Andrea Eleazar, MHS

Jaypirca therapy improved progression-free survival versus bendamustine plus Rituxan a phase 3 trial for untreated CLL/SLL: © stock.adobe.com.

Treatment with Jaypirca (pirtobrutinib) monotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared with bendamustine plus Rituxan (rituximab; BR), according to results from the first phase 3 trial evaluating a noncovalent Bruton tyrosine kinase (BTK) inhibitor for treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

 indicate that Jaypirca reduced the risk of disease progression or death by approximately 80% versus standard chemoimmunotherapy. Investigators noted that the data support the agent as a potential new standard of care for untreated patients particularly older adults who may be limited to a single line of therapy.

“It was a knockout,” Dr. Wojciech Jurczak, Department of Clinical Oncology at the Maria Sklodowska-Curie National Research Institute of Oncology, in Poland, said during the presentation. “If we compare the similar comparisons of bendamustine, other BTK inhibitors like Imbruvica [ibrutinib] or Brukinsa [zanubrutinib], the hazard ratio is about 0.35.”

“Jaypirca was effective in whichever subgroup we analyzed,” she added.

Efficacy Outcomes Demonstrate Strong Disease Control With Jaypirca

At the 24-month landmark, the progression-free survival rate was 93.4% for patients treated with Jaypirca versus 70.7% for those treated with BR. This benefit was consistent across key subgroups including patients with mutated IGHV and unmutated IGHV.

Although overall survival data remain immature, a notable trend favored the Jaypirca arm. The 24-month overall survival rate was 97.8% for the Jaypirca group compared with 90.8% for the BR group. This survival signal is particularly relevant given the high crossover rate allowed in the study design; 52.9% of patients in the BR arm crossed over to receive Jaypirca following confirmed disease progression.

Study Design Highlights Robust Comparison Against Chemoimmunotherapy

The open-label phase 3 trial enrolled 282 patients with previously untreated CLL/SLL meeting International Workshop on Chronic Lymphocytic Leukemia 2018 criteria for therapy. Patients were randomized to receive oral Jaypirca once daily or up to six cycles of BR. Randomization was stratified by IGHV mutation status and Rai stage.

Key exclusion criteria included the presence of del(17p), known central nervous system involvement, Richter transformation or significant cardiovascular disease. The data cutoff for the current analysis was July 11, 2025.

Safety and Tolerability Profile Shows Lower Rates of Severe Side Effects

Jaypirca exhibited a favorable safety profile consistent with previous reports in the relapsed/refractory setting. Despite a significantly longer median treatment duration for Jaypirca (32.3 months) compared with the fixed-duration BR regimen (5.6 months) the rate of severe side effects was lower in the experimental arm.

Grade 3 or higher treatment-emergent side effects occurred in 40% of patients receiving Jaypirca compared with 67.4% of those receiving BR. Furthermore, treatment discontinuation due to treatment-emergent side effects was significantly less frequent with Jaypirca (4.3%) than with BR (15.2%).

Specific side effects of interest for BTK inhibitors showed low incidence rates in the Jaypirca arm. Atrial fibrillation and atrial flutter (any grade) were reported in 1.4% of patients treated with Jaypirca compared with 0.7% in the BR arm. Among patients aged 75 years or older receiving Jaypirca, only 1 experienced atrial fibrillation or flutter. Rates of grade 3 or higher infections were also lower with Jaypirca (13.6%) compared with BR (57.1%) as were rates of grade 3 or higher neutropenia (7.1% versus 12.1%).

“Now, if we took this data together with the BRUIN CLL-314 study which was presented this conference where Jaypirca was opposed to Imbruvica and was also a positive study we can be optimistic about the approval of the compound possibly in early 2026,” concluded Jurczak.

“Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL/SLL: First results from a randomized phase III study Examining a non-covalent BTK inhibitor in untreated patients,” by Dr. Wojciech Jurczak. 

“Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor,” by Dr. Wojciech Jurczak. 

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Articles

Jaypirca (pirtobrutinib) monotherapy significantly improved progression-free survival in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) compared to bendamustine plus Rituxan (BR). The phase 3 trial showed Jaypirca reduced disease progression or death risk by 80%, suggesting it as a potential new standard of care, especially for older adults. The 24-month progression-free survival rate was 93.4% with Jaypirca versus 70.7% with BR. Jaypirca also demonstrated a favorable safety profile with lower severe side effects and treatment discontinuation rates.

Jaypirca therapy improved progression-free survival versus bendamustine plus Rituxan a phase 3 trial for untreated CLL/SLL.

Jaypirca Significantly Improves PFS Outcomes in Untreated CLL/SLL 

Xervyteg improved responses and was safe in steroid- and Jakafi-resistant acute graft-versus-host disease affecting the GI tract in a phase 3 trial.

Treatment with Xervyteg (MaaT013) generated encouraging results and demonstrated an acceptable safety profile in patients with acute graft-vs-host disease that affects the gastrointestinal tract and does not respond to corticosteroids or Jakafi (ruxolitinib), according to primary findings from the ARES trial.

Data from the phase 3 study were presented by Dr. Florent Malard at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.

As of the data cutoff on November 11, 2024, the study met its primary end point with a GI overall response rate of 62% among 66 patients treated with Xervyteg on day 28 of treatment, significantly exceeding the historical control of 22%. The all-organ overall response rate was 64%. Notably, both GI and all-organ responses exhibited a similar average duration of response of 6 months.

Furthermore, data describing key secondary end points revealed that responses were maintained through later time points. At day 56 and month 3, the GI overall response rates were 49% and 44% respectively; likewise the all-organ overall response rates were 48% and 44% respectively. Responses across all time points showed exceptionally high rates of complete response and very good partial response.

Importantly, the deep and durable responses translated into survival benefits. A Kaplan-Meier graph displayed a separation of curves between responders and non-responders beginning shortly after the first administration of Xervyteg, widening substantially over the course of 1 year with responders maintaining a clear survival advantage over time. Median overall survival data were immature at the time of analysis, but the estimated probability of survival at 1 year was 54%, a clinically meaningful improvement for this patient population with historically poor clinical outcomes.

Xervyteg's safety profile was determined to be acceptable. There were 157 serious treatment-emergent side effects reported across 76% of patients, with the most common being escherichia sepsis, general physical health deterioration, and septic shock.

There was a total of 34 treatment-related side effects across 29% of patients, which mainly comprised various bacterial infections and GI disorders. Of these events, 7 were considered serious. There were 26 fatal side effects, with 1 event of septic shock determined to be related to Xervyteg investigators.

The phase 3 ARES trial is a single-arm multicenter open-label trial in Europe investigating Xervyteg, a pooled allogeneic fecal microbiotherapy, as salvage therapy in adult patients with refractory GI acute graft-versus-host disease (GVHD). The primary end point of the trial is GI overall response rate at day 28 assessed by an independent review committee; secondary end points include GI overall response rate at day 56 and month 3, all-organ overall response rate at day 28, and duration of response per independent review committee and investigator assessment, as well as overall survival. In the study, Xervyteg was administered as a rectal suspension as a 150 mL enema.

Patients were included if they had undergone allogeneic hematopoietic stem cell transplant, experienced an acute GVHD episode with lower GI symptoms per MAGIC guidelines, and were resistant to systemic steroids and either resistant or intolerant to Jakafi. Key exclusion criteria included having active cytomegalovirus colitis, lines of acute GVHD treatment other than steroids and Jakafi, hyperacute GVHD, and active uncontrolled infection.

Of the 66 total patients, the majority (77%) had acute GVHD with involvement limited to the GI tract. Others had GI and skin involvement (17%), GI and liver involvement (3%), and involvement of all 3 organs (3%). Regarding the hypothesized mechanisms of action driving responses in the skin and liver, Malard offered preliminary insights based on earlier research.

“So far, based on this study, we don’t have the translational data to investigate how this is working, but from the previous 2 HERACLES study we already have some data on the fact that we have some systemic immunomodulatory effect of the drug with some decrease in the proinflammatory cytokine at the systemic level and also an increase in essential fatty acid… in the serum of the patient,” Malard explained in the question-and-answer session. “We are also going to evaluate in another study all the immune cell subsets, in particular Tregs and so on, to find if this is how it’s working.”

Xervyteg is currently under regulatory review by the EMA following submission of a marketing authorization application in June 2025, with a decision regarding approval anticipated in the second half of 2026. If approved, Xervyteg would become the first microbiome-based therapy for the treatment of this high-need disease.

“MaaT013 for ruxolitinib-refractory acute graft-versus-host disease with gastrointestinal involvement: Results from the ARES phase III trial,” by Dr. Florent Malard. 

“MaaT013 as salvage therapy in ruxolitinib-refractory GI-aGVHD patients (ARES),” by ClinicalTrials.gov. Updated October 17, 2024. https://clinicaltrials.gov/study/NCT04769895

“Maat Pharma announces positive phase 3 results evaluating Xervyteg® (MaaT013) in acute graft-versus-host disease selected for oral presentation at ASH Congress 2025,” by MaaT Pharma. News release; Nov. 3, 2025.

Zervyteg (MaaT013) has shown promising results in treating corticosteroid and Jakafi-resistant acute graft-versus-host disease (GVHD) affecting the gastrointestinal tract. The phase 3 ARES trial reported a 62% GI overall response rate at day 28, surpassing historical controls. Responses were durable, with survival benefits observed over one year. The safety profile was acceptable, with serious side effects in 76% of patients, including infections and GI disorders. Zervyteg is under EMA review, potentially becoming the first microbiome-based therapy for this condition.

Xervyteg Shows Strong Responses in Acute Graft-Versus-Host Disease  

Among fit patients with acute myeloid leukemia, azacitidine plus Venclexta was shown to be superior to intensive chemotherapy.

Among fit patients with acute myeloid leukemia, the combination of azacitidine plus Venclexta (venetoclax) was associated with a significantly improved event-free survival (EFS) compared with intensive induction chemotherapy, study results have shown.

Results from the phase 2 PARADIGM trial were presented at the 2025 ASH Annual Meeting. In the trial, patients receiving azacitidine/Venclexta had a 39% reduction in risk of progressive disease, persistent disease prompting therapy change, relapse, hospice or death compared with those receiving conventional intensive induction chemotherapy. Patients also had improved quality of life (QOL) with azacitidine/Venclexta.

Induction chemotherapy with cytarabine plus anthracycline has been the standard of care for decades but is not tolerable in older or less fit patients and can still yield suboptimal long-term outcomes in fitter patients. The hypomethylating agent (HMA) azacitidine plus the BCL2 inhibitor Venclexta was established as the regimen of choice for patients who were not eligible for induction chemotherapy based on the phase 3 VIALE-A trial, but no prospective randomized trials have shown an advantage with direct comparison.

Event-Free Survival (EFS): The length of time after treatment during which a patient has no major problems related to the cancer—such as the disease coming back, getting worse, or needing new treatment.

Mucositis: Soreness and inflammation of the lining of the mouth or digestive tract. It can cause mouth sores, pain, and difficulty eating, and is a common side effect of some cancer treatments.

Complete Response (CR): When all signs of cancer disappear on tests after treatment. It does not always mean the cancer is cured, but it means doctors cannot detect it.

CR with Partial Hematologic Recovery (CRh): A type of complete response where the cancer is gone, but blood counts—especially platelets and certain infection-fighting cells—have only partially recovered.

CR with Incomplete Hematologic Recovery (CRi): A type of complete response where the cancer is gone, but some blood counts are still below normal. Patients may still need monitoring and support while blood levels improve.

Hematopoietic Cell Transplant: A procedure that replaces damaged or diseased blood-forming cells with healthy ones. The cells may come from the patient (autologous transplant) or from a donor (allogeneic transplant). This helps rebuild the blood and immune system after intensive treatment.

“Intensive induction chemotherapy comes with substantial burden and cost,” said Dr. Amir Fathi, program director of the Center for Leukemia at the Massachusetts General Hospital Cancer Center, in a press briefing. “It’s associated with significant morbidity, including deep and prolonged marrow suppression, weeks’ long hospitalizations, frequent infections and bleeding complications, mucositis, malnutrition, deleterious psychosocial effects, and an increased risk of cardiac injury and secondary malignancies.”

The open-label, multicenter, investigator-initiated PARADIGM clinical trial randomly assigned 172 patients with previously untreated AML at nine centers in the United States to receive induction chemotherapy or azacitidine/Venclexta. Patients were excluded if they were below 60 years old and had NPM1 mutations, or if they had core binding factor fusions or FLT3 mutations.

The median age was 64 years in the experimental arm and 65 years in the comparator arm, and 55% versus 60% were male in these respective arms. Seventy-two percent had adverse risk with 15% having intermediate and 12% having favorable risk status. The arms were balanced for risk status as well as TP53, NPM1 and IDH1/IDH2 mutations.

The induction chemotherapy used was a 7+3 regimen (cytarabine plus an anthracycline) in 54% with the remaining 46% receiving liposomal daunorubicin plus cytarabine (CPX351).

Results were reported as of July 25, 2025. The median number of treatment cycles was four with azacitidine/Venclexta versus two with induction chemotherapy.

The overall response rate was 88% with azacitidine/Venclexta versus 62% with the comparator. The rate of complete response (CR), CR with partial hematologic recovery and CR with incomplete hematologic recovery was 81% versus 55%, respectively. Although these were statistically significant, the CR rates were not significantly different (59% versus 50%). Both arms were allowed to proceed to hematopoietic cell transplant (HCT); 52 patients (61%) received HCT after azacitidine/Venclexta versus 34 patients (40%) after induction chemotherapy. HCT had a significant protective effect for EFS, but after adjustment in univariate and multivariate models, azacitidine/Venclexta still showed protective effect on EFS.

The median EFS was 14.6 months for azacitidine/Venclexta versus 6.2 months for induction chemotherapy, and the one-year rate of EFS was 53% versus 39%, respectively.

Fathi stated that overall survival improvement was not statistically significant, but this was a difficult end point to interpret compared with EFS because patients could benefit from receiving the trial regimens as subsequent therapy. “Even if we were to do a larger phase 3 study, overall survival, in my opinion is going to be fraught with challenge because of this extensive crossover in both directions, but mainly from intensive therapy to azacitidine/[Venclexta],” he said.

In terms of side effects, there were similar rates of grade 3 (severe) or 4 (life-threatening) treatment-related side effects, which were mainly hematologic. Grade 3 or 4 lung infections were reported in 12% in the experimental arm versus 15% in the comparator arm, and grade 3/4 sepsis occurred in 7% versus 11%, respectively. There was no 30- and 60-day mortality with azacitidine/Venclexta, whereas 30-day mortality was 3.5% and 60-day mortality was 4.7% with induction chemotherapy.

Quality of life was also assessed, with patients in the experimental arm reporting significantly better QOL in the first two weeks. Symptom burden and depression symptoms were also significantly improved.

Intensive care unit care during index hospitalization was not needed in any patients receiving azacitidine/Venclexta compared with 9.8% with induction chemotherapy. They also had fewer days of inpatient index hospitalization versus those receiving induction chemotherapy (15 versus 36) and fewer days hospitalized in the first six months (41 versus 58).

Fathi noted that those with favorable risk, such as CEBPA-associated AML and those with targetable mutations, were excluded to maintain equipoise and characterize the patient population who would likely receive HCT as consolidation. “This was really a study aimed at patients who were transplant eligible for consolidation, and in that patient population, it met its primary end point,” he said.

“We therefore believe these data support the use of azacitidine and [Venclexta] in functionally fit patients eligible for transplant with intermediate or adverse risk, FLT3 wild-type AML,” Fathi concluded.

1. “Results from paradigm - a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia,” by Dr. Amir Fathi et al., 

The combination of azacitidine and Venclexta significantly improved event-free survival (EFS) in fit acute myeloid leukemia (AML) patients compared to intensive induction chemotherapy, as demonstrated in the phase 2 PARADIGM trial. This regimen also enhanced quality of life and reduced hospitalization duration. Despite similar overall survival rates, azacitidine/Venclexta showed a protective effect on EFS, even after hematopoietic cell transplant adjustments. The trial highlighted the tolerability and reduced side effects of azacitidine/Venclexta, supporting its use in transplant-eligible patients with intermediate or adverse risk AML.

Azacitidine Plus Venclexta Superior to Chemo in Acute AML

Sac-TMT improved progression-free survival in patients with HR+/HER2– breast cancer.

Patients with previously treated, locally advanced or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer experienced superior progression-free survival when treated with the TROP2-targeted antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT; SKB264; MK-2870) compared with chemotherapy, clinical trial results have shown.

Updated findings from the phase 3 OptiTROP-Breast02 trial were presented at the 2025 ESMO Congress in Berlin.

Notably, sac-TMT elicited a 65% reduction in the risk of disease progression or death versus chemotherapy and showed a consistent benefit across subgroups. At a median follow-up of 7.4 months, the median PFS (mPFS) in patients receiving sac-TMT (8.3 months) was approximately twice that of patients receiving chemotherapy (4.1 months).

Progression-free survival (PFS): the length of time a person lives with cancer without the cancer getting worse.

Overall survival (OS): the percentage of people in a study who are still alive after a certain period of time.

Objective response rate (ORR): the percentage of patients in a study whose cancer shrinks or disappears after treatment.

Disease control rate (DCR): the percentage of patients in a study whose cancer either shrinks, disappears, or remains stable with treatment.

Duration of response (DOR): the length of time a patient continues to have a response to a treatment without the cancer progressing.

ECOG performance status: a scale that doctors use to describe a patient's general well-being and how capable they are of performing ordinary daily tasks.

Anemia: a condition where your body does not have enough healthy red blood cells to carry adequate oxygen to your tissues, often leading to fatigue.

Neutropenia: a condition in which a person has a low number of neutrophils, which are a specific type of white blood cell important for fighting infection.

Stomatitis: a general term for inflammation or soreness inside the mouth, which can include mouth sores.

Additionally, an interim analysis of overall survival (OS) revealed a positive trend among those receiving sac-TMT compared to those receiving chemotherapy.

“The current chemotherapy options [for HR-positive/HER2-negative breast cancer] show limited efficacy,” said Man Li, professor at the Second Affiliated Hospital of Dalian Medical University, during the presentation. “Sac-TMT has shown promising activity in pretreated patients with HR-positive/HER2-negative metastatic breast cancer in [a] phase 2 study.”

These new statistically significant and clinically meaningful efficacy data from OptiTROP-Breast02, along with an observed manageable safety profile, strengthen the case for sac-TMT as a potential new treatment option for this patient population who comprise a vast majority of global breast cancer cases.

“The OptiTROP-Breast02 study supports sac-TMT as a new treatment option for patients with HR+/HER2– breast cancer following endocrine-based therapy and chemotherapy,” said Li.

OptiTROP-Breast02 is a global randomized open-label study evaluating the efficacy and safety of sac-TMT versus investigator’s choice of chemotherapy (ICC) in adult patients with unresectable, locally advanced or metastatic HR-positive/HER2-negative breast cancer who had failed at least one line of systemic chemotherapy. The study is assessing the primary end point of PFS, along with secondary end points of investigator-assessed OS, objective response rate, disease control rate and duration of response.

Patients were eligible for participation if they had HR-positive/HER2-negative breast cancer, had between one and four lines of chemotherapy, and had at least one endocrine therapy, CDK 4/6 inhibitor and taxane in any setting. Of 399 patients randomized to either the investigational arm (200 patients) or control arm (199 patients), 200 received 5 mg/kg of intravenous sac-TMT every 2 weeks, while 196 received ICC including eribulin, capecitabine, gemcitabine and vinorelbine.

What Were the Patient Characteristics in the OptiTROP-Breast02 Trial?

Patient characteristics were well balanced between the study arms. Across both arms, the median age was 54 years, two-thirds had an ECOG performance status of 1, about 53% were HER2 zero and 47% were HER2 low. About 96% of patients had visceral metastases and over three-fourths had liver metastases. About three-fourths of patients had received neoadjuvant chemotherapy and all patients had received prior taxane, endocrine therapy and a CDK 4/6 inhibitor. About 56% of patients had received at least two lines of chemotherapy in the advanced/metastatic setting and a little over one-fourth of patients had primary endocrine resistance.

This most recent report of safety data revealed a manageable safety profile, with no new safety signals. In terms of treatment-related side effects, the incidence of all-grade and at least grade 3 (severe) treatment-related side effects was comparable between investigational and control arms. The most common treatment-related side effects for both sac-TMT and chemotherapy were hematologic toxicities, including decreased white blood cell count, anemia and neutropenia. While stomatitis was more frequent in patients receiving sac-TMT (63% versus 8%), Li noted that these side effects were primarily low-grade and manageable.

Treatment discontinuation occurred in 87 and 138 patients in the investigational and control arms, respectively. The most common reason for discontinuation was radiographic disease progression in both the investigational arm (80 patients) and control arm (122 patients).

Regarding next steps Li said, “Phase 3 studies of sac-TMT as a monotherapy and/or in combination with Keytruda (pembrolizumab) in patients with chemotherapy-naïve HR-positive/HER2-negative breast cancer are ongoing globally and in China.”

“Sacituzumab tirumotecan (sac-TMT) vs investigator's choice of chemotherapy (ICC) in previously treated locally advanced or metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC): results from the randomized, multi-center phase 3 OptiTROP-Breast02 study” by Man Li, presented at: ESMO 2025 Congress; October 17–20, 2025; Berlin Germany. Abstract LBA23.

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Sacituzumab tirumotecan (sac-TMT) demonstrated superior progression-free survival (PFS) compared to chemotherapy in patients with previously treated, locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer, according to the OptiTROP-Breast02 trial. Sac-TMT reduced the risk of disease progression or death by 65% and showed a positive trend in overall survival. The trial confirmed sac-TMT's manageable safety profile, with hematologic toxicities being the most common side effects. Ongoing phase 3 studies are evaluating sac-TMT as monotherapy and in combination with pembrolizumab.

Andrea Eleazar, MHS

Jaypirca Significantly Improves PFS Outcomes in Untreated CLL/SLL

Xervyteg Shows Strong Responses in Acute Graft-Versus-Host Disease

Azacitidine Plus Venclexta Superior to Chemo in Acute AML

HR+/HER2- Metastatic Breast Cancer Progression Improved With Sac-TMT

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