal adverse reactions occurred in 3% of patients receiving LENVIMA + pembrolizumab, including gastrointestinal perforation, RPLS with intraventricular hemorrhage, and intracranial hemorrhage.

Serious adverse reactions occurred in 52% of patients receiving LENVIMA + pembrolizumab. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).

Permanent discontinuation due to adverse reaction (Grade 1-4) occurred in 21% of patients who received LENVIMA + pembrolizumab. The most common adverse reactions (>2%) resulting in discontinuation of LENVIMA were gastrointestinal perforation or fistula (2%), muscular weakness (2%), and pancreatitis (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 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.
Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
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. Febrile neutropenia occurred in 0.9% of patients with liposarcoma or leiomyosarcoma, and fatal neutropenic sepsis occurred in 0.9% of patients. 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%).

In patients with liposarcoma and leiomyosarcoma receiving HALAVEN, the most common adverse reactions (≥25%) reported in patients receiving HALAVEN were fatigue (62%), nausea (41%), alopecia (35%), constipation (32%), peripheral neuropathy (29%), abdominal pain (29%), and pyrexia (28%). The most common (≥5%) Grade 3-4 laboratory abnormalities reported in patients receiving HALAVEN were neutropenia (32%), hypokalemia (5.4%), and hypocalcemia (5%). Neutropenia (4.9%) and pyrexia (4.5%) were the most common serious adverse reactions. The most common adverse reactions resulting in discontinuation were fatigue and thrombocytopenia (0.9% each).

Use in Specific Populations
Lactation: Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose.

Hepatic and Renal Impairment: A reduction in starting dose is recommended for patients with mild or moderate hepatic impairment and/or moderate or severe renal impairment.

For more information about HALAVEN, click here for the full Prescribing Information.

About the Eisai and Merck Strategic Collaboration
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 LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in 13 different tumor types (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer, and triple-negative breast cancer) across 19 clinical trials.

On September 10, 2020, Rexahn Pharmaceuticals, Inc. (the "Company") reported that entered into Warrant Exchange Agreements (the "Agreements") with each of Empery Asset Master, Ltd. ("EAM"), Empery Tax Efficient, LP ("ETE") and Empery Tax Efficient II, LP ("ETE II" and together with EAM and ETE, the "Empery Entities") (Filing, 8-K, Rexahn, SEP 10, 2020, View Source [SID1234565015]). The Company previously issued to the Empery Entities (a) warrants to purchase an aggregate of 104,168 shares (on a post-reverse stock split basis) of its common stock, par value $.0001 per share (the "Common Stock") pursuant to the offering described in the Company’s Current Report on Form 8-K filed with the Securities and Exchange Commission ("SEC") on November 6, 2015 (the "2015 Warrants"), (b) warrants to purchase an aggregate of 27,212 shares (on a post-reverse stock split basis) of Common Stock pursuant to the offering described in the Company’s Current Report on Form 8-K filed with the SEC on October 13, 2017 (the "2017 Warrants"), and (c) warrants to purchase an aggregate of 83,335 shares (on a post-reverse stock split basis) of Common Stock pursuant to the offering described in the Company’s Current Report on Form 8-K filed with the SEC on January 25, 2019 (the "2019 Warrants" and together with the 2015 Warrants and the 2017 Warrants, the "Warrants"). Pursuant to the Agreements, on September 10, 2020, the Company issued an aggregate of 16,324, 9,081 and 30,774 shares of Common Stock to EAM, ETE and ETE II, respectively, in exchange for the surrender and cancellation of the Warrants held by such holder.

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On September 10, 2020 Junshi Biosciences (HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development and commercialization of novel therapies ,reported that the US Food and Drug Administration (FDA) has recently granted Breakthrough Therapy designation (BTD) to Toripalimab for the treatment of nasopharyngeal carcinoma (Press release, Shanghai Junshi Bioscience, SEP 10, 2020, View Source [SID1234565012]). Toripalimab is the first anti-PD-1 antibody from China to receive the Breakthrough Therapy designation, which is another important regulatory milestone for Toripalimab after FDA granted orphan drug designation for this indication in May 2020.

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"The Breakthrough Therapy designation granted by FDA recognizes the significant clinical benefits Toripalimab has shown for the treatment of nasopharyngeal carcinoma," commented Dr. Ning Li, Chief Executive Officer of Junshi Biosciences. "Junshi prioritizes cancer types with high prevalence in China such as nasopharyngeal carcinoma, lung and liver cancer, but we found that great unmet medical needs also exist in other countries where patients are endangered by this deadly disease. The BTD will allow us to work with the FDA closely to bring the therapy to patients worldwide expeditiously."

The Breakthrough Therapy designation is derived from the provisions of the US Food and Drug Administration Safety and Innovation Act (FDASIA) and aims to expedite the development and review process of drugs intended to treat a serious condition when preliminary clinical evidence indicates that the drug may result in substantial improvement over available therapies on a clinically significant endpoint. BTD is another important new drug review channel for the FDA following the fast track, accelerated approval, and priority review. According to regulations, the drug development process that has obtained breakthrough drug therapy certification will receive closer guidance and various forms of support, including from senior FDA officials, to ensure that patients are provided with new treatment options in the shortest time. The FDA Breakthrough Therapy designation for Toripalimab for the treatment of nasopharyngeal carcinoma can significantly support and accelerate the commercial development plan of Toripalimab in the United States.

About NPC
Nasopharyngeal carcinoma (NPC) is a malignant tumor that occurs in the mucosal epithelium of the nasopharynx, mostly in the parietal and lateral walls of the nasopharynx, especially in the pharyngeal recess. There were 129,000 new cases worldwide in 2018. NPC is one of the most common malignant tumors in China. The incidence of NPC in Chinese population is significantly higher than the world average. It is particularly higher in certain geographical areas. For example, the annual incidence of NPC in Guangdong is 20 to 40 per 100,000. Early nasopharyngeal carcinoma patients have a good therapeutic effect with 90% can be cured or be tumor-free for a long time. However, early nasopharyngeal carcinoma patients lack specific clinical symptoms. About 80% of them have entered the middle and advanced stage when clinically diagnosed, with lymph node metastasis or distant metastasis. After development of distant metastasis, the 5-year survival rate is less than 50%.

About Toripalimab
Toripalimab is an anti-PD-1 monoclonal antibody developed by Junshi Biosciences.

Toripalimab received its first approval for 2nd line treatment of metastatic melanoma on December 17, 2018 in China and was commercially launched in February 2019. So far, more than 30 clinical studies covering more than ten indications have been carried out in China, the United States and other countries.

In April 2020, the supplemental New Drug Application ("NDA") of Toripalimab Injection for the treatment of new indications of recurrent/metastatic nasopharyngeal carcinoma after failure of second-line and above systemic treatment has been accepted by the NMPA. The supplemental NDA is the world’s first NDA of anti-PD-1 monoclonal antibody for the treatment of recurrent/metastatic nasopharyngeal carcinoma. In addition, JUPITER-02 study (NCT03581786), a Phase III clinical study of Toripalimab Injection combined with chemotherapy as a first-line treatment in patients with recurrent or metastatic nasopharyngeal carcinoma has completed the enrollment. In May 2020, the supplemental NDA of Toripalimab Injection for the treatment of new indications of locally advanced or metastatic urothelial carcinoma after systemic treatment has been accepted by the NMPA.

In March 2020, Toripalimab in combination with axitinib in the treatment of mucosal melanoma was granted the orphan-drug designation by the FDA. In May 2020, Toripalimab was granted the orphan-drug designation by the FDA in the treatment of nasopharyngeal carcinoma.

On September 10, 2020 Codiak BioSciences, a company developing therapies based on tiny bubbles secreted by cells, reported that it is lining up an IPO as it prepares for the first tests of its technology in humans later this year (Press release, Codiak Biosciences, SEP 10, 2020, View Source [SID1234564997]).

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In paperwork filed with securities regulators late Wednesday, Codiak set a preliminary $100 million goal for its stock market debut. The Cambridge, MA-based biotech has applied for a Nasdaq listing under the stock symbol "CDAK."

The research of Codiak focuses on exosomes, extracellular vesicles that carry proteins, genetic material, and other substances in and out of cells. Exosomes function as a messenger system between cells, transporting molecules that alter the function of a recipient cell, Codiak says in its filing. Because these vesicles evolved with humans naturally, they don’t trigger an immune response. Exosomes can also be engineered for selective targeting of particular cells, and they can carry an array of payloads.

Codiak produces its therapies by engineering exosomes to carry drug molecules, either on the surface or the inside of the vesicle. The company says that its proprietary technology, called engEx, can produce therapeutic exosomes at scale and according to pharmaceutical standards.

The lead Codiak program, exoSTING, is being developed as a treatment for solid tumors. This Codiak exosome is engineered to carry molecules inside the vesicle that are intended to elicit an anti-tumor immune response by hitting the stimulator of interferon genes (STING) pathway of the innate immune system. Other attempts to drug this pathway have run into problems delivering the therapy to a cell while also avoiding toxic effects to healthy cells, Codiak says in its filing. The company says its exosome drug could overcome those limitations.

The cancers that Codiak aims to treat with exoSTING include metastatic head and neck squamous cell cancer, triple-negative breast cancer, cutaneous squamous cell carcinoma, and anaplastic thyroid carcinoma. If a Phase 1/2 clinical trial begins later this year as expected, the company says preliminary data could become available by the middle of 2021.

The next program in Codiak’s pipeline is exoIL-12, an exosome that’s engineered with the cytokine interleukin 12 (IL-12) on the surface of the vesicle. Other companies are also pursuing therapies that incorporate IL-12. Codiak notes IL-12 has elicited an anti-tumor immune response in its preclinical research and the clinical studies of others. But the company adds that experimental IL-12 therapies have been hampered by the unwanted spread of the therapy’s effects throughout the body, particularly the liver. Codiak says its exosome-delivered IL-12 drug could avoid such problems.

Codiak is developing exoIL-12 to treat solid tumors for which the IL-12 pathway has been established. These cancers include melanoma, Merkel cell carcinoma, Kaposi sarcoma, glioblastoma, and triple-negative breast cancer. The initial focus for this drug is early-stage cutaneous T cell lymphoma. A Phase 1 study is planned to start later this year; preliminary data are expected by the end of 2020. Additional data, including efficacy results, could become available by the middle of next year.

Other companies developing exosome therapies include Aruna Bio, AstraZeneca (NYSE: AZN), Evox Therapeutics, and PureTech Health. Startups are also getting into the mix. Harvard University spinout Vesigen emerged in July with $28.5 million in Series A financing to fund the development of its extracellular vesicle-based therapies.

The Wednesday IPO filing is Codiak’s second attempt to join the public markets. The company initially filed to go public in April 2019 but withdrew those plans three months later. Codiak’s timeline for the start of clinical trials is unchanged from last year. But Codiak can now make its case to investors with some additional validation. In June, Codiak inked a two-year research deal with Sarepta Therapeutics (NASDAQ: SRPT), which agreed to pay its new partner $72.5 million in upfront and near-term milestone payments. Sarepta is interested in exploring Codiak’s exosome technology as a way to deliver genetic medicines for muscular disorders without triggering an immune response.

The Sarepta deal is Codiak’s second partnership with a larger biopharmaceutical company. Early last year, the company began an alliance with Jazz Pharmaceuticals (NASDAQ: JAZZ), which paid $56 million up front in a deal spanning five cancer therapies.

Codiak launched in 2015 with financial backing from an investor group that included Flagship Pioneering (known then as Flagship Ventures), Arch Venture Partners, and Fidelity Management & Research. Those firms are Codiak’s largest stockholders, owning 28.3 percent, 18.9 percent, and 14.1 percent of the company respectively, according to the filing.

Codiak reported that its cash holdings as of June 30 totaled $50.9 million. The company says it will use the IPO proceeds to fund clinical tests of its two lead exosome drug candidates, and to finance further development of programs in earlier stages of development.