On June 9, 2023 AbbVie (NYSE: ABBV) reported new findings demonstrating sustained long-term safety and efficacy of VENCLYXTO/ VENCLEXTA (venetoclax)-based combination therapies in patients with previously untreated CLL with co-existing conditions, as well as R/R CLL (Press release, AbbVie, JUN 9, 2023, View Source [SID1234632624]). The results are being presented during oral sessions at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in Frankfurt, Germany.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Results from the CLL14 and MURANO studies demonstrate the long-term benefits of fixed-duration venetoclax combinations for patients living with CLL," said Mariana Cota Stirner, M.D., Ph.D., vice president, hematology, AbbVie. "These results underscore our commitment to transform how blood cancers are treated today and show that venetoclax can give patients lasting results with time off treatment."

CLL14 Long-Term Analysis

New six-year follow-up results from the Phase 3 CLL14 study showcase updated outcomes in previously untreated patients with CLL and co-existing conditions. Patients treated with fixed-duration venetoclax plus obinutuzumab continued to experience improved PFS (95% Confidence Interval (CI) 0.31-0.52; Hazard Ratio (HR) 0.40) and higher rates of undetectable minimal residual disease (uMRD) when treated with fixed-duration venetoclax plus obinutuzumab compared to those who received chlorambucil plus obinutuzumab (53.1% vs 21.7%, respectively).

The data also showed significantly improved rates of time to next treatment (TTNT) with venetoclax plus obinutuzumab at 65.2 percent (95% CI 0.33-0.58; HR 0.44) compared to chlorambucil plus obinutuzumab at 37.1 percent.1 The observed differences in PFS and TTNT benefits between venetoclax-based treatment and chemoimmunotherapy were maintained across all risk groups, including patients with high-risk molecular features of CLL.

No new safety signals were observed in this six-year analysis. The most frequently occurring Grade 3 (≥2%) adverse events (AEs) in patients receiving the venetoclax-based combination were neutropenia, thrombocytopenia, infusion-related reaction (during treatment), anemia, febrile neutropenia, pneumonia and leukopenia.1

"The latest findings show that patients can experience long-term disease control, five years after stopping treatment," said Othman Al-Sawaf, M.D., investigator in the CLL14 study, hematologist-oncologist at the University Hospital Cologne in Germany, and study physician at the German CLL Study Group. "These results confirm the treatment benefits of fixed-duration venetoclax and obinutuzumab for previously untreated CLL patients with co-existing conditions."

Results will also be featured at EHA (Free EHA Whitepaper)’s Press Briefing.

MURANO Long-Term Analysis

Final data from the Phase 3 MURANO trial showcase that R/R CLL patients treated with two-year fixed-duration venetoclax plus rituximab sustained significantly longer median PFS at 54.7 months (95% CI 52.3, 59.9), the study’s primary endpoint, compared to 17.0 months (95% CI 15.5, 21.7; HR 0.23) with bendamustine plus rituximab after 7 years of median follow-up.2

Seven-year OS rates were 69.6 percent (95% CI 62.8, 76.5) for patients treated with the venetoclax-based combination versus 51 percent (95% CI 43.3, 58.7) for study participants who received bendamustine-based combination (HR 0.53).2 Furthermore, most of the patients treated with the full two-year venetoclax-based combination achieved uMRD (70.3%) at the end of their treatment course, and those patients were shown to have improved PFS and OS compared to patients with detectable MRD (29.7%).

The safety profile of the venetoclax-rituximab combination is consistent with the known safety profile of each individual therapy alone. No new serious safety issues were observed in the MURANO updated analysis. The most common adverse reactions (ARs) (≥20%) of any grade were neutropenia, diarrhea, upper respiratory tract infection, fatigue, and nausea.

"We are pleased to find that uMRD was associated with prolonged PFS in R/R CLL patients after seven years," said study investigator Prof. John Seymour, Director of the Integrated Haematology Department of the Peter MacCallum Cancer Center and the Royal Melbourne Hospital in Melbourne. "Overall, these findings continue to support the use of treatment with venetoclax plus rituximab in this patient population."

VENCLYXTO/VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the CLL14 Phase 3 Trial1,3
The prospective, multicenter, open-label, randomized Phase 3 CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (GCLLSG), evaluated the efficacy and safety of a combined regimen of VENCLYXTO/VENCLEXTA and obinutuzumab (n=216) versus obinutuzumab and chlorambucil (n=216) in previously untreated patients with CLL and co-existing medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed-duration of 12 months for VENCLYXTO/VENCLEXTA in combination with six cycles of obinutuzumab. The trial enrolled 432 patients, all of whom were previously untreated, according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on PFS, as assessed by an independent review committee.

Key secondary endpoints were rates of MRD in peripheral blood and bone marrow, overall and complete response rates, MRD in complete response in peripheral blood and bone marrow, and OS.

In patients with CLL receiving venetoclax combination therapy with obinutuzumab, the most frequently occurring ≥ Grade 3 AEs (≥2%) were neutropenia (51.9%), thrombocytopenia (14.2%), infusion-related reaction (9.0%), anemia (7.5%), febrile neutropenia (4.2%), pneumonia (3.8%) and leukopenia (2.4%). Serious ARs were most often due to febrile neutropenia and pneumonia (5% each). The most common ARs (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal ARs that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2 percent (4/212) of patients, most often from infection.

About the MURANO Phase 3 Trial2,4
A total of 389 patients with R/R CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of VENCLYXTO/VENCLEXTA and rituximab (n=194) compared with bendamustine and rituximab (n=195). The median age of patients in the trial was 65 years (range: 22 to 85).

The trial met its primary efficacy endpoint of investigator (INV)-assessed PFS. At the time of the primary analysis, median PFS with VENCLYXTO/VENCLEXTA and rituximab was not reached compared with 17.0 months for bendamustine and rituximab (HR: 0.17; 95% CI: 0.11- 0.25; p<0.0001). In the primary efficacy analysis, the median follow-up for PFS was 23.8 months (range: 0 to 37.4). Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), OS and rates of MRD-negativity.

In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (AR; ≥5%) was pneumonia (9%). The most common ARs (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal ARs that occurred in the absence of disease progression and within 30 days of the last venetoclax treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.

About VENCLYXTO (venetoclax)

VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. Venetoclax is approved in more than 80 countries, including the U.S.

Indication and Important VENCLYXTO (venetoclax) EU Safety Information5

Indications

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as Venclyxto efficacy may be reduced.

Special Warnings & Precautions for Use

Tumour Lysis syndrome, including fatal events, has occurred in patients when treated with Venclyxto. For CLL and AML, please refer to the indication-specific recommendations for prevention of TLS in the Venclyxto summary of product characteristic (SmPC).

Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. Venclyxto poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclyxto and at each dose increase.

Neutropenia (grade 3 or 4) has been reported. Complete blood counts should be monitored throughout the treatment period.

In patients with AML, neutropenia (grade 3 or 4) is common before starting treatment. The neutrophil counts can worsen with Venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Dose modification and interruptions for cytopenias are dependent on remission status.

For CLL and AML, please refer to the indication-specific recommendations for dose modifications for toxicities in the Venclyxto SmPC.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

In CLL and AML CYP3A inhibitors may increase Venclyxto plasma concentrations.

In CLL, at initiation and dose-titration phase, Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, please refer to the recommendations for dose modifications in the Venclyxto SmPC.

In AML, please refer to the AML-specific recommendation for dose modifications for potential interactions with CYP3A inhibitors, in the VENCLYXTO SmPC.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease Venclyxto plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

CLL

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.

AML

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in combination with azacitidine or decitabine in the VIALE-A and M14-358, respectively, were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite, haemorrhage, dizziness/syncope, hypotension, headache, abdominal pain, and anaemia.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358, the most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

Discontinuations due to adverse reactions occurred in 24% of patients treated with venetoclax in combination with azacitidine in the VIALE-A study, and 26% of patients treated with venetoclax in combination with decitabine in the M14-358 study, respectively.

Dosage reductions due to adverse reactions occurred in 2% of patients in VIALE-A, and in 6% of patients in M14-358. Venetoclax dose interruptions due to adverse reactions occurred in 72% and 65% of patients, respectively. The most common adverse reaction that led to dose interruption (>10%) of Venetoclax in VIALE-A, were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia. The most common adverse reactions that led to dose interruption (≥5%) of venetoclax in M14-358 were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Special Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

Venclyxto may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See Venclyxto (venetoclax) SmPC at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

On June 9, 2023 Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, reported updated data from the Phase 1 trial of TIBSOVO (ivosidenib tablets) as monotherapy for patients with isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS) (Press release, Servier, JUN 9, 2023, View Source [SID1234632623]). The results presented today at the European Hematology Association (EHA) (Free EHA Whitepaper) 2023 Annual Congress in Frankfurt, Germany demonstrate that the efficacy and safety profile of TIBSOVO may provide an important new treatment option for MDS patients within this molecularly defined subset.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Phase 1, open-label study included an evaluation of the safety, tolerability, and clinical activity of TIBSOVO in patients with IDH1-mutated R/R MDS. The primary endpoint was complete remission (CR) plus partial remission (PR) rate and key secondary endpoints included duration of CR plus PR, duration of transfusion independence, and time to transfusion independence.

In the efficacy analysis set (n=18), a complete remission (CR) rate of 38.9% and overall response rate (ORR) of 83.3% were documented in patients treated with TIBSOVO. In addition, the median time to CR was 1.87 months (range: 1.0, 5.6). At the time of data cutoff, the median duration of CR had not been reached (range: 1.9, 80.8*) and the median overall survival was 35.7 months (range: 3.7*, 88.7*).

"We are pleased to share these updated efficacy results that demonstrate durable remissions and an acceptable safety profile in patients with IDH1-mutated relapsed or refractory MDS at this year’s EHA (Free EHA Whitepaper) Congress," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "These data add to the growing body of evidence behind targeted IDH inhibition, and we look forward to taking the next steps with regulatory authorities to potentially expand the use of TIBSOVO in the United States to include the treatment of IDH1-mutated relapsed or refractory MDS."

Additionally, of the nine patients who were transfusion dependent with red blood cells or platelets at baseline, 66.7% (n=6) became independent of transfusions during any ≥56-day post-baseline period. Further, of the nine patients who were transfusion independent with red blood cells or platelets at baseline, 77.8% (n=7) maintained transfusion independence during any ≥56-day post-baseline period.

"Patients with IDH1-mutated relapsed or refractory MDS currently have no targeted therapy options, and outcomes are generally poor for those who experience disease progression after treatment with standard care," said Courtney D. DiNardo, M.D., MSCE, Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and investigator on the study. "This updated analysis demonstrates that TIBSOVO has the potential to improve outcomes in the treatment of IDH1-mutated relapsed or refractory MDS and reinforces the importance of molecular analysis to ensure we’re harnessing the potential benefit of targeted therapies."

Overall, treatment-related adverse events (TRAEs) were consistent with the known safety profile of TIBSOVO. Among 19 patients included in the safety analysis set, TRAEs occurred in eight (42.1%) patients, including a grade 1 QTc interval increase in one (5.3%) patient, grade 3 fatigue in one patient, and grade 3 hyponatremia in one patient, none of which led to discontinuation with treatment.

In 2019, the U.S. FDA granted Breakthrough Therapy designation for TIBSOVO (ivosidenib) for the treatment of adult patients with relapsed or refractory myelodysplastic syndromes with a susceptible isocitrate dehydrogenase 1 (IDH1) mutation as detected by an FDA-approved test. Servier plans to submit a supplemental New Drug Application (sNDA) based on these results to the U.S. FDA for TIBSOVO in adult patients with R/R IDH1-mutated myelodysplastic syndromes.

TIBSOVO is currently approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML and in monotherapy or in combination with azacitidine for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. TIBSOVO was recently approved by the European Commission as a targeted therapy in two indications: in combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive standard induction chemotherapy; as well as in monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy. TIBSOVO has also been approved in the U.S. and Australia for patients with previously treated IDH1-mutated cholangiocarcinoma. TIBSOVO is also approved in China[i] for the treatment of adult patients with relapsed or refractory AML who have a susceptible IDH1 mutation. Servier has granted CStone a co-exclusive license for the development and an exclusive license agreement for the commercialization of TIBSOVO in Mainland China, Taiwan, Hong Kong, Macao and Singapore.

* Denotes a censored observation.

About the Study
In the Phase 1 dose-escalation and expansion study evaluating TIBSOVO in adults with advanced hematologic malignancies with IDH1 mutations, the clinical activity, safety, tolerability, pharmacokinetics and pharmacodynamics of TIBSOVO in adult patients with relapsed or refractory MDS with a susceptible IDH1 mutation is being assessed. (NCT03503409)

About Myelodysplastic Syndromes (MDS)
MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The Leukemia and Lymphoma Society estimates that more than 20,000 people are diagnosed with MDS in the U.S. each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML1. Chemotherapy, supportive therapy, stem cell transplant, growth factors, and similar approaches are used to treat MDS.

On June 9, 2023 MEDSIR reported the results of the PALMIRA trial (Press release, MedSIR, JUN 9, 2023, View Source;advanced-breast-cancer-patients-301847256.html [SID1234632622]). This randomized phase 2 study evaluated the safety and efficacy of palbociclib maintenance in combination with second-line endocrine therapy in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer who had showed a confirmed progressive disease on first-linepalbociclib plus endocrine therapy-based treatment after having achieved clinical benefit to this regimen. The results of this trial demonstrate that palbociclib maintenance does not significantly improve progression-free survival, the primary endpoint of the study, compared with second-line endocrine therapy alone in this patient population.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The PALMIRA study is sponsored by MEDSIR, a company dedicated to advancing clinical research in oncology, and was led by Dr. Antonio Llombart-Cussac along with Dr. Javier Cortés and Dr. José Pérez as Scientific Coordinators. The trial involved 198 patients with HR+/HER2- advanced breast cancer from 41 centers in 6 European countries.

Endocrine therapy is the mainstay of treatment for patients with HR+/HER2- advanced breast cancer. Several studies have demonstrated that the addition of cyclin-dependent kinases 4 and 6 (CDK4/6) to first- and second-line endocrine therapy leads to an improved progression-free survival and overall survival. However, the optimal treatment after progression on a CDK4/6 inhibitor in patients with HR+/HER2- advanced breast cancer remains undetermined.

One of the therapeutic options that have been evaluated in this scenario is the maintenance of CDK4/6 inhibition beyond progression switching the endocrine therapy and maintaining or shifting the CDK4/6 inhibitor or continuing the same endocrine therapy and changing to a different CDK4/6 inhibitor. Some of these studies had already suggested a continued benefit from this clinical approach but they must be interpreted with caution due to potential biases, mainly the use of a different CDK4/6 inhibitor.

The PALMIRA study aimed to determine if palbociclib maintenance could improve the antitumor activity of second-line endocrine therapy in HR+/HER2- advanced breast cancer patients who had showed a confirmed progressive disease on first-linepalbociclib plus endocrine therapy-based treatment after having achieved clinical benefit to this regimen.

"Results of the PALMIRA trial, while negative, will guide further research on the optimal treatment upon progression to CDK4/6 inhibitors and our clinical practice," said Dr. Llombart-Cussac, principal investigator of the study and Head of Service at Arnau de Vilanova Hospital in Valencia, Spain. Findings from the PALMIRA study indicate that "re-treatment with the same CDK4/6 inhibitor and switching the endocrine therapy does not improve patient outcomes."

Dr. Cortés, director of the International Breast Cancer Center, stated, "based on the results of the PALMIRA study, we suspect that there is a subgroup of patients that could benefit from maintaining palbociclib after prior progression on a palbociclib-based regimen. Biomarkers are the way to identify these patients and optimize the best future treatment options for them."

On June 9, 2023 The Menarini Group ("Menarini"), a leading Italian pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. ("Stemline"), a wholly-owned subsidiary of the Menarini Group, reported important new data on NEXPOVIO (selinexor) at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress 2023 (Press release, Menarini, JUN 9, 2023, View Source [SID1234632621]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The two abstracts at EHA (Free EHA Whitepaper) bring new subgroup data from the Phase 3 BOSTON study (NCT03110562) in relapsed refractory multiple myeloma (RRMM). In patients with just one prior line of treatment, median progression-free survival (mPFS) was 21 months for those treated with SVd, versus 10.7 months for those treated with Vd alone (HR 0.62). In proteasome inhibitor (PI)-naïve patients, the mPFS was 29.5 months with SVd compared to 9.7 months with Vd alone (HR 0.29). In patients who were refractory to lenalidomide, overall survival was 26.7 months for the SVd arm, compared to 18.6 months for the Vd arm (HR 0.53). These efficacy analyses were based on the final data cut from the BOSTON trial in February 2021, representing a one-year update of previously presented data from 2020.

"The data presented today emphasize the synergy between selinexor and bortezomib, highlighting the importance of a double mode of action switch. These results are particularly relevant considering the increased use of the daratumumab lenalidomide dexamethasone combination in clinical practice today," said Professor Maria-Victoria Mateos, MD, PhD, University Hospital Salamanca, Spain. "These findings further support the use of selinexor in combination with bortezomib in PI / bortezomib-naïve or lenalidomide-refractory RRMM patients, as well as for patients at first relapse."

"We are proud to present these new subgroup data on selinexor," said Elcin Barker Ergun, CEO of the Menarini Group. "We are committed to bringing transformative new therapeutic options to the patients and families affected by cancer, including multiple myeloma."

The most common (≥25%) treatment-emergent adverse events (AEs) with SVd versus Vd in patients with one prior line of treatment were thrombocytopenia (61.6% vs 28.6%), nausea (52.5% vs 11.2%), fatigue (45.4% vs 17.3%), peripheral neuropathy (38.4% vs 52.0%), diarrhea (34.3% vs 24.5%), and anemia (30.3% vs 26.5%). Safety findings were similar in the PI-naïve and bortezomib-naïve subgroups, as well as the lenalidomide refractory subgroup. Safety data in these subgroups were consistent with those observed in the overall BOSTON study population.

2023 EHA (Free EHA Whitepaper) Annual Meeting Presentation Details
Abstract Title: Efficacy, Survival and Safety of Selinexor, Bortezomib and Dexamethasone (SVd) in Patients with Lenalidomide-Refractory Multiple Myeloma: Subgroup Data from the BOSTON Trial
Poster #: P886
Session Title: Myeloma and other monoclonal gammopathies – Clinical
Session Date and Time: June 9, 2023 18:00-19:00 CET
Presentation Type: Poster
Presenting Author: Dr. Maria-Victoria Mateos

Abstract Title: Selinexor, bortezomib, and dexamethasone in patients with previously treated multiple myeloma: updated results of BOSTON trial by prior therapies
Poster #: P917
Session Title: Myeloma and other monoclonal gammopathies – Clinical
Session Date and Time: June 9, 2023 18:00-19:00 CET
Presentation Type: Poster
Presenting Author: Dr. Maria-Victoria Mateos

In December 2021, Karyopharm Therapeutics Inc. and Menarini established an exclusive licensing partnership. Under this agreement, which was later amended in May 2022 and in March 2023, Menarini holds the responsibility for commercializing all existing and upcoming indications of NEXPOVIO in the European Economic Area, United Kingdom, Switzerland, CIS countries, Turkey, Middle East & Africa, and Latin America. Stemline Therapeutics B.V., a wholly-owned subsidiary of Menarini, is leading all commercialization activities in Europe.

About Multiple Myeloma in Europe
Multiple myeloma is an incurable cancer with significant morbidity and the second most common hematologic malignancy. According to the World Health Organization, in 2020, there were approximately 51,000 new cases and 32,000 deaths from multiple myeloma in Europe1. While the treatment of multiple myeloma has improved over the last 20 years, and overall survival has increased considerably, the disease remains incurable, and nearly all patients will eventually relapse and develop disease that is refractory to all approved anti-myeloma therapies. Therefore, there continues to be a high unmet medical need for new therapies, particularly those with novel mechanisms of action.

About the BOSTON study
The FDA and EMA approvals of selinexor with bortezomib and dexamethasone are based on the Phase 3 BOSTON study, which was a multi-center, randomized study that evaluated 402 adult patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy. The study was designed to compare the efficacy, safety, and certain health-related quality of life parameters of once-weekly SVd versus twice-weekly Vd. The primary endpoint of the study was progression-free survival and key secondary endpoints included overall response rate, rate of peripheral neuropathy, and others. To learn more about this study, please refer to the Karyopharm press release announcing the publication of the BOSTON study results in The Lancet, issued on November 12, 2020.

About NEXPOVIO (selinexor)
NEXPOVIOhas been approved in the following oncology indications by the European Commission: (i) in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy; and (ii) in combination with bortezomib and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy. The marketing authorization of NEXPOVIO is valid in the EU Member States as well as Iceland, Liechtenstein, Norway, and Northern Ireland. NEXPOVIO has been commercially available in Germany and Austria since Q4 2022.

NEXPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor. NEXPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). NEXPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion.

Please see NEXPOVIO Summary of Product Characteristics (SmPC) and European Public Assessment Report at www.ec.europa.eu

Please refer to local prescribing information where NEXPOVIO is approved for full information.

IMPORTANT SAFETY INFORMATION
Contraindications: Hypersensitivity to selinexor or to any of the excipients listed in the SmPC.

Special warnings and precautions for use:

Recommended concomitant treatments
Patients should be advised to maintain adequate fluid and caloric intake throughout treatment. Intravenous hydration should be considered for patients at risk of dehydration.
Prophylactic concomitant treatment with a 5-HT3 antagonist and/or other anti-nausea agents should be provided prior to and during treatment with NEXPOVIO.

Haematology:
Patients should have their complete blood counts (CBC) assessed at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment.

Thrombocytopenia:
Thrombocytopenic events (thrombocytopenia and platelet count decreased) were frequently reported in adult patients receiving selinexor, which can be severe (Grade 3/4).
Grade 3/4 thrombocytopenia can sometimes lead to clinically significant bleeding and in rare cases may lead to potentially fatal haemorrhage. Thrombocytopenia can be managed with dose interruptions, modifications, platelet transfusions, and/or other treatments as clinically indicated.
Patients should be monitored for signs and symptoms of bleeding and evaluated promptly.

Neutropenia:
Severe neutropenia (Grade 3/4) has been reported with selinexor. In a few cases concurrent infections occurred in patients with Grade 3/4 neutropenia. Patients with neutropenia should be monitored for signs of infection and evaluated promptly.

Gastrointestinal toxicity:
Nausea, vomiting, diarrhoea, which sometimes can be severe and may require the use of anti-emetic and anti-diarrhoeal medicinal products. Prophylaxis with 5HT3 antagonists and/or other anti-nausea agents should be provided prior to and during treatment with selinexor. Fluids with electrolytes should be administered to prevent dehydration in patients at risk. Nausea/vomiting can be managed by dose interruptions, modifications, and/or initiation of other antiemetics medicinal products as clinically indicated. Diarrhoea can be managed with dose interruptions, modifications and/or administration of anti-diarrhoea medicinal products.

Weight loss and anorexia:
Patients should have their body weight, nutritional status and volume checked at baseline, during treatment, and as clinically indicated. Monitoring should be more frequent during the first two months of treatment. Patients experiencing new or worsening decreased appetite and weight may require dose modification, appetite stimulants, and nutritional consultations.

Confusional state and dizziness:
Patients should be instructed to avoid situations where dizziness or confusional state may be a problem and to not take other medicinal products that may cause dizziness or confusional state without adequate medical advice. Patients should be advised not to drive or operate heavy machinery until symptoms resolve.

Hyponatraemia:
Patients should have their sodium levels checked at baseline, during treatment, and as clinically indicated. Monitoring should be more frequent during the first two months of treatment. Hyponatraemia should be treated as per medical guidelines (intravenous sodium chloride solution and/or salt tablets), including dietary review.

Cataract:
Selinexor can cause new onset or exacerbation of cataract. Ophthalmologic evaluation may be performed as clinically indicated. Cataract should be treated as per medical guidelines, including surgery if warranted.

Tumour lysis syndrome (TLS):
TLS has been reported in patients receiving therapy with selinexor. Patients at a high risk for TLS should be monitored closely. Treat TLS promptly in accordance with institutional guidelines.

Fertility, pregnancy and lactation
Women of childbearing potential should be advised to avoid becoming pregnant or abstain from sexual intercourse while being treated with selinexor and for at least 1 week following the last dose of selinexor.

Women of childbearing potential/contraception in males and females:
Women of childbearing potential and male adult patients of reproductive potential should be advised to use effective contraceptive measures or abstain from sexual intercourse while being treated with selinexor and for at least 1 week following the last dose of selinexor.

Pregnancy:
There are no data from the use of selinexor in pregnant women. Selinexor is not recommended during pregnancy and in women of childbearing potential not using contraception.
If the patient becomes pregnant while taking selinexor, selinexor should be immediately discontinued, and the patient should be apprised of the potential hazard to the foetus.

Breast-feeding:
It is unknown whether selinexor or its metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with selinexor and for 1 week after the last dose.

Undesirable effects
Summary of the safety profile
The most frequent adverse reactions (≥30%) of selinexor in combination with bortezomib and dexamethasone were nausea, thrombocytopenia, fatigue, anaemia, decreased weight, diarrhea, and peripheral neuropathy.

The most commonly reported serious adverse reactions (≥3%) were pneumonia, cataract, sepsis, diarrhoea, vomiting and anaemia.

The most frequent adverse reactions (≥30%) of selinexor in combination with dexamethasone were nausea, thrombocytopenia, fatigue, anaemia, decreased appetite, decreased weight, diarrhoea, vomiting, hyponatraemia, neutropenia and leukopenia.

The most commonly reported serious adverse reactions were pneumonia, sepsis thrombocytopenia, acute kidney injury, and anaemia.

Description of selected adverse reactions
Infections: Infection was the most common non-haematological toxicity.
In patients who received selinexor in combination with bortezomib and dexamethasone, upper respiratory tract infection and pneumonia were the most commonly reported infections in 21% and 15% of patients, respectively.

In patients who received selinexor in combination with dexamethasone, upper respiratory tract infection and pneumonia were the most commonly reported infections (in 15% and 13% of patients, respectively) with 25% of reported infections being serious and fatal infections occurring in 3% of treated patients.

Elderly population
Patients 75 years and older had a higher incidence of discontinuation due to an adverse reaction, higher incidence of serious adverse reactions, and higher incidence of fatal adverse reactions.

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

On June 9, 2023 Sumitomo Pharma Oncology, Inc., a clinical-stage company focused on novel cancer therapeutics, reported updated preliminary data from the ongoing Phase 1/2 study evaluating TP-3654, an investigational selective oral PIM1 kinase inhibitor, in patients with myelofibrosis (MF) previously treated with or ineligible for JAK inhibitor therapy (Press release, Sumitomo Pharmaceuticals, JUN 9, 2023, View Source [SID1234632620]). Initial preliminary data was presented at American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition 2022. Updated results were presented in a poster presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) 2023 Hybrid Congress, being held June 8-11, 2023 in Frankfurt, Germany as well as virtually on the Congress platform from June 8-11, 2023.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Preliminary data of TP-3654 monotherapy in relapsed/refractory myelofibrosis (MF) patients showed spleen volume reduction (SVR), and total symptom score (TSS) improvement.1 Further, TP-3654 may prompt early cytokine changes that may correlate with symptoms response.

"We are encouraged by these preliminary clinical data and are pleased that in dose ranges evaluated to date, TP-3654 has been well-tolerated with no myelosuppressive treatment-related adverse events (TRAEs). Our commitment remains to continue to advance this program with additional clinical sites and contributing to the progress of potential treatment options, which may improve outcomes for patients with myelofibrosis," said Patricia S. Andrews, Chief Executive Officer and Global Head of Oncology, Sumitomo Pharma Oncology, Inc.

As of February 9, 2023, 15 patients were enrolled across 5 dose levels from 480mg QD to 720 mg BID. The results showed SVR observed in 7 of 10 evaluable patients treated for ≥ 12 weeks. TSS improvements were observed in 9 of 10 evaluable patients. Broad reductions in cytokines were observed after TP-3654 treatment. At week 12 analysis, patients with higher cytokine reductions correlated with higher TSS improvement. BM fibrosis reduction from grade 3 to 2 was seen in one patient who also achieved spleen and symptoms responses and showed reductions in MF associated cytokines: IL6 (68%), IL12p40 (83%), MMP9 (56%), and EN-RAGE (68%), and is on active treatment for more than 18 months.1 Overall, TP-3654 appears to be well tolerated with no dose limiting toxicity (DLT) observed to date. The most common adverse events are Grade 1 and 2 diarrhea, nausea, and vomiting.1

"These updated preliminary data of oral TP-3654 as a monotherapy in patients with MF presented at EHA (Free EHA Whitepaper) 2023 are encouraging as we evaluate the pharmacodynamic markers changes in MF patients treated with TP-3654," said Jatin J. Shah, M.D., Chief Medical Officer and Global Head of Development, Sumitomo Pharma Oncology (SMP Oncology). "We look forward to continuing to advance this study to evaluate the potential role of TP-3654 as a monotherapy, in addition to exploring combination opportunities with JAK inhibitors, for patients with myelofibrosis." Below are the details for the SMP Oncology presentation:

Abstract Title

Details

Presenter

Preliminary Data From the Phase 1/2 Study of TP-3654, an Investigational Selective PIM1 Kinase
Inhibitor, Showed Cytokine Reduction and Clinical Responses in Relapsed/Refractory Myelofibrosis

Abstract P1031

June 9, 2023 at 6:00 PM CEST

Poster Presentation

Firas El Chaer, MD, Division of Hematology/Oncology,
University of Virginia Health System,
Charlottesville, VA

About TP-3654

TP-3654 is an oral investigational inhibitor of PIM 1 kinase, which has shown potential antitumor and anti-fibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.2,3 TP-3654 was observed to inhibit proliferation and increased apoptosis in murine and human hematopoietic cells expressing clinically relevant JAK2V617F mutation.3 TP-3654 alone and in combination with ruxolitinib also showed normalized WBC and neutrophil counts, and reduced spleen size and bone marrow fibrosis in JAK2V617F and MPLW515L murine models of myelofibrosis.3 TP-3654 is currently being evaluated in a Phase 1/2 study of oral TP-3654 in patients with intermediate and high-risk myelofibrosis (NCT04176198). The Food and Drug Administration (FDA) granted Orphan Drug Designation for TP-3654 for the indication of myelofibrosis in May 2022.

About Myelofibrosis

Myelofibrosis is rare hematological malignancy with debilitating symptoms, splenic enlargement, cytopenia, and bone marrow fibrosis. The expression of PIM 1, which is known to contribute to cancer activation, is significantly elevated in hematopoietic cells from patients with myelofibrosis. It has been suggested to be a therapeutic target for myelofibrosis.