On December 11, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers harboring ESR1 mutations, reported that results of its two Phase 2 Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) studies were published in Annals of Oncology, the peer-reviewed journal of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) and the Japanese Society of Medical Oncology (Press release, Sermonix Pharmaceuticals, DEC 11, 2023, View Source [SID1234638500]).

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The articles, published online and with open access in the December edition of the journal, are as follows:

Lasofoxifene versus fulvestrant for ER+/HER2- advanced breast cancer with an ESR1 mutation: Results from the randomized, phase 2 ELAINE 1 trial
Open-label, phase 2, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after progression on prior therapies: ELAINE 2
"These Phase 2 ELAINE studies ideally position Sermonix for the initiated global registrational ELAINE-3, Phase 3 study comparing lasofoxifene in combination with abemaciclib versus fulvestrant plus abemaciclib," said Dr. David Portman, Sermonix founder and chief executive officer. "We are excited to share the results of our recent studies in this prestigious journal and to continue our path toward potential approval and commercial development of our novel targeted endocrine therapy."

Top-line data for ELAINE-1, a study of postmenopausal women with locally advanced or metastatic estrogen receptor-positive (ER+)/HER2- breast cancer with an ESR1 mutation, were shared as an oral presentation at the 2022 ESMO (Free ESMO Whitepaper) Congress. The study demonstrated that lasofoxifene, a novel targeted and tissue-selective oral endocrine therapy that acts as an ER antagonist at the breast, numerically prolonged median progression-free survival (PFS) compared with fulvestrant (5.6 months vs. 3.7 months; P=0.138) in metastatic breast cancer patients with ESR1 mutations who had progressed taking a prior aromatase inhibitor (AI) and CDK4/6i, with a favorable safety profile. Also, 30.7% of patients on lasofoxifene achieved a PFS of 12 months compared to 14.1% on fulvestrant.

ELAINE-1 also demonstrated an objective response rate (ORR) of 13.3% for lasofoxifene compared to 2.9% for fulvestrant (P=0.124), and saw on lasofoxifene the first-ever known finding of a durable complete response – ongoing at 2.5 years – that could be characterized as complete clinical remission in a metastatic ER+/HER2- breast cancer patient with an ESR1 mutation after prior CDK4/6 inhibitor treatment and subsequent treatment with a single-agent hormonal therapy.

An exploratory ELAINE-1 analysis, shared in March 2023 at the International Society for the Study of Women’s Sexual Health (ISSWSH) Annual Meeting, found in patients presenting at baseline with moderate to severe vaginal and vulvar dryness/pain on a validated measurement scale that lasofoxifene numerically improved these symptoms compared to fulvestrant.

ELAINE-2 (NCT04432454), an open-label study of lasofoxifene in combination with Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib, evaluated 29 heavily pre-treated women with ER+/HER2- locally advanced or metastatic breast cancer and an ESR1 mutation. Results were initially shared at a poster discussion session during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and updated in June at ASCO (Free ASCO Whitepaper) 2023.

The primary endpoint for ELAINE-2 was safety/tolerability, with secondary endpoints including PFS and ORR. With patient follow-up through Jan. 31, 2023, the combination of lasofoxifene and abemaciclib continued to be well-tolerated, with clinically meaningful efficacy in women with ER+/HER2- metastatic breast cancer and an ESR1 mutation. The PFS, a median of 13 months, and ORR of 56% were promising.

"Lasofoxifene has demonstrated compelling anti-tumor activity against tumors with increasingly prevalent ESR1 mutations, and potential benefit on quality of life with respect to vaginal and sexual health," said Paul Plourde, M.D., vice president of oncology clinical development for Sermonix. "We look forward to the results of ELAINE-3, and a greater understanding of lasofoxifene’s potential."

An accompanying invited (closed-access) editorial by Dr. Seth Wander of Massachusetts General Hospital addresses the context of these two seminal trials in the current and future treatment landscape of ER+/HER2- advanced breast cancer.

Annals of Oncology provides rapid and efficient peer-review publications on innovative cancer treatments or translational work related to oncology and precision medicine.

To learn more about Sermonix Pharmaceuticals and lasofoxifene, visit SermonixPharma.com. To learn more about the ELAINE studies, visit elainestudy.com.

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with a CDK4/6 inhibitor in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies, with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue selective oral endocrine therapy could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

On December 11, 2023 Defence Therapeutics Inc. ("Defence" or the "Company"), (CSE: DTC, USOTC: DTCFF, FSE: DTC), one of the leading Canadian biotechnology companies working in the field of immune-oncology reported that the U.S. FDA has cleared today "Study May Proceed" its Investigational New Drug (IND) application for a Phase I clinical trial of ACCUM-002TM Dimer CDCA-SV40 commonly named "AccuTOX", as an injectable anticancer molecule, for the treatment of solid cancer tumors (Press release, Defence Therapeutics, DEC 11, 2023, View Source;utm_medium=rss&utm_campaign=defence-receives-fda-approval-for-phase-i-clinical-trial-targeting-solid-cancer-tumors-with-accutox [SID1234638490]). The approval granted to AccuTOX, the company’s first first-in-class therapy, marks another key advancement for Defence in the immune-oncology field.

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The successful filing and safety review by the U.S. FDA of our protocol entitled "Phase 1 trial of ACCUM-002TM administered intratumorally as monotherapy and in combination with Opdualag (fixed IV doses), in patients with unresectable, stage IIIB to IV melanoma refractory to or relapse from standard therapy" marks a significant milestone for the company’s strategy featuring diverse pipelines. Alongside its cancer vaccine-related therapies, AccuTOX will become Defence’s flagship asset in the anti-cancer therapeutics field. Defence remains committed to its mission of addressing unmet clinical needs and in pursuing its goals to become a global leader in the development of innovation anti-cancer therapies.

About AccuTOX

AccuTOX is a derivative of the initial Accum backbone molecule. It was initially designed to various cellular processes including endosomal membranes to impair intracellular transport mechanisms, triggering genotoxic effects, blocking DNA repair mechanisms, and eliciting immunogenic cell death to stimulate the immune system. The use of AccuTOX in preclinical animal models with T-cell lymphoma, melanoma or breast cancer, under Dr. Moutih Rafei supervision, Defence’s CSO, resulted in impaired tumor growth with 70% of treated animals showing complete responses.

"We are very proud, thrilled, and we look forward to beginning this Phase I trial as its aim is to test one of our leads and most advanced therapeutic candidate for the treatment of solid tumors for the benefits of the cancer patients. Defence is becoming a clinical stage company," said Sébastien Plouffe, President & CEO of Defence Therapeutics.

The primary objective of this upcoming Phase I clinical trial, is to identify the safest dosing range in order to co-administer AccuTOX with Opdulag, a BMS product containing both anti-LAG3 and anti-PD-1. Several other secondary parameters including therapeutic efficacy will be monitored in treated patients in preparation for a Phase II clinical trial on a basket of tumors. More details about the beginning of the Phase I will be announced in the near future.

According to Data Bridge Market Research, the solid tumors market was valued at USD 209.61 billion in 2021 and is expected to reach USD 901.27 billion by 2029, registering a CAGR of 20.0% during the forecast period of 2022 to 2029.

On December 11, 2023 Bristol Myers Squibb (NYSE: BMY) reported updated results from three key programs within its broad multiple myeloma research pipeline, highlighting its diverse targets and molecular approaches to address unique patient needs within the disease (Press release, Bristol-Myers Squibb, DEC 11, 2023, View Source [SID1234638482]). These data were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, California.

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"The data from our multiple myeloma pipeline at ASH (Free ASH Whitepaper) this year continue to demonstrate the progress we are making to deliver the best possible outcomes for patients, leveraging an array of targets matched to the right therapeutic modality based on insights from causal human biology," said Michael Pourdehnad, M.D., senior vice president, Head of Early Clinical Development, Hematology Oncology and Cell Therapy Development, Bristol Myers Squibb. "These programs also represent the strength of our promising pipeline with a growing wave of registrational assets. As we continue to advance these programs, these data provide further evidence of the transformational potential of our cell therapy, protein degradation, and cell engager platforms."

Results being presented at ASH (Free ASH Whitepaper) provide updated evidence for programs including chimeric antigen receptor (CAR) T cell therapies, novel CELMoD agents from our leading protein degradation research platform, and bispecific T cell engagers (TCE):

Updated data from the Phase 1 study of CAR T BMS-986393, a potential first-in-class cell therapy targeting GPRC5D, show deepening responses, a tolerable safety profile, and activity across both B-cell maturation antigen (BCMA)-naïve and -exposed patients (Oral Presentation #219)
New results from the Phase 1 CC-92480-MM-002 study of oral CELMoD agent mezigdomide, including first results for cohorts evaluating mezigdomide and dexamethasone with monoclonal antibodies (anti-CD38 mAbs) daratumumab and elotuzumab (Oral Presentation #1013)
Updated results of the Phase 1 study of alnuctamab, a 2+1 BCMA x CD3 bispecific TCE, show deepening and durable responses, including minimal residual disease (MRD) negativity, along with manageable safety (Poster Presentation #2011)
"Despite continuing advances in care for multiple myeloma, critical unmet needs remain as patients reflect a diverse spectrum of characteristics. Moreover, the disease remains marked by eventual relapse, making the long-term management of the disease paramount," said Joseph Mikhael, M.D., Professor in the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute and Chief Medical Officer of the International Myeloma Foundation. "Because of this heterogenous profile, having a broad array of options across the treatment path is extremely valuable. Seeing the range of new and updated data being presented at this meeting is encouraging as we look toward the future of myeloma therapy."

GPRC5D CAR T (BMS-986393) Phase 1 Study Results

BMS-986393 is a first-in-class GPRC5D-directed autologous CAR T cell therapy that has the potential to be a best-in-class option for this emerging target.

This Phase 1, first-in-human, multicenter, open-label study is evaluating BMS-986393 in patients with relapsed/refractory multiple myeloma (RRMM) who had received three or more prior lines of therapy. Prior BCMA-targeted treatment, including CAR T cell therapy, was allowed. Primary objectives of the study were to determine safety and tolerability of BMS-986393 and inform the recommended dose for future development.

At the data cutoff of September 11, 2023 (median follow-up of 8.8 months), BMS-986393 continued to demonstrate an efficacy benefit with deep and durable responses in these heavily pretreated patients, including those with prior exposure to BCMA-targeted treatment. The overall response rate (ORR) was 91% (48% complete response rate) among patients treated with the recommended Phase 2 dose (RP2D, n=23), including an ORR of 100% (n=8) in patients with previous exposure to anti-BCMA targeting therapy. Minimal residual disease-negativity was observed in 86% (n=14) of evaluable patients.

BMS-986393 demonstrated a well-tolerated safety profile, and the RP2D was declared as 150 x 106 CAR T cells without reaching the maximum tolerated dose. The benefit-risk profile remained consistent with earlier, previously presented data cuts. Overall, most patients regardless of treatment dose experienced a treatment emergent adverse event (n=84; any Grade: 91.7%, Grade 3/4: 82.1%). Cytokine release syndrome (CRS) was common with the majority of events being manageable and low grade (any Grade: 76.2%, Grade 3/4: 3.6%) including in patients treated at RP2D where all CRS events were Grade 1 (88.5%). ICANS-type neurotoxicity events were not common across all dose levels (any Grade: 9.5%, Grade 3: 2.4%) and were reversible with or without intervention; among patients treated at RP2D all ICANS events were low grade (any Grade: 3.8%, Grade 3/4: 0%). The incidence of non-ICANS neurotoxicity was similar for patients treated at RP2D as compared with all patients (15.4% vs. 10.7%, respectively). On-target/off-tumor skin, nail, and oral adverse events (AEs) were all low-grade, transient, and the majority (86%) did not require treatment.

These early clinical data suggest a single infusion of BMS-986393 is tolerable and efficacious in RRMM, including in those with prior exposure to BCMA-targeted therapy​, and a single-arm Phase 2 trial of BMS-986393 in patients with RRMM exposed to four or more classes of therapy (quadruple-class exposed) is planned to open in the first half of 2024.

Novel oral CELMoD agent mezigdomide Phase 1/2 Study Results

Cereblon E3 ligase modulators (CELMoDs), representing one of three modalities from the company’s leading protein degradation platform, are a class of oral therapeutics that are optimized to both stimulate the immune system and directly kill cancer cells by inducing the degradation of tumor-promoting proteins. The CELMoD agents, mezigdomide and iberdomide, are adaptable combination and sequencing partners being investigated in multiple myeloma.

The mezigdomide CC-92480-MM-002 trial is an ongoing open-label, international Phase 1/2 study evaluating the safety and efficacy of mezigdomide with different treatment combinations in patients with RRMM. At ASH (Free ASH Whitepaper), first results were presented for combinations of mezigdomide and dexamethasone plus monoclonal antibodies (anti-CD38 mAbs) elotuzumab (MeziEd, Cohort H=21/28 days) or one of three dosing schedules of daratumumab (MeziDd, Cohort B1= 21/28 days, Cohort B2=14/21 days, Cohort B3=7/14 days x2). Patients had a median of 3 (range 2-5) prior therapies including stem cell transplantation, proteasome inhibitors, anti-CD38 agents or IMiD agents. The primary objectives of the study were to determine the RP2D, safety, and preliminary overall response rate (ORR).

Results at ASH (Free ASH Whitepaper) showed mezigdomide combined with anti-CD38 mAbs showed encouraging efficacy in previously treated patients. Patients treated with MeziDd achieved a response regardless of dose and schedule, with ORR observed in 82.6% of patients in Cohort B1 (n=23), 62.1% of patients in Cohort B2 (n=18) and 88.9% of patients in Cohort B3 (n=18). MeziEd was active in patients who were refractory to prior anti-CD38 mAb therapy, with an ORR of 45% in Cohort H (n=20). MeziDd and MeziEd were pharmacodynamically active at all schedules and dose levels tested. Further investigation is underway to determine the optimal dose and schedule for MeziDd based on Cohort B3.

The safety profile of mezigdomide in combination with anti-CD38 mAbs was manageable and consistent with prior reports. Most Grade 3/4 treatment-emergent adverse events (TEAEs) following treatment with MeziDd or MeziEd were hematologic, with neutropenia being the most common and ranging from 40-70% across cohorts. The occurrence of Grade 3/4 non-hematologic TEAEs was relatively low with either combination.

Mezigdomide is currently being evaluated in two randomized pivotal Phase 3 studies, including SUCCESSOR-1 (NCT05519085: mezigdomide, bortezomib and dexamethasone vs. pomalidomide, bortezomib and dexamethasone in patients with lenalidomide-exposed RRMM) and SUCCESSOR-2 (NCT05552976: mezigdomide with carfilzomib and dexamethasone vs. carfilzomib and dexamethasone in patients with anti-CD38 and lenalidomide exposed RRMM).

Alnuctamab (BMS-986349/CC -93269) Phase 1 Study Results

Alnuctamab is a bispecific T cell engager (TCE) that simultaneously binds myeloma cells expressing BCMA and T cells (via CD3) in a unique 2:1 fashion. This interaction aims to drive myeloma cell death by inducing T cell activation and release of proinflammatory cytokines and cytolytic enzymes.

In the ongoing alnuctamab CC-93269-MM-001 open-label, Phase 1 study, 78 patients with RRMM were treated with subcutaneous (SC) alnuctamab in two step-up doses (3 mg and 6 mg) followed by escalating target doses of 10, 15, 30, and 60 mg, given every one week for three months, then every two weeks for three months, followed by every four weeks after those six months.

In updated results, SC alnuctamab showed durable responses with high anti-tumor activity observed at target dose of 30 mg (n=32), the dose selected for Phase 3. In the efficacy-evaluable patients treated with SC alnuctamab (n=73), the ORR was 53% across all doses and 67% at the 30 mg target dose. Median time to response was 1.2 months (range, 0.9–4.0) and responses deepened over time. Median progression-free survival (PFS) was 10.1 months (95% CI, 2.8–17.8) across all dose levels and 11.4 months (95% CI, 1.8 to not estimable) in the 30 mg target dose. Median duration of response (DOR) had not been reached at the time of data cutoff. All patients who achieved a response at the 30 mg target dose (14/14) were MRD-negative.

The safety profile was manageable and no Grade 3/4 CRS was observed. The most common Grade 3 or higher hematologic TEAEs across target doses (n=78) were neutropenia (46%), anemia (26%) and thrombocytopenia (17%) with the most common non-hematologic Grade 3 or higher TEAE being infections (17%).

A Phase 3 study of alnuctamab in patients with RRMM exposed to lenalidomide and an anti-CD38 monoclonal antibody is planned and will be initiated in the first half of 2024.

On December 11, 2023 Agenus Inc. ("Agenus") (Nasdaq: AGEN), a leader in developing novel immunological agents to treat various cancers, reported that it has triggered the second development milestone payment under its global licensing agreement with Bristol Myers Squibb for BMS-986442, an Fc-enhanced bispecific TIGIT antibody (Press release, Agenus, DEC 11, 2023, View Source [SID1234638470]). Agenus will receive a $25 million cash payment from Bristol Myers Squibb with the dosing of the first patient in the phase 2 dose expansion portion of the ongoing CA115-001 clinical trial of BMS-986442.

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BMS-986442 (also known as AGEN1777) is a dual TIGIT and CD96 antagonist with an enhanced Fc region to improve tumor-reactive T cell responses. Bristol Myers Squibb licensed BMS-986442 from Agenus in 2021. The phase 1 dose escalation study in solid tumors is complete and the phase 2 portion of the dose expansion combination study evaluating the combination of BMS-986442 with nivolumab +/- chemotherapy is ongoing.

"The start of the phase 2 portion of the dose expansion study marks an exciting milestone for this differentiated anti-TIGIT program and an important step in potentially delivering a meaningful new option for cancer patients," said Chief Executive Officer, Garo Armen, Ph.D. "Similar to our lead program botensilimab, we engineered this bispecific TIGIT antibody with an Fc-enhanced design, which we believe to be a pivotal feature for boosting clinical activity. We look forward to the future development of this program together with our partner Bristol Myers Squibb, as we remain committed to delivering innovation in cancer research."

The agreement also includes up to $1.32 billion in additional development, regulatory and commercial milestones plus tiered double-digit to mid-teens royalties. Bristol Myers Squibb is solely responsible for the development and any subsequent commercialization of BMS-986442 and its related products worldwide. Agenus retains options to conduct clinical studies under the development plan, to conduct combination studies with certain other Agenus pipeline assets, to co-fund global development for increased U.S. royalties, and to co-promote BMS-986442 in the U.S. upon commercialization.

On December 11, 2023 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company (the Company), reported the design of the Phase II trial of alisertib for the treatment of patients with HER2-negative, hormone receptor-positive metastatic breast cancer (PUMA-ALI-1201) (Press release, Puma Biotechnology, DEC 11, 2023, View Source [SID1234638469]). Based on the Company’s interactions with the U.S. Food and Drug Administration (FDA), the Company will be initiating a Phase II trial of alisertib in combination with endocrine treatment (consisting of either anastrozole, exemestane, letrozole, fulvestrant or tamoxifen) in patients with chemotherapy-naïve HER2-negative, hormone receptor-positive metastatic breast cancer. Patients must have been previously treated with CDK 4/6 inhibitors and received at least two prior lines of endocrine therapy in the recurrent or metastatic setting to be eligible for the trial. The Company has updated the presentation on its website to include a slide that describes the PUMA-ALI-1201 trial. The Company plans to initiate this trial in the second half of 2024.

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Patients will be dosed with alisertib given at either 30 mg, 40 mg or 50 mg twice daily (BID) on days 1-3, 8-10 and 15-17 on a 28-day cycle in combination with the endocrine therapy of the investigator’s choice. Patients must not have been previously treated with the endocrine treatment that will be given in combination with alisertib in the trial. Each dose level will enroll up to 50 patients. Patients must provide blood samples and tissue-based biopsies so that biomarkers can be evaluated. The primary efficacy end points will include objective response rate (ORR), duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS). As a secondary objective, the Company will be evaluating each of these efficacy endpoints within biomarker subgroups in order to determine whether any biomarker subgroup correlates with better efficacy as has been seen in preclinical and clinical studies in other cancers including breast cancer and small cell lung cancer. The Company will then look to focus the future clinical development of alisertib in combination with endocrine therapy for patients with HER2-negative hormone receptor-positive breast cancer in patients with these biomarkers.

Based on its interactions with the FDA, the Company believes that this trial design will satisfy the FDA’s Project Optimus intended to find the optimal dose of alisertib in combination with endocrine therapy in patients with HER2-negative, hormone receptor-positive metastatic breast cancer to move into a pivotal Phase III trial. Once the optimal alisertib dose is identified, the Company plans to engage with global regulatory agencies regarding the design of a pivotal Phase III trial, which it anticipates will be a randomized trial of alisertib plus investigator’s choice endocrine therapy versus placebo plus investigator’s choice endocrine therapy in patients with chemotherapy naïve HER2-negative, hormone receptor-positive metastatic breast cancer.

"There continues to be a need for new drugs for the treatment of metastatic HER2-negative, hormone receptor-positive breast cancer," said Alvin Wong, PharmD, Chief Scientific Officer of Puma Biotechnology. "The clinical trials of alisertib to date in HER2-negative, hormone receptor-positive metastatic breast cancer have demonstrated alisertib’s potential clinical benefit in this patient population, and we look forward to initiating the PUMA-ALI-1201 trial in 2024."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are excited to move forward with the development of alisertib in HER2-negative hormone receptor-positive metastatic breast cancer. We believe that the data from TBCRC 041, which tested alisertib alone and with fulvestrant and the randomized trial of alisertib plus paclitaxel versus paclitaxel alone, have demonstrated that alisertib is active in patients with HER2-negative hormone receptor-positive metastatic breast cancer and in biomarker focused subgroups. We also recognize our fiscal responsibility to the shareholders of the Company and will be carefully managing the development expenses for alisertib in order to protect the Company’s future profitability."