On March 29, 2021 F-star Therapeutics, Inc. (NASDAQ: FSTX), a clinical-stage biopharmaceutical company dedicated to developing next generation immunotherapies to transform the lives of patients with cancer, reported 2020 full-year financial results and provides corporate update (Press release, F-star, MAR 29, 2021, View Source [SID1234577277]).

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2020 was a year of transformation for F-star. The Company successfully listed on NASDAQ and advanced multiple programs into the clinic. F-star also presented Phase 1 data on its most advanced program FS118, and dosed patients in two additional clinical trials with FS222 and FS120. The Company continued to deliver on its long-term collaborations and ended the year with a total of four clinical stage programs, and a robust pipeline generated from its unique tetravalent bispecific platform technology.

Eliot Forster, CEO of F-star Therapeutics, Inc., said, "F-star finished the year in a strong position, having made significant progress towards our mission of transforming the lives of patients with cancer. Listing on NASDAQ at the end of 2020 has accelerated our plans and we now have four programs in the clinic with the potential to help patients where there is currently significant unmet need. FS118 (LAG-3/PD-L1 bispecific), the most advanced of these, showed encouraging signs of clinical activity with a novel mechanism of action for acquired resistance patients and a proof-of-concept trial in PD-1 resistant head and neck cancer patients is now underway. FS222, a potentially best-in-class bispecific antibody targeting CD137 (4-1BB) and PD-L1, is in Phase 1. FS120, a first-in-class CD137/OX40 mAb² dual agonist bispecific antibody, is underway with a Phase 1 in monotherapy and PD-1 combination. SB 11285, a second-generation STING agonist for intravenous administration continues in Phase 1/2 trial, including combination with TecentriqTM."

PROGRAM DEVELOPMENTS

First Patient Dosed in FS222 Phase 1 Clinical Trial: The first patient dosed in a Phase 1 trial evaluating FS222, a potentially best-in-class bispecific antibody targeting CD137 and PD-L1. With Clinical Trial Application (CTA) acceptance in Spain announced in November 2020, this multicenter, open-label, first-in-human trial will evaluate the safety, tolerability, and early signs of efficacy of FS222 in adult patients diagnosed with advanced malignancies.

FS118 European patent protection granted: The European Patent Office (EPO) granted a patent in January 2021 with claims protecting the composition of matter of F-star’s FS118 molecule. The expiry date of the patent, not including any potential extensions to the standard 20-year term of protection, is expected to be June 2037.

First Patient Dosed in FS120 Phase 1 Clinical Trial: The first patient was dosed in December of 2020. Preclinical data for FS120, a first-in-class dual-agonist tetravalent bispecific antibody targeting CD137 (4-1BB) and OX40, showed potential for improved efficacy with either checkpoint inhibitors or chemotherapy to drive anti-tumor responses without the need for Fcg receptor activation.

Multiple Posters at 2020 SITC (Free SITC Whitepaper) Conference: In November of 2020, posters were presented on the FS118 Phase 1 trial, the FS118 unique bispecific mechanism of action and on the SB 11285 second generation STING agonist progress, both in monotherapy and in combination with PD-L1.

FS222 Poster Presentation at AACR (Free AACR Whitepaper): F-star will present a poster at AACR (Free AACR Whitepaper) on April 10, 2021 titled ‘FS222, a Tetravalent Bispecific Antibody Targeting CD137 and PD-L1, is Designed for Optimal CD137 Interactions Resulting in Potent T cell Activation Without Toxicity’.

SUMMARY OF ANTICIPATED PROGRAM MILESTONES

FULL-YEAR 2020 FINANCIAL UPDATE

Cash Position – Cash and cash equivalents totalled $18.5M for the year ended December 31, 2020, compared to $4.9M for the year ended December 31, 2019. The increase in cash and cash equivalents was driven primarily by proceeds from the PIPE financing and cash resulting from the business combination in November 2020, and proceeds from our collaborations, offset by the Company’s operational needs during 2020.

R&D Expense – R&D expenses were $14.1M for the year ended December 31, 2020, compared to $31.4 M for the 2019 prior year end. The decrease in R&D expense was primarily due to the near completion of the FS118 Phase 1 study and the start-up costs of the FS118 proof of concept study in late 2020, decreased manufacturing costs resulting from manufacturing batch runs incurred in late 2019 supplying 2020 needs, a decrease in other R&D costs due to timing of development activities and the annual UK research and development tax credit.

G&A Expense – G&A expenses were $19.5M for the year ended December 31, 2020, compared to $15.3M for the full year 2019. This increase in G&A expense was primarily due to increased compensation related costs, non-cash share-based compensation expense, transaction costs, facilities and IT costs offset by reduced travel and conferences costs, primarily related to COVID-19 travel restrictions.

Net Loss Attributable to Common Shareholders – Net loss attributable to common shareholders was $25.6 million or ($9.69) per share, for the year ended December 31, 2020, as compared to a net loss of $23.0 million or ($14.89) per share for the year ended December 31, 2019.CONFERENCE CALL AND WEBCAST

F-star will host a conference call today, March 29, 2021 beginning at 9:00 AM EDT. To join the webcast, go to website. The recording will be available on the company’s website in the Investors & News section.

On March 19, 2021 Xenetic Biosciences, Inc. (NASDAQ:XBIO) ("Xenetic" or the "Company"), a biopharmaceutical company focused on advancing XCART, a personalized CAR T platform technology engineered to target patient- and tumor-specific neoantigens, reported it has received approval to commence its exploratory patient biopsy study in Eastern Europe evaluating XCART (Press release, Xenetic Biosciences, MAR 29, 2021, View Source [SID1234577276]).

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"The start of this study represents an important step forward in our preclinical development program, and we look forward to evaluating the XCART platform applied to tumor samples from NHL patients currently under evaluation or in treatment at the study site. Access to biopsy and blood samples from patients with various subtypes and stages of disease will allow us to refine the XCART upstream workflow for isolating and screening tumor-specific neoantigens in order to identify and characterize potential tumor-specific CAR constructs. Importantly, the format of this study will also allow us to evaluate certain clinical parameters relevant to potential Phase 1 studies in the future that would involve dosing of patients with XCART-designed autologous CAR T products. We expect the data generated under this exploratory study to position the Company to conduct U.S. IND-enabling studies," stated Curtis Lockshin, Ph.D., Chief Scientific Officer of Xenetic.

The exploratory study will be conducted at the Vitebsk Regional Clinical Oncological Center in Minsk, Belarus, and will enroll adult B-Cell NHL patients. When sufficient experience is gained through this exploratory study, the collaborations being leveraged in the XCART development program may be expanded to include development and qualification of manufacturing processes for producing autologous XCART T-Cells. The work being performed under these collaborations is expected to position the Company to conduct IND-enabling studies in the United States.

Xenetic is leveraging academic collaborations with Scripps Research and PJSC Pharmsynthez to advance the development of the XCART technology for B-Cell malignancies. Both Scripps Research as well as Pharmsynthez and its collaborators have extensive experience with XCART, having co-invented the technology, and have integral roles in the Company’s preclinical development activities.

On March 29, 2021 Adagene Inc. (Nasdaq: ADAG), a platform-driven, clinical-stage biopharmaceutical company committed to transforming the discovery and development of novel antibody-based immunotherapies, reported the interim dose-escalation data up to 0.3 mg/kg in its ongoing Phase 1 clinical trial in Australia evaluating the safety and tolerability of ADG116 in patients with advanced/metastatic solid tumors (Press release, Adagene, MAR 29, 2021, View Source [SID1234577275]). ADG116 is a fully human, anti-CTLA-4 monoclonal antibody (mAb), designed to target a unique conserved epitope of CTLA-4 and utilizes Adagene’s proprietary NEObody platform technology. ADG116 is designed to balance safety and efficacy through a novel mechanism of action; ADG116 maintains its original physiological function via partial blocking of CTLA-4 ligand binding, and in conjunction, depletes Treg in the tumor microenvironment via strong antibody-dependent cellular cytotoxicity (ADCC).

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Interim data for the ongoing Phase 1 clinical trial:

· Safety: Analysis of all safety data generated to date demonstrates that ADG116 has been well-tolerated in more than 10 patients with no dose-limiting toxicities or unexpected safety signals. No drug related Grade 3 and Grade 4 toxicities have been observed.

·Notable findings in pharmacodynamics: A dose-dependent change in CD8+ and CD4+ TEM / Treg ratios, important pharmacodynamic (PD) biomarkers indicating immune activation, was observed for patients dosed by ADG116. In particular, a patient, refractory to prior pembrolizumab therapy (> 25 cycles), demonstrated striking increases in T and NK cells, and CD8+ and CD4+ TEM / Treg ratios. The Grade 1 treatment-related pruritus of this patient is a clinical symptom consistent with immune-mediated action of ADG116 treatment.

· Pharmacokinetics: The terminal half-life of ADG116 was within the normal range of IgG1 based antibodies.

·Clinical proof of mechanism: The Phase 1 dose escalation data demonstrates the clinical proof of mechanism for ADG116 in targeting CTLA-4, consistent with preclinical observations for the potency of ADG116 starting from 0.03 to 0.3 mg/kg.

"We are encouraged by the positive PD marker signals and safety data," said Peter Luo, Ph.D., Co-founder, Chief Executive Officer and Chairman of Adagene. "It is particularly striking to observe immune activation biomarkers at 0.03 mg/kg, especially in the patient refractory to prior pembrolizumab therapies. We believe ADG116 has the potential to overcome the limitations of anti-CTLA-4 checkpoint inhibitors, extending the market potential beyond current anti-CTLA-4 inhibitors in both monotherapy and combination settings. Our highly differentiated anti-CTLA-4 therapeutics hold the potential to improve the clinical benefits by expanding clonal diversity, infiltrating into cold tumors, and treating patients resistant/refractory to current immuno-therapies."

"We look forward to developing a comprehensive clinical program to evaluate each of our anti-CTLA-4 assets," continued Dr. Luo. "We will leverage the modality-specific features demonstrated in the preclinical setting, that enable high-fidelity translation into the clinic by targeting unique, highly conserved epitope of CTLA-4 with broad species cross-reactivity. We remain committed to maximizing the full potential of our unique anti-CTLA-4 approach."

The progression of the Phase 1 dose-escalation trial to the 5th dose, a 0.3mg/kg dose level, builds on encouraging signs of PD markers, normal PK data, strong early clinical data, extensive preclinical and safety tolerability data and a successful Safety Review Committee meeting. Multiple clinical sites are currently open in Australia. In this ongoing Phase 1 clinical trial of ADG116 in patients with advanced/metastatic solid tumors, no dose-limiting toxicity (DLT), treatment-related serious adverse events (SAEs), colitis or hepatitis have been observed. With favorable clinical data to date, Adagene looks forward to expanding the ongoing global Phase 1 trial, with the acceptance of revised study protocol by FDA to expand the trial in the U.S. Adagene has also obtained confirmation from China NMPA to proceed with revised protocol submission at higher starting dose than that in the original submission. Additional information about this clinical trial is available at ClinicalTrials.gov using the identifier: NCT04501276.

About ADG116

ADG116 is a fully human ligand-blocking anti-CTLA-4 mAb generated using NEObody technology. ADG116 is a differentiated anti-CTLA-4 approach, which leverages Adagene’s Dynamic Precision technology to target a conserved epitope with broad species cross-reactivity for translational fidelity and a unique CTLA-4 mechanism of action. In preclinical studies, ADG116 was observed to have softer CTLA-4 ligand blocking and stronger ADCC for depleting regulatory T-cells than ipilimumab. In a head-to-head in vivo efficacy study, ADG116 was observed to have at least a five-fold greater preclinical antitumor activity in comparison with ipilimumab. In preclinical studies, ADG116 was well tolerated in rats and cynomolgus monkeys in four-week repeat-dose GLP toxicology studies at doses up to 30 mg/kg, and demonstrated an encouraging antitumor response in multiple immune-competent mouse tumor models in a dose-dependent manner both as a single agent (showing initial response at 0.02mg/kg, and complete response at 0.1 mg/kg for tumor size of ~100mm3 in sensitive tumor models) and in combination with other therapies.

On March 29, 2021 TG Therapeutics, Inc. (NASDAQ: TGTX), reported the completion of the rolling submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) requesting approval of ublituximab, the Company’s investigational glycoengineered anti-CD20 monoclonal antibody, in combination with UKONIQTM (umbralisib) , the Company’s once-daily, oral, inhibitor of PI3K-delta and CK1-epsilon, as a treatment for patients with chronic lymphocytic leukemia (CLL) (Press release, TG Therapeutics, MAR 29, 2021, View Source [SID1234577274]). The U.S. FDA previously granted Fast Track designation to the combination of ublituximab and umbralisib (U2) for the treatment of adult patients with CLL and orphan drug designation for ublituximab in combination with umbralisib for the treatment of CLL. The BLA submission was based on the results of the UNITY-CLL trial, a global Phase 3 trial evaluating the combination of umbralisib plus ublituximab (U2) compared to obinutuzumab plus chlorambucil in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL).

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Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics stated, "The rapid completion of this BLA submission is a critical step forward in our mission to bring our first proprietary combination regimen to patients with both treatment naïve and relapsed or refractory chronic lymphocytic leukemia. The FDA has previously granted the U2 combination both fast track designation as well as orphan drug designation for patients with CLL and we look forward to continuing to work closely with the FDA with the goal of bringing this novel treatment regimen to patients as quickly as possible." Mr. Weiss continued, "I want to thank the patients, their families and caregivers, as well as the research teams who participated in the UNITY-CLL trial, and also commend the TG team for their hard work to get this submission completed ahead of schedule."

ABOUT UNITY-CLL PHASE 3 TRIAL
UNITY-CLL is a global Phase 3 randomized controlled clinical trial comparing the combination of ublituximab plus UKONIQ (umbralisib), or U2, to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL). The trial randomized patients into four treatment arms: ublituximab single agent, UKONIQ single agent, ublituximab plus UKONIQ, and an active control arm of obinutuzumab plus chlorambucil. A prespecified interim analysis was conducted to assess the contribution of ublituximab and UKONIQ in the U2 combination arm and allowed for the termination of the single agent arms. Accordingly, the UNITY-CLL Phase 3 trial continued enrollment in a 1:1 ratio into the two combination arms: the investigational arm of U2 and the control arm of obinutuzumab plus chlorambucil. Approximately 420 subjects enrolled to the two combination arms and approximately 60% of patients were treatment-naïve and 40% were relapsed or refractory. The primary endpoint for this study was superior progression-free survival (PFS) for the U2 combination compared to the control arm to support the submission of the U2 combination in CLL. The trial met its primary endpoint and results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. The UNITY-CLL Phase 3 trial is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA).

ABOUT CHRONIC LYMPHOCYTIC LEUKEMIA
Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. It is estimated there will be more than 20,000 new cases of CLL diagnosed in the United States in 2020 and approximately 45,000 new cases globally in 2020.1,2 Although signs and symptoms of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of malignant cells.

ABOUT FAST TRACK
Fast Track is a program designed to expedite the development and review of drugs that treat serious conditions and that demonstrate the potential to address an unmet medical need. Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy that may be potentially better than available therapy.

A drug that receives Fast Track designation is eligible for more frequent interactions with the FDA, priority review if relevant criteria are met, and rolling submission of the Biologics License Application or New Drug Application.

ABOUT ORPHAN DRUG DESIGNATION
Orphan drug designation is granted by the FDA to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S. Orphan drug designation provides certain incentives which may include tax credits towards the cost of clinical trials and prescription drug user fee waivers. If a product that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan product exclusivity.

On March 29, 2021 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that the European Medicines Agency (EMA) has confirmed it has accepted for review applications for the use of its in-house discovered multiple receptor tyrosine kinase inhibitor, lenvatinib mesylate (product name: LENVIMA / Kisplyx, "lenvatinib"), in combination with anti-PD-1 therapy pembrolizumab (brand name: KEYTRUDA), developed by Merck & Co., Inc., Kenilworth, N.J., U.S.A., (known as MSD outside the United States and Canada) as a treatment f or patients with advanced renal cell carcinoma (RCC) and advanced endometrial carcinoma (EC), respectively (Press release, Eisai, MAR 29, 2021, View Source [SID1234577273]) (Press release, Eisai, MAR 29, 2021, View Source [SID1234577273]).

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The application requesting an indication of lenvatinib in combination with pembrolizumab for RCC is based on the results of the pivotal Phase 3 CLEAR study (Study 307/KEYNOTE-581) for the first-line treatment of patients with advanced RCC, which were presented at 2021 Genitourinary Cancers Symposium (ASCO GU), and simultaneously published in the New England Journal of Medicine in February 2021. In this trial, lenvatinib plus pembrolizumab demonstrated statistically significant and clinically meaningful improvements in the primary endpoint of progression-free survival (PFS) as well as key secondary endpoints of overall survival (OS) and objective response rate (ORR) versus sunitinib.

In addition, the application requesting an indication of lenvatinib in combination with pembrolizumab for EC is based on the results of the pivotal Phase 3 Study 309/KEYNOTE-775 for the treatment of patients with advanced endometrial carcinoma, following one prior platinum-based regimen in any setting, which were presented at the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer in March 2021. In this trial, lenvatinib plus pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in the primary endpoints of PFS and OS as well as the secondary endpoint of ORR versus chemotherapy (treatment of physician’s choice of doxorubicin or paclitaxel).

The safety profile of the lenvatinib plus pembrolizumab combination in these studies was generally consistent with previously reported studies.

Worldwide, it is estimated that there were more than 430,000 new cases of kidney cancer diagnosed and nearly 180,000 deaths from the disease in 2020.1 In Europe, there were more than 138,000 new cases and more than 54,000 deaths in 2020.1 RCC is by far the most common type of kidney cancer; about nine out of 10 kidney cancers are RCC.2 Approximately 30% of patients with RCC will have metastatic disease at diagnosis, and as many as 40% will develop metastases after primary surgical treatment for localized RCC.3,4

In 2020, it is estimated there were more than 417,000 new cases of uterine body cancer diagnosed worldwide and nearly 97,000 deaths from the disease.5 In Europe, there were more than 130,000 new cases and more than 29,000 deaths in 2020.5 EC is the most common type of uterine body cancer. It is considered that more than 90% of uterine body cancers occur in the endometrium.6

Survival rates vary highly depending on the stage of diagnosis, and the five-year survival rates for metastatic RCC and metastatic EC are 12% and 17%, respectively. Both diseases have poor prognoses.

In March 2018, Eisai and Merck & Co., Inc., Kenilworth, N.J., U.S.A., 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 the anti-PD-1 therapy pembrolizumab from Merck & Co., Inc., Kenilworth, N.J., U.S.A.

Eisai positions oncology as a key therapeutic area and is aiming to discover innovative new medicines with the potential to cure cancer. Eisai is committed to expanding the potential clinical benefits of lenvatinib for cancer treatment, as it seeks to contribute to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families and healthcare professionals.

1. About lenvatinib mesylate (product name: LENVIMA / Kisplyx)
Lenvatinib, discovered and developed by Eisai, is an orally available kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib 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.

In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.

Currently, lenvatinib has been approved for monotherapy as a treatment for thyroid cancer in over 70 countries including Japan, in Europe, China and in Asia, and the United States for radioiodine-refractory differentiated thyroid cancer. In addition, lenvatinib has been approved for monotherapy as a treatment for unresectable hepatocellular carcinoma in over 65 countries including Japan, the United States, in Europe, China and in Asia. It is also approved in combination with everolimus as a treatment for renal cell carcinoma following prior antiangiogenic therapy in over 60 countries, including the United States, in Europe and Asia. In Europe, the agent was launched under the brand name Kisplyx for renal cell carcinoma. In addition, it is approved in combination with pembrolizumab as a treatment for endometrial cancer 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 in over 10 countries including the United States, Canada and Australia. Continued approval for this indication is contingent upon verification and description of clinical benefit in the confirmatory trials. Lenvima has also been approved for monotherapy as a treatment for unresectable thymic carcinoma in Japan.

2. About the CLEAR Study (Study 307/KEYNOTE-581)
The CLEAR Study (Study 307/KEYNOTE-581) is a Phase 3, multi-center, randomized, open-label trial (ClinicalTrials.gov, NCT02811861(New Window)) evaluating lenvatinib in combination with pembrolizumab or in combination with everolimus versus sunitinib for the first-line treatment of patients with advanced RCC. The primary endpoint is PFS by independent review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key secondary endpoints include OS, ORR and safety. A total of 1,069 patients were randomized to one of three treatment arms to receive lenvatinib (20 mg orally once daily) in combination with pembrolizumab (200 mg intravenously every three weeks); or lenvatinib (18 mg orally once daily) in combination with everolimus (5 mg orally once daily); or sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks off treatment).

In the trial’s primary endpoint of PFS, as assessed by independent review per RECIST v1.1, lenvatinib plus pembrolizumab reduced the risk of disease progression or death by 61% (HR=0.39 [95% CI: 0.32-0.49]; p<0.001), with a median PFS of 23.9 months (95% CI: 20.8-27.7) versus 9.2 months (95% CI: 6.0-11.0) for patients who received sunitinib. In the trial’s key secondary endpoints, lenvatinib plus pembrolizumab reduced the risk of death by 34% (HR=0.66 [95% CI: 0.49-0.88]; p=0.005) versus patients who received sunitinib. Median OS was not reached in either treatment arm after a median follow-up of 27 months. Treatment with lenvatinib plus pembrolizumab resulted in an ORR of 71.0% (95% CI: 66.3-75.7), with a complete response (CR) rate of 16.1% and a partial response (PR) rate of 54.9%, versus an ORR of 36.1% (95% CI: 31.2-41.1), with a CR rate of 4.2% and a PR rate of 31.9%, for patients who received sunitinib (relative risk=1.97 [95% CI: 1.69-2.29]). Median duration of response (DOR) for patients who received lenvatinib plus pembrolizumab was 25.8 months (95% CI: 22.1-27.9) versus 14.6 months (95% CI: 9.4-16.7) for patients who received sunitinib.

In the lenvatinib plus pembrolizumab arm, treatment-related adverse events (TRAEs) led to discontinuation of lenvatinib in 18.5% of patients, of pembrolizumab in 25.0% of patients, and of both in 9.7% of patients. In the sunitinib arm, TRAEs led to discontinuation of sunitinib in 10.0% of patients. Grade 5 TRAEs occurred in 1.1% of patients in the lenvatinib plus pembrolizumab arm versus 0.3% of patients in the sunitinib arm. Grade ≥3 TRAEs occurred in 71.6% of patients in the lenvatinib plus pembrolizumab arm versus 58.8% of patients in the sunitinib arm. The most common TRAEs of any grade occurring in at least 20% of patients in the lenvatinib plus pembrolizumab arm were diarrhea (54.5%), hypertension (52.3%), hypothyroidism (42.6%), decreased appetite (34.9%), fatigue (32.1%) and stomatitis (32.1%). In the sunitinib arm, the most common TRAEs of any grade occurring in at least 20% of patients were diarrhea (44.4%), hypertension (39.1%), stomatitis (37.4%), hand-foot syndrome (35.9%), fatigue (32.1%) and nausea (27.6%).

3. About Study 309/KEYNOTE-775
Study 309/KEYNOTE-775 is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT03517449(New Window)) evaluating lenvatinib in combination with pembrolizumab in patients with advanced endometrial cancer following one prior platinum-based regimen in any setting. The dual primary endpoints are PFS, as assessed by blinded independent central review (BICR) per RECIST v1.1, and OS. Select secondary endpoints include ORR by BICR per RECIST v1.1 and safety/tolerability. Of the 827 patients enrolled, 697 patients had tumors that were mismatch repair proficient (pMMR), and 130 patients had tumors that were mismatch repair deficient (dMMR). Patients were randomized 1:1 to receive lenvatinib (20 mg orally once daily) in combination with pembrolizumab (200 mg intravenously [IV] every three weeks) for up to 35 cycles (approximately two years); or chemotherapy treatment of physician’s choice (TPC) of either doxorubicin 60 mg/m2 IV every three weeks for up to a maximum cumulative dose of 500 mg/m2 or paclitaxel 80 mg/m2 IV on a 28-day cycle [three weeks of receiving weekly paclitaxel and one week of not receiving paclitaxel]).

The study met the dual primary endpoints of PFS, as assessed by BICR per RECIST v1.1, OS, as well as the secondary efficacy endpoint of ORR, as assessed by BICR per RECIST v1.1, in the all-comer population (pMMR and dMMR) and in the pMMR subgroup. Median follow-up was 11.4 months for both the all-comer population and pMMR subgroup. A statistically significant and clinically meaningful improvement in PFS was seen in the all-comer population, in which lenvatinib plus pembrolizumab (n=411) reduced the risk of disease progression or death by 44% (HR=0.56 [95% CI: 0.47-0.66]; p<0.0001), with a median PFS of 7.2 months (95% CI: 5.7-7.6; number of events=281) versus 3.8 months (95% CI: 3.6-4.2; number of events=286) for patients who received TPC (n=416). Additionally, a statistically significant and clinically meaningful improvement in OS was seen in the all-comer population, in which lenvatinib plus pembrolizumab reduced the risk of death by 38% (HR=0.62 [95% CI: 0.51-0.75]; p<0.0001), with a median OS of 18.3 months (95% CI: 15.2-20.5; number of events=188) versus 11.4 months (95% CI: 10.5-12.9; number of events=245) for patients who received TPC. The safety profile of lenvatinib plus pembrolizumab was generally consistent with the established safety profiles of the individual monotherapies.

In the all-comer population, the secondary efficacy endpoint of ORR was 31.9% (95% CI: 27.4-36.6), with a CR rate of 6.6% and a PR rate of 25.3%, for patients who received lenvatinib plus pembrolizumab versus 14.7% (95% CI: 11.4-18.4), with a CR rate of 2.6% and a PR rate of 12.0% for patients who received TPC (ORR difference versus TPC: 17.2 percentage points; p<0.0001). For patients who responded, the median duration of response (DOR) was 14.4 months (range: 1.6-23.7) for patients who received lenvatinib plus pembrolizumab versus 5.7 months (range: 0.0-24.2) for patients who received TPC.

Results were similar across the all-comer population and the pMMR subgroup. In the pMMR subgroup, lenvatinib plus pembrolizumab reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI: 0.50-0.72]; p<0.0001), with a median PFS of 6.6 months (95% CI: 5.6-7.4; number of events=247) versus 3.8 months (95% CI: 3.6-5.0; number of events=238) for patients who received TPC. Lenvatinib plus pembrolizumab reduced the risk of death by 32% (HR=0.68 [95% CI: 0.56-0.84]; p =0.0001), with a median OS of 17.4 months (95% CI: 14.2-19.9; number of events=165) versus 12.0 months (95% CI: 10.8-13.3; number of events=203) for patients who received TPC. The secondary endpoint of ORR was 30.3% (95% CI: 25.5-35.5), with a CR rate of 5.2% and a PR rate of 25.1%, for patients who received lenvatinib plus pembrolizumab versus 15.1% (95% CI: 11.5-19.3), with a CR rate of 2.6% and a PR rate of 12.5%, for patients who received TPC (ORR difference versus TPC: 15.2 percentage points: p<0.0001). For patients who responded, the median DOR was 9.2 months (range: 1.6-23.7) for patients who received lenvatinib plus pembrolizumab versus 5.7 months (range: 0.0-24.2) for patients who received TPC.

In the all-comer population, in the lenvatinib plus pembrolizumab arm (n=406), any grade treatment-emergent adverse events (TEAEs) led to discontinuation of lenvatinib in 30.8% of patients, of pembrolizumab in 18.7% of patients, and of both in 14.0% of patients. In the TPC arm (n=388), any grade TEAEs led to discontinuation of chemotherapy in 8.0% of patients. Grade 5 TEAEs of any cause occurred in 5.7% of patients in the lenvatinib plus pembrolizumab arm and in 4.9% of patients in the TPC arm. Grade ≥3 TEAEs occurred in 88.9% of patients in the lenvatinib plus pembrolizumab arm and in 72.7% of patients in the TPC arm. In the lenvatinib plus pembrolizumab arm, the most common TEAEs of any grade occurring in at least 25% of patients were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), decreased appetite (44.8%), vomiting (36.7%), weight decrease (34.0%), fatigue (33.0%), arthralgia (30.5%), proteinuria (28.8%), anemia (26.1%), constipation (25.9%), and urinary tract infection (25.6%). In the TPC arm, the most common TEAEs of any grade occurring in at least 25% of patients were anemia (48.7%), nausea (46.1%), neutropenia (33.8%), alopecia (30.9%), and fatigue (27.6%). Median treatment duration was 231 days (range: 1-817) with lenvatinib plus pembrolizumab and 104.5 days (range: 1-785) with TPC.

4. About the Merck & Co., Inc., Kenilworth, N.J., U.S.A. and Eisai Strategic Collaboration
In March 2018, Eisai and Merck & Co., Inc., Kenilworth, N.J., U.S.A., 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. Under the agreement, the companies will jointly develop, manufacture and commercialize lenvatinib, both as a monotherapy and in combination with pembrolizumab, the anti-PD-1 therapy from Merck & Co., Inc., Kenilworth, N.J., U.S.A.

In addition to ongoing clinical studies evaluating the lenvatinib plus pembrolizumab 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 14 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, pancreatic cancer and triple-negative breast cancer) across more than 20 clinical trials.

5. Eisai’s Focus on Cancer
Eisai focuses on the development of anticancer drugs, targeting the tumor microenvironment (with experience and knowledge from existing in-house discovered compounds, such as eribulin mesylate (product name: Halaven) and Lenvatinib) and the driver gene mutation and aberrant splicing (leveraging RNA Splicing Platform) as areas (Ricchi) where real patient needs are still unmet, and where Eisai can aim to become a frontrunner in oncology. Eisai aspires to discover innovative new drugs with new targets and mechanisms of action from these Ricchi, with the aim of contributing to the cure of cancers.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., U.S.A.

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