On September 12, 2022 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported the presentation of positive data from multiple expansion cohorts of an initial Phase 1 trial for an investigational combination of LAG-3 inhibitor fianlimab and PD-1 inhibitor Libtayo (cemiplimab) in advanced melanoma (Press release, Regeneron, SEP 12, 2022, View Source [SID1234619390]). The results were shared in a mini-oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris.

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"After regulatory approvals of our PD-1 inhibitor Libtayo in two advanced non-melanoma skin cancers, we are expanding our efforts in dermato-oncology to address advanced melanoma," said Israel Lowy, M.D., Ph.D., Senior Vice President, Translational and Clinical Sciences, Oncology at Regeneron. "Combining LAG-3 and PD-1 inhibition has shown promise in advanced melanoma but achieving response rates above 50% has been challenging. In two independent dose expansion cohorts from a Phase 1 clinical trial of patients naïve to PD-1 or PD-L1 inhibitors, our LAG-3 inhibitor fianlimab combined with Libtayo demonstrated greater than 60% response rates. Notably, the safety profile for this combination appears in line with Libtayo monotherapy. A Phase 3 trial in first-line metastatic melanoma is currently enrolling patients, and we look forward to opening additional trials with this combination in the near future."

Data presented at ESMO (Free ESMO Whitepaper) were from three dose expansion cohorts in advanced melanoma, including two that enrolled patients who had not previously been treated with a PD-1 or PD-L1 inhibitor (PD-1/PD-L1-naïve) and one of patients who had received prior PD-1 or PD-L1 inhibitor therapy (PD-1/PD-L1-experienced). The objective response rate (ORR) in the PD-1/PD-L1-experienced cohort was 13%. Results from the PD-1/PD-L1-naïve cohorts were as follows:

In updated results for one cohort (n=40), a 62.5% ORR (25 of 40 patients; 6 complete reponses [CR], 19 partial responses [PR]). Median duration of response (DOR) was not reached (range: 12 months to not evaluable [NE]) and the median progression-free survival (PFS) was 24 months (95% confidence interval [CI], 4 months to NE), per Kaplan-Meier estimates.
In a newly presented independent confirmatory cohort (n=40), a 65% ORR (26 of 40 patients; 1 CR, 25 PRs). The median DOR (range: 6 months to NE) and median PFS (95% CI, 7.5 to NE) were not reached, per Kaplan-Meier estimates.
Tumor responses were based on RECIST 1.1 criteria and per investigator assessment. AEs of any grade in the two PD-1/PD-L1-naïve cohorts (n= 80) occurred in 96% of patients, with 29% considered serious. The most common immune-mediated AEs in ≥15% patients were rash (n=19) and pruritus (n=12). AEs that were ≥grade 3 occurred in 40% of patients. The treatment discontinuation rate due to AEs was 16%, with two deaths considered possibly related to treatment (colitis and cardiac shock).

The potential use of fianlimab and Libtayo described above is investigational, and safety and efficacy of this combination have not been evaluated by any regulatory authority.

About Regeneron in Oncology
At Regeneron, we’re applying more than three decades of scientific innovation with the goal of developing paradigm-changing therapies for patients with cancer. Our oncology portfolio is built around two foundational approaches – our approved PD-1 inhibitor Libtayo and investigational bispecific antibodies – which are being evaluated both as monotherapies and in combination with emerging therapeutic modalities. Together, they provide us with unique combinatorial flexibility to develop potentially synergistic treatments for a wide range of solid tumors and blood cancers.

If you are interested in learning more about our clinical trials, please contact us ([email protected] or 844-734-6643) or visit our clinical trials website.

About fianlimab
Fianlimab is a fully human monoclonal antibody targeting the immune checkpoint receptor LAG-3 on T cells and was invented using Regeneron’s proprietary VelocImmune technology. In melanoma, LAG-3 expression on cancer cells is associated with therapeutic resistance to PD-1 inhibitors. Fianlimab is being investigated in combination with Regeneron’s PD-1 inhibitor Libtayo to determine whether concurrent blockade of LAG-3 and PD-1 can help overcome this resistance and release the brakes on T cell activation.

About Libtayo
Libtayo is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T cells and was invented using Regeneron’s proprietary VelocImmune technology. By binding to PD-1, Libtayo has been shown to block cancer cells from using the PD-1 pathway to suppress T-cell activation. In the U.S. and other countries Libtayo is indicated in certain patients with advanced basal cell carcinoma (BCC), advanced cutaneous squamous cell carcinoma (CSCC) and advanced non-small cell lung cancer (NSCLC), as well as in advanced cervical cancer in Canada and Brazil. As of July 1, 2022, Libtayo is developed and marketed globally by Regeneron.

In the U.S., the generic name for Libtayo in its approved indications is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA). Outside of the U.S. the generic name of Libtayo in its approved indication is cemiplimab.

The extensive clinical program for Libtayo is focused on difficult-to-treat cancers. Libtayo is currently being investigated in trials as a monotherapy, as well as in combination with either conventional or novel therapeutic approaches for other solid tumors and blood cancers. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority.

U.S. FDA-approved Indications Libtayo is a prescription medicine used to treat people with:

A type of skin cancer called advanced CSCC that has spread or cannot be cured by surgery or radiation.
A type of skin cancer called BCC:
That cannot be removed by surgery (locally advanced BCC) and have received treatment with a hedgehog pathway inhibitor (HHI), or cannot receive treatment with an HHI.
That has spread (metastatic BCC) and have received treatment with an HHI, or cannot receive treatment with an HHI. This use is approved based on how many patients responded to treatment and how long they responded. Studies are ongoing to provide additional information about clinical benefit.
A type of lung cancer called NSCLC. Libtayo may be used as your first treatment when your lung cancer has not spread outside your chest (locally advanced lung cancer) and you cannot have surgery or chemotherapy with radiation, or your lung cancer has spread to other areas of your body (metastatic lung cancer), and your tumor tests positive for high "PD-L1" and your tumor does not have an abnormal "EGFR", "ALK "or "ROS1" gene.
It is not known if Libtayo is safe and effective in children.

About Regeneron’s VelocImmune Technology
Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s co-Founder, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create approximately one in five of all original, FDA-approved or authorized fully human monoclonal antibodies. This includes REGEN-COV (casirivimab and imdevimab), Dupixent (dupilumab), Libtayo (cemiplimab-rwlc), Praluent (alirocumab), Kevzara (sarilumab), Evkeeza (evinacumab-dgnb) and Inmazeb (atoltivimab, maftivimab and odesivimab-ebgn).

IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. PATIENTS

What is the most important information I should know about Libtayo?
Libtayo is a medicine that may treat certain cancers by working with your immune system. Libtayo can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:

Lung problems: cough, shortness of breath, or chest pain
Intestinal problems: diarrhea (loose stools) or more frequent bowel movements than usual, stools that are black, tarry, sticky or have blood or mucus, or severe stomach area (abdomen) pain or tenderness
Liver problems: yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach area (abdomen), dark urine (tea colored), or bleeding or bruising more easily than normal
Hormone gland problems: headache that will not go away or unusual headaches, eye sensitivity to light, eye problems, rapid heartbeat, increased sweating, extreme tiredness, weight gain or weight loss, feeling more hungry or thirsty than usual, urinating more often than usual, hair loss, feeling cold, constipation, your voice gets deeper, dizziness or fainting, or changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Kidney problems: decrease in your amount of urine, blood in your urine, swelling of your ankles, or loss of appetite
Skin problems: rash, itching, skin blistering or peeling, painful sores or ulcers in mouth or nose, throat, or genital area, fever or flu-like symptoms, or swollen lymph nodes
Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with Libtayo. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: chest pain, irregular heartbeat, shortness of breath or swelling of ankles, confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs, double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight, persistent or severe muscle pain or weakness, muscle cramps, low red blood cells, or bruising
Infusion reactions that can sometimes be severe. Signs and symptoms of infusion reactions may include: nausea, chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness, feel like passing out, fever, back or neck pain, or facial swelling.
Rejection of a transplanted organ. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.
Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with Libtayo. Your healthcare provider will monitor you for these complications.
Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with Libtayo. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with Libtayo if you have severe side effects.

Before you receive Libtayo, tell your healthcare provider about all your medical conditions, including if you:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ transplant
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome are pregnant or plan to become pregnant. Libtayo can harm your unborn baby
Females who are able to become pregnant:

Your healthcare provider will give you a pregnancy test before you start treatment.
You should use an effective method of birth control during your treatment and for at least 4 months after your last dose of Libtayo. Talk with your healthcare provider about birth control methods that you can use during this time.
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Libtayo.
are breastfeeding or plan to breastfeed. It is not known if Libtayo passes into your breast milk. Do not breastfeed during treatment and for at least 4 months after the last dose of Libtayo.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. The most common side effects of Libtayo include muscle or bone pain, tiredness, rash, and diarrhea. These are not all the possible side effects of Libtayo. Call your doctor for medical advice about side effects.

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.