Glioblastoma | Image Credit: 
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B7-H3–targeted CAR T-cell therapy (CAR B7H3) was found to have an acceptable safety profile through intraventricular (IVH) administration with no dose-limiting toxicities (DLTs) and no moderate or severe cytokine release syndrome (CRS) in patients with recurrent glioblastoma, according to data from a phase 1 study (NCT05366179) presented at the 2025 Society of Neuro-Oncology Annual Meeting.

Results showed that patients who received CAR B7H3 through IVH administration (n = 9) at 2 x 10

 cells (n = 3) per infusion did not experience any instances of immune effector cell–associated neurotoxicity syndrome of any grade. Mild CRS occurred in 2 patients, and no CAR T-cell therapy–related adverse effects (AEs) of grade 3 or above were reported. Two patients experienced moderate headaches.

Regarding efficacy, best radiographic responses led to a 44% disease control rate (n = 4), comprising a 22% partial response rate (n = 2) and a 22% stable disease rate (n = 2).

“Glioblastoma remains the most aggressive primary brain tumor, with a median survival of 14.6 months and 5-year survival rates below 5%. B7-H3 is a promising therapeutic target due to its widespread expression in glioblastoma and minimal expression in normal brain tissue,” lead study author Yasmeen Rauf, MD, and colleagues wrote in a poster presentation of the data. Rauf is an assistant professor of neurology and neurosurgery in the Department of Neurology at the University of North Carolina in Chapel Hill.

What was the rationale and design of the trial?

This trial is the first evaluating the safety and tolerability of CAR B7H3 administered through IVH infusion in human patients to help determine the recommended phase 2 dose (RP2D) of the drug.

CAR B7H3 administered through IVH infusion demonstrated a favorable safety profile in patients with recurrent glioblastoma.

Both safety profiles and early efficacy results encourage continued dosage escalation.

No DLTs were reported, and no instances of ICANS of moderate/severe CRS occurred.

The single-center, open-label, dose-escalation study is enrolling patients who are at least 18 years of age with histologically confirmed glioblastoma, a Karnofsky score greater than 60%, and measurable disease of at least 1 cm. Current or previous exposure to antiangiogenic agents is not permitted, and patients are required to have undergone at least 4005 cGy of radiation with concurrent temozolomide.

Patients who are pregnant or lactating, have prior or concurrent malignancy whose natural history or treatment has the potential to interfere with efficacy or safety assessment, or active HIV or hepatitis B or C infection were not included in the study.

Patients in the trial are receiving up to 3 weekly IVH infusions of CAR B7H3 across six different doses: 2 x 10

 The escalation of dosages is determined by the DLTs experienced by patients for each dose.

What was the safety profile and additional efficacy data reported from the trial?

The trial’s primary end points are number of patients with AEs, incidence of CRS, and incidence of neurotoxicity.

Data reported from phase 1 of the trial indicates that primary safety objectives have been met, with CAR B7H3 being well tolerated in patients at doses up to 1x10

Secondary end points from the trial include identification of RP2D, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and duration of response (DOR).

Among patients treated thus far, the median OS was reported 10.2 months from the time of first infusion of CAR B7H3. Data for other secondary endpoints like ORR, PFS, RP2D, and DOR has yet to be reported.

Rauf Y, Dominique H, Buchannan B, et al. Safety and tolerability of intraventricular infusion of CAR B7H3 in recurrent glioblastoma. Presented at 2025 Society of Neuro-Oncology Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTIM-32

Autologous CAR-T cells targeting B7-H3 in recurrent or refractory GBM CAR.B7-H3Tc. ClinicalTrials.gov. Updated October 10, 2025. Accessed November 24, 2025. https://www.clinicaltrials.gov/study/NCT05366179

Articles

B7-H3–targeted CAR T-cell therapy (CAR B7H3) demonstrated an acceptable safety profile in a phase 1 study for recurrent glioblastoma, with no dose-limiting toxicities or severe cytokine release syndrome observed. Administered intraventricularly, the therapy showed a 44% disease control rate, including partial responses and stable disease. The study aims to determine the recommended phase 2 dose, with patients receiving up to three weekly infusions across six dose levels. The trial's primary endpoints focus on adverse events, cytokine release syndrome, and neurotoxicity, with secondary endpoints including survival metrics.

B7-H3–directed CAR T cell therapy was well-tolerated and demonstrated an acceptable safety profile in recurrent glioblastoma.

Intraventricular B7-H3–Targeted CAR T-Cell Therapy Displays Safety in Recurrent Glioblastoma 

Image by Ashling Wahner & MJH Life Sciences Using AI

The FDA has granted orphan drug designation to OBI-902 for the treatment of patients with cholangiocarcinoma, according to an announcement from OBI Pharma.

Cholangiocarcinoma is a rare and aggressive type of cancer found in bile ducts between the liver and small intestine. As a TROP2-targeted antibody-drug conjugate (ADC), OBI-902 utilizes a strong topoisomerase 1 inhibitor payload that effectively kills tumor cells. OBI-902 more specifically, is a novel site-specific glycan-conjugated ADC that uses OBI’s GlycOBI® technology which boosts hydrophilicity and stability. Throughout preclinical studies, OBI-902 has shown promising data with antitumor efficacy, a favorable safety profile, and improved pharmacokinetic characteristics. Notably, there are currently no FDA-approved ADCs for patients with cholangiocarcinoma.

"Based on our preclinical data, OBI-902 has several important advantages over other TROP2 ADCs either approved or in development; including high stability in blood circulation, excellent bystander effect that extends the killing to neighboring cancer cells lacking TROP2 expression, potential ability to overcome drug resistance, and outstanding activity in animal and organoid models of cancer,” Heidi Wang, PhD, chief executive officer of OBI Pharma, stated in a news release.

The FDA has granted orphan drug designation to OBI-902 for the treatment of patients with cholangiocarcinoma.

The agent is being evaluated in patients with solid tumors, including cholangiocarcinoma in a phase 1/2 study (NCT07124117).

How was the phase 1/2 study of OBI-902 in solid tumors designed?

OBI-902 is being evaluated for the treatment of patients with advanced solid tumors in a phase 1/2 trial (NCT07124117).

 The open-label, dose-escalation, cohort-expansion study is enrolling patients who are at least 18 years old, have histologically or cytologically confirmed metastatic or advanced solid tumors that are uncurable through local therapies, and an ECOG performance status of 0 or 1.

Patients who are less than 3 weeks from prior cytotoxic chemotherapy or radiation therapy, have received less than 5 half-lives or 3 weeks from prior biologic therapies, underwent major surgical procedure (as defined by the investigator) or significant traumatic injury within 28 days prior to first dose, had sensory or motor neuropathy of grade 2 or greater, or had history of solid organ transplant are being excluded from the trial.

During the dose-escalation portion of the study, patients will receive OBI-902 at dose levels ranging from 1.6 mg/kg to 10 mg/kg every 3 weeks. The cohort-expansion phase of the trial will divide patients into arms based on tumor type; patients in the cholangiocarcinoma arm will receive OBI-902 at the putative recommended phase 2 dose (RP2D). 

The trial’s primary objectives are safety and tolerability, determining the maximum tolerated dose and RP2D, objective response rate, clinical benefit rate, and disease control rate of OBI-902 in patients with cholangiocarcinoma and other advanced solid tumors.

Secondary objectives include progression-free survival, duration of response, and overall survival in patients with cholangiocarcinoma and other advanced solid tumors.

What are the key takeaways concerning OBI-902 in cholangiocarcinoma?

“Importantly, this marks the first time an ADC that incorporates OBI's proprietary GlycOBI® ADC technology is being evaluated in patients, including those diagnosed with cholangiocarcinoma. We look forward to investigating this potential best-in-class TROP2 ADC in the clinic." Wang added in the news release.

OBI-902 has been granted by US FDA for orphan drug designation for the treatment of cholangiocarcinoma. News Release. OBI Pharma. November 16, 2025. Accessed November 20, 2025. https://www.obipharma.com/news/obi-902-has-been-granted-by-us-fda-for-odd/

A study evaluating OBI-902 in participants with advanced solid tumors. Clinicaltrials.gov. Updated August 29, 2025. Accessed November 20, 2025. https://clinicaltrials.gov/study/NCT07124117

OBI-902, a TROP2-targeted antibody-drug conjugate (ADC), has received orphan drug designation from the FDA for treating cholangiocarcinoma, a rare bile duct cancer. This ADC employs a topoisomerase 1 inhibitor payload and OBI’s GlycOBI® technology, enhancing its hydrophilicity and stability. Preclinical studies have shown promising antitumor efficacy and safety. A phase 1/2 trial is underway to evaluate its safety, tolerability, and efficacy in advanced solid tumors, including cholangiocarcinoma, with primary objectives focusing on safety, maximum tolerated dose, and response rates.

OBI-902 received orphan drug designation from the FDA for the treatment of patients with cholangiocarcinoma.

FDA Grants Orphan Drug Designation to OBI-902 in Cholangiocarcinoma

Stephen Freedland, MD, discusses how the efficacy findings of each arm of the phase 3 EMBARK trial in prostate cancer stacked up with one another. 

Dr Freedland on the Efficacy Results From the EMBARK Trial of Enzalutamide in Prostate Cancer

“What we are seeing is significantly improved OS with a 40% reduction in the risk of death [with enzalutamide plus ADT vs ADT alone], a profound reduction.”

Stephen Freedland, MD, a professor, a urologic surgeon, and the Warschaw, Robertson, Law Families Chair in Prostate Cancer at Cedars-Sinai; as well as associate director of Education & Training and director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer Institute, discussed the phase 3 EMBARK trial (NCT02319837) evaluating overall survival (OS) with enzalutamide (Xtandi) in patients with biochemically recurrent prostate cancer.


Protocol-defined on-trial treatment lasted for 37 weeks. Notably, the trial enrolled a patient population that had no metastases on bone scans, CT scans, or MRIs per central read.


Freedland dove into the OS results from the EMBARK trial and how each arm of the trial performed. Freedland pointed out that patients who received the combination of enzalutamide and androgen deprivation therapy (ADT; n = 355) had the most significant improvement in OS that translated to an approximately 40% reduction in the risk of death vs ADT alone (n = 358; HR, 0.597; 95% CI, 0.444-0.804; P = .0006). Freedland then went on to discuss how the enzalutamide monotherapy arm decreased the risk of death by 17% but that this reduction ultimately failed to reach statistical significance (HR, 0.830; 95% CI, 0.630-1.095; P = .1867).


Freedland mentioned updates on efficacy data from the trial, bringing up secondary end points like skeletal events and time to prostate-specific antigen progression. Freedland noted that even know the enzalutamide monotherapy arm (n = 355) did not reach statistical significance for the primary end point of OS, it did accomplish such for many secondary end points. Freedland also stated that there have been no new updates or signals regarding safety with longer follow-up.


Disclosures: Freedland reported having consultant roles with Astellas Pharma Inc., AstraZeneca, Bayer, Eli Lilly, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Novartis, Pfizer Inc., Sanofi, Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), and Tolmar.


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Stephen Freedland, MD, discusses how the efficacy findings of each arm of the phase 3 EMBARK trial in prostate cancer stacked up with one another.

 
Kristi Rosa joined MJH Life Sciences in 2016 and has since held several positions within the company. She helped launch the rapidly growing infectious disease news resource 

. Prior to working at the company, she served as lead copywriter and marketing coordinator at The Strand Theater. Email: krosa@onclive.com

Soft Tissue Sarcoma | Image 
Credit: © Anna - 
stock.adobe.com

Treatment with the AXL-targeting antibody-drug conjugate mecbotamab vedotin (Mec-V) led to a median overall survival (OS) of 21.5 months (95% CI, 14.2-29.9) in patients with treatment-refractory leiomyosarcoma (LMS), liposarcoma, and undifferentiated pleomorphic sarcoma (UPS; n = 44), according to data from part 1 of a phase 2 trial (NCT03425279).

The findings, which were shared during the 

, showed that Mec-V led to meaningful longer median OS compared with approved agents. When administered as a monotherapy at a dose of 1.8 mg/kg every 2 weeks (Q2W; n = 33), the median OS was 18.4 months (95% CI, 7.2-not evaluable [NE]). When given at the same dose in combination with nivolumab (Opdivo; n = 11), the median OS was 22.9 months (95% CI, 14.2-NE). In comparison, the median OS observed with other approved agents like eribulin (Halaven), pazopanib (Votrient), and dacarbazine was 13.5 months (95% CI, 10.9-15.6), 12.5 months (95% CI, 10.6-12.8), and 11.5 months (95% CI, 9.6-13.0), respectively.

Moreover, in those with LMS, liposarcoma, and UPS, the median OS with the ADC was 19.0 months (95% CI, 7.9-29.9), 21.7 months (95% CI, 3.7-NE), and 21.5 months (95% CI, 5.0-NE), respectively. The 12-month OS rate was 73%, which compares favorably with a historic 12-month OS rate of approximately 50% that has been reported for approved agents in recurrent soft tissue sarcoma.

Mec-V monotherapy led to a disease control rate (DCR) of 52%. Moreover, the objective response rate (ORR) was 3%, which included a partial response (PR); 49% of patients had stable disease (SD) and 46% experienced disease progression. The DCR achieved with Mec-V plus nivolumab was slightly higher, at 55%. The combination induced an ORR of 9%, which included a PR; 46% of patients had SD and 46% experienced PD. The median progression-free survival (PFS) with the monotherapy and the combination were 2.5 months (95% CI, 1.4-5.8) and 2.7 months (95% CI, 1.3-8.8), respectively, which was noted to be generally consistent with current approved drugs, which have median PFS ranging from 1.5 months to 4.6 months.

“The data presented at SITC 2025 underscore the potential of Mec-V to meaningfully extend survival in patients with treatment-refractory soft tissue sarcomas—a population with few effective options,” Jay M. Short, PhD, chairman, chief executive officer, and co-founder of BioAtla, stated in a news release.

 “The prolonged OS observed suggests that early exposure to Mec-V may change the long-term clinical outcome among patients suffering from these advanced sarcomas, potentially by helping to selectively eliminate AXL-expressing cancer cells that contribute to subsequent treatment resistance and poor outcomes.”

What is the study design for part 1 of the phase 2 trial examining Mec-V?

The open-label study included patients who were at least 18 years of age and who had AXL-expressing, locally advanced, unresectable, or metastatic sarcoma and measurable disease by RECIST v1.1 criteria.

 Patients were required to have previously received at least 1 anthracycline-containing regimen and no more than 3 prior lines of approved systemic treatment if they had a histologic subtype that is generally treated with chemotherapy.

After undergoing a screening period, patients received the ADC at 1.8 mg/kg Q2W or the ADC at 1.8 mg/kg plus nivolumab Q2W. Patients received at least 3 cycles of treatment, which were comprised of 15 days each. Tumor assessments were done during the screening period, on day 15 of cycle 2, and on day 1 of cycle 3+. The key end points of the study were DCR, number of responders, PFS rate at week 12, OS, and treatment-emergent adverse effects (TEAEs).

The data cutoff date for the findings shared at SITC 2025 was March 25, 2025. In the total population (n = 79), the mean age was 56 years (range, 23-80). More than half of patients had an ECOG performance status of 1 (56%). Sarcoma subtypes included LMS (34%), UPS (10%), liposarcoma (11%), or other soft tissue sarcoma (44%). Moreover, 20% of patients had received 1 prior systemic therapy, 37% received 2 prior lines, and 42% had received 3+ prior lines; this information was not available for 1 patient. Patients had received a mean of 15 weeks of the ADC (range, 2-63). The efficacy analysis set was comprised of those with LMS, liposarcoma, and UPS (n = 44).

What was learned about the safety profile of Mec-V?

The ADC was reported to be generally well tolerated. Ninety-five percent of all patients (n = 79) experienced any adverse effects (AEs); these effects were related to treatment for 81% of patients. Among those who experienced treatment-related AEs, 29% experienced a grade 3 AE and 5% experienced a grade 4 AE. Any related serious AEs were observed in 11% of patients.

AEs were reported to be generally low grade, transient, and manageable. The most common TEAEs reported in those who received Mec-V monotherapy (n = 54) were fatigue, nausea, peripheral neuropathy, abdominal pain, diarrhea, headache, anemia, decreased appetite, neutropenia, vomiting, increased aspartate aminotransferase level, and constipation. For those given Mec-V plus nivolumab (n = 25), the most common TEAEs included decreased appetite, fatigue, anemia, nausea, constipation, peripheral neuropathy, vomiting, increased alanine and aspartate aminotransferase levels, diarrhea, headache, neutropenia, pain in the extremity, pruritus, COVID-19, hypokalemia, muscular weakness, and pyrexia.

Ten percent of patients experienced related AEs that ultimately led to discontinuation; 5 cases were due to grade 2 peripheral neuropathy, 1 case was due to grade 2 ileus, 1 was due to grade 1 fatigue, and 1 was due to grade 3 pancreatitis. Notably, no ocular toxicities nor cases of interstitial lung disease were reported, and no patients experienced related AEs that proved fatal.

“The observed safety profile of Mec-V as monotherapy, and in combination with anti–PD-1 antibody, was manageable and consistent with conditional binding of the AXL target restricted to the tumor microenvironment,” Mihaela Druta, MD, of Moffitt Cancer Center in Tampa, FL, and coauthors, concluded.

Disclosures: Druta disclosed affiliations with Adaptimmune, Cogent Biosciences, and Deciphera Pharmacueticals.

Druta M, Pollack SM, Conley AP, et al. Median OS of 21.5 months among 44 patients with treatment-refractory leiomyosarcoma, liposarcoma, and undifferentiated pleomorphic sarcoma treated with mecbotamab vedotin, an AXL-targeting ADC. Presented at: 2025 SITC Annual Meeting; November 5-9, 2025; National Harbor, MD. Abstract 523.

BioAtla’s mecbotamab vedotin (Mec-V), an AXL-targeting ADC, demonstrates a median overall survival (OS) of 21.5 months in subtypes of refractory soft tissue sarcomas. News release. BioAtla, Inc. November 7, 2025. Accessed November 18, 2025. https://ir.bioatla.com/news-releases/news-release-details/bioatlas-mecbotamab-vedotin-mec-v-axl-targeting-adc-demonstrates

Mecbotamab vedotin (Mec-V), an AXL-targeting antibody-drug conjugate, shows promise in treating refractory soft tissue sarcomas, achieving a median overall survival (OS) of 21.5 months in a phase 2 trial. Administered alone or with nivolumab, Mec-V outperformed existing treatments like eribulin, pazopanib, and dacarbazine. The study reported a disease control rate of 52% with monotherapy and 55% with combination therapy. The safety profile was manageable, with most adverse effects being low grade and transient, and no fatal treatment-related adverse events were observed.

Mecbotamab vedotin showed promising survival gains and manageable safety in treatment-refractory soft tissue sarcomas.

Mecbotamab Vedotin Shows Potential to Extend Survival in Treatment-Refractory Soft Tissue Sarcomas

As 4-drug regimens have become a staple in the standard management of newly diagnosed multiple myeloma, using a modified quadruplet such as daratumumab (Darzalex), lenalidomide (Revlimid), ixazomib (Ninlaro), and dexamethasone (D-Rid) could potentially aid in toxicity management and treatment adherence without affecting efficacy outcomes in patients who are older or frailer, according to Andrew Yee, MD.

the phase 2 Alliance Foundation Trial 41 (NCT04009109)

22nd International Myeloma Society (IMS) Annual Meeting and Exposition

 showed that patients with newly diagnosed multiple myeloma who were ineligible for or deferred autologous stem cell transplant (n = 79) treated with D-RId experienced an overall response rate (ORR) of 92.4% (95% CI, 84.2%-97.2%), including a very good partial response or better rate of 69.6% (95% CI, 58.3%-79.5%) and a complete response or better rate of 22.8% (95% CI, 14.1%-33.6%).

 The 12-month progression free survival (PFS) rate was 92% (95% CI, 86.1%-98.4%), and the 12-month overall survival rate was 93.6% (95% CI, 88.3%-99.2%).

, Yee discussed current challenges with utilizing 4-drug multiple myeloma regimens in older or frailer patient populations, detailed the rationale for exploring D-Rid in this study, and highlighted key efficacy data reported from the first year of treatment.

Yee is an associate professor of medicine at Harvard Medical School and clinical director of the Center for Multiple Myeloma at Massachusetts General Hospital in Boston.

What was the rationale for evaluating a modified 4-drug regimen in patients with transplant-ineligible or -deferred, newly diagnosed multiple myeloma?

: We know that 4-drug regimens are increasingly a standard for [patients with] newly diagnosed multiple myeloma, and that does not matter if you are a younger [patient who is] transplant-eligible or [a patient who is] transplant-ineligible. [This 4-drug approach] is based on randomized phase 3 studies that showed outstanding responses. However, with the regimens used for older [patients who are] transplant-ineligible, they took the same regimens that were meant for younger, fit [patients who were] transplant-eligible…without making any modifications. We know that older, more frail patients can be more sensitive to the [adverse] effects [AEs] of these regimens in general.

In our trial, we [asked] how we could optimize this 4-drug regimen. How could we make it more patient friendly, especially for older and frail patients? We [attempted to address this] through a couple [methods]. First, we reduced the dose of lenalidomide from 25 mg to 15 mg. Next, we replaced the proteasome inhibitor bortezomib [Velcade] with the oral proteasome inhibitor, ixazomib.

Bortezomib is a well-established drug, but it has a couple limitations, one [being] that it requires an injection in the stomach, which means you have to go the clinic to receive it. Additionally, [bortezomib] is associated with peripheral neuropathy, and peripheral neuropathy can be an issue, especially if [a patient is] older, less fit or robust, and prone to falls. [Peripheral] neuropathy can be a more significant AE for [older] patients.

Since ixazomib is an oral medication, it is much easier for [older] patients [to receive] because they do not have to go to clinic to receive it, and it is also not associated with peripheral neuropathy. The combination of [ixazomib] being an oral medication that lacks peripheral neuropathy means that [older] patients can stay on this medication for longer periods of time to potentially gain the benefit of having a proteasome inhibitor as part of their overall treatment regimen.

The trial accrued 79 patients; the intended [patient population] size was approximately 188 patients, but the COVID-19 pandemic did affect the [trial’s] accrual. In first year of treatment, [all patients] received the same regimen [of D-Rid]; after 1 year patients were assigned through randomization, either continuing maintenance lenalidomide as a standard treatment or the combination of daratumumab, lenalidomide, and ixazomib.

The primary end point is longer-term PFS [in order to] to see the effect of daratumumab, lenalidomide, and ixazomib as maintenance or extended therapy. [At IMS 2025], we showed results for the first year’s worth of treatment.

What data were presented from this study at IMS 2025?

After the first year of treatment, [we saw] a high ORR [at 92.4%], which translates to a 1-year PFS [rate of 92%]—similar to what we have seen reported with the traditional randomized phase 3 studies looking at older and frailer patients. Moreover, you can get similar efficacy but with significantly lower rates of neutropenia, no high-grade peripheral neuropathy, and a much lower rate of [any-grade] neuropathy. This was an important point to emphasize from the study. You can adapt a regimen meant for younger patients and apply it to older patients to make for a more pleasurable and positive patient experience.

What does this study underscore regarding personalized treatment approaches for patients with multiple myeloma?

[Patients who are] older and frailer need regimens that are adapted, customized, and tailored to them to make for an overall positive patient experience. When it comes to patient regimens and treatments, you have to tailor the regimen for the patient in front of you. Can we adjust and modify the dosing and schedule of a treatment? We were able to accomplish that [here] with the lower dose of lenalidomide and by using the oral proteasome inhibitor ixazomib. [These factors] help move the ball forward in terms of how we customize treatments to help ensure optimal patient outcomes.

Yee AJ, O’Donnell EK, Nadeem O, et al. A randomized phase 2 study of daratumumab, lenalidomide, ixazomib, and dexamethasone in transplant-ineligible/deferred patients with newly diagnosed multiple myeloma: Alliance Foundation Trial 41. Clin Lymphoma Myeloma Leuk. 2025;25(2):S362. doi:10.1016/S2152-2650(25)04004-2

Ryan C. Daratumumab/ixazomib quadruplet yields durable efficacy in transplant-ineligible or -deferred, newly diagnosed myeloma. OncLive.com. September 19, 2025. Accessed November 19, 2025. 

https://www.onclive.com/view/daratumumab-ixazomib-quadruplet-yields-durable-efficacy-in-transplant-ineligible-or-deferred-newly-diagnosed-myeloma

A modified quadruplet regimen comprising daratumumab, lenalidomide, ixazomib, and dexamethasone (D-Rid) shows promise in managing newly diagnosed multiple myeloma in older or frailer patients. The phase 2 Alliance Foundation Trial 41 demonstrated a high overall response rate of 92.4% and a 12-month progression-free survival rate of 92%. The regimen, which substitutes ixazomib for bortezomib, aims to reduce adverse effects like peripheral neuropathy and improve treatment adherence. Personalized treatment approaches are emphasized to optimize outcomes for older, frailer patients.

Andrew Yee, MD, discusses data for a modified four-drug regimen studied in older patients with newly diagnosed multiple myeloma.

Modified Daratumumab-Based Quadruplet Shows Feasibility in Older Multiple Myeloma

Stephen Freedland, MD discusses the rationale for conducting the phase 3 EMBARK trial evaluating enzalutamide plus leuprolide in high-risk prostate cancer.

Dr Freedland on the Rationale Behind the EMBARK Trial in Prostate Cancer

"Adding an androgen receptor pathway inhibitor like enzalutamide to ADT significantly improves survival, delays progression, and has an adverse effect profile that is relatively well manageable. The question is: Can we apply that one step earlier in this high-risk, biochemical-recurrent, conventional imaging–negative patient population?”

Stephen Freedland, MD, a professor, a urologic surgeon, and the Warschaw, Robertson, Law Families Chair in Prostate Cancer Cedars-Sinai; as well as associate director of Education & Training and director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer Institute, discussed the phase 3 EMBARK trial (NCT02319837) evaluating overall survival with enzalutamide (Xtandi) plus leuprolide in high-risk nonmetastatic prostate cancer progressing after radical prostatectomy, radiotherapy, or both.


Freedland stated that the rationale behind the EMBARK trial was to evaluate the already-known benefits of combining androgen receptor pathway inhibitors like enzalutamide with androgen deprivation therapy (ADT) in metastatic settings in a high-risk, biochemical-recurrent, conventional imaging–negative patient population. Data from the EMBARK trial shows that enzalutamide combined with ADT reduced the risk of death by more than 40% in the high-risk patient population compared with leuprolide alone.


Freedland highlighted key elements of EMBARK trial, noting its 3-arm design. He also explained that the primary end point of the trial was metastasis-free survival as assessed by blinded independent central review in patients with high-risk, biochemical-recurrent prostate cancer.


In the experimental arm evaluating enzalutamide plus leuprolide, patients received enzalutamide at a daily oral dose of 160 mg, administered as 4, 40-mg capsules. This regimen was combined with leuprolide delivered as a single intramuscular or subcutaneous injection every 12 weeks.

Disclosures: Freedland reported having consultant roles with Astellas Pharma Inc., AstraZeneca, Bayer, Eli Lilly, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Novartis, Pfizer Inc., Sanofi, Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), and Tolmar.

Stephen Freedland, MD, discusses the rationale for conducting the phase 3 EMBARK trial evaluating enzalutamide plus leuprolide in high-risk prostate cancer.

The FDA has granted orphan drug designation to ZEN-3964 for treatment for patients with NUT carcinoma, according to an announcement from Zenith Epigenetics.

NUT carcinoma is a rare and aggressive form of cancer with no currently approved treatments. ZEN-3694 is a once daily, oral BET bromodomain inhibitor that interferes with the NUTM1 gene fusing with transcriptional regulator, helping disrupt the root activity of NUT carcinoma. During early clinical studies, more than 550 patients have been dosed with ZEN-3694, which has produced strong evidence of clinical efficacy, on-target safety, and combinability with other approved targeted therapies.

“Orphan drug status underscores the unmet need for novel treatment options in [ NUT carcinoma], where patients face poor prognoses and currently have no approved targeted therapies,” Donald McCaffery, president and chief executive officer of Zenith Epigenetics, stated in a news release. “We believe ZEN-3694, through its epigenetic mechanism and combinatorial approach, has the potential to significantly improve outcomes and survival for people with NUT carcinoma. Orphan drug designation and the recently announced fast track designation help us advance this program with the goal of making ZEN-3694 available to those who may benefit from it.”

How are the studies of ZEN-3694 for NUT carcinoma designed?

ZEN-3694 is currently being investigated in NUT carcinoma in two ongoing clinical trials. The first of which is a phase 1/2 trial (NCT05019716) that is evaluating ZEN-3694 combined with cisplatin and etoposide as treatment for patients 12 years of age or older with metastatic and unresectable NUT carcinoma, including patients who have undergone prior surgery.

 Patients in this trial are required to be diagnosed with NUT carcinoma, based on standard criteria including ectopic expression of NUT protein per World Health Organization (WHO) criteria; or NUT gene translocation detection as determined by DNA/RNA sequencing or fluorescence in situ hybridization testing.

Patients are receiving ZEN-3694 orally once or twice daily on days 1 to 14 or days 1 to 21 of each cycle, depending on the dosage assignment of patients. Within cycles, patients are receiving cisplatin on day 1 and etoposide on days 1 to 3 intravenously (IV) for cycles 1 to 4 or up to 8 cycles.

Phase 1 of this trial is determining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ZEN-3694 given in combination with etoposide and cisplatin. Phase 2 of this trial is evaluating overall response rate (ORR) with the combination of ZEN-3694, cisplatin, and etoposide.

ZEN-3694 is also being investigated in a phase 1 trial (NCT05372640) evaluating the proper dosage of the drug when combined with abemaciclib (Verzenio) as a treatment for patients with NUT carcinoma, breast cancer, and other metastatic, unresectable solid tumors.

 Participants in this trial are required to have a histologically confirmed malignancy that is both unresectable and metastatic without any effective or existing standard curative or palliative measures. A dose-expansion cohort is enrolling patients specifically with NUT carcinoma per standard diagnostic criteria.

In this trial, patients are receiving ZEN-3694 orally once daily on days 1 to 28 or on a 5-days-on, 2-days-off schedule, in combination with abemaciclib orally twice per day in 28-day cycles.

The trial’s primary objective is to determine the MTD as well as the RP2D for ZEN-3694 and abemaciclib. Researchers are also evaluating preliminary rates of antitumor activity, including progression-free survival, overall survival, ORR, time to response, and duration of response as a secondary objective.

Zenith Epigenetics’ ZEN-3694 receives orphan drug designation from FDA. News Release. Zenith Epigenetics. October 27, 2025. Accessed November 14, 2025. https://www.zenithepigenetics.com/newsroom/news-releases?article=64

Testing the safety and efficacy of the addition of a new anti-cancer drug, ZEN003694, to chemotherapy treatment (etoposide and cisplatin) for adult and pediatric patients (12-17 years) with NUT carcinoma. ClinicalTrials.gov. Updated September 3, 2025. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT05019716

Testing the safety and efficacy of the combination of two anti-cancer drugs, ZEN003694 and abemaciclib, for adult and pediatric patients (12-17 years) with metastatic or unresectable NUT carcinoma, breast cancer and other solid tumors. ClinicalTrials.gov. Updated September 19, 2023. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT05372640

ZEN-3694, a BET bromodomain inhibitor, has received orphan drug designation from the FDA for treating NUT carcinoma, a rare and aggressive cancer with no approved treatments. The drug disrupts the NUTM1 gene's fusion with transcriptional regulators, showing clinical efficacy and safety in early studies. Two ongoing clinical trials are evaluating ZEN-3694's effectiveness in combination with other therapies. The trials aim to determine the maximum tolerated dose, recommended phase 2 dose, and assess antitumor activity, including progression-free survival and overall response rate.

ZEN-3694 obtained orphan drug designation from the FDA for the treatment of NUT carcinoma.

FDA Awards Orphan Drug Designation to ZEN-3694 for NUT Carcinoma

The integration of radioligand therapy into the metastatic hormone-sensitive prostate cancer (mHSPC) setting inched closer to reality with the initial readout of data from the phase 3 PSMAddition trial (NCT04720157), according to Scott Tagawa, MD, MS, FACP, FASCO.

 demonstrated that patients with prostate specific-membrane antigen (PSMA)–positive mHSPC treated with lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in combination with an androgen receptor pathway inhibitor (ARPI) and androgen deprivation therapy (ADT; n = 572) achieved a median radiographic progression-free survival (rPFS) that was not reached (NR; 95% CI, not evaluable [NE]-NE) vs NR (95% CI, 29.7-NE) in those treated with an ARPI plus ADT alone (n = 572; HR, 0.72; 95% CI, 0.58-0.90; 

, Tagawa discussed past and present factors that impacted the investigation of lutetium Lu 177 vipivotide tetraxetan in the mHSPC setting. He also reviewed the important efficacy and safety findings from the trial, in addition to the next steps for evaluating lutetium Lu 177 vipivotide tetraxetan in mHSPC.

Tagawa is a professor of medicine and urology at Weill Cornell Medicine and an attending physician at NewYork-Presbyterian – Weill Cornell Medical Center.

With demonstrated efficacy and regulatory approvals

 in the metastatic castration-resistant prostate cancer setting, why was lutetium Lu 177 vipivotide tetraxetan evaluated in patients with mHSPC?

: It's nice that we have approvals in the later, more heavily pretreated patient population, but we do not think that's optimal. For tumors that are more heavily pretreated, we believe they are more likely to lose PSMA [expression] to some extent, or be PSMA-low, and have more inherent radio-resistance, which we think is the mechanism of action with lutetium products. Moving [lutetium Lu 177 vipivotide tetraxetan] earlier to a disease state that is more universally PSMA expressing and less likely to be radio-resistant made sense.

PSMAddition was a true combination study. We know that at least pre-clinically, when we add hormonal therapy to a prostate cancer cell that has the androgen receptor, there is upregulation of PSMA, and there are also separate data that there may be radio-sensitization. All of that together made sense to move [lutetium Lu 177 vipivotide tetraxetan] forward, and we tend to do this anyway in drug development: start with the biggest unmet need when there is nothing else available, and then try to improve upon what we have [by] moving [drugs] earlier [in the treatment paradigm].

What's important to know about PSMAddition’s design and the patients involved?

This [trial] took a [standard-of-care (SOC)] backbone, which hopefully almost all patients [with mHSPC] are getting [in real-world practice]. We know it is not 100%, and we want to make it close to 100% because ADT plus ARPI is very effective. [This trial] took that backbone, [and it was given] with or without up to 6 cycles of lutetium Lu 177 vipivotide tetraxetan at the regular dose of 7.4 GBq every 6 weeks, looking to improve rPFS as the primary end point.

[Patients needed to have] metastatic disease on CT, bone scan, or MRI, not just a PSMA PET [scan]. [However], a PSMA PET [scan] was done, and there had to be at least 1 tumor that lit up visually more than the liver. The normal performance status and organ function criteria that we would expect in a phase 3 trial [were included].

What else can you tell us about efficacy data for the primary and secondary end points in PSMAddition?

The phase 3 PSMAddition trial evaluated the addition of lutetium Lu 177 vipivotide tetraxetan to an ARPI and ADT in patients with PSMA-positive mHSPC.

The study met its primary end point, with the triplet generating a statistically significant improvement in rPFS (HR, 0.72; 95% CI, 0.58-0.90; 

Ongoing evaluation of the trial will further explore key secondary end points, quality-of-life outcomes, and PET data.

Fortunately, [the addition of lutetium Lu 177 vipivotide tetraxetan] led to a positive trial in terms of the primary end point, where vs a very effective SOC therapy, we improved rPFS by 28%. We were trying to hit a minimum of 23.5%, and we hit 28%, which made it a positive trial.

This was an early readout, as it was the first interim analysis for efficacy. At that time point, approximately 60% of the patients in the control arm had confirmed progression [and were allowed to] cross over to lutetium Lu 177 vipivotide tetraxetan as part of the study design—partly for ethical reasons and to ensure the integrity of the study, because it was an open-label study. [The crossover design] may impact more than one of the secondary end points, but more specifically, overall survival [OS]. That secondary end point is very premature, but at the first planned interim analysis, and the hazard ratio [HR] was in favor of the lutetium Lu 177 vipivotide tetraxetan, despite that early crossover. The HR confidence intervals currently cross 1, but we'll see what happens. I don't know that we need to have clear OS benefit because of the crossover, since we know the drug already has OS benefit [in the mCRPC setting].

Additional secondary efficacy end points favored lutetium Lu 177 vipivotide tetraxetan, such as changes in prostate-specific antigen [levels], response [rate], time to symptomatic skeletal events, and other secondary end points, so that was nice to also see.

What are the safety findings of the trial?

This was the third phase 3 with [lutetium Lu 177 vipivotide tetraxetan], so there was not much in the way of surprise. What we saw for the common adverse effects [AEs] were what we expect from the 3 components: ADT, ARPI, and lutetium Lu 177 vipivotide tetraxetan. Many of the most common AEs that were more common in the lutetium arm were related, at least in part, to sites of normal PSMA expression, such as salivary glands, lacrimal glands, and small intestine; dry mouth was the most common. Dry eye also happened more commonly with lutetium Lu 177 vipivotide tetraxetan, and then gastrointestinal toxicity because of small intestine uptake included nausea, vomiting, diarrhea, and constipation, which were expected. Fatigue was also more [common], which is not surprising with radiation flowing throughout the body at certain timepoints.

Interestingly, some of the purer hormonal AEs were more common in the non–lutetium Lu 177 vipivotide tetraxetan arm, even though both groups got ADT and an ARPI—maybe it was just more noticeable [in the control arm] in terms of hot flashes and hypertension. There was also more in the way of cytopenias. [Lutetium Lu 177 vipivotide tetraxetan] is a little bit different than chemotherapy, where we don't expect a high amount of neutropenia, but there was some neutropenia, [and] certainly anemia and thrombocytopenia, which we do expect with this particular drug. At least separately, none of them were more than 5% at grade 3/4. High-grade cytopenias were limited to a small proportion [of patients].

How could data from PSMAddition affect clinical practice in the mHSPC setting?

We will potentially have 4 different triplets, and I don't think that 100% of patients necessarily are going to need a triplet—100% do not necessarily need a doublet, either. There is going to be some clinical patient selection, as well as some biomarker patient selection. We know [lutetium Lu 177 vipivotide tetraxetan] has a biomarker of PSMA PET, so that will be part of the patient selection. We do know that because the available data points toward improved efficacy that some patients should get [lutetium Lu 177 vipivotide tetraxetan].

Most patients in the [mHSPC] disease state are in the hands of urologists, some are in the hands of oncologists, but neither medical oncologists nor urologists are what we would call authorized users, so we can't administer [radioligand therapies]. We can [administer] ADT and an ARPI, but we need to refer to either radiation oncologists or nuclear medicine physicians, or both, [for lutetium Lu 177 vipivotide tetraxetan]. [The integration of radiation oncologists and nuclear medicine physicians] started to happen a long time ago with Radium-223 [Xofigo] for [patients with] painful bone metastases. That is a more limited patient population than the PSMA-targeted radionuclides, which are much more common in hormone-resistant disease. Moving [lutetium Lu 177 vipivotide tetraxetan] earlier really expands the patient population. We need to make sure that we are able to coordinate and increase the number of senders and authorized users across the country.

What are the next steps planned for this investigation, and what questions would you like to see answered?

The earliest one [being analyzed] right now is quality of life. Broadly speaking, there was no major differences in terms of the patient outcomes, but there might be a tendency to have a little bit of a detriment at least at certain time points in the lutetium Lu 177 vipivotide tetraxetan arm.

Another one that is a little bit behind but will be analyzed hopefully sometime next year are the PET data. Everyone had a PSMA PET [scan] at study entry, and then there was an amendment at progression to also have a PSMA PET [scan]. The baseline PET analysis will be first, and [we] will also look at are their differences in progression [between the 2 arms]. Then, we have archival tissue that was collected, as well as blood biomarkers, so we'll have plasma and buffy coat to assess. All of those will be interesting for the future.

Tagawa ST, Sartor O, Piulats JM, et al. Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA6.

FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed November 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer

FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed November 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication

Scott Tagawa, MD, MS, FACP, FASCO, discusses data for lutetium Lu 177 vipivotide tetraxetan in mHSPC from the PSMAddition trial.

Riley Kandel