On May 26, 2022 Aadi Bioscience, Inc. (NASDAQ: AADI), a biopharmaceutical company focused on developing and commercializing precision therapies for genetically defined cancers with alterations in mTOR pathway genes, reported presentation of a poster entitled, "nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program" at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held online and in person from June 3-7 in Chicago, IL (Press release, Aadi Bioscience, MAY 26, 2022, View Source [SID1234615176]).

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The data represent exploratory biomarker results reported from the final analysis of mTOR inhibitor-naïve advanced malignant PEComa patients treated with nab-sirolimus in Aadi’s Advanced Malignant PEComa Trial (AMPECT) trial as well as an analysis of prior mTOR inhibitor exposed advanced malignant PEComa patients treated with nab-sirolimus in the Expanded Access Program (EAP) through June 2021. While the AMPECT and EAP studies cannot be directly compared, the findings of each show a greater clinical benefit in the patients harboring TSC1 or TSC2 alterations who received nab-sirolimus compared to all evaluable patients, regardless of prior mTOR inhibitor exposure.

"Given that inactivating alterations in TSC1 or TSC2 are potentially targetable biomarkers for mTOR inhibition, the exploratory biomarker results from these studies are encouraging as they support the rationale for our ongoing PRECISION 1 Phase 2 registrational trial," said Neil Desai, Ph.D., Founder, President and Chief Executive Officer of Aadi. "The response rates to nab-sirolimus in both AMPECT and the EAP showed similar positive trends in patients with TSC1 or TSC2alterations, regardless of prior mTOR inhibitor exposure."

Nab-sirolimus is an albumin-bound mTOR inhibitor approved by the U.S. Food and Drug Administration (FDA) as FYARRO for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa. The data to be presented include 31 mTOR inhibitor naïve patients from the AMPECT trial and 16 patients with prior mTOR inhibitor treatment from the EAP, all of which were treated with nab-sirolimus. Of those patients with TSC1or TSC2 alterations in the AMPECT trial, 64% had a complete or partial response versus a 39% response rate for all evaluable patients in the trial. Of those patients with TSC1 or TSC2 alterations in the EAP, 44% had a partial response versus 25% for all evaluable patients in the program.

Presentation details:

Presentation details:

Abstract Title: "nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program" (Dickson, et al.)
Abstract Number: 11574
Session Title: Sarcoma
Session Date: Sunday, June 5, 2022
Session Time: 6 am ET/9am PT
Presenter: Mark Andrew Dickson, MD
About the AMPECT Trial

The AMPECT trial (NCT02494570) evaluated the efficacy and safety of nab-sirolimus and was the first prospective registrational study in advanced malignant PEComa. AMPECT was a Phase 2, open-label, single-arm, multi-center study in patients with advanced malignant PEComa to determine the efficacy and safety of nab-sirolimus (data cutoff as of June 2021). Data from this trial were the basis of the FDA approval of FYARRO in advanced malignant PEComa.

In the trial, the overall response rate as assessed by independent review was 39% (12/31), with 2 patients converting from a Partial Response to a Complete Response after prolonged follow up. The median duration of response has not been reached with a median follow-up of 36 months, and a range of 5.6 to 55.5+ months and ongoing. Among responders, 92% had a response lasting greater than or equal to 6 months; 67% had a response lasting greater than or equal to 12 months; and 58% had a response lasting greater than or equal to 2 years. As is the case with other therapeutics of the mTOR class, the FYARRO prescribing information includes warnings and precautions related to stomatitis, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease/non-infectious pneumonitis, hemorrhage, and hypersensitivity reactions. Grade 3 non-hematologic events occurring in ≥ 10% of patients included stomatitis, rash, fatigue and infections. Grade 3 laboratory abnormalities occurring in ≥ 10% of patients that worsened from baseline included lymphocytopenia, increased glucose, and decreased potassium.

About the Aadi Expanded Access Program (EAP) for nab-sirolimus

Between closure of the AMPECT trial and nab-sirolimus commercial availability, an expanded access program (EAP; NCT03817515) allowed for the treatment of advanced malignant PEComa patients as well as other malignancies with relevant genetic mutations or mTOR pathway activation.

Amongst the patients on the EAP, sixteen with advanced malignant PEComa and prior mTOR inhibitor exposure were treated from July 2019 to July 2021. Prior mTOR inhibitor treatments included sirolimus, everolimus, temsirolimus and sapanisertib. Twelve patients had exposure to one prior mTOR inhibitor and four patients had exposure to >2 prior mTOR inhibitors. Fifty percent had progressive disease as best response on previous mTOR inhibitor treatment. Adverse events reported by treating physicians in the EAP were consistent with what was reported in AMPECT.

For detailed important safety information, please see below.

About FYARRO

FYARRO is an mTOR inhibitor indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

Important Safety Information

Contraindication

FYARRO is contraindicated in patients with a history of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin.

Warnings and Precautions

Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, occurred in 79% of patients treated with FYARRO, including 18% Grade 3. Stomatitis was most often first reported within 8 weeks of treatment. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Myelosuppression

FYARRO can cause myelosuppression including anemia, thrombocytopenia and neutropenia. Anemia occurred in 68% of patients; 6% were Grade 3. Thrombocytopenia and neutropenia occurred in 35% of patients each. Obtain blood counts at baseline and every 2 months for the first year of treatment and every 3 months thereafter, or more frequently if clinically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Infections

FYARRO can cause infections. Infections such as urinary tract infections (UTI), upper respiratory tract infections and sinusitis occurred in 59% of patients. Grade 3 infections occurred in 12% of patients, including a single case each of a UTI, pneumonia, skin, and abdominal infections. Monitor patients for infections, including opportunistic infections. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Hypokalemia

FYARRO can cause hypokalemia. Hypokalemia occurred in 44% of patients including 12% Grade 3 events. Monitor potassium levels prior to starting FYARRO and implement potassium supplementation as medically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Hyperglycemia

FYARRO can cause hyperglycemia. Hyperglycemia occurred in 12% of patients treated with FYARRO, all of which were Grade 3 events. Monitor fasting serum glucose prior to starting FYARRO. During treatment, monitor serum glucose every 3 months in non-diabetic patients, or as clinically indicated. Monitor serum glucose more frequently in diabetic patients. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Interstitial Lung Disease / Non-Infectious Pneumonitis

FYARRO can cause interstitial lung disease (ILD) / non-infectious pneumonitis. ILD / non-infectious pneumonitis occurred in 18% of patients treated with FYARRO, of which all were Grades 1 and 2. Based on the severity of the adverse reaction, withhold, reduce the dose, or permanently discontinue FYARRO.

Hemorrhage

FYARRO can cause serious and sometimes fatal hemorrhage. Hemorrhage occurred in 24% of patients treated with FYARRO, including Grade 3 and Grade 5 events in 2.9% of patients each. Monitor patients for signs and symptoms of hemorrhage. Based on the severity of adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Hypersensitivity Reactions

FYARRO can cause hypersensitivity reactions. Hypersensitivity reactions, including anaphylaxis, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been observed with administration of the oral formulation of sirolimus. Hypersensitivity reactions including anaphylaxis have been observed with human albumin administration. Monitor patients closely for signs and symptoms of infusion reactions during and following each FYARRO infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion. Reduce the rate, interrupt infusion, or permanently discontinue FYARRO based on severity and institute appropriate medical management as needed.

Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action, FYARRO can cause fetal harm when administered to a pregnant woman. In animal studies, mTOR inhibitors caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use effective contraception while using FYARRO and for 12 weeks after the last dose.

Male Infertility

Azoospermia or oligospermia may be observed in patients treated with FYARRO. FYARRO is an anti-proliferative drug and affects rapidly dividing cells such as germ cells.

Immunizations and Risks Associated with Live Vaccines

No studies in conjunction with immunization have been conducted with FYARRO. Immunization during FYARRO treatment may be ineffective. Update immunizations according to immunization guidelines prior to initiating FYARRO, if possible. Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while on FYARRO. The interval between live vaccinations and initiation of FYARRO should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

Risk of Transmission of Infectious Agents with Human Albumin

FYARRO contains human albumin, a derivative of human blood. Human albumin carries only a remote risk of transmission of viral diseases because of effective donor screening and product manufacturing processes. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been associated with albumin.

Adverse Reactions

Adverse Reactions in PEComa

The most common adverse reactions (≥30%) were stomatitis in 27 (79%) patients; fatigue and rash in 23 (68%) patients each; infection in 20 (59%) patients; nausea and edema in 17 (50%) patients each; diarrhea, musculoskeletal pain and decreased weight in 16 (47%) patients each; decreased appetite in 15 (44%) patients; cough in 12 (35%) patients; and vomiting and dysgeusia in 11 (32%) patients each.

Laboratory Abnormalities in PEComa

The most common Grade 3 to 4 laboratory abnormalities (≥6%) were decreased lymphocytes in 7 (21%) patients; increased glucose and decreased potassium in 4 (12%) patients each; decreased phosphate in 3 (9%) patients; and decreased hemoglobin and increased lipase in 2 (6%) patients each.

Dosage interruptions

Dose interruptions of FYARRO due to an adverse reaction occurred in 22 (65%) patients. Adverse reactions which required dosage interruption in >5% of patients included stomatitis in 6 (18%) patients, pneumonitis in 5 (15%) patients, anemia in 3 (9%) patients, and dehydration, dermatitis acneiform, and thrombocytopenia in 2 (6%) patients each.

Dose reduction

Dose reductions of FYARRO due to an adverse reaction occurred in 12 (35%) patients. Adverse reactions which required dose reductions in > 5% of patients included stomatitis and pneumonitis in 3 (9%) patients each.

Drug Interactions

Reduce the dosage of FYARRO to 56 mg/m2 when used concomitantly with a moderate or weak cytochrome P-450 3A4 (CYP3A4) inhibitor. Avoid concomitant use with drugs that are strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors and inducers and with grapefruit and grapefruit juice.

Use in Specific Populations

Pregnancy

Based on the mechanism of action and findings in animals, FYARRO can cause fetal harm when administered to a pregnant woman. Advise females of the potential risk to a fetus and to avoid becoming pregnant while receiving FYARRO.

Lactation

Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action. Because of the potential for serious adverse reactions in breastfed infants from FYARRO, advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

FYARRO can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to starting treatment with FYARRO. Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with and for at least twelve weeks after the last dose of FYARRO. Advise males with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with FYARRO and for at least twelve weeks after the last dose of FYARRO. Although there are no data on the impact of FYARRO on fertility, based on available clinical findings with oral formulation of sirolimus and findings in animals, male and female fertility may be compromised by the treatment with FYARRO.

Pediatric

The safety and effectiveness of FYARRO in pediatric patients have not been established.

Geriatric Use

Of the 34 patients treated with FYARRO, 44% were 65 years of age and older, and 6% were 75 years of age and older. Clinical studies of FYARRO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Hepatic Impairment

FYARRO is not recommended for use in patients with severe hepatic impairment. Reduce FYARRO dosage in patients with mild or moderate hepatic impairment.

Full prescribing information can be found here.

About the PRECISION 1 Trial

The PRECISION 1 trial is a multi-center, open-label, tumor-agnostic pivotal study, of nab-sirolimus designed as a basket trial that will evaluate approximately 120 adult and adolescent patients with solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes. The trial will have two independent arms of 60 patients each to separately evaluate patients with either TSC1or TSC2 inactivating alterations. Aadi has received Fast Track designation to evaluate nab-sirolimus in this indication from the FDA. The first patient in the PRECISION 1 trial was dosed in March 2022.

On May 26, 2022 Candel Therapeutics, Inc. (Nasdaq: CADL), a late clinical stage biopharmaceutical company developing novel oncolytic viral immunotherapies, reported the publication of abstract #9037 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place June 3-7, 2022, in Chicago (Press release, Candel Therapeutics, MAY 26, 2022, View Source [SID1234615170]). The abstract summarizes initial data as of January 10, 2022, from Candel’s open-label phase 2 clinical trial evaluating CAN-2409 in combination with anti-PD-1 or PD-L1 agents in patients with stage III/IV non-small cell lung cancer (NSCLC) who have had an inadequate response to immune checkpoint inhibitor treatment. The data presented in the poster will include additional data not included in the abstract from a total of 20 patients as of April 20, 2022, including 16 patients from cohort 2.

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"The achievement of an 87.5 percent disease control rate in patients whose cancer was progressing on anti-PD-1 treatment at enrollment bolsters the evidence of CAN-2409’s potential to induce immunization against cancer neoantigens in both injected tumors and uninjected metastases so that resistance to checkpoint blockade can be overcome," said Paul Peter Tak, MD, PhD, FMedSci, President and CEO of Candel. "The occurrence of abscopal effects and clinically meaningful and durable activity, supported by significant biomarker responses and prior monotherapy activity data, strengthens our belief that this investigational agent has the potential to improve outcomes for patients with NSCLC who are progressing on anti-PD-1 agents."

Experimental treatment with CAN-2409 plus valacyclovir in combination with anti-PD-1 agents appeared to be well tolerated. The most common treatment-related adverse events were transient flu-like symptoms, such as chills, fever and fatigue, with no grade 4 and two grade 3 events reported.

Additional data highlights include:

Most patients experienced a reduction in tumor burden.
There were three objective responses in cohorts 1 and 2 (patients with stable disease or progressive disease upon entry, respectively). A fourth patient with PR initially reported in the abstract became ineligible for RECIST assessment due to an irradiated lesion; the patient still showed an absence of disease progression for more than 6 months.
Two of the three patients with a PR had PD-L1 expression below 1 percent, the third being unknown; 19 of 20 patients in the trial had negative or low PD-L1 expression.
CAN-2409 treatment induced 1) increased tumor infiltration by cytotoxic T cells, 2) a systemic increase in actively proliferating, granzyme B positive T cells, 3) an increase in interferon gamma producing effector cells in both CD4+ and CD8+ compartments, and 4) increased levels of soluble granzymes A, B and H, all consistent with the hypothesized mechanism of action of CAN-2409.
"As a physician who cares for patients with NSCLC, I am frequently confronted with the problem faced by the majority of patients with lung cancer who ultimately progress on immune checkpoint therapy," said Daniel Sterman, M.D., Professor at NYU Langone Heath, and a principal investigator for the phase 2 clinical trial. "The data from this clinical trial are incredibly exciting, suggesting that the addition of CAN-2409 to pembrolizumab or nivolumab containing treatment regimens in patients experiencing progression may offer a new therapeutic option where few good alternatives exist. Importantly, CAN-2409 was administered only two times in this setting, with intratumoral administration providing a simple and straightforward approach."

Details on the abstract are below:

Abstract Title: First report of safety/tolerability and preliminary antitumor activity of CAN-2409 in inadequate responders to immune checkpoint inhibitors for stage III/IV NSCLC

Presenter: Charu Aggarwal, MD, MPH, Associate Professor of Lung Cancer Excellence, Perelman School of Medicine, University of Pennsylvania
Session Date and Time: June 6, 2022, from 8:00 – 11:00 am CDT
Session Title: Lung Cancer – Non-Small Cell Metastatic
Location: McCormick Convention Center, Hall A
Abstract Number: 9037
Candel also announced that an in-person and webcast investor event will be held on Saturday, June 4, 2022, from 6:30 – 7:45 am CDT.

Key speakers will be:

Dr. Roy Herbst, Professor of Medical Oncology and Chief of Medical Oncology at the Yale Cancer Center, and member of Candel’s Research Advisory Board
Dr. Daniel S. Sterman, Professor of Pulmonary and Critical Care Medicine, at the New York University, Director of the Multidisciplinary Pulmonary Oncology Program at NYU Langone Health, and a principal investigator on the phase 2 clinical trial
Dr. Paul Peter Tak, President and CEO of Candel Therapeutics
The webcast and slides will be accessible live under "Events and Presentations" on the Investors page of the company’s website at View Source or by clicking here. A replay will be available on the website for approximately 90 days after the event.

Dr. Charu Aggarwal is serving as the co-principal investigator of this phase 2 clinical trial. For more information on the clinical trial please visit: View Source

About CAN-2409

CAN-2409, Candel’s most advanced oncolytic viral immunotherapy candidate, is a replication-deficient adenovirus that delivers the herpes simplex virus thymidine kinase (HSV-tk) gene to cancer cells. HSV-tk is an enzyme that locally converts orally administered valacyclovir into a toxic metabolite that kills nearby cancer cells. The intra-tumoral administration results in the release of tumor-specific neoantigens in the microenvironment. At the same time, the adenoviral serotype 5 capsid protein elicits a strong pro-inflammatory signal in the tumor microenvironment. This creates the optimal conditions to induce a specific CD8+ T cell mediated response against the injected tumor and uninjected distant metastases for broad anti-tumor activity. Because of its versatility, CAN-2409 has the potential to treat a broad range of solid tumors. Monotherapy activity as well as combination activity with standard of care radiotherapy, surgery, chemotherapy, and immune checkpoint inhibitors have previously been shown in several preclinical and clinical settings. Furthermore, CAN-2409 presents a favorable tolerability profile; more than 700 patients have been dosed to date, supporting the potential for combination with other therapeutic strategies without inordinate concern of overlapping adverse events. Currently, Candel is evaluating the effects of treatment with CAN-2409 in non-small cell lung cancer, high-grade glioma, pancreatic cancer, and localized, non-metastatic prostate cancer in ongoing clinical trials.

On May 26, 2022 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported the presentation of research across various types of cancer from its oncology portfolio during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (#ASCO22), which is taking place virtually and in-person in Chicago from June 3 to 7 (Press release, Eisai, MAY 26, 2022, View Source [SID1234615166]). Notable presentations include a poster discussion of safety and efficacy data (NCT03386942(New Window); Abstract: #5513) from the platinum-resistant ovarian cancer cohort expansion of a Phase 1 study evaluating the antibody drug conjugate (ADC) co-developed by Eisai and Bristol Myers Squibb (Headquarters: the United States), farletuzumab ecteribulin (MORAb-202), as well as a poster presentation featuring dose optimization findings for farletuzumab ecteribulin (NCT03386942(New Window); Abstract: #3090).

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"Safety and efficacy analyses in platinum-resistant ovarian cancer for farletuzumab ecteribulin suggest antibody drug conjugates may represent a promising therapeutic strategy for these patients with limited treatment options," said Dr. Takashi Owa, President, Oncology Business Group at Eisai. "Eisai’s first antibody drug conjugate combines our in-house developed anti-folate receptor alpha antibody and our anticancer agent eribulin using an enzyme cleavable linker, illustrating our dedication to building on our medicines to improve cancer care for more patients."

New research from the LEAP (LEnvatinib And Pembrolizumab) clinical program evaluating lenvatinib (LENVIMA) plus pembrolizumab (KEYTRUDA), the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA, includes subgroup analyses from the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial evaluating the combination in patients with advanced renal cell carcinoma (RCC) and Phase 3 Study 309/KEYNOTE-775 trial evaluating the combination in patients with advanced endometrial carcinoma (EC). A poster discussion will evaluate the impact of subsequent therapies in patients with advanced RCC receiving the combination (NCT02811861(New Window); Abstract: #4514); while a poster presentation will discuss the efficacy of next line therapy after treatment with lenvatinib plus pembrolizumab in advanced EC (NCT03517449(New Window); Abstract: #5587).

"The combination of lenvatinib plus pembrolizumab has helped to expand physicians’ arsenal of treatment options for patients living with advanced renal cell carcinoma and advanced endometrial carcinoma around the world," said Richard C. Woodman, MD, Chief Clinical Officer, Oncology Business Group at Eisai. "Our data at ASCO (Free ASCO Whitepaper) 2022 demonstrate our commitment to continuing to investigate the combination through post-hoc analyses with the goal of providing healthcare professionals with tools to support them in making better-informed treatment decisions for their patients."

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 lenvatinib, both as monotherapy and in combination with pembrolizumab. To date, more than 20 trials have been initiated under the LEAP clinical program, which is evaluating the combination across more than 10 different tumor types.

In June 2021, Eisai and Bristol Myers Squibb entered into an exclusive global strategic collaboration agreement for the co-development and co-commercialization of farletuzumab ecteribulin, a folate receptor alpha (FRα)-targeting ADC. Eisai and Bristol Myers Squibb are currently investigating farletuzumab ecteribulin in FRα-positive solid tumors (inclusive of endometrial, ovarian, lung and breast cancers) in two studies: a Phase 1 clinical study in Japan and a Phase 1/2 clinical study in the United States.

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

The full list of Eisai presentations is included below. The majority of abstracts have been made available on Thursday, May 26, 2022, at 5:00 PM EDT and will be available on demand via ASCO (Free ASCO Whitepaper)’s website.

　

Cancer Type Study/Compound Abstract Title Abstract Type & Details
Pipeline
Gynecologic Cancer Farletuzumab Ecteribulin Safety and Efficacy of MORAb-202 in Patients (pts) With Platinum-Resistant Ovarian Cancer (PROC): Results From the Expansion Part of a Phase 1 Trial.
Poster Discussion
Abstract #5513
June 4, 2022
5:30 PM EDT

Shin Nishio, MD, PhD
Kurume University School of Medicine

Farletuzumab Ecteribulin Dose Optimization for MORAb-202, an Antibody-Drug Conjugate (ADC) Highly Selective for Folate Receptor-Alpha (FRα), Using Population Pharmacokinetic (PPK) and Exposure-Response (E-R) Efficacy and Safety Analyses.
Poster Presentation
Abstract #3090
June 5, 2022
9:00 AM EDT

Seiichi Hayato
Eisai
Lenvatinib Combinations

(Plus Pembrolizumab, Pembrolizumab and Chemotherapy or Pembrolizumab and Belzutifan)

Genitourinary Cancer CLEAR (Study 307)/ KEYNOTE-581 Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study
Poster Discussion
Abstract #4514
June 4, 2022
5:42 PM EDT

Martin H. Voss, MD
Memorial Sloan Kettering Cancer Center
Gynecologic Cancer Study 309/ KEYNOTE-775 Efficacy of next line of therapy after treatment with lenvatinib (LEN) in combination with pembrolizumab (pembro) versus treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): exploratory analysis of Study 309/KEYNOTE-775
Poster Presentation
Abstract #5587
June 4, 2022
2:15 PM EDT

Vicky Makker, MD
Memorial Sloan Kettering Cancer Center
Gastrointestinal Cancers LEAP-014 First-line lenvatinib plus pembrolizumab plus chemotherapy in esophageal squamous cell carcinoma: LEAP-014 trial in progress
Poster Presentation
Abstract #TPS4167
June 4, 2022
9:00 AM EDT

Jong-Mu Sun, MD
Samsung Medical Center, Sungkyunkwan University School of Medicine
MK-6482-016 Phase 2 Open-label Study of Pembrolizumab Plus Lenvatinib and Belzutifan in Patients With Advanced Solid Tumors
Poster Presentation
Abstract #TPS4173
June 4, 2022
9:00 AM EDT

Robin K. Kelley, MD
University of California San Francisco
Lenvatinib
Gastrointestinal Cancer REFLECT Characterization of tumor responses in patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib in REFLECT
Poster Presentation
Abstract #4078
June 4, 2022
9:00 AM EDT

Masatoshi Kudo, MD
Kindai University Faculty of Medicine
Additional Research
Gynecologic Cancer ECHO EU Treatment Pattern Treatment patterns and outcomes among patients with recurrent or advanced endometrial cancer in Europe: Endometrial Cancer Health Outcomes Europe (ECHO EU) Study
Online Publication
Abstract #e17627
May 26, 2022
5:00 PM EDT

Vimalanand S Prabhu, PhD
Merck & Co., Inc., Rahway, NJ, USA
Genitourinary Cancer Translational Research Exploratory analysis on crosstalk between intra-tumor immunity and FGF/FGFR pathway in clear cell renal cell carcinoma
Online Publication
Abstract #e16525
May 26, 2022
5:00 PM EDT

Takafumi Narisawa, MD
Yamagata University Faculty of Medicine

On May 26, 2022 Race Oncology Limited ("Race") reported the dose escalation Phase 1b stage of the relapsed or refractory Acute Myeloid Leukaemia (R/R AML) trial running at the Chaim Sheba Medical Centre, Israel has successfully completed after the treatment of the first six patients (Press release, Race Oncology, MAY 26, 2022, View Source [SID1234615165]).

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The six patients were heavily pre-treated and had received a median of four prior lines of AML treatment (range 2-8).

By design, the primary endpoint of the initial phase of this 2-stage clinical trial is establishing the recommended dose to be used in the subsequent Phase 2 expansion (efficacy) stage. This first stage requires identifying the treatment dose level that achieves two or fewer dose-limiting toxicities (DLTs) from six consecutively treated patients. In the initial six patients treated, two DLTs were reported (one Grade 3 elevated liver enzymes and one Grade 5 infection). Both DLTs occurred in the most heavily pre-treated patients who had received five and eight prior lines of treatment, respectively.

"The positive results from the first stage of this trial in such a heavily pre-treated relapsed or refractory Acute Myeloid Leukaemia population is encouraging, especially with three of the patients being subsequently bridged to transplant. We look forward to the next stage of this study which, together with data from the EMD AML Trial (RAC-006) which is soon to commence recruitment in Australia, is extending our understanding of Zantrene in a modern AML setting."

Race CMO Dr David Fuller
Efficacy results in this refractory patient population were very encouraging, with one patient showing a complete response (CR) based on morphology, two patients having a partial response (PR) including one with extramedullary disease, two showing no response (NR), and one patient not assessable (NA) due to death from infection. Infection is a known side effect of all intensive chemotherapeutic regimens and is one of the leading causes of death in AML patients.

"The encouraging results of our Phase I study with Zantrene monotherapy and moreover the current Phase II study altogether with Zantrene in combination in extremely heavily treated advanced high risk AML patients are encouraging and may indicate a role for Zantrene in modern AML treatment paradigm to the benefit of our patients."

Study Lead Prof Arnon Nagler
Three patients (1 CR and 2 PR) were bridged to an allogeneic stem cell transplant. Bridging a patient to transplant is an important positive outcome in AML treatment as it offers the patient the potential of long-term remission. Of note, these three patients had all received less than five prior lines of treatment. Poor or no response to known efficacious treatments is common and expected in heavily pre-treated cancer patients.

"We are very excited about the positive data from the first stage of this trial in such a heavily pre-treated R/R AML population, and we now look forward to the next phase, where we expect to see more patients respond favourably and with a consistently tolerable side effect profile. It appears that bridging to transplantation with long-term disease control can be achieved with confidence, given we can since perceive that the side effects reverse within a few weeks of the course being completed."

Race Clinical Advisory Board Chair Prof Borje Andersson
The trial will now progress to the Phase 2 efficacy (expansion) stage using a 4-day schedule of Zantrene (bisantrene dihydrochloride) in combination with fludarabine and clofarabine.

On May 26, 2022 Biomea Fusion, Inc. (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported it will present new data at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting demonstrating BMF-219’s activity in ex vivo preclinical models of CLL (Press release, Biomea Fusion, MAY 26, 2022, View Source [SID1234615164]). In addition, the company will present a Trial In Progress (TIP) poster presentation detailing the design of COVALENT-101. Once released at the ASCO (Free ASCO Whitepaper) Annual Meeting, the preclinical and TIP presentations can be viewed on Biomea’s website at View Source

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"Given our leadership team’s involvement with the discovery and development of ibrutinib and, thus, its demonstrated efficacy in CLL, we were highly encouraged to see BMF-219 demonstrate greater activity than ibrutinib ex vivo, especially in patient samples with TP53 alterations and NOTCH1 mutations," said Thomas Butler, Biomea’s Chief Executive Officer and Chairman of the Board. "BMF-219’s powerful cell-killing activity across ex vivo CLL models as a single agent, at similar concentrations as our prior experiments of BMF-219 in ex vivo models of other cancer types, is a very important finding. We are eager and very excited to fully explore the clinical potential of a covalent menin inhibitor across multiple liquid and solid tumor types."

BMF-219 demonstrated potency across ex vivo CLL tumor models with varying cytogenetic risk profiles and Rai stages, indicating broad activity with over 98% cell lethality in all of these models. Additionally, BMF-219 showed consistently strong activity compared to venetoclax (used as a positive control) and significantly greater activity than a clinical non-covalent (reversible) menin inhibitor. Additionally, BMF-219 exhibited robust growth inhibition in patient samples that were less responsive to bendamustine and ibrutinib.

Poster Presentation Details:

Preclinical activity of irreversible Menin inhibitor, BMF-219, in chronic lymphocytic leukemia. (Abstract #7541)
Session Title: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
Session Date and Time: Saturday, June 4, 2022, 8:00 AM-11:00 AM CDT
Full Text:
Background: Menin is a scaffold protein that drives oncogenic function through transcriptional modulation directed by its various cofactors. A previous report demonstrated that menin regulates a distinct set of gene targets independent of its function with the MLL proteins in hematopoiesis and is essential for B-cell maturation (Li et al.Blood.2013;122(12):2039-46.). Chronic Lymphocytic Leukemia (CLL) is a disease of malignant B lymphocytes, for which standard-of-care agents are generally well tolerated; however, CLL patients with certain genetic backgrounds demonstrate inferior outcomes to these regimens. A major driving feature of CLL is overexpression of the anti-apoptotic marker, BCL2. We previously reported the ability of BMF-219, a selective, irreversible menin inhibitor, to downregulate the expression of BCL2 in acute leukemia cells. Additionally, we have reported the synergy of BCL2-targeted agent, venetoclax, with BMF-219 in potent cell killing of diffuse large B-cell lymphoma (DLBCL) preclinical models, prompting our exploration of BMF-219 activity in CLL. Here, we provide the first preclinical evidence for menin as a therapeutic target in CLL, by demonstrating high potency of BMF-219 against a diverse collection of CLL patient specimens.

Methods: A comprehensive panel of CLL samples isolated from patients with Rai Stages 1 to 3 disease, including relapsed or refractory disease, were cultured ex vivo in the presence of BMF-219 or clinical reversible menin inhibitors to assess the antileukemic activity of the compounds. Samples were analyzed for differential gene expression of select targets in response to treatment.

Results: BMF-219 demonstrated high potency, achieving >98% cell lethality at 1 μM exposure in all patient samples tested, with IC50 values in the range of 0.1 to 0.38 μM. Specimens isolated from patients with clinical profiles of high-risk genetic backgrounds associated with inferior outcomes to standard therapy, such as mutations in TP53 and NOTCH1, and chromosomal aberrations such as del(13q), trisomy 12 and complex karyotype, exhibited high sensitivity to BMF-219 treatment. BMF-219 was also highly effective against patient samples with clinical profiles of resistance to bendamustine, ibrutinib and venetoclax therapy. In comparison, clinical reversible menin inhibitors demonstrated no significant activity across all patient samples tested, with incalculable IC50 values and <15% reduction in cell viability at 1 μM exposure. Expression of select target genes in treated CLL cell lines was explored and will be reported.

Conclusions: Collectively, our data demonstrate the potent preclinical activity of BMF-219 against CLL patient specimens harboring various mutational and cytogenetic backgrounds, including categories of high-risk. These data highlight the unique potential of irreversible menin inhibition as a novel therapeutic option for patients with CLL.

COVALENT-101: A phase 1 study of BMF-219, a novel oral irreversible menin inhibitor, in patients with relapsed/refractory (R/R) acute leukemia (AL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). (Abstract #TPS7064)
Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Session Date and Time: Saturday, June 4, 2022, 8:00 AM-11:00 AM CDT
Full Text:
Background: Menin, a protein involved in transcriptional regulation, impacting cell cycle control, apoptosis, and DNA damage repair, plays a direct role in oncogenic signaling in multiple cancers. Inhibition of menin is therefore a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable, small-molecule irreversible inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 exhibited a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, DLBCL lines representing Double/Triple Hit Lymphoma (DHL/THL) and Double Expressor Lymphoma (DEL), and MM cell lines with diverse mutational backgrounds. BMF-219 also showed high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, and bone marrow mononuclear cells from treatment-naive and R/R MM.

Methods: COVALENT-101 (NCT05153330) is an open-label, multi-cohort, non-randomized, multicenter Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of once daily oral BMF-219 in patients with R/R AL, DLBCL and MM who have received standard therapy. Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication until 1 subject experiences either a ≥ Grade 2 related-adverse event or dose limiting toxicity (DLT). At that point, the cohort will switch to a classical "3 +3" design. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data. Patients with R/R AL, R/R DLBCL ≥ 2 but ≤ 5 therapies, and R/R MM who received ≥ 3 therapies and failed or are ineligible for any standard therapies are eligible. Patients must have ECOG PS ≤ 2, and adequate organ function. Key exclusion criteria include known CNS disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease.

The primary objective is to determine independently for each cohort/indication the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of its antitumor activity based on best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to progression (TTP) per disease-specific response criteria as assessed by the investigator. Food-effect studies will be performed in DLBCL and MM patients at certain dose levels. The enrollment commenced in January 2022. Clinical trial information: NCT05153330.

About Chronic Lymphocytic Leukemia (CLL)

CLL is a chronic leukemia that progresses relatively slowly and typically impacts older adults. In the United States, approximately 20,000 patients are diagnosed with CLL each year. While the existing treatments options produce 5-year survival outcomes greater than 87%, there is an unmet need for patients that have high- or medium-risk cytogenetic profiles and those that are relapsed or refractory to existing treatments.