Dylann Cohn-Emery

Treatment with Brukinsa was associated with improved efficacy in patients with treatment-naïve CLL or SLL. 

Patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) experienced long-term improved efficacy when treated with Brukinsa (zanubrutinib) compared with bendamustine plus Rituxan (rituximab), study results have shown.

Findings from a five-year follow-up of the phase 3 SEQUOIA trial were presented at the 2024 ASH Annual Meeting.

In cohort 1 of the trial, patients who were randomly assigned to Brukinsa (241 patients) experienced improved progression-free survival (PFS) regardless of disease risk status and COVID-19 impact compared with patients randomly assigned to Rituxan (238 patients). Brukinsa also showed better overall response rate (ORR) and adverse event (AE, side effects) incidence.

Progression-free survival: the time a patient lives without their disease spreading or worsening.

Overall response rate: patients who responded partially or completely to treatment.

Complete response: the disappearance of cancer.

Overall survival: how long a patient lives, regardless of disease status.

Neutropenia: low count of neutrophils, a type of white blood cell.

Atrial fibrillation: Irregular and often rapid heart rate, according to the Mayo Clinic.

Bruton tyrosine kinase (BTK) inhibitors offer improved outcomes for patients with CLL/SLL, and the next-generation BTK inhibitors such as Brukinsa are designed for better efficacy and tolerability through increased potency, greater BTK specificity and more exposure coverage.

“With a median study follow-up of 61.2 months, [Brukinsa] has been shown to offer a sustained superior PFS over [Rituxan] in [patients with] treatment-naive CLL with 71% reduction of the risk of progression or death,” Dr. Mazyar Shadman, medical director of cellular immunotherapy at Fred Hutchinson Cancer Center, said in his presentation of the data.

Median PFS was not reached in patients given Brukinsa versus 44.1 months in those given Rituxan. The 54- and 60-month PFS rates were 80.1% and 75.8% with Brukinsa versus 44.6% and 40.1% with Rituxan, respectively.

Additionally, the degree of PFS difference was similar when the investigators adjusted for the impact of COVID-19 on the treatment outcomes, with 83.2% versus 45.2% 54-month PFS rates and 78.7% versus 40.6% 60-month PFS rates for Brukinsa versus Rituxan, respectively.

Regardless of IGHV status, Brukinsa showed consistent PFS benefit. However, treatment with Rituxan displayed lower PFS rates which were affected by IGHV status. Shadman noted that in prior reports from cohort 2 of the SEQUIOA trial, patients with deletion 17p (del[17p]) and TP53 mutations showed similar PFS rates in those without the high-risk features. “This suggests that the treatment with [Brukinsa] may overcome negative prognostic factors such as IGHV [mutation], del(17p) or TP53 mutation,” he said.

The ORR with long-term follow-up was 97.5% with Brukinsa versus 88.7% with Rituxan. With Brukinsa, the complete response (CR)/CR with incomplete bone marrow recovery (CRi) rates was 20.7% compared with Rituxan at 23.5%. The CR/CRi rate is the highest reported with an inhibitor monotherapy, according to Shadman.

In total, 34 deaths occurred in each arm at the time of follow-up. The estimated overall survival (OS) rates at 54 and 60 months with Brukinsa were 87.7% and 85.5%, respectively; after adjusting for COVID-19, it was 91.3% and 89.4%. For treatment with Rituxan, the estimated 54- and 60-month OS rates were 86% and 85%; then with COVID-19 adjustment, 87.8% and 86.8%.

In terms of toxicity, Brukinsa was well tolerated over the extended treatment period in these patients with CLL/SLL. The most common grade 3 (severe) or higher treatment-emergent and post-treatment AEs included COVID-19 (Brukinsa, 9% versus Rituxan, 2%), hypertension (12% versus 6%) and neutropenia (10% versus 41%).

There were “low rates of atrial fibrillation/flutter [afib/flutter], infections or AEs that limit daily living activities like [gastrointestinal] toxicities,” Shadman explained.

In the original readout of the SEQUOIA trial, Brukinsa showed statistically significant and clinically meaningful improvement in PFS over Rituxan in patients with CLL/SLL without del(17p) at 26.2 months median follow-up.

Brukinsa was given at 160 milligrams twice daily until disease progression or intolerable toxicity and Rituxan was given for a maximum of six cycles. The primary end point was PFS, with ORR and CR rate as the key secondary end points. Crossover was allowed after progression and prior to starting any other therapy for CLL/SLL.

The median treatment duration with Brukinsa at the 61.2-month follow-up was 60.5 months, with 163 patients (67.6%) still receiving treatment. For Rituxan, 79% completed all six cycles of treatment and 13% discontinued early due to AEs. Fifty-nine patients overall crossed over from Rituxan to Brukinsa after experiencing disease progression.

“The result of this extended follow-up support the use of [Brukinsa] as the standard first-line treatment option for patients, regardless of the disease risk factors,” Shadman concluded.

“Sustained superiority of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: 5-year follow-up of cohort 1 from the SEQUOIA study” by Dr. Mazyar Shadman et al., 

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Articles

Brukinsa (zanubrutinib) demonstrated superior long-term efficacy over bendamustine plus Rituxan (rituximab) in treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients, as shown in the five-year SEQUOIA trial follow-up. Brukinsa improved progression-free survival (PFS) and overall response rate (ORR), with a 71% reduction in progression or death risk. It was well tolerated, with fewer severe adverse events compared to Rituxan. The study supports Brukinsa as a standard first-line treatment, overcoming negative prognostic factors like IGHV mutation, del(17p), or TP53 mutation.

Patients with treatment-naive CLL/SLL experienced long-term improved efficacy when treated with Brukinsa compared with bendamustine plus Rituxan.

Brukinsa Supported as First-Line Treatment for Patients With CLL/SLL

Aspects of myelofibrosis, such as spleen size, were improved after receiving pelabresib plus Jakafi. 

Pelabresib (CPI-0610) plus Jakafi (ruxolitinib) continued to reduce splenomegaly, anemia, symptoms and bone marrow fibrosis in patients with JAK inhibitor-naive myelofibrosis, recent study findings demonstrated.

Results from the phase 3 MANIFEST-2 study were presented in a poster during the 

At a median follow-up of 72 weeks, the primary end point of spleen volume reduction of 35% (SVR35) was maintained, with a 48-week response rate of 57% with pelabresib and Jakafi versus 37.5% with Jakafi plus placebo. Total symptom score (TSS) improvement of at least 50% at week 48 was 45.3% versus 39.4%, respectively. Fewer patients required red blood cell transfusions, and bone marrow fibrosis improvement of at least one grade was reported in 41% versus 15%, respectively.

BET inhibitor: a treatment that targets BET proteins, which play a role in regulating gene expression.

Nadir: the lowest point a blood cell count reaches after a course of chemotherapy.

Proinflammatory cytokines: small proteins secreted by immune cells that play a role in the body’s inflammatory response.

Mutant clone burden: the proportion of cells in a tumor that contains a specific genetic mutation.

Variant allele frequency reduction: the decrease in the proportion of tumor cells that carry a specific genetic mutation within a tumor sample.

Thrombocytopenia: lower than normal number of platelets in the blood.

Accelerated and blast-phase progression: worsening stages of certain types of blood cancers.

“Results at 48 weeks showed deep and sustained SVR35 response with biomarker evidence suggesting additional benefit of the combination of pelabresib plus [Jakafi] versus [Jakafi] alone,” said Dr. John O. Mascarenhas, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai, in his poster presentation.

Pelabresib is an investigational small molecule BET inhibitor that can decrease the BET-mediated gene expression associated with MF.

 is a study that assigned 430 patients to receive Jakafi twice daily plus pelabresib or placebo once daily for 14 consecutive days of 21-day cycles. At the 2023 ASH Meeting, the MANIFEST-2 trial investigators reported that it had met its primary end point of 24-week SVR. Key secondary end points were absolute change in TSS and 50% or greater reduction in TSS from baseline (TSS50) at week 24, with other end points including SVR35 at week 48, hemoglobin response, bone marrow fibrosis and safety.

Patients had to have intermediate-1 or higher risk myelofibrosis, platelet count of at least 100,000/μL, spleen volume of at least 450 cm

, TSS of 10 or greater (≥3 for two symptoms), and ECOG performance status of 2 or lower.

At the data cutoff of March 29, 2024, 126 of 214 patients (58.9%) receiving the combination and 134 of 216 patients (62%) receiving Jakafi plus placebo were still being treated.

In addition to a higher number of patients showing SVR35 response at week 48, 13.1% of patients had a loss of SVR35 response and an increase of 25% from nadir with pelabresib versus 20% with placebo, or 21% versus 36.8%, respectively by alternate definition of loss of SVR35 response. The mean change was -54.5% with the combination versus -33.5% with Jakafi plus placebo, and 82.2% had a response at any time with the combination versus 57.9% with Jakafi plus placebo.

The absolute change from baseline TSS was -15.99 for 

 versus -14.05 for Jakafi plus placebo at week 24, and -16.24 versus -14.11, respectively at week 48. TSS individual domain scores were similar between the two groups and similar to national norms for people without MF, according to the investigators. An analysis of the Myelofibrosis Symptom Assessment Form excluding fatigue showed a least square mean change from baseline of -16.19 with pelabresib plus Jakafi versus -13.86 with placebo plus Jakafi. Mascarenhas said that “additional symptom benefit of pelabresib could be difficult to detect due to a ceiling effect in TSS, especially in the fatigue domain.”

When looking at patients who had both SVR35 and TSS improvement of 50%, there were 77 (36%) who received the combination versus only 41 (19%) in the placebo group.

A hemoglobin response as defined as a 1.5 g/dL or greater mean increase from baseline in the absence of transfusions in the past 12 weeks was observed in a numerically greater proportion of patients who received pelabresib (13.1% versus 7.9%), and hemoglobin levels rose and approached baseline in patients with anemia. In the combination group, 27.6% required transfusion in the first 24 weeks and 21.8% required it in the next 24 weeks, compared with 38.6% and 33.2%, respectively, in the placebo plus Jakafi group.

At week 48, bone marrow fibrosis had improved in 41%, remained unchanged in 45%, and worsened in 14% of those receiving pelabresib versus improving in 15%, remaining unchanged in 54.2%, and worsening in 30.8% of those receiving placebo. The improvement of bone marrow fibrosis of at least one grade at week 24 was 38.3% versus 25.3% in the respective groups, showing that the difference widened at week 48.

Disease-relevant proinflammatory cytokines showed a numerically greater reduction at week 48 in the pelabresib plus Jakafi group. The level of proinflammatory cytokines was lower in those who had an SVR35 response, regardless of which treatment they received.

Another exploratory end point was the change in mutant clone burden in peripheral blood samples by next-generation sequencing. At week 48, there was greater reduction in the pelabresib plus Jakafi group, with a variant allele frequency reduction of 50% in 15% versus 9% of those receiving placebo plus Jakafi. The mean change from baseline was -24.1% versus -16.3% in the respective groups, and a correlation was found between SVR35 response and reduced mutation clone burden.

In terms of safety, grade 3 (severe) or higher treatment-emergent side effects were reported in 57.1% of the pelabresib plus Jakafi group versus 62.1% of the placebo plus Jakafi group. Grade 3 or higher anemia was reported in 25.9% and 38.3%, respectively, and grade 3 or higher thrombocytopenia was reported in 15.1 and 6.1%, respectively. The most common nonhematologic treatment-emergent side effects include diarrhea, constipation, dysgeusia, cough and nausea. Death occurred in 20 of 214 patients (9.3%) in the pelabresib plus Jakafi group and 18 of 216 (8.3%) in the placebo plus Jakafi group.

Accelerated and blast-phase progression to leukemia transformation was reported in 6.1% of the pelabresib plus Jakafi group and 4.2% of the placebo plus Jakafi group at a data cutoff of August 30, 2024. Newly acquired mutations were detected in 26% and 22%, respectively, and high molecular risk mutations were seen in 4% and 2%, respectively. Mutations were no longer detectable in 11% and 12%, and high molecular risk mutations were no longer detectable in 3% and 1%, respectively. Investigators proposed that a similar number of patients indicated that pelabresib does not have an additional mutagenic effect when combined with Jakafi.

The investigators intend to present longer follow-up data from MANIFEST-2 at future medical congresses. “Rates of grade 3 or greater [treatment-emergent side effects] were similar in both groups and leukemia transformation continues to be followed up closely,” said Mascarenhas.

The combination of pelabresib and Jakafi demonstrated significant efficacy in reducing splenomegaly, anemia, symptoms, and bone marrow fibrosis in JAK inhibitor-naive myelofibrosis patients. The MANIFEST-2 study showed sustained spleen volume reduction and symptom improvement at 48 weeks, with fewer transfusions and better bone marrow fibrosis outcomes compared to Jakafi alone. Safety profiles were comparable, with similar rates of severe side effects and leukemia transformation. The study also indicated a reduction in proinflammatory cytokines and mutant clone burden, suggesting additional benefits of the combination therapy.

Adding pelabresib to a JAK inhibitor may improve multiple aspects of myelofibrosis, including spleen size, symptoms and bone marrow fibrosis.

Pelabresib Plus Jakafi Maintains Efficacy in JAK-Naive Myelofibrosis 

Long-term benefits were improved in some patients with advanced non-small cell lung cancer (NSCLC) enrolled in experimental combination groups, although none of the groups met the study’s desired result, according to data presented at the 

Of these combinations, Imfinzi (durvalumab) plus monalizumab and Imfinzi plus ceralasertib were the stand-out treatments in terms of benefit, according to Dr. Pascale Tomasini, an associate professor of thoracic oncology in the Multidisciplinary Oncology and Therapeutic Innovations Department of the Cancer Research Center in Marseille, France.

Although the trial didn't meet its primary endpoint, some patients with advanced NSCLC experienced promising long-term benefits from the Imfinzi plus monalizumab and Imfinzi plus ceralasertib combinations.

Although the primary goal of 12-week disease control rate (DCR) wasn't met, some patients experienced disease control and responses, indicating potential benefits.

The combinations were generally well-tolerated, suggesting that these treatments might be suitable for many patients.

The results of the PIONeeR trial highlight the ongoing importance of research to develop new and effective treatments for NSCLC and other cancers.

In a live presentation, Tomasini explained that the PIONeeR trial “used an innovative and adaptive design to identify signal of efficacy of new types of immunotherapy combinations.”

To explore new ways to overcome PD-(L)1 inhibitor resistance, 114 patients with advanced NSCLC were randomly assigned to one of four experimental groups or a control group. Patients on group A received Imfinzi plus monalizumab (28 patients), group B received Imfinzi plus oleclumab (MEDI9447; three patients), group C received Imfinzi plus ceralasertib (32 patients), group E received Imfinzi plus Orpathys (savolitinib; 20 patients), and the control group, group D, received Taxotere (docetaxel) (31 patients).

For this trial, the primary goal was the 12-week disease control rate (DCR; the proportion of a population that is protected against a specific disease), and secondary goals included objective response rate (ORR; the percentage of people whose disease shrinks or disappears after treatment), overall survival (OS; the time from the start of treatment when a patient with cancer is still alive), progression-free survival (PFS; how long a person lives without their disease getting worse), duration of response (DOR; the length of time a person's disease remains in remission after treatment) and safety and tolerability. The adaptive design of the trial was to let investigators stop groups quickly when there was a lack of efficacy and open new combination groups when data emerged.

The mean estimated 12-week DCR was 24.1% in group A, 50% in group C, 13.6% in group E, and 54.5% in the control group. The ORR, consisting of all partial responses, was 17.9% (five patients) in group C and 25% (five patients) in the control group in the evaluable population. In the total intention-to-treat population, the ORR was 15.6% in group C and 16.1% in the control group, respectively. Stable disease was observed in 42.9% of patients in group A, 66.7% in group B, 57.1% in group C, 30% in group E, and 50% in the control group.

“In the control [group] with [Taxotere], 31 patients were enrolled, but only 23 were treated mainly due to consent withdrawal,” Tomasini said. “Two [groups] had to be closed prematurely during the trial. [Group] B with the oleclumab was closed after only three patients enrolled because of lack of efficacy shown in a concomitant trial, the HUDSON study. In [group] E with Orpathys was closed after 20 patients enrolled because of lack of efficacy shown in the first interim analysis of the PIONeeR trial.”

The secondary goals of PFS and OS were available for groups A, C, E, and the control group. The median PFS was 1.6 months in group A, 4.1 months in group C, 1.4 months in group E, and 4.4 months in the control group. In these respective groups, the median OS was 11.7 months, 17.4 months, 7.1 months, and 13.8 months, although group C’s median OS was biased based on length of follow-up.

In terms of safety, treatment-related side effects were observed in 82.1% of group A, 100% of group B, 93.5% of group C, 95% of group E and 100% of the control group. Grade 3 (severe) or worse side effects related to treatment occurred in 7.1% of patients in group A, 33.3% in group B, 54.8% in group C, 30% in group E, and 43.5% in the control group. There was one treatment-related death, which occurred in group C.

There were three treatment interruptions and two discontinuations in group A, one each in group B, 10 interruptions and eight discontinuations in group C, nine interruptions and seven discontinuations in group E, and six each in the control group.

All the patients enrolled on PIONeeR had disease progression after more the six weeks of anti–PD-(L)1 therapy in the second or third line or more than 12 weeks of anti–PD-(L)1 plus platinum-based chemotherapy, and ECOG performance status of 0 or 1. Patients were stratified by center, squamous vs non-squamous histology, and progression on prior treatment before or after 24 weeks.

In the intention-to-treat population, the median age was 63 years, most patients were male (61.4%), 53.5% had ECOG performance status of 1 (meaning patients were able to complete most daily tasks independently), and 46.5% had a status of 0 (completing daily tasks entirely independently). A small number of patients had liver (10.5%) or brain (7.9%) metastases. Sixty-six percent of patients experienced disease worsening or spreading on a prior line of therapy for more than 24 weeks before enrollment.

“In conclusion, the PIONeeR trial is an academic collaborative success in exploring how to overcome resistance to PD-1 and PD-L1 inhibitors in advanced NSCLC,” Tomasini said. “[While] no experimental group formally met the efficacy target, we observed that some patients derived a long-term clinical benefit from some combinations, especially including ceralasertib and monalizumab and comprehensive biomarker analysis are ongoing to be able to predict among the patients who are likely to have this long-term clinical benefit.”

Imfinzi with monalizumab and ceralasertib showed promising long-term benefits in advanced NSCLC, but no other combinations significantly improved results.

Adaptive NSCLC Study Fails to Produce Improved Results, Clinical Benefits in Some

Receiving Calquence during earlier lines of treatment led to better survival outcomes for patients with CLL.  

Patients with chronic lymphocytic leukemia (CLL) who received Calquence (acalabrutinib) during earlier lines of treatment experienced better survival outcomes than patients who received Calquence after other treatments, according to a presentation at the 2024 European Hematology Association (EHA) Congress.

Specifically, overall survival (OS; time patients live until death of any cause), progression-free survival (PFS; time patients live until disease worsening) and time to next treatment (TTNT) were better in patients who received Calquence earlier.

A combined analysis of the phase 3 ELEVATE-TN, ELEVATE-RR and ASCEND trials demonstrated these benefits with earlier Calquence in the overall patient population and for patients with deletion 17p, which is a genetic aberration associated with poorer prognosis.

Calquence is a Bruton tyrosine kinase (BTK) inhibitor that works by blocking the activity of the BTK enzyme, which helps develop and mature B cells. BTK inhibitors may help prevent the growth of cancer cells, according to the National Cancer Institute.

“In the overall population, those with no prior lines of therapy had improved outcomes versus those with one prior line of therapy,” Dr. Paolo Ghia said in his presentation of the pooled analysis at the EHA Congress. “Those with one prior line of therapy also had consistently improved outcome versus those with two or more prior lines of therapy in the overall population, as well as those with the [deletion 17p].”

Researchers from this presentation evaluated the impact of the number of prior lines of therapy for Calquence in treatment naïve (patients who have not received any treatment) or relapsed or refractory CLL, which was previously unknown.

Data from the Calquence monotherapy groups of the phase 3 trials were also reviewed.

The ELEVATE-TN trial had a data cut-off of March 3, 2023; a median follow-up of 74.5 months; and 179 patients who received zero prior lines of therapy. The ELEVATE-RR had a data cut-off of Sept. 15, 2020; median follow-up of 40.9 months; 132 patients who received one prior lines of therapy and 135 patients with two or more prior lines of therapies. The ASCEND trial had a data cut-off of Sept. 3, 2021; median follow-up of 46.5 months; 82 patients who received one prior lines of therapy and 73 patients with two or more prior lines.

The outcomes for the analysis included OS, PFS and TTNT, comparing zero versus one prior lines of therapy and one versus two or more prior lines of therapy.

In total, 601 patients were treated with Calquence monotherapy (Calquence alone): 179 with zero prior lines of therapy, 214 with one prior line of therapy and 208 with two or more prior lines of therapy. The number of patients with high-risk features and stage 4 disease was higher in the groups of pretreated patients.

In the overall population, patients with zero prior lines of therapy had a 45% lower risk of death than those with one prior line of therapy; 92% versus 85% of patients were alive at 36 months, respectively.

There was 56% lower risk of disease progression or death and 52% lower risk of initiating subsequent therapy for patients with zero prior lines of therapy versus one prior line. At 36 months, 84% of patients with zero prior lines of therapy were progression free and had not initiated subsequent therapy versus 73% and 75% with one prior line of therapy, respectively.

There was a 46% lower risk of death in patients with one prior line of therapy than in those with two or more prior treatments. At 36 months, 85% of the patients who received one prior line of therapy were alive versus 76% of patients who received two or more therapies.

The risk of disease progression or death was 39% lower in patients with one prior line compared two or more prior lines of therapy, and 73% of patients were progression free versus 58% at 36 months. In patients with one prior line, there was a 33% lower risk of initiating subsequent therapy, and 75% had not initiated subsequent therapy compared with 64% at 36 months.

Increased risk of death in the overall population was associated with prior lines of therapy, 

 mutation, ECOG performance status of 2 or more (which indicates that patients cannot independently perform their daily tasks), disease stage 3 or more, 65 years of age or more and being male.

Regarding patients with deletion 17p with zero versus one prior line of therapy, there were not enough patients to calculate outcome differences. Researchers reviewed the OS, PFS and TTNT in patients with deletion 17p who had one and two or more prior lines of therapy.

“Findings were consistent in patients with deletion 17p, where patients with one prior line of therapy had a significantly lower risk of disease progression or death and initiating subsequent therapy compared with those with two or more prior lines of therapy,” Ghia explained.

At 36 months, 81% versus 65% of patients were alive; 74% versus 45% of patients were progression free; and 72% versus 56% of patients had not initiated subsequent therapy of those who received one prior lines of therapy versus two or more, respectively.

The discontinuation of Calquence monotherapy was most commonly due to side effects in 17.9%, 13.1% and 22.6% in the zero, one and two or more prior lines of therapy groups, respectively, and disease progression was seen in 14.0%, 23.4% and 31.7%, respectively.

“In conclusion, improved OS, PFS and TTNT were consistently observed when [Calquence] was initiated in earlier versus later [lines of therapy],” Ghia said.

Patients with chronic lymphocytic leukemia had better survival when treated with Calquence during earlier lines of therapy.

Dylann Cohn-Emery

Brukinsa Supported as First-Line Treatment for Patients With CLL/SLL

Pelabresib Plus Jakafi Maintains Efficacy in JAK-Naive Myelofibrosis

Adaptive NSCLC Study Fails to Produce Improved Results, Clinical Benefits in Some

Earlier Calquence Leads to Improved Survival Outcomes in CLL

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