On December 12, 2024 Agendia, Inc., reported it will be presenting new data highlighting MammaPrint and BluePrint utility in guiding treatment decisions for patients with early-stage breast cancer (Press release, Agendia, DEC 12, 2024, View Source [SID1234649093]). The findings will be presented in two spotlight presentations and two posters at the San Antonio Breast Cancer Symposium 2024 (SABCS), on Wednesday, December 11th and Thursday, December 12th.

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One poster spotlight, titled "Association of MammaPrint with gene expression pathways predictive of resistance to cyclin-dependent kinase inhibition," presented by Adam Brufsky, MD, PhD, Professor and Associate Chief of Hematology and Oncology at UPMC Hillman Cancer Center, examined 5,657 patients with early-stage HR+HER2- tumors enrolled in the ongoing prospective, observational FLEX Trial (NCT03053193). The analysis evaluated the correlation between MammaPrint and gene expression patterns associated with Retinoblastoma (Rb) loss-of-function and CDK4 independent cellular proliferation to identify which MammaPrint Risk categories may be resistant to CDK4/6 inhibition.

A linear correlation was observed between increasing MammaPrint Risk and increasing Rb loss-of-function gene expression, suggesting that MammaPrint High 2 tumors have the highest probability of CDK4/6 resistance. Additionally, MammaPrint High 2 tumors were most likely to exhibit high cell proliferation independent of CDK4 activity (43.0%), in comparison to Ultra Low (0.1%), Low (0.5%), and High 1 (1.8%) tumors (p < 0.001). These data provide the first evidence for the utility of a commercially available signature to potentially predict resistance to CDK4/6 inhibition and help patients receive more targeted and individualized therapies.

The second poster spotlight, titled "MammaPrint and BluePrint Predict Pathological Response to Neoadjuvant Chemotherapy in Patients with HR+HER2- Early-Stage Breast Cancer Enrolled in FLEX," presented by Joyce O’Shaughnessy, MD, National Principal Investigator of the FLEX Study, Director, Breast Cancer Research, Baylor University Medical Center, Texas Oncology and the Sarah Cannon Research Institute in Dallas, TX, evaluated MammaPrint and BluePrint in predicting pathological response to neoadjuvant chemotherapy among 457 HR+HER2- breast cancer patients enrolled in FLEX.

Rates of Pathological Response (PR), including pathological Complete Response (pCR) and minimal residual cancer burden (RCB-I), were highest in High 2 Basal (43.4%) and Luminal B (21.4%) tumors, with High 2 tumors overall showing better PR rates (32.7%) compared to High 1 tumors (9.5%). Multivariate analysis indicated that only MammaPrint High 2 was significantly associated with likelihood of PR, after adjusting for clinical confounders. Overall, MammaPrint and BluePrint proved effective in predicting neoadjuvant chemosensitivity in HR+HER2- breast cancer, which may enable downstaging and improve overall outcomes.

"The findings from these two studies highlight the ability of genomic testing using MammaPrint and BluePrint to predict patient response to therapies like chemotherapy, and may be able to predict benefit from CDK4/6 inhibitors," said Dr. O’Shaughnessy. "The ongoing data that continues to be generated through FLEX is building evidence that these tests may help unlock optimal treatment plans based on the patient’s tumor biology."

Abstracts Accepted as Posters

Neoadjuvant Chemotherapy for T3 Tumors in the Era of Precision Medicine – Biology is Still King (Rahman, R., et al.)
A pooled analysis was conducted on 404 clinical T3 breast cancer patients from the NBRST, FLEX, and MINT trials undergoing neoadjuvant chemotherapy. MammaPrint (MP) and BluePrint (BP) subtyping showed higher pathological complete response (pCR) rates across all MP High Risk subtype tumors (Basal (32.5%, HER2 53.7%, Luminal B 8.6%) compared to MP Low Risk Luminal A subtype tumors (0% pCR). Menopausal status, nodal status, and grade were not significant predictors of pCR response. High Risk tumors had significantly higher pCR rates, suggesting MammaPrint Low Risk, cT3 tumors are unlikely to achieve pCR to neoadjuvant chemotherapy, suggesting these patients may avoid neoadjuvant chemotherapy despite their large tumor size.

FLEX: A Real-World Evidence, Full Transcriptome Study in 30,000 Patients with Early-Stage Breast Cancer (Maganini, R., et al.)
The FLEX Study, a large, multi-center, real-world evidence, whole transcriptome, observational breast cancer study (NCT03053193), has grown substantially since its launch in April 2017. With more than 17,000 patients enrolled across 100 sites in the US and around the world, FLEX includes over 40 sub-studies in several topics. Participants are of all racial and ethnic backgrounds with stage I, II, or III early-stage breast cancer, aiming for a representative data set. The study has produced more than 10 clinical evidence pieces on diversity and includes 1,377 self-identified Black, 530 Latin American/Hispanic, and 353 Asian and Pacific Islanders, making FLEX the most diverse study on EBC patients to date.

"These data significantly enhance our understanding of MammaPrint and BluePrint’s growing clinical applications," said William Audeh, MD, MS, Chief Medical Officer at Agendia. "Our findings reinforce the importance of precision medicine, as it allows us to tailor treatment strategies, including neoadjuvant chemotherapy consideration, incorporating immunotherapies, and potentially sparing patients from the harms of unnecessary chemotherapy. As we continue to gather data from studies like FLEX, we are solidifying the role of these genomic assays in guiding personalized treatment decisions for breast cancer patients."

About Agendia

On December 12, 2024 CEL-SCI Corporation (NYSE American: CVM) reported strong biological rationale for the use of Multikine in the confirmatory registration head and neck cancer study (Press release, Cel-Sci, DEC 12, 2024, View Source [SID1234649092]). This study of 212 newly diagnosed locally advanced, resectable head and neck cancer patients was given the go-ahead as a confirmatory registration study by FDA and will focus on those patients who showed a 73% survival with Multikine vs. a 45% for the control patients not treated with Multikine in the prior Phase 3 study.

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"I am hopeful that this report will help investors understand why we believe that we have developed a potentially very effective and safe new medicine for newly diagnosed head and neck cancer, a horrible disease with very few treatment options. Our goal is to make the first cancer treatment more successful by activating an anti-tumor immune response BEFORE surgery, radiotherapy and chemotherapy weaken the immune system," said Geert Kersten, Chief Executive Officer of CEL-SCI Corporation.

Multikine (Leukocyte Interleukin, Injection)* is an immunotherapy intended for use in treating cancer. CEL-SCI has long hypothesized that to achieve maximum stimulation of a patient’s immune system, it is best to administer an immunotherapy as a neo-adjuvant (pre-surgical) therapy, prior to standard of care treatments, when the immune system is still intact. Multikine Phase 2 studies showed significant tumor regression resulting from Multikine treatment in just three-weeks of neoadjuvant therapy with no excess toxicity beyond the standard of care. Following these positive results, CEL-SCI conducted a 928-patient randomized controlled Phase 3 clinical trial to confirm Multikine’s ability to cause tumor regressions prior to surgery, confirm its safety profile and ultimately longer overall survival versus the standard of care.

The Phase 3 study missed the primary endpoint of 10% improvement in overall survival (OS) in the ITT population (all patients in the study) but showed a 46.5-month (almost 4 years) OS benefit vs control (101.7 months vs. 55.2 months) in the patients who received Multikine followed by surgery and radiotherapy. In the other group of about 50% of patients who had chemotherapy added to radiotherapy after surgery, there was no survival benefit. Because the decision to administer chemotherapy is made after surgery, CEL-SCI had to develop selection criteria that would identify at screening those patients who would be most likely to benefit from Multikine neoadjuvant (pre-surgery) treatment. After this analysis was done and the evidence collected, CEL-SCI presented these selection criteria to FDA. The agency accepted these selection criteria and gave CEL-SCI the go-ahead to conduct a 212-patient confirmatory registration study in the patient population defined by the selection criteria. The study will include patients with newly diagnosed locally advanced primary (disease stage III and IVa) head and neck cancer presenting with: No lymph node involvement (N0) (determined via PET imaging) and having low PD-L1 tumor expression (determined via biopsy).

There are many factors that support going ahead with the confirmatory registration study, including the following:

Multikine was shown to be highly active in the full Phase 3 study population, leading to significant rates of tumor regression, including 5 complete regressions, before surgery, following just 3 weeks of Multikine treatment. Refer to slide 31 in the corporate slide presentation posted on the Company’s website. In this advanced disease stage, tumors do not shrink spontaneously, and the control group in the study had no reported pre-surgical tumor regressions. Therefore, the regressions had to be due to Multikine.
Pre-surgical tumor regressions were confirmed by pathology at surgery, where biological evidence of Multikine’s activity, inducing cellular infiltration of anti-tumor immune cells, could be seen at the tumor microenvironment.
Pre-surgical tumor regressions were also seen in prior published Phase 2 studies, further supporting the validity of the Phase 3 results showing Multikine’s anti-cancer activity.
The pre-surgical tumor regressions forecasted increased long-term survival benefit in responders. That is, subjects who had tumor regressions lived longer than those who did not. Refer to slide 20 of the corporate slide presentation for these data in the full study population.
In the target population selected for the confirmatory study the rate of pre-surgical tumor regressions was substantially higher than what was seen in the full Phase 3 population. Refer to slide 21 of the corporate slide presentation. This shows that the selected population is highly likely to show a significant survival prolongation in the confirmatory registration study.
CEL-SCI addresses some criticisms that are often levelled against any subgroup analysis. These criticisms are often applied dogmatically without considering specific facts.

Strong statistical significance
Criticism: Clinical trials are typically designed to detect effects in the overall population, not within subgroups. Analyzing smaller subgroups reduces the sample size, which decreases statistical power and increases the likelihood of false positives (Type I error) or false negatives (Type II error).
Response: the selected group from the Phase 3 study is large. It includes 114 Intention-to-Treat (ITT) patients, leading to results with strong statistical significance (p=0.0015). Refer to slide 16 of the corporate slide presentation. The hazard ratio of 0.35 (less than 1 is beneficial) and its statistical 95% confidence interval upper limit of 0.66 are below the 0.7 usually needed for approval. The Kaplan-Myer survival curve shows a clear survival benefit for Multikine-treated patients over control at all times during the 5-year follow-up of the Phase 3 study.
Multiple comparisons require a higher level of significance
Criticism: When multiple subgroups are analyzed, the probability of finding a significant result by chance increases. This can lead to spurious findings.
Response: The subgroup analysis by risk was pre-specified in the original Phase 3 protocol, so these results do not arise from a post hoc search for pockets of favorable results after the fact. It should be noted that at the time of Phase 3 study initiation PD-L1 was not available. However, as the study progressed, the statistical analysis plan (SAP) was updated to specify analysis by cellular markers including tumor PD-L1. The SAP also stated: "For each biomarker (including the pre-defined ratio and differences), proportional hazard models for OS, LRC, and PFS will be run first for just stage, location, lower biomarker cutoff, higher biomarker cutoff, and treatment as covariates; the models will be repeated by adding treatment interactions with stage, location, and the biomarker cutoffs". Moreover, the statistical strength of these results is very strong. For example, it is universally accepted that a p-value of less than 0.05 denotes a statistically significant result. When multiple subgroups are analyzed, however, the threshold for significance becomes much stricter, i.e., a need for a lower p-value to show statistical significance. The data meet these stricter standards because the p-value is only 0.0015, which is much better than a p-value of 0.05.
Are the results post hoc or not?
Criticism: Subgroup analyses are often conducted after the trial is completed and not pre-specified in the protocol or the SAP. This exploratory nature increases the risk of data dredging or p-hacking, where investigators may unintentionally focus on results that appear significant by chance.
Response: The subgroup analyses in the Phase 3 study were pre-specified in the original protocol including analysis of cellular markers; for markers not available at the time of study initiation, analysis by these markers was pre-specified in the SAP (signed and issued prior to database lock).
Is there a biological basis for the results?
Criticism: Subgroup analyses can show positive results in populations that have no biological connection to the outcome. A famous example is the ISIS-2 trial where researchers, somewhat jokingly, analyzed results by zodiac sign and found seemingly negative effects of aspirin on people born under Gemini or Libra, highlighting the pitfalls of analyzing data in extremely small subgroups.
Response: The results in the selected subgroup are based on factors that tie directly to Multikine’s mechanism of action. They therefore have a strong biological rationale that explains why this particular group should be expected to do well with Multikine pre-surgery treatment. In other words, we did not select patients based on factors, like the zodiac, that bear no relation to Multikine. Rather, the selection criteria for the patient population is supported by Multikine’s biological mechanism of action.
Were the treatment and control groups well balanced?
Criticism: Subgroup effects may not truly reflect differences in treatment but rather random variation in patient characteristics. It can be difficult to distinguish genuine treatment effects from noise without a strong biological rationale.
Response: The baseline and demographics of the two comparator groups in the confirmatory registration study are well balanced. There was a small disadvantage to Multikine because the Multikine treated group had a higher percentage of sicker stage IVa patients, but the Multikine arm still showed a highly significant overall survival advantage versus control. Refer to slide 35 of the corporate slide presentation.
There is a strong biological rationale for the selection criteria that help identify the patients who best respond to Multikine

The confirmatory registration study will be conducted in patients with newly diagnosed locally advanced primary (disease stage III and IVa) head and neck cancer, presenting with:

no lymph node involvement (N0) (determined via PET imaging) and
low PD-L1 tumor expression (determined via biopsy).
There are three biological factors supporting this population definition. First, it is widely recognized that the timing of surgery is an important factor for patients depending on their tumor burden. Secondly, Multikine’s mechanism of action will result in greater therapeutic effect in patients with intact local immune architecture and lower-disease burden. Thirdly, tumors with low PD-L1 expression (having lower defenses to anti-tumor immune cellular attack) should be more susceptible to the cellular immune attack incited by Multikine. Together, this gives a biological basis for how the effect of Multikine will vary across the locally advanced head and neck cancer population in the neoadjuvant setting, provides biological rationale and supports the selection criteria.

This biological basis is evidenced by the Phase 3 clinical trial results, which showed a higher rate of pre-surgical responses among subjects with lower disease burden. Pre-specified histopathology and immunohistochemistry performed blinded to the study confirmed a similar heterogeneity of Multikine’s effect on the tumor microenvironment, as well as Multikine’s greater effect in subjects with low PD-L1 tumor expression (TPS < 10, which included TPS = 0 to <10) vs those with higher PD-L1 tumor expression (TPS ≥ 10).

These outcomes were expected in view of Multikine’s biological mechanism of action. Specifically, because the timing of surgery is important to individual patients depending on their tumor burden and lymph node involvement, it was expected that the three-week delay of surgery necessary for the administration of Multikine would mostly negatively affect subjects with higher disease burden, while subjects with lower disease burden at entry may have a better chance of benefiting from Multikine administration. Additionally, because Multikine relies on activating the patient’s local antitumor immune response, it should be expected that Multikine will have greater effect in patients with an intact local immune architecture and increased immune competency, lower-disease burden, and the anti-tumor cellular immune response incited by Multikine will have an increased anti-tumor effect in tumors with lower PD-L1 tumor expression (where tumor defenses to, and ability to hide from, the immune system are reduced).

When these criteria were retrospectively applied to subjects in the Phase 3 study by selecting those with N0 and low PD-L1 tumor expression, the results of this analysis showed a 5-year OS advantage over control (73% vs 45%), unstratified log rank p=0.0015, and a hazard ratio of 0.35 [0.18, 0.66], Wald 0.0012, as shown on slide 16 in the corporate slide presentation.

On December 12, 2024 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global oncology company that intends to change its name to BeOne Medicines Ltd., reported it has entered into a global licensing agreement with CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. ("CSPC") for SYH2039, a novel methionine adenosyltransferase 2A (MAT2A)-inhibitor being explored for solid tumors (Press release, BeiGene, DEC 12, 2024, View Source [SID1234649091]).

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SYH2039 targets solid tumors that have a mutation called MTAP deletion, which is estimated to be present in approximately 15 percent of all cancer types with the most common including glioblastoma, pancreatic cancer and non-small cell lung cancer.

"With one of the most dynamic solid tumor portfolios in the industry, we are continually assessing opportunities that align with our strategic focus and address significant unmet needs for patients. This MAT2A inhibitor is a valuable addition to our solid tumor pipeline, and we’re eager to explore its potential, particularly in combination with our internally developed PRMT5 inhibitor, BGB-58067. Together, these assets hold promise for advancing treatment across a range of solid tumors," said Lai Wang, Ph.D., Global Head of R&D at BeiGene.

BGB-58067, which is on track to enter the clinic before the end of the year, is designed to avoid on-target hematological toxicity seen with first-generation PRMT5 inhibitors. It has best-in-class potential with high potency, selectivity, and brain penetrability.

Under the terms of the agreement, BeiGene has an exclusive license to develop, manufacture and commercialize SYH2039 worldwide. CSPC will receive upfront and time-based payments totaling $150 million and will be eligible for payments upon the achievement of certain development and commercial milestones and tiered royalties.

BeiGene is focused on growing its leadership in solid tumors with its PD-1 inhibitor TEVIMBRA (tislelizumab) and by advancing potential best-in-class assets for lung, breast and gastrointestinal cancers, including several differentiated antibody drug conjugates, multi-specific antibodies, targeted protein degraders, and small molecule inhibitors. The Company recently announced its intent to change its name to BeOne, reaffirming its commitment to develop innovative medicines to eliminate cancer by partnering with the global community to serve as many patients as possible.

On December 12, 2024 Laekna (2105.HK) reported that the company will present an internally discovered preclinical candidate at the 2024 San Antonio Breast Cancer Symposium (SABCS) on December 13, 2024 (Press release, Laekna Therapeutics, DEC 12, 2024, View Source [SID1234649090]). The presentation will feature preclinical characterization of LAE118, a novel allosteric pan-mutant selective PI3Kα inhibitor.

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"We appreciate this recognition of our expertise and strength in pre-clinical developments of novel drugs", said Dr. Justin Gu, Chief Scientific Officer of Laekna. "The development of LAE118 was led by Dr. Ming Li, with collaborative contributions from the Med Chem, Biology and AIDD (AI-driven Drug Discovery) teams of Laekna. We have significantly accelerated the development of our preclinical drug candidate with cutting-edge artificial intelligence tools".

"As a novel allosteric inhibitor, LAE118 demonstrates excellent potency and selectivity towards various PI3Kα mutants. With superior efficacy and higher tolerability than its competitors in animal models, LAE118 has great potential to become the best-in-class pan-mutant-selective PI3Kα inhibitor. We look forward to bringing this novel therapy to the patients", said Dr. Justin Gu.

PI3Kα mutations are prevalent in patients with breast, colorectal, lung, endometrial, and numerous other cancers. Targeting PI3Kα in cancer has been validated as a therapeutic strategy, as evidenced by the approved drugs. However, the first-generation drugs inhibit the wild-type PI3Kα with equal potency, which raises concerns of tolerability and therapeutic efficacy. Therefore, there is a pressing need to develop novel PI3Kα-targeted therapies that can minimize on-target toxicities and overcome drug resistance.

While making significant progress in pre-clinical developments of drug candidates in cancer, Laekna has also established a comprehensive Activin-ActRII portfolio in metabolism. Following the clinical collaboration with Eli Lilly on LAE102 (ActRIIA selective antibody), Laekna has progressedLAE103, an ActRIIB selective inhibitor and LAE123, a dual inhibitor against ActRIIA/IIB, into IND-enabling studies, aiming to advance them to the clinical stage swiftly.

The San Antonio Breast Cancer Symposium is an annual event cosponsored by the AACR (Free AACR Whitepaper) and UT Health San Antonio’s Mays Cancer Center. The meeting is the largest and most prestigious scientific gathering on breast cancer research.

Presentation details are as follows:

Abstract Number: SESS-3548

Poster Number: P5-06-16

Title: Preclinical characterization of LAE118, a novel allosteric pan-mutant selective PI3Kα inhibitor

Authors: Ming Li, Ruipeng Zhang, Junyan Chen, Meijuan Hu, Xiaofen Lin, Minhua Zhang, Xiang-Ju Justin Gu

Time: Friday, Dec. 13, 2024, 12:30 p.m. – 14:00 p.m. CST

Location: Halls 2-3, Henry B. Gonzalez Convention Center, San Antonio, Texas

Abstract Highlights:

LAE118 is a novel allosteric pan-mutant selective PI3Kα inhibitor. LAE118 demonstrates excellent in vitro anti-proliferation activities in PI3Kα mutant cell lines and remains active against cells resistant to orthosteric PI3Kα inhibitors. LAE118 shows strong anti-tumor growth effect in Xenograft models at a dose that is much lower than other allosteric inhibitors and has less effect on glucose homeostasis compared to orthosteric PI3Kα inhibitors. In pre-clinical toxicology studies, LAE118 also demonstrated good tolerability. These data indicate that LAE118 offers improved efficacy and larger safety window. LAE118 is currently in IND enabling stage and Laekna aims to submit the IND application at the earliest opportunity.

On December 12, 2024 The Menarini Group ("Menarini"), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. ("Stemline"), a wholly-owned subsidiary of the Menarini Group focused on bringing transformational oncology treatments to cancer patients, along with MEDSIR, a leading global independent clinical research company in oncology and part of Oncoclínicas & Co., the largest specialized oncology treatment group in Latin America, reported research on the pioneering clinical trial ADELA (Press release, Menarini, DEC 12, 2024, View Source [SID1234649089]). This important research addresses therapeutic resistance in advanced ER+/HER2- breast cancer. Presented at the San Antonio Breast Cancer Symposium 2024 (SABCS), the study represents a key milestone in the quest for more effective and personalized treatment options for patients with disease progression.

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The standard first-line treatment for advanced ER+/HER2- breast cancer combines endocrine therapy with CDK4/6 inhibitors. ESR1 mutations develop as a result of prior exposure to endocrine therapy during metastatic treatment, and up to 50% of ER+, HER2- advanced or metastatic breast cancers will develop these mutations. ESR1 mutations cause the tumors to become resistant to endocrine therapy, in turn causing the cancer to progress; therefore, it is important to test for ESR1 whenever mBC progresses. Longer exposure to endocrine therapy during first-line treatment increases the chance of a patient’s tumor developing an ESR1 mutation. With the goal of addressing this unmet medical need, the ADELA phase III clinical trial investigates a new therapeutic option combining elacestrant, a next generation, oral selective estrogen receptor degrader, with everolimus, an mTORC1 inhibitor.

This combination is being evaluated in patients with advanced ER+/HER2- breast cancer that harbors ESR1 mutations, and who have experienced progression after standard first-line treatment. Results from the phase III EMERALD study were the basis for elacestrant’s approval. Meanwhile, everolimus has shown efficacy in inhibiting other resistance mechanisms in this type of cancer. The elacestrant and everolimus combination has demonstrated preliminary efficacy with a manageable safety profile in the phase 1b/2 ELEVATE study (NCT05563220).

"We at Menarini Stemline are delighted to announce the collaboration with MEDSIR to continue advancing the clinical research to explore the combination therapy with elacestrant," said Nassir Habboubi, MD, Chief Medical Officer of Stemline Therapeutics. "We are committed to driving innovation in cancer treatment by delivering transformational therapies aiming to extend the lives of people living with cancer."

The primary objective of this international, randomized, double-blind trial is to evaluate whether the combination of elacestrant and everolimus offers greater efficacy in delaying disease progression compared to elacestrant monotherapy. Additionally, it investigates other crucial aspects, such as overall survival, toxicity profile, and the impact on patients’ quality of life.

The ADELA study represents a critical step in understanding how to overcome tumor resistance challenges in patients with ESR1 mutations, with the goal of advancing towards more effective and safer treatments.

"At MEDSIR, we understand innovation not only as achieving clinical results but as the ability to transform patients’ lives on a global scale. With ADELA, we take a decisive step toward accomplishing less invasive and more accessible treatments, aiming to offer new hope to those facing the most complex forms of the disease. This advancement reinforces our commitment to increasingly personalized and patient-centered medicine, a fundamental pillar in shaping the future of oncology," said Dr. Antonio Llombart-Cussac, Senior Scientific Leader at MEDSIR.

The phase III study not only has significant clinical objectives, but also holds the potential to pave the way for regulatory approval of this therapeutic combination, enabling its use in a broader population of patients with advanced breast cancer. Moreover, the international scope of the study, which includes participation from multiple countries, including Spain, Italy, France, Austria, the Czech Republic, Greece, Germany, and the United Kingdom, underscores the study’s global importance and relevance in the scientific community.

The presentation of the ADELA study at an event as prominent as SABCS 2024 reinforces MEDSIR’s leadership in excellence-driven oncology research and highlights its focus on addressing unmet needs in breast cancer treatment. The ADELA study is active and already recruiting patients.

About ORSERDU (elacestrant)

U.S. Indication: ORSERDU (elacestrant), 345 mg tablets, is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

Full prescribing information for the U.S. can be found at www.orserdu.com.

Important Safety Information
Warning and Precautions

Dyslipidemia: Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively. Monitor lipid profile prior to starting and periodically while taking ORSERDU.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the final dose.

Adverse Reactions

Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).
The most common adverse reactions (≥10%), including laboratory abnormalities, of ORSERDU were musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite(15%), diarrhea(13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%).

Drug interactions

Concomitant use with CYP3A4 Inducers and/or inhibitors: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU. Avoid concomitant use of strong or moderate CYP3A4 inducers with ORSERDU.

Use in specific populations

Lactation: Advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose.
Hepatic Impairment: Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B).
The safety and effectiveness of ORSERDU in pediatric patients have not been established.

To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.