On June 17, 2024 AstraZeneca reported that Imfinzi (durvalumab) in combination with carboplatin and paclitaxel followed by Imfinzi monotherapy has been approved in the US as treatment for adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) (Press release, AstraZeneca, JUN 17, 2024, View Source [SID1234644379]).

The approval by the Food and Drug Administration (FDA) was based on the results of a prespecified exploratory subgroup analysis by MMR status in the DUO-E Phase III trial. Results from DUO-E were published in the Journal of Clinical Oncology.

In the trial, Imfinzi plus carboplatin and paclitaxel followed by Imfinzi monotherapy (Imfinzi arm) reduced the risk of disease progression or death by 58% in patients with dMMR endometrial cancer versus chemotherapy alone (hazard ratio 0.42; 95% confidence interval 0.22-0.80).2

In the US, endometrial cancer is the fourth most common cancer in women, with more than 66,000 patients diagnosed and almost 12,000 deaths in 2022.3,4 Patients diagnosed at an early stage of disease have a five-year survival rate of approximately 80-90%, but there is a significant need for new treatment options for people with advanced disease, where the survival rate falls to less than 20%.5,6

Shannon N. Westin, Professor of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, and principal investigator of the trial, said, "With the incidence and mortality of endometrial cancer expected to continue to increase significantly in the coming decades, it is more important than ever that we bring new treatment options to patients at the earliest possible moment in their care. This approval underlines clear evidence that durvalumab plus chemotherapy followed by durvalumab monotherapy delivers important clinical benefits for patients with mismatch repair deficient endometrial cancer."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "There have been limited advances in the treatment of endometrial cancer in the last few decades, and continued innovation is critical as the burden of this cancer is expected to grow in the future. Immunotherapy in combination with chemotherapy is emerging as a new standard of care in this setting, and the approval of Imfinzi offers an important new option for patients with mismatch repair deficient disease."

The safety and tolerability profile of the Imfinzi and chemotherapy regimen was generally manageable, well tolerated and broadly consistent with prior clinical trials with no new safety signals.1,2

The Lynparza (olaparib) and Imfinzi arm, which investigated Imfinzi plus chemotherapy followed by Imfinzi plus Lynparza as maintenance therapy, also met the primary endpoint of progression-free survival (PFS). The trial continues to assess OS as a key secondary endpoint for both arms. Regulatory applications for both Imfinzi as well as Imfinzi and Lynparza regimens are currently under review in the EU, Japan and several other countries based on the DUO-E results.

Notes

Endometrial cancer
Endometrial cancer is a highly heterogeneous disease that originates in the tissue lining of the uterus and is most common in women who have already been through menopause, with the average age at diagnosis being over 60 years old.7-10 It is the sixth most common cancer in women worldwide.11,12 Incidence and mortality of endometrial cancer are expected to increase by approximately 61% and 87% respectively (from 420,400 cases and 97,700 deaths in 2022 to 676,300 cases and 183,100 deaths) in 2050.13

The majority of patients with endometrial cancer are diagnosed at an early stage of disease, where the cancer is confined to the uterus.9,10 They are typically treated with surgery and/or radiation, and the five-year survival rate is high (approximately 80-90%).5,6 Patients with advanced disease (Stage III-IV) usually have a much poorer prognosis, with the five-year survival rate falling to less than 20%.5,6 Immunotherapy combined with chemotherapy is emerging as a new standard of care for advanced endometrial cancer, particularly for patients with dMMR disease, who make up approximately 20-30% of all patients with this type of cancer.6,14,15,16 There remains a high unmet need for treatments for the remaining 70-80% of endometrial cancer patients with pMMR disease.15,16

DUO-E
The DUO-E trial (GOG 3041/ENGOT-EN10) is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line Imfinzi (durvalumab) plus platinum-based chemotherapy (carboplatin and paclitaxel) followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib) as maintenance therapy versus platinum-based chemotherapy alone as a treatment for patients with newly diagnosed advanced or recurrent endometrial cancer.

The DUO-E trial randomised 699 patients with newly diagnosed advanced or recurrent epithelial endometrial carcinoma to receive either Imfinzi (1120mg) or placebo, given every three weeks in addition to standard-of-care platinum-based chemotherapy. After 4-6 cycles of chemotherapy, patients (whose disease had not progressed) then received either Imfinzi (1500mg) or placebo every four weeks as maintenance, plus 300mg Lynparza (300mg BID [2x150mg tablets, twice a day]) or placebo until disease progression.

The dual primary endpoint was PFS of each treatment arm versus standard of care. Key secondary endpoints included overall survival (OS), safety and tolerability. The trial continues to assess OS for both Imfinzi monotherapy and Imfinzi plus Lynparza as maintenance therapy in the overall trial population. Mismatch repair (MMR) status, recurrence status and geographic location were stratification factors. The trial was sponsored independently by AstraZeneca and conducted in 253 study locations across 22 countries including the US, Europe, South America and Asia.

For more information about the trial, please visit ClinicalTrials.gov.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

In addition to its indications in unresectable, Stage III NSCLC and ES-SCLC, Imfinzi is currently approved in a number of countries in combination with a short course of tremelimumab (Imjudo) and chemotherapy for the treatment of metastatic NSCLC.

Imfinzi is also approved in a number of countries in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU.

Since the first approval in May 2017, more than 220,000 patients have been treated with Imfinzi. As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, breast cancer, several gastrointestinal cancers and other solid tumours.

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On June 17, 2024 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported that the first patient has been dosed in the ACESOT-1051 Phase 1 study evaluating daily oral WEE1 inhibitor APR-1051 as monotherapy in advanced solid tumor patients with unmet medical need (Press release, Aprea, JUN 17, 2024, View Source [SID1234644378]).

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APR-1051 was discovered and preclinically evaluated by Aprea’s team of chemists and scientists. APR-1051 is a potent and highly selective small molecule designed to limit off-target toxicity that may provide good safety and tolerability and has shown a potentially favorable drug exposure in pre-clinical models.

APR-1051 targets WEE1 kinase, an enzyme involved in the DNA damage response pathway. Based on preclinical studies, we believe APR-1051 may solve liabilities associated with other WEE1 inhibitors and is differentiated based on: 1) molecular structure; 2) selectivity for WEE1 versus off-target inhibition of the polo-like kinase, or PLK, family of kinases; 3) potentially improved pharmacokinetic (PK) properties; and 4) potential absence of QT prolongation at doses that significantly inhibit WEE1. No head-to-head studies with APR-1051 have been conducted.

ACESOT-1051 is a focused biomarker-driven study with advanced/metastatic solid tumors harboring the following cancer-associated gene alterations:

Amplification/overexpression of CCNE1 or CCNE2 regardless of tumor type, or
Deleterious mutations in FBXW7 or PPP2R1A regardless of tumor type, or
Colorectal cancer with KRAS-GLY12 and TP53 co-mutation, or
Uterine serous carcinoma regardless of biomarker status
"Dosing of the first patient in the ACESOT-1051 study is an important milestone in our APR-1051 development program and represents a key advancement of our clinical pipeline," said Oren Gilad, Ph.D., President and Chief Executive Officer of Aprea. "Adding a second clinical program enriches our asset portfolio. We are initially evaluating single agent activity of APR-1051 to provide the basis for future rational combination treatments. We hope to confirm APR-1051’s safety profile in this Phase 1 study and generate the necessary data that will help us understand how it can be best utilized to treat patients. We plan to provide a clinical update by year-end 2024 and generate preliminary efficacy data during 2025."

The first patient was enrolled at NEXT Oncology, San Antonio, Texas. Additional centers, including The University of Texas MD Anderson Cancer Center, are expected to participate.

Anthony Tolcher M.D., Founder of Next Oncology commented, "NEXT Oncology is committed to exploring new treatment options for cancer patients and we are pleased to begin this important clinical trial. Cancers that over express Cyclin E (CCNE1 and CCNE2) represent a high unmet medical need, and patients with Cyclin E over expression have poor prognosis and no effective therapies. WEE1 kinase is a validated oncology target and we look forward to the results of this study."

ACESOT-1051 Study Design

ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) is designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in advanced solid tumors harboring cancer-associated gene alterations. Oral APR-1051 will be administered once daily for 28-day cycles. The study consists of two parts: Part 1 is dose escalation and is expected to enroll up to 39 patients with advanced solid tumors. The first three dose levels will use accelerated titration followed by Bayesian Optimal Interval (BOIN) design for the remaining dose levels; Part 2 (up to 40 patients) is designed for dose optimization, with the goal of selecting the Recommended Phase 2 Dose (RP2D).

The primary objectives of the study are to measure safety, dose-limiting toxicities (DLTs), maximum tolerated dose or maximum administered dose (MTD/MAD), and RP2D; secondary objectives are to evaluate pharmacokinetics, preliminary efficacy according to RECIST or PCWG3 criteria; pharmacodynamics is an exploratory objective. The University of Texas MD Anderson Cancer Center is the lead site, and the study will be performed at between 3 and 10 sites in the U.S.

The ACESOT-1051 design was featured in a poster at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting which took place in April 2024 in San Diego. A copy of the poster can be found here. For more information, refer to ClinicalTrials.gov NCT06260514.

On June 17, 2024 Alivexis, Inc. (Headquartered in Minato-ku, Tokyo; CEO S. Roy Kimura) reported that the Company has entered into a Research Collaboration Agreement with Astellas Pharma Inc. ("Astellas") to identify small molecule compounds for a new drug target selected by Astellas, utilizing Alivexis’ drug discovery platform ModBind and other technologies (Press release, Alivexis, JUN 17, 2024, View Source [SID1234644376]).

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The collaboration aims to utilize Alivexis’ computational drug discovery platform, including ModBind, to discover new small molecule compounds which will regulate the function of a novel drug target molecule selected by Astellas. As this target has no reported functional modulators to-date, the collaboration will accelerate the drug discovery of novel therapeutics against the target. In addition to in silico evaluation using the computational drug discovery platform, Alivexis will be responsible for integrated drug discovery research, including the development of experimental assays and compound evaluation using those assays. Under the terms of the collaboration, Astellas will have the option to acquire rights to the research deliverables.

About ModBind.
Alivexis has established a computational drug discovery platform that greatly accelerates small molecule drug discovery, which includes physics-based molecular dynamics simulations using GPUs (Graphics Processing Units), large-scale virtual screening algorithms, and deep learning models. With the help of their computational drug discovery platform, Alivexis has already delivered several clinical candidate molecules for both in-house drug discovery projects and external collaborations. Among Alivexis’ various computational drug discovery tools, the newly developed ModBind is a molecular simulations-based algorithm that can predict the efficacy of drug candidate compounds with high accuracy, yet performs more than 100 times faster than the other state-of-the-art technologies in the field. ModBind is based on a theoretical approach that is fundamentally different from industry standard simulations-based prediction technologies. One significant advantage of ModBind is that it is an absolute predictor of ligand efficacy and does not require known reference compounds, which are usually necessary for other methodologies. Therefore, ModBind is useful in all stages of preclinical drug discovery – from screening large random chemical libraries for initial hit finding to delivering clinical candidates in the lead-optimization stage. This capability has already been proven by Alivexis’ in-house research and external collaborations and is contributing to the progression of many drug discovery projects.

【CEO S. Roy Kimura’s Comments】
"I am excited to announce the signing of our drug discovery collaboration with Astellas focused on the use of our proprietary and ground-breaking ModBind simulation technology to accelerate early drug discovery for a particular disease target. Through our collaboration, we look forward to gaining further validation of our technology while contributing to the discovery of novel clinical candidate compounds for diseases with high patient need."

On June 16, 2024 Astrazeneca reported Positive results from the ECHO Phase III trial showed Calquence (acalabrutinib) in combination with bendamustine and rituximab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and showed a favourable trend in overall survival (OS) compared to standard-of-care chemoimmunotherapy (bendamustine plus rituximab) in previously untreated patients with mantle cell lymphoma (MCL) (Press release, AstraZeneca, JUN 16, 2024, View Source [SID1234644358]).

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These results will be presented today in a late-breaking oral presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Hybrid Congress in Madrid, Spain (#LBA3439).

Results showed the Calquence combination regimen reduced the risk of disease progression or death by 27% compared to standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57-0.94; p=0.016). Median PFS was 66.4 months for patients treated with the Calquence combination (n=299) versus 49.6 months with standard-of-care chemoimmunotherapy (n=299).

The secondary endpoint of OS showed a favourable trend for the Calquence combination compared to standard-of-care chemoimmunotherapy, further supporting the clinical benefit of this combination (HR 0.86; 95% CI 0.65-1.13; p=0.2743). The OS data were not mature at the time of this analysis and the trial will continue to assess OS as a key secondary endpoint.

The ECHO trial enrolled during the pandemic period, and a pre-specified analysis censoring for COVID-19-related deaths was conducted to assess the impact. PFS was further improved in both arms, with the Calquence combination reducing the risk of disease progression or death by 36% (HR 0.64; 95% CI; 0.48-0.84; p=0.0017). Median PFS was not reached among patients treated with the Calquence combination versus 61.6 months for standard-of-care chemoimmunotherapy (HR 0.64, 95% CI, 0.48-0.84; p=0.0017). A favourable trend was seen for OS in this analysis for the Calquence combination (HR 0.75; 95% CI 0.53-1.04; p=0.0797).

Michael Wang, MD, Puddin Clarke Endowed Professor, Director of Mantle Cell Lymphoma Program of Excellence, Co-Director of Clinical Trials at MD Anderson Cancer Center in Houston, US and principal investigator in the trial, said: "For people living with mantle cell lymphoma, a typically aggressive form of non-Hodgkin’s lymphoma, the ECHO results offer promise of a new, effective treatment option for adults older than 65, who represent the majority of MCL patients. The improved progression-free survival seen in patients treated with the Calquence combination compared to chemoimmunotherapy demonstrate its potential to change the standard of care as the only BTK inhibitor in this first-line setting."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "The ECHO trial data demonstrate important progress in improving outcomes for patients with mantle cell lymphoma. The 16.8 months of additional time patients can live without their disease progressing is highly clinically meaningful, together with a trend to improvement in overall survival. We therefore believe Calquence plus chemoimmunotherapy will be an important new option for patients living with this disease."

Summary of Results: ECHO

Calquence plus bendamustine and rituximab

(n = 299)

Placebo plus bendamustine and rituximab

(n = 299)

Median PFS

(months)

66.4

49.6

PFS HR (95% CI)

0.73 (0.57-0.94)

PFS p-value

0.0160

OS HR (95% CI)

0.86 (0.65-1.13)

OS p-value

0.2743

Censoring for COVID-19 deaths

Median PFS

NR

61.6

PFS HR (95% CI)

0.64 (0.48-0.84)

PFS p-value

0.0017

OS HR (95% CI)

0.75 (0.53-1.04)

OS p-value

0.0797

NR=Not reached

The safety and tolerability of Calquence was consistent with its known safety profile, and no new safety signals were identified. Grade 3 or higher adverse events (AEs) due to any cause occurred in 88.9% (n=264) of patients treated with the Calquence combination and 88.2% (n=262) of patients treated with standard-of-care chemoimmunotherapy, including Grade 3 or higher atrial fibrillation in 3.7% (n=11) and 1.7% (n=5) of patients, Grade 3 or higher hypertension in 5.4% (n=16) and 8.4% (n=25), Grade 3 or higher major bleeding in 2.0% (n=6) and 3.4% (n=10), and Grade 3 or higher infections in 41.1% (n=122) and 34.0% (n=101), respectively. Serious AEs and Grade 5 events were balanced across arms (69% [n=205] versus 62% [n=184], and 12.1% [n=36] versus 10.1% [n=30], respectively). AEs leading to discontinuation were observed in 10.4% (n=31) and 6.4% (n=19) of patients for the Calquence combination and placebo arms respectively. AEs related to COVID-19 were seen in the trial, including Grade 5 events which occurred in 9.4% (n=28) of patients treated with the Calquence combination and 6.7% (n=20) of patients treated with standard-of-care chemoimmunotherapy.

Additional AstraZeneca data at EHA (Free EHA Whitepaper)
In addition to these compelling data, AstraZeneca data at EHA (Free EHA Whitepaper) 2024 shows how the Company is advancing a diverse and innovative pipeline spanning multiple modalities including next-generation T cell engagers, cell therapy and antibody drug conjugates, to enable the creation of novel combination regimens across a range of blood cancers.

Results from the ongoing Phase I, dose-escalation trial of AZD0486, a novel CD19xCD3 T cell engager, showed durable responses in patients with heavily pretreated relapsed/refractory follicular lymphoma with a median follow up of 11 months. Complete response rates of 84% were seen at doses of AZD0486 of 2.4 mg and above. Data also showed how cytokine release syndrome (CRS) events were effectively mitigated by the double step-up dosing schedule and no immune effector cell-associated neurotoxicity syndrome (ICANS) events were observed.

In an oral presentation, preliminary data was shared from an investigator-initiated trial of AstraZeneca’s first haematology cell therapy, GC012F (AZD0120), in patients with transplant-eligible high-risk, newly diagnosed multiple myeloma. Early results showed that GC012F had an overall response rate of 100%, a minimal residual disease-negative stringent complete response rate of 95%, and was well tolerated. Grade 1-2 CRS was experienced by 27% (6/22) of patients and no ICANS or neurotoxicity was observed. GC012F is a novel BCMAxCD19 dual-targeting autologous chimeric antigen receptor T therapy (CAR-T) created using the next-day FasTCAR manufacturing platform pioneered by Gracell Biotechnologies, a wholly owned subsidiary of AstraZeneca.

Notes

Mantle cell lymphoma
MCL is a rare and typically aggressive form of non-Hodgkin lymphoma (NHL), often diagnosed as a late-stage disease, resulting when B-lymphocytes mutate into malignant cells within a region of the lymph node known as the mantle zone.1,2 While MCL patients initially respond to treatment, patients do tend to relapse.3 MCL comprises about 3-6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries; in the US, it is estimated that approximately 4,000 new patients are diagnosed with MCL each year.3,4 It is estimated that there are more than 27,500 people living with MCL worldwide.5,6

ECHO
ECHO is a randomised, double-blind, placebo-controlled, multi-centre Phase III trial evaluating the efficacy and safety of Calquence plus bendamustine and rituximab compared to standard of care chemoimmunotherapy (bendamustine and rituximab) in adult patients at or over 65 years of age (n=635) with previously untreated MCL.7 Patients were randomised 1:1 to receive either Calquence or placebo administered orally twice per day, on 28 day treatment cycles, plus bendamustine on days 1 and 2 and rituximab on day 1 of each cycle. After six cycles of induction therapy, all patients continued Calquence or placebo in combination with bendamustine and rituximab, patients receive Calquence or placebo plus maintenance rituximab for two years and then either Calquence or placebo only until disease progression.7

The primary endpoint is PFS assessed by an Independent Review Committee and key secondary endpoints include OS, overall response rate (ORR), duration of response (DoR) and time to response (TTR).7 The trial includes 27 countries across North and South America, Europe, Asia and Oceania.7

The ECHO trial enrolled patients from May 2017 to March 2023, continuing through the COVID-19 pandemic. Patients with blood cancer remain at a disproportionately high risk of severe outcomes from COVID-19, including hospitalisation and death compared to the general population.8

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.9 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.

Calquence has been used to treat more than 80,000 patients worldwide and is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US and Japan, approved for CLL in the EU and many other countries worldwide and approved in China for relapsed or refractory CLL and SLL. Calquence is also approved in the US, China and several other countries for the treatment of adult patients with MCL who have received at least one prior therapy. Calquence is not currently approved for the treatment of MCL in Japan or the EU.

As part of an extensive clinical development programme, Calquence is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL, diffuse large B-cell lymphoma and follicular lymphoma.

On June 16, 2024 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported that 14-month median follow-up data from the pivotal Phase 1/2 LINKER-MM1 trial of linvoseltamab in patients with relapsed/refractory (R/R) multiple myeloma (MM) were shared during an oral presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress 2024 and published in the Journal of Clinical Oncology (Press release, Regeneron, JUN 16, 2024, View Source [SID1234644354]). These longer-term results show a deepening of responses following the 11-month median follow-up data presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April. Linvoseltamab is an investigational bispecific antibody designed to bridge B-cell maturation antigen (BCMA) on multiple myeloma cells with CD3-expressing T cells to facilitate T-cell activation and cancer-cell killing.

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"Previous results from LINKER-MM1 have demonstrated that linvoseltamab has compelling efficacy characterized by deep and durable responses. With 14-months of median follow-up, 50% of patients achieved a complete response or better, despite their cancer being refractory to or relapsing on standard therapies," said Suzanne Lentzsch, MD, PhD, Director of the Multiple Myeloma and Amyloidosis Program at Columbia University. "Additionally, a study using US-based electronic health record data to indirectly compare linvoseltamab to real-world standard-of-care treatment also support the overall body of evidence for this investigational medicine in heavily pretreated multiple myeloma. Collectively, these presentations underscore the exciting potential of linvoseltamab as we await decisions from regulatory authorities."

The 14-month median follow-up LINKER-MM1 data for linvoseltamab among patients treated at the 200 mg dose (N=117) reinforce the durability and increasing depth of response shown in previous data cuts. Per the presentation and publication, results showed:

71% objective response rate (ORR), with 50% of patients achieving a complete response (CR) or better and 63% achieving a very good partial response (VGPR) or better, as determined by an independent review committee.
Median duration of response (DoR) of 29 months for all responders, while median DoR was not reached for those who achieved a CR or better. In analyses that were not pre-specified, there was an 81% and 95% estimated probability of maintaining a response at 12 months after achieving a partial response or better among all patients and those who achieved a CR or better, respectively.
Median progression-free survival (PFS) was not reached. There was a 70% estimated probability of being progression free at 12 months among all patients; the estimated probability was 96% among those who achieved a CR or better, per an analysis that was not pre-specified.
Median overall survival (OS) of 31 months for all patients (95% CI: 22 months to NE). In analyses that were not pre-specified, the median OS was not reached for patients who achieved a CR or better, and there was a 75% and 100% estimated probability of survival at 12 months among all patients and those who achieved a CR or better, respectively.
High rates of CRs or better in prespecified subgroups, including 55% (17 of 31 patients) among those aged 75 years or older, 48% (22 of 46 patients) among those with high cytogenetic risk, 45% (9 of 20 patients) among Black or African American patients, and 28% (10 of 36 patients) among those with plasmacytomas (including extramedullary and paramedullary).
Safety data at the 14-month median follow-up was generally consistent with those at the 11-month median follow-up. Cytokine release syndrome (CRS) was the most commonly occurring treatment-emergent adverse event (TEAE) and was observed in 46% of patients; 35% were Grade 1, 10% were Grade 2 and one case (1%) was Grade 3. Adjudicated immune effector cell-associated neurotoxicity syndrome (ICANS) events of any grade occurred in 8% of patients, including three cases that were Grade 3 and no cases that were ≥Grade 4. Infections occurred in 74% of patients – including 36% that were Grade 3 or 4 – and decreased in frequency and severity after 6 months. The most common Grade 3 or 4 TEAEs (≥20%) were neutropenia (42%) and anemia (31%). Six deaths considered due to TEAEs by investigators occurred on treatment or within 30 days of the last treatment dose; five were due to infection, and one was due to renal failure.

Also shared at EHA (Free EHA Whitepaper) was a retrospective study comparing outcomes of linvoseltamab 200 mg Phase 2 patients (N=105) in LINKER-MM1 at 14-months of median follow-up to those of real-world external control patients (N=101) who received standard-of-care (SOC) treatment in clinical practice (approximately 80 varied regimens). Patients receiving SOC treatment also met similar inclusion/exclusion criteria to the LINKER-MM1 trial. Comparing linvoseltamab to SOC treatment, the ORR was 70% versus 32% (odds ratio [OR] 5.4), median PFS was 20 months versus 3 months (hazard ratio [HR]: 0.23), and median OS was not reached versus 12 months (HR: 0.40).

In the U.S., linvoseltamab has been granted Fast Track Designation and was accepted for Priority Review for the treatment of R/R MM by the U.S. Food and Drug Administration with a target action date of August 22, 2024. Linvoseltamab is also under review for R/R MM by the European Medicines Association.

The Phase 3 confirmatory trial (LINKER-MM3) for linvoseltamab in patients with R/R MM is ongoing. Linvoseltamab is currently under clinical development, and its safety and efficacy have not been fully evaluated by any regulatory authority.

About Multiple Myeloma
As the second most common blood cancer, there are over 176,000 new cases of MM diagnosed globally, and 35,000 cases are diagnosed in the U.S. every year. In the U.S., there are approximately 8,000 people who have MM that has progressed after three lines of therapy, and 4,000 whose disease has progressed after four or more therapies. The disease is characterized by the proliferation of cancerous plasma cells (MM cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Despite treatment advances, MM is not curable and while current treatments are able to slow progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies.

About the Linvoseltamab Phase 1/2 Trial and Clinical Development Program
The ongoing, open-label, multicenter Phase 1/2 dose-escalation and dose-expansion LINKER-MM1 trial is investigating linvoseltamab in 282 enrolled patients with relapsed/refractory MM. The Phase 1 dose-escalation portion of the trial – which is now complete – primarily assessed safety, tolerability and dose-limiting toxicities across nine dose levels of linvoseltamab and explored different administration regimens. The ongoing Phase 2 dose expansion portion is assessing the safety and anti-tumor activity of linvoseltamab, with the primary endpoint of ORR. Key secondary endpoints include DoR, PFS, rate of minimum residual disease (MRD) negative status and OS.

Eligibility in the Phase 2 portion requires patients to have received at least three prior lines of therapy or have triple-class refractory MM. Linvoseltamab is administered with an initial step-up dosing regimen followed by the full 200 mg dose administered weekly. At week 16, all patients transition to every two-week dosing. A response-adapted regimen further enables patients to shift to every four-week dosing if they achieve a VGPR or better and have completed at least 24 weeks of therapy. The regimen requires a total of two 24-hour hospitalizations for safety monitoring.

The broader linvoseltamab clinical development program includes additional trials in earlier lines of therapy and stages of disease that are planned or underway. They include a Phase 1/2 trial in first-line MM, a Phase 2 trial in high-risk smoldering MM, and a Phase 2 trial in monoclonal gammopathy of undetermined significance. A Phase 1 trial of linvoseltamab in combination with a Regeneron CD38xCD28 costimulatory bispecific in MM is also planned. For more information, visit the Regeneron clinical trials website, or contact via [email protected] or 844-734-6643.