On September 12, 2022 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that results from a post hoc analysis of three randomized, pivotal, Phase 3 studies (EMBRACE trial/Study 305, Study 301 and Study304) evaluating the efficacy of eribulin mesylate (marketed as HALAVEN) versus other chemotherapies (Treatment of Physician’s Choice [TPC], capecitabine, and vinorelbine, respectively) in patients living with metastatic breast cancer (mBC) whose tumors have low or no HER2 expression (Press release, Eisai, SEP 12, 2022, View Source [SID1234619388]). These data were presented as a poster (Presentation: #259P) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting (#ESMO22), held virtually and in-person in Paris, France from September 9-13, 2022.

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The HER2-low breast cancer subtype is a newly defined subset consisting of tumors that would have previously been considered HER2-negative based on an immunohistochemistry (IHC) assay and an in situ hybridization (ISH) assay. HER2-low tumors express low amounts of the HER2 protein, but not enough to be considered HER2-positive. HER2-low is defined as an IHC of 1+ or 2 with a negative ISH. Of the approximate 288,000 new cases of female breast cancer expected to be diagnosed in the U.S. in 2022,1 it is estimated that approximately 80-85% of patients would previously have been considered to have the HER2-negative subtype. Of those patients, about 60% would now be considered to have the HER2-low subtype.2

"In this post-hoc analysis, the outcomes seen in mBC patients whose tumors are considered HER2-low are consistent with the results of the three pivotal Phase 3 clinical trials," said Dr. Takashi Owa, Chief Scientific Officer, Senior Vice President, Eisai Co., Ltd. "As the oncology community’s understanding of mBC continues to evolve, it’s important that we continue to evaluate the role of existing therapies in new contexts to contribute to the body of knowledge that is available to health care professionals."

Data from the Post Hoc Analysis

The post hoc analysis included data from three trials — eribulin vs. TPC (NCT00388726(New Window), EMBRACE trial/Study 305), eribulin vs. capecitabine (NCT00337103(New Window), Study 301), and eribulin vs. vinorelbine (NCT02225470(New Window), Study 304) in patients with locally recurrent or mBC who had prior lines of chemotherapy treatments (≤2 for Study 301; 2-5 for Study 304 and EMBRACE Trial/Study 305) including an anthracycline and a taxane. A total of 1,589 eligible patients were enrolled in the EMBRACE trial/Study 305, Study 301 and Study 304, and baseline characteristics were generally balanced between treatment arms in all studies.

Median overall survival (OS), median progression free survival (PFS) and objective response rate (ORR) were analyzed. PFS and ORR were measured per Response Evaluation Criteria in Solid Tumors Version (RECIST) (v1.0 for EMBRACE trial/Study 305 and Study 301; v1.1 for Study 304) by independent imaging review. ORR was measured in evaluable patients (EMBRACE trial/Study 305) and in the intent-to-treat population (Study 301 and Study 304).

In the post hoc analysis, OS, PFS, and ORR among patients with HER2-low or HER2-negative status were generally similar to those of the eribulin treatment arms overall in each of the EMBRACE trial/Study 305, Study 301 and Study 304.3,4,5 Efficacy results for patients with HER2-low and HER2-negative status across all three studies are summarized in the table below:

1. About Metastatic Breast Cancer

Metastatic breast cancer (mBC) is an advanced stage of the disease that occurs when cancer spreads beyond the breast to other parts of the body. It is estimated there were more than 2,261,000 new cases of breast cancer and more than 684,000 deaths from the disease globally in 2020.6 In Japan, it is estimated there were more than 92,000 new cases of breast cancer diagnosed and more than 17,000 deaths from this disease in 2020.7 In the United States, it is estimated that approximately 288,000 women will be diagnosed with breast cancer and over 43,000 women will die from the disease in 2022.1 It is estimated that 30% of people with early-stage breast cancers will go on to develop metastatic disease,8 and approximately 6% of women with breast cancer will have metastatic disease at the time of diagnosis. Metastatic breast cancer has a poor prognosis compared to non-metastatic breast cancer.9 The estimated 5-year relative survival rate for women with mBC is 28%.10

2. About eribulin mesylate (product name: Halaven, "eribulin")
Eribulin is a microtubule dynamics inhibitor in the halichondrin class with a novel mechanism of action, developed in-house by Eisai. Structurally, eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, non-clinical studies showed eribulin’s unique actions in the tumor microenvironment such as an increase in vascular perfusion and permeability in tumor cores,11 promotion of the epithelial state, decrease in capacity of breast cancer cells to migrate,12 etc.

Eribulin has been approved for the indications below.

Breast cancer (Approved in over 80 countries Japan, the United States, China, and countries in Europe and Asia)

Japan: Inoperable or recurrent breast cancer

The United States: The treatment for patients with metastatic breast cancer who have 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.

Europe: The treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments.

Sarcoma (Approved in over 80 countries Japan, the United States, and countries in Europe and Asia)

Japan: Soft tissue sarcoma

The United States: The treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen

Europe: The treatment of adult patients with unresectable liposarcomas who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease

On September 12, 2022 Clarity Pharmaceuticals (ASX: CU6) ("Clarity"), a clinical-stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported that the patent application covering Clarity’s optimised Prostate Specific Membrane Antigen (PSMA) targeting agent, SAR-bisPSMA, has been Granted in China (Press release, Clarity Pharmaceuticals, SEP 12, 2022, View Source [SID1234619387]).

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The patent had been previously granted in the USA, Australia and Mexico and has an expiry date of 5 June 2038. The patent application remains under review in other major jurisdictions, including Europe and Japan.

SAR-bisPSMA is a Targeted Copper Theranostic (TCT) for diagnosis and treatment of prostate cancer as well as other cancers expressing PSMA. The prostate cancer market is a key focus for Clarity as the company continues to hit key milestones in the development of SAR-bisPSMA in three clinical trials:

SECuRE theranostic trial in the US

Phase I/IIa theranostic study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA for identification and treatment of PSMA-expressing metastatic castrate resistant prostate cancer (mCRPC) (NCT04868604)1
Status: Therapy phase open for recruitment
PROPELLER diagnostic trial in Australia

Positron Emission Tomography (PET) imaging of participants with confirmed prostate cancer using 64Cu-SAR-bisPSMA: a multi-centre, blinded review, dose ranging Phase I study (NCT04839367)2
Status: Recruitment complete
COBRA diagnostic trial in the US

Phase I/II PET imaging trial of participants with biochemical recurrence (BCR) of prostate cancer following definitive therapy using 64Cu SAR-bisPSMA in the US (NCT05249127)3
Status: Recruiting
Clarity’s Executive Chairman, Dr Alan Taylor, commented, "We are very pleased with our broad and evolving patent protection for all of our products, but in particular for one of our core products, with this composition-of-matter patent now granted in the USA, Australia, China and Mexico. This further strengthens our position as we progress the clinical development of SAR-bisPSMA. This milestone continues Clarity’s strong emphasis on Intellectual Property (IP) protection covering the SAR Technology platform and each new product that stems from it.

"Clarity’s aggressive patenting strategy enables us to successfully leverage our IP to achieve strong protection and develop a pipeline of next-generation radiopharmaceuticals. This allows us to gain a sustainable competitive advantage in the field as we continue pursuing our ultimate goal of developing better treatments for children and adults with cancer."

On September 11, 2022 Eisai (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") and Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada) reported the first presentation of results from the final analysis of the Phase 3 LEAP-002 trial investigating LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, plus KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA versus LENVIMA monotherapy, as a first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC) (Press release, Eisai, SEP 11, 2022, View Source [SID1234619389]). Results are being presented during a proffered paper session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, being held in Paris, France and virtually from Sept. 9-13 (abstract #LBA34).

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In the final analysis of the trial, there was a trend toward improvement for one of the study’s dual primary endpoints, overall survival (OS), for patients treated with LENVIMA plus KEYTRUDA versus LENVIMA monotherapy; however, the results did not meet statistical significance per the pre-specified statistical plan (HR=0.84 [95% CI: 0.71-1.00]; p=0.0227). The median OS was 21.2 months (95% CI: 19.0-23.6) for LENVIMA plus KEYTRUDA and 19.0 months (95% CI: 17.2-21.7) for LENVIMA monotherapy. Additionally, treatment with LENVIMA plus KEYTRUDA resulted in a trend toward improvement in the trial’s other dual primary endpoint of progression-free survival (PFS) versus LENVIMA monotherapy; however, the results did not meet the pre-specified threshold at the first interim analysis for statistical significance (HR=0.87 [95% CI: 0.73-1.02]; p=0.0466).

"The LEAP-002 trial reflects our research strategy to build on evolving standards of care to further improve outcomes for more people with unresectable hepatocellular carcinoma," said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck & Co., Inc., Rahway, NJ, USA Research Laboratories. "The median overall survival of 21.2 months seen with KEYTRUDA plus LENVIMA provides critical insights for further research into the potential role of this combination."

"While the outcome is not what we had hoped, it is important for us to see that patients in the trial treated with LENVIMA monotherapy had a median overall survival of 19.0 months," said Corina Dutcus, M.D., Senior Vice President, Clinical Research, Oncology at Eisai Inc. "Findings from the LEAP-002 trial will not only help advance our understanding and application of LENVIMA plus KEYTRUDA across our clinical development program but will also provide physicians with additional information on LENVIMA monotherapy’s use in unresectable hepatocellular carcinoma, where it is currently approved as a treatment option in multiple regions around the world, including the U.S., the European Union (EU), Japan and China."

LENVIMA monotherapy is approved for the first-line treatment of patients with uHCC in the U.S., the EU and China and for patients with uHCC in Japan. The approval of LENVIMA was based on results of the Phase 3 REFLECT trial, which evaluated the efficacy and safety of LENVIMA versus sorafenib for the first-line treatment of patients with uHCC.

LENVIMA (marketed as KISPLYX for renal cell carcinoma [RCC] in the EU) plus KEYTRUDA is approved in the U.S., the EU and Japan for the treatment of certain types of advanced endometrial carcinoma and advanced RCC. Eisai and Merck & Co., Inc., Rahway, NJ, USA are studying the LENVIMA plus KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in multiple tumor types, including but not limited to endometrial carcinoma, HCC, melanoma, non-small cell lung cancer, RCC, head and neck cancer, colorectal cancer, gastric cancer and esophageal cancer, across more than 15 clinical trials.

LEAP-002 study design and final analysis results (abstract #LBA34)

LEAP-002 is a multicenter, randomized, double-blinded, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT03713593(New Window)) evaluating LENVIMA plus KEYTRUDA versus LENVIMA monotherapy for the first-line treatment of adult patients with uHCC. Patients were randomized 1:1 to receive LENVIMA (12 mg orally once daily [for patients with screening body weight of at least 60 kg] or 8 mg orally once daily [for patients with screening body weight less than 60 kg]) plus KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle); or LENVIMA (12 mg orally once daily [for patients with screening body weight of at least 60 kg] or 8 mg orally once daily [for patients with screening body weight less than 60 kg]) plus saline placebo (IV administered on Day 1 of each three-week cycle). LENVIMA was administered until progressive disease or unacceptable toxicity. KEYTRUDA/placebo was administered for up to 35 cycles (approximately two years).

The dual primary endpoints were PFS, as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1; RECIST v1.1 has been modified for this study to follow a maximum of 10 target lesions in total and a maximum of five target lesions per organ), and OS. Objective response rate (ORR), as assessed by BICR per RECIST v1.1, was a key secondary endpoint. The trial was designed with two interim analyses and a final analysis for OS. Pre-specified efficacy boundaries were one-sided p=0.002 for PFS at interim analysis 1 and p=0.0185 for OS at the final analysis.

As of the data cut-off for the final analysis (June 21, 2022), a total of 794 patients were enrolled and treated, with a median follow-up of 32.1 months (range, 25.8-41.1). A total of 534 OS events had occurred, with 36 patients (9.1%) in the combination arm and 24 patients (6.1%) in the LENVIMA monotherapy arm remaining on study treatment.

The median OS was 21.2 months (95% CI: 19.0-23.6) for LENVIMA plus KEYTRUDA versus 19.0 months (95% CI: 17.2-21.7) for LENVIMA monotherapy at the final analysis. The median PFS was 8.2 months (95% CI, 6.4-8.4) for LENVIMA plus KEYTRUDA versus 8.0 months (95% CI: 6.3-8.2) for LENVIMA monotherapy at the first interim analysis and 8.2 months (95% CI: 6.3-8.3) versus 8.1 months (95% CI: 6.3-8.3), respectively, at the final analysis. The ORR was 26.1% (95% CI: 21.8-30.7) for LENVIMA plus KEYTRUDA versus 17.5% (95% CI: 13.9-21.6) for LENVIMA monotherapy at the final analysis. Median duration of response was 16.6 months (range, 2.0+ to 33.6+) in the KEYTRUDA plus LENVIMA arm versus 10.4 months (range, 1.9 to 35.1+) in the LENVIMA monotherapy arm at the final analysis.

The safety profile of LENVIMA plus KEYTRUDA was consistent with previously reported data on the combination. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 61.5% of patients treated with LENVIMA plus KEYTRUDA versus 56.7% of patients treated with LENVIMA monotherapy. Grade 5 TRAEs occurred in 1.0% of patients treated with LENVIMA plus KEYTRUDA versus 0.8% of patients treated with LENVIMA monotherapy. In patients treated with LENVIMA plus KEYTRUDA, the five most common TRAEs of any grade were hypertension (43.3%), diarrhea (40.3%), hypothyroidism (40.0%), palmar-plantar erythrodysesthesia (PPE) syndrome (33.2%) and proteinuria (30.6%). In patients treated with LENVIMA monotherapy, the five most common TRAEs of any grade were hypertension (46.8%), hypothyroidism (35.7%), proteinuria (34.9%), diarrhea (33.9%) and PPE syndrome (30.6%). Post-study systematic anti-cancer treatments were given for 44.1% of patients receiving LENVIMA plus KEYTRUDA versus 52.1% of those receiving LENVIMA monotherapy.

About hepatocellular carcinoma (HCC)

Hepatocellular carcinoma is the most common type of primary liver cancer1 and the most rapidly increasing cause of cancer deaths in the United States.2 Hepatocellular carcinoma accounts for approximately 90% of primary liver cancers.3 It is estimated there were more than 905,000 new cases of liver cancer and more than 830,000 deaths from the disease globally in 2020,4 making it the sixth most frequently diagnosed cancer worldwide5 and one of the leading causes of cancer deaths around the world. In Japan, it is estimated there were more than 45,000 new cases of liver cancer diagnosed and more than 28,000 deaths from this disease in 2020.6 In the United States, it is estimated there will be over 41,000 new cases of liver cancer and over 30,000 deaths from this disease in 2022.5 Risk factors for liver cancer include gender, ethnicity, chronic viral hepatitis (Hep-B or Hep-C) infection, cirrhosis, alcohol use and metabolic syndrome.7 Hepatocellular carcinoma, which is often diagnosed at an advanced stage,8 has a five-year survival rate of approximately 20% in the United States.9

About LENVIMA (lenvatinib) Capsules

LENVIMA, discovered and developed by Eisai, is an orally available 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. In syngeneic mouse tumor models, LENVIMA 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. LENVIMA has been approved for the indications below.

Thyroid cancer

・Indication as monotherapy

(Approved in over 80 countries including Japan, the United States, China, and countries in Europe and Asia)

Japan: Radically unresectable thyroid cancer

The United States: The treatment of patients with locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid cancer (DTC)

Europe: The treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI)

Hepatocellular carcinoma

・Indication as monotherapy

(Approved in over 80 countries including Japan, the United States, China, and countries in Europe and Asia)

Japan: Unresectable hepatocellular carcinoma

The United States: The first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)

Europe: The treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy

Thymic carcinoma

・Indication as monotherapy (Approved in Japan)

Japan: Unresectable thymic carcinoma

Renal cell carcinoma (In Europe, the agent was launched under the brand name Kisplyx)

・Indication in combination with everolimus

(Approved in over 65 countries including the United States, and countries in Europe and Asia)

The United States: The treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy

Europe: The treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF) targeted therapy

・Indication in combination with KEYTRUDA (generic name: pembrolizumab)

(Approved in over 40 countries including Japan, the United States, and countries in Europe and Asia)

Japan: Radically unresectable or metastatic renal cell carcinoma

The United States: The first-line treatment of adult patients with advanced renal cell carcinoma

Europe: The first-line treatment of adult patients with advanced renal cell carcinoma

Endometrial carcinoma

・Indication in combination with KEYTRUDA

(Approved [including conditional approval] in over 45 countries including Japan, the United States, and countries in Europe and Asia)

Japan: Unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer chemotherapy

The United States: The treatment of patients with advanced endometrial carcinoma (EC) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Europe: The treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck & Co., Inc., Rahway, NJ, USA has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

About Eisai and the Merck & Co., Inc., Rahway, NJ, USA Collaboration

In March 2018, Eisai and Merck & Co., Inc., Rahway, NJ, USA, 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 KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA.

In addition to ongoing clinical studies evaluating the LENVIMA plus KEYTRUDA 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 multiple tumor types across more than 15 clinical trials.

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) 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.

On September 11, 2022 I-Mab (the "Company") ( Nasdaq: IMAB), a clinical-stage biopharmaceutical company committed to the discovery, development, and commercialization of novel biologics, reported encouraging data from its Phase 2 clinical trial (NCT04202003) of lemzoparlimab (also known as TJC4) in combination with azacitidine (AZA) in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS), presented in an oral presentation on September 10 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 (Press release, I-Mab Biopharma, SEP 11, 2022, View Source [SID1234619384]).

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The open-labeled Phase 2 clinical trial is designed to investigate the efficacy and safety of lemzoparlimab in combination with AZA in patients with newly diagnosed HR-MDS. A total of 53 patients were enrolled as of March 31, 2022, receiving lemzoparlimab at a weekly dose of 30 mg/kg intravenously (IV) and AZA at 75 mg/m2 subcutaneously (SC) on Days 1–7 in a 28-day cycle.

Top-line data showed that for patients who began treatments 6 months or longer prior to the analysis (n=15), the overall response rate (ORR) and complete response rate (CRR) was 86.7% and 40% respectively. For patients who began treatment 4 months or longer prior to the analysis (n=29), the ORR and CRR was 86.2% and 31% respectively. While the study enrolled more patients with worse baseline conditions due to underlying disease (74% of patients had grade ≥3 anemia and 51% of patients had grade ≥3 thrombocytopenia), the results showed that lemzoparlimab combined with AZA was well-tolerated and the safety profile was consistent with AZA monotherapy.

Decreased red blood cells, measured as hemoglobin, and decreased platelets are major causes of morbidity for patients with HR-MDS and the median hemoglobin and platelet levels for patients on study increased in response to treatment. Of the 29 patients who were dependent upon blood transfusions at baseline, 9 patients (31%) became transfusion independent at the time of analysis. Furthermore, the majority of CR patients showed reduction in variant allele frequency (VAF) of MDS-related gene mutation including TP53, TET2 and RUNX1, with 56% achieving minimal residual disease negativity (≤10-4) by flow cytometry. These data are consistent with the anti-leukemic activities and expected drug safety of lemzoparlimab.

"Without the need of priming dose, the latest Phase 2 data show clinically meaningful efficacy of lemzoparlimab treatment in combination with AZA among patients with newly diagnosed HR-MDS," said Prof. Zhijian Xiao, Professor at Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, and leading principal investigator of the study. "The results are encouraging and provide further clinical validation to the promise of lemzoparlimab as a potential best-in-class CD47 antibody, especially for patients with HR-MDS or who are unfit for intensive therapy."

"The clinical activity seen with lemzoparlimab in combination with AZA thus far, in addition to the favorable safety profile, continues to show promise in this difficult-to-treat patient population," said Prof. Chunkang Chang, Director of Hematology Department of Shanghai Sixth People’s Hospital, and leading principal investigator of the study. "Lemzoparlimab represents a potentially important novel treatment option for patients with HR-MDS as well as many other hematological malignancies. We’re very enthusiastic about the results to date and look forward to advancing the trial and broadening its application into other malignancies."

"We are excited about the topline data of lemzoparlimab in HR-MDS selected for proffered oral presentation at ESMO (Free ESMO Whitepaper) Congress 2022," said Dr. Andrew Zhu, President of I-Mab. "The Phase 2 clinical data demonstrated a good safety profile, along with promising efficacy, and underscored I-Mab’s commitment to bring transformational therapies to patients in need. These results warrant our focused efforts to advance lemzoparlimab towards initiation of a Phase 3 registrational trial."

The Company is on track to initiate a Phase 3 clinical trial in patients with MDS in China.

About CD47 and Lemzoparlimab

CD47 is a cell surface protein over-expressed in a wide variety of cancers and can act to protect tumors by delivering a "don’t eat me" signal to otherwise tumor-engulfing macrophages. CD47 antibody blocks this signal and enables macrophages to attack tumor cells. However, development of CD47 antibody as a cancer therapy has been hampered by its hematologic side effects, such as severe anemia, caused by natural binding of CD47 antibody to red blood cells. Scientists at I-Mab discovered a novel CD47 antibody, lemzoparlimab, that is designed to target tumor cells while exerting a minimal untoward effect on red blood cells.

Multiple clinical studies of lemzoparlimab are ongoing to explore indications in treating patients with myelodysplastic syndrome (MDS), acute myelocytic leukemia (AML), non-Hodgkin’s lymphoma (NHL), and advanced solid tumors in combination with chemotherapy and immune checkpoint inhibitors.

On September 11, 2022 IDEAYA Biosciences, Inc. ( Nasdaq:IDYA), a synthetic lethality focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported that interim results from its Phase 2 clinical trial evaluating darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma (MUM) patients (ClinicalTrials.gov Identifier: NCT03947385) (Press release, Ideaya Biosciences, SEP 11, 2022, View Source [SID1234619383]).

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"The confirmed partial responses and high percentage of patients with tumor shrinkage shown in these interim Phase 2 data are extremely encouraging for patients with metastatic uveal melanoma. The 50% overall response rate and greater than 5 months median progression free survival observed in first-line MUM patients reflects the potential for a compelling clinical efficacy profile irrespective of haplotype (HLA-A*02:01) status. The partial responses shown in first-line and any-line MUM patients are clinically significant and build on previously-reported results for any-line MUM patients, now with a larger patient data set," said Dr. Marlana Orloff, M.D., Associate Professor, Sidney Kimmel Cancer Center, Jefferson Health.

"The clinical efficacy observed in first-line patients in these interim Phase 2 data presents an opportunity to pursue a front-line strategy and provides a rationale for a potential registration-enabling clinical trial in MUM," said Dr. Matt Maurer, M.D., Vice President, Head of Clinical Oncology and Medical Affairs, IDEAYA Biosciences.

There are currently no FDA approved therapies for GNAQ and GNA11 solid tumors, and current therapies for MUM have relatively low objective response rates and short median progression free survival (PFS), highlighting the high unmet medical need. Approximately 90% of MUM has either a GNAQ or GNA11 mutation that activates the protein kinase C (PKC) signaling pathway. The historical overall response rate (ORR) in MUM clinical trials has generally been reported with an ORR ranging from approximately 0 to 5%, including: pembrolizumab and tebentafusp (each ~5%); MEK inhibitor selumetinib in combination with dacarbazine (~3%); and cMET inhibitor cabozantinib monotherapy (~0%). In addition, the historical median PFS in MUM clinical trials has been reported ranging from approximately 2.0 to 2.8 months, including: tebentafusp (~2.8 months, IMCgp100-102 study); MEK inhibitor selumetinib in combination with dacarbazine (~2.8 months); and cMET inhibitor cabozantinib monotherapy (~2.0 months).

Darovasertib (IDE196) is a small molecule, potential first-in-class protein kinase C (PKC) inhibitor. IDEAYA is evaluating the synthetic lethal combination of darovasertib and crizotinib, a small molecule cMET inhibitor, in MUM and other GNAQ/11 tumors pursuant to a clinical trial collaboration and drug supply agreement with Pfizer.

Clinical Data Update – Darovasertib and Crizotinib Combination in MUM
The interim Phase 2 clinical data update is based on an initial thirty-seven (37) patients enrolled in the darovasertib and crizotinib combination study at the expansion dose of 300mg twice-a-day darovasertib and 200mg twice-a-day crizotinib, as of the data analysis cutoff date of June 26, 2022. Out of the thirty-seven (37) patients enrolled, there were thirty-five (35) evaluable patients and two (2) non-evaluable patients. The two (2) non-evaluable patients were both pretreated and withdrew from the trial prior to the first scan. Neither of the two non-evaluable patients progressed due to disease: one (1) patient withdrew consent and one (1) patient discontinued early due to fatigue. Reported data are preliminary and based on an unlocked database as of the data analyses cutoff date, except one confirmatory scan after the data cutoff date or as otherwise noted. Enrollment in the darovasertib and crizotinib combination expansion dose cohort of the clinical trial is ongoing.

The company observed encouraging clinical activity in Phase 2 clinical trial evaluating darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma (MUM) patients in the expansion dose cohort. These investigator-reviewed data by RECIST 1.1 include:

89% of Patients show Tumor Shrinkage in Any-Line MUM: 31 of 35 evaluable patients showed tumor shrinkage as determined by target lesion size reduction
83% Disease Control Rate (DCR) in Any-Line MUM: 29 of 35 evaluable patients showed stable disease or better as determined by target lesion size reduction
50% Overall Response Rate (ORR) in First-Line MUM: 4 of 8 evaluable patients had a confirmed partial response (PR)
31% Overall Response Rate (ORR) in Any-Line MUM: 11 of 35 evaluable patients had a confirmed partial response (PR)
43% of Patients with >30% Tumor Reduction in Any-Line MUM: 15 of 35 evaluable patients observed partial responses with >30% tumor reduction, including 11 confirmed and 4 unconfirmed partial responses
Median Study Follow-Up of 6.5 months for First-Line MUM patients and 7.8 months for Any-Line MUM patients
Median Duration of Response (DOR) in evaluable First-Line MUM patients has not yet been reached and 4 of 4 patients with confirmed PR’s in First-Line MUM remain in response; median DOR in evaluable Any-Line MUM patients has not yet been reached and 7 of 11 patients with confirmed PR’s in Any-Line MUM remain in response
Median Progression Free Survival (PFS) in First-Line MUM patients has not yet been reached and is >5 months in evaluable First-Line MUM patients; median PFS for evaluable Any-Line MUM patients is ~ 5 months
These data provide robust clinical proof-of-concept for the efficacy of the darovasertib and crizotinib synthetic lethal combination treatment.

The darovasertib and crizotinib combination therapy has a manageable adverse event profile in MUM patients (n=37), with a low rate of drug-related serious adverse events (SAE’s). Patients reported predominantly Grade 1 or 2 drug-related adverse events: all patients experienced a drug-related AE, of which 76% were reported as Grade 1 or 2 and 24% were reported as Grade 3. No patients observed Grade 4 or Grade 5 AE’s. One patient discontinued treatment due to a drug-related adverse event.

The potentially addressable patient population for metastatic uveal melanoma is estimated to include over 4,000 patients across US and Europe, based on estimated annual incidence. As an orally-administered small molecule precision medicine therapeutic, with demonstrated anti-tumor activity and manageable adverse event profile, the company considers the darovasertib and crizotinib combination therapy to have the potential to be broadly impactful to the MUM patient population.

IDEAYA is currently targeting to initiate a potential registration-enabling trial in Q1 2023. The company is evaluating first-line MUM as a potential registrational regulatory strategy. As of August 31, 2022, IDEAYA has enrolled 21 first-line MUM patients at the expansion dose of the darovasertib and crizotinib combination study.

Darovasertib – (Neo)Adjuvant Uveal Melanoma and Other Potential Expansion Opportunities
IDEAYA is also evaluating the potential for darovasertib in other oncology indications, including as (neo)adjuvant therapy in primary uveal melanoma (UM), in cMET-driven tumors and in KRAS-mutation tumors.

(Neo)Adjuvant UM represents a significant expansion opportunity for darovasertib – with a potential annual incidence of approximately 8,700 patients aggregate in US and Europe.

The company has observed preliminary proof of concept for potential darovasertib use in the (neo)adjuvant uveal melanoma setting, including responses of the primary orbital tumor. Clinical data reflects an observed tumor shrinkage by investigator review of primary ocular lesions in 5 of 5 (100%) UM or MUM patients treated as monotherapy or in combination with Crizotinib, including preliminary observation of tumor reductions in uvea lesion of two patients after the data cut-off date of August 19, 2022:

a darovasertib monotherapy patient with metastatic disease and an intact primary lesion in the eye observed a reduction of approximately 74% in the eye lesion by PET Standard Uptake Value (SUV) at an initial scan after approximately 2 weeks on therapy, with observed improvement in visual symptoms in the affected eye; this patient remained on therapy for approximately 7 months;
a darovasertib and crizotinib combination patient with metastatic disease and an intact primary lesion in the eye observed tumor shrinkage of approximately 67% by RECIST 1.1 as a contribution to an overall confirmed PR, with improvement in visual symptoms in the affected eye; this patient is continuing on therapy as of approximately 5 months; a second darovasertib and crizotinib combination MUM patient with an intact primary lesion observed a reduction of the ocular lesion based on preliminary scan after the data cut-off date; and
a darovasertib monotherapy neoadjuvant uveal melanoma patient with a primary ocular lesion observed a reduction of approximately 20% by RECIST 1.1 at the first scan after 27 days on therapy, with an observed decrease in ocular vasculature; a second darovasertib monotherapy neoadjuvant UM patient observed a reduction in the primary ocular lesion based on preliminary scan after the data cut-off date; these two patients are enrolled in the NADOM IST and are continuing on therapy as of approximately 1 month.
"I am excited to explore the potential for darovasertib as a (neo)adjuvant approach for the treatment of uveal melanoma patients. The observed clinical experience provides a basis for clinical investigation to evaluate whether darovasertib, can improve current primary treatment paradigms, which typically include radiotherapies and/or enucleation of the eye," said Dr. Marcus Butler, Medical Oncologist, Tumor Immunotherapy Program, Melanoma/Skin Oncology Site Lead at Princess Margaret Cancer Centre in Toronto, Canada, and Ocular Melanoma Physician Task Force of Canada Co-Lead.

IDEAYA is supporting St. Vincent’s Hospital Sydney Limited, which has initiated an Investigator Sponsored Trial, or IST, captioned as the "Neoadjuvant / Adjuvant trial of Darovasertib in Ocular Melanoma" (NADOM) study, to evaluate darovasertib monotherapy in a neo-adjuvant and adjuvant setting in primary UM patients. IDEAYA is targeting initiation of a company-sponsored clinical trial in Q4 2022 to further evaluate darovasertib monotherapy in (neo)adjuvant uveal melanoma, and is evaluating potential near-term clinical endpoints such as vision and organ preservation.

IDEAYA Investor Webcast and Conference Call
IDEAYA will host an investor webcast and conference tomorrow morning, September 12, 2022 at 8:00 am ET, to present darovasertib and crizotinib Phase 2 interim clinical efficacy and tolerability data, as well as clinical landscape, potential registrational strategies and expansion opportunities.

Presenters at the investor webcast and conference call will include Dr. Marlana Orloff, M.D., Associate Professor, Sidney Kimmel Cancer Center, Jefferson Health, and Dr. Marcus Butler, Medical Oncologist, Tumor Immunotherapy Program, Melanoma/Skin Oncology Site Lead at Princess Margaret Cancer Centre in Toronto, Canada, and Ocular Melanoma Physician Task Force of Canada Co-Lead, each of whom are key opinion leaders and clinical investigators. Yujiro S. Hata, President and Chief Executive Officer, and other members of the IDEAYA management team will also present.

IDEAYA’s darovasertib investor webcast presentation, as well as an updated corporate presentation, will be available on the company’s website, at its Investor Relations portal (View Source) in advance of the investor webcast presentation at approximately 6:00 am ET.

Corporate Updates
IDEAYA had cash, cash equivalents and marketable securities of approximately $324 million as of June 30, 2022, which it currently projects will be sufficient to fund its planned operations into 2025.