Ukoniq (umbralisib) / Rhizen, TG Therap - LARVOL DELTA

Limited Duration Loncastuximab Tesirine Induces a High Rate of Complete Responses in Patients with Relapsed/Refractory Marginal Zone Lymphoma - Report of First Planned Interim Futility Analysis of a Multicenter Phase II Study (ASH 2024) - P2 | "Premedication with dexamethasone 4 mg twice daily for 3 days and prophylaxis with spironolactone 100 mg (to prevent fluid overload) was required...At the time of study design, the best reported CR rate in r/r MZL was 16% achieved with umbralisib, that we used as P0 assumption under the null hypothesis...Across all lines of treatment, the most common treatments were R-chemotherapy (n=18), targeted/immuno-modulatory agents (n=7) and single-agent rituximab (n=7); 1 patient had CAR-T...The patient clinically fully recovered with normalization in LFTs abnormalities. Conclusion : Lonca is demonstrating clinically meaningful activity with robust CR rate in r/r MZL patients in our ongoing phase 2 study."

Clinical • IO biomarker • P2 data • Hematological Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology

Umbralisib antagonizes multidrug resistance in ABCB1-overexpressing cancer cells. (PubMed, Front Oncol) - "Umbralisib significantly sensitized ABCB1-overexpressing cells to paclitaxel, vincristine, and doxorubicin in a concentration-dependent manner, but did not markedly reverse ABCC1-, ABCG2-, or ABCC10-mediated MDR. Umbralisib also enhanced paclitaxel-induced apoptosis and restored chemosensitivity in 3D tumor spheroids. Umbralisib reverses ABCB1-mediated MDR mainly by inhibiting ABCB1 drug efflux rather than altering transporter expression or localization, providing mechanistic insight into the modulation of ABCB1-mediated chemoresistance."

Journal • Oncology • ABCB1 • ABCC1 • ABCC10 • ABCG2 • PIK3CD

Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Sep 2025 ➔ Jul 2026

Trial completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CCND1 • CD20

SWOG S1608: Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma (clinicaltrials.gov) - P2 | N=73 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Jan 2027

Trial completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology • CD4

Clinical efficacy and safety of umbralisib, a dual PI3Kδ/CK1-ϵ inhibitor, in treatment of hematologic malignancies. (PubMed, Front Oncol) - "Further studies are needed to optimize combination strategies, explore alternative administration routes, and refine dosing approaches. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251018098."

Journal • Review • Diffuse Large B Cell Lymphoma • Fatigue • Hematological Malignancies • Infectious Disease • Marginal Zone Lymphoma • Neutropenia • Thrombocytopenia • PIK3CD

Clinical efficacy and safety of umbralisib, a dual PI3Kδ/CK1-ϵ inhibitor, in treatment of hematologic malignancies (Frontiers) - "Umbralisib monotherapy was associated with frequent hematologic AEs such as thrombocytopenia, neutropenia, and anemia, along with common non-hematologic toxicities including diarrhea, nausea, and fatigue. Liver enzyme elevation and diarrhea represented the more severe AEs. Combination therapy showed a distinct AE profile, with infusion reactions and infections being more prominent, but generally demonstrated fewer severe toxicities....Umbralisib shows promising efficacy in hematologic malignancies such as MZL, FL, and DLBCL, though its clinical use is limited by frequent AEs."

Retrospective data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Marginal Zone Lymphoma

Representation of Older Adults in Registrational Trials Associated with Therapeutic Approvals in Follicular Lymphoma (SIOG 2025) - "FL trials had low OA enrolment, with inadequate reporting and participation of adults over 75 yrs. Enhanced age subgroup reporting and OA enrolment are needed to ensure that trial outcomes are more representative of the broader patient population, particularly the elderly, who are most affected by FL."

Clinical • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Representation of Older Adults in Registrational Trials Associated with Therapeutic Approvals in Follicular Lymphoma (SIOG 2025) - "FL trials had low OA enrolment, with inadequate reporting and participation of adults over 75 yrs. Enhanced age subgroup reporting and OA enrolment are needed to ensure that trial outcomes are more representative of the broader patient population, particularly the elderly, who are most affected by FL."

Clinical • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Representation of Older Adults in Registrational Trials Associated with Therapeutic Approvals in Follicular Lymphoma (SIOG 2025) - "FL trials had low OA enrolment, with inadequate reporting and participation of adults over 75 yrs. Enhanced age subgroup reporting and OA enrolment are needed to ensure that trial outcomes are more representative of the broader patient population, particularly the elderly, who are most affected by FL."

Clinical • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Representation of Older Adults in Registrational Trials Associated with Therapeutic Approvals in Follicular Lymphoma (SIOG 2025) - "FL trials had low OA enrolment, with inadequate reporting and participation of adults over 75 yrs. Enhanced age subgroup reporting and OA enrolment are needed to ensure that trial outcomes are more representative of the broader patient population, particularly the elderly, who are most affected by FL."

Clinical • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Representation of older adults in registrational trials associated with therapeutic approvals in follicular lymphoma (ASH 2025) - "Of the drugs approved, 2 were bispecific antibodies (BsAb,epcoritamab, mosunetuzumab), 3 were chimeric antigen receptor-T (CAR-T) products (lisocabtagene,axicabtagene, tisagenleucel), 3 were PI3K inhibitors (umbralisib, copanlisib, duvelisib), 2 were monoclonalantibodies (obinutuzumab with chemotherapy, obinutuzumab with bendamustine), and 1 each ofselective EZH2 inhibitor (tazemetostat), immunomodulator (lenalidomide with rituximab), and BTKinhibitor (zanubrutinib). Most registrational trials for FL do report a subgroup of OA, although inclusion of OAremains suboptimal at 37%. Representation and reporting of pts≥ 75 yrs is significantly low at only 8%,despite this group representing 20% pts at diagnosis. Reporting of trials should include and distinguishpts ≥65 yrs and ≥75 yrs for subgroup analyses."

Clinical • Follicular Lymphoma • Geriatric Disorders • Hematological Malignancies • Lymphoma

Trial in progress: A study of roginolisib in combination with ruxolitinib in patients with myelofibrosis who are unresponsive to JAK inhibitors (HEMA-MED) (ASH 2025) - P1, P1/2 | "In contrast to the first generation PI3K inhibitors, suchas parsaclisib and umbralisib, roginolisib is a novel, oral, non-ATP competitive, allosteric small moleculeinhibitor of PI3Kδ. The study is currentlyactively enrolling at 8 sites in Italy and Spain.Conclusions. Given the safety profile of roginolisib in patients of the FiH dose study, the combination ofruxolitinib and roginolisib is expected to provide a safe combination treatment in patients with MF whoare no longer responding to JAK inhibition."

Clinical • Combination therapy • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Myelofibrosis • Solid Tumor • Thrombocytosis • PIK3CD

Acalabrutinib, Umbralisib and Ublituximab Regimen (AU2) Demonstrates High Response Rate and Undetectable Molecular Minimal Residual Disease (MRD) in Patients (pts) with De Novo Mantle Cell Lymphoma (MCL) (ASH 2024) - P2 | "Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies."

Clinical • IO biomarker • Minimal residual disease • Residual disease • Alzheimer's Disease • CNS Disorders • Dementia • Genito-urinary Cancer • Hematological Malignancies • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Oncology • Prostate Cancer • Solid Tumor • TP53

A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (ASH 2023) - P2 | "Immune-related adverse events were frequently observed and required dose reduction of umbralisib in 38% of the patients but most were then able to stay on therapy. Longer follow-up is required to determine durability of remission off therapy."

IO biomarker • P2 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Gastroenterology • Gastrointestinal Disorder • Gene Therapies • Hematological Malignancies • Hypertension • Immunology • Infectious Disease • Leukemia • Oncology • Pneumonia • Respiratory Diseases • Richter's Syndrome • ATM • IGH • NOTCH1 • PIK3CD • SF3B1 • TP53

Clonal Evolution during Dual B Cell Receptor Pathway Inhibitor Therapy with Acalabrutinib and Umbralisib in CLL Patients (ASH 2024) - "We have reported interim results of a phase 2 study combining acalabrutinib with the PI3K inhibitor umbralisib for 6 months, followed by the addition of the anti-CD20 antibody ublituximab (AU2) for months 7-12, with end of therapy at 12 months for those in complete response (CR) or 24 months for others (Ahn et al., ASH 2023). Overall, these findings highlight that even in the setting of clinical response with dual BCR pathway inhibitor therapy, clonal evolution is ongoing in genes potentially associated with resistance. Further clinical follow-up of this study will be required to associate evolving mutations with duration of response or progression-free survival."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BIRC3 • CARD11 • DNMT3A • FAT2 • IGH • JAK2 • NCOR2 • NFKBIE • NOTCH1 • SF3B1 • SMARCA2 • STAT3 • TET2 • TNFRSF14 • TP53 • TSC2 • ZFP36 • ZFP36L1

Development of isogenic models of marginal zone lymphoma for therapeutic target discovery in TET2-deficient disease (AACR-NCI-EORTC 2025) - "Pharmacological screening in wt and mut-TET2 monoclonal cells showed that several drugs, such as pictilisib, rapamycin, romidepsin, tucidinostat, and umbralisib, were more active in mut-TET2 cells, and their targets largely agreed with what was observed at the transcriptome level.Conclusions. Further, mut-TET2 conferred increased sensitivity to the TET inhibitor TETi76 and to multiple targeted agents, particularly those targeting PI3K, MTOR, and histone deacetylases. Our findings provide novel insights into the role of mut-TET2 in lymphomagenesis and reveal potential drug-targetable pathways for lymphomas with mut-TET2."

Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • TET2

Industry promotion of oncology drugs with accelerated approval that failed confirmatory trials. (PubMed, J Natl Cancer Inst) - "Among other 4, average monthly payments in the year preceding announcement of negative results to the period between results and market withdrawal went from $138 to $183 for vinCRIStine sulfate, $12,317 to $4,606 for Panobinostat, $152,417 to $119,066 for belantamab mafodotin, and $23,139 to $13,588 for umbralisib. While payments for oncology drugs with accelerated approvals mostly decreased, industry promotion continued for certain drugs after confirmatory studies failed until drugs were withdrawn from market."

Journal • Oncology

S1608: RANDOMIZED PHASE II TRIAL COMPARING LENALIDOMIDE/OBINUTUZUMAB AND UMBRALISIB/OBINUTUZUMAB WITH CHEMOIMMUNOTHERAPY IN EARLY PROGRESSING FOLLICULAR LYMPHOMA (POD24) (ICML 2025) - "53% and 47% had received first-line CHOP and bendamustine-based therapy respectively and 43% had received rituximab maintenance. POD24 FL remains an unmet need as the overall survival for this relatively young prospective cohort is similar to historical outcomes. There was no difference in CR rates or PFS between the targeted regimens and second line chemoimmunotherapy although L+O appeared to demonstrate a longer response duration. Patients who received consolidative high-dose therapy have yet to progress."

Clinical • P2 data • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Industry promotion of oncology drugs with accelerated approval that failed confirmatory trials. (ASCO 2025) - "Pepaxto was excluded from our analysis as it had no reported payments on OpenPayments...Following announcement of negative postapproval confirmatory study results, average monthly payments received by all physicians increased for Marqibo (vinCRIStine sulfate) from $138 in the year preceding announcement to $164 during the period between announcement of negative results and market withdrawal, but decreased for Farydak (panobinostat) ($12,317 to $4,916), Blenrep (belantamab mafodotin) ($152,417 to $119,394), and Ukoniq (umbralisib) ($23,139 to $14,130). Lartruvo (olaratumab) and Aliqopa (copanlisib) had almost no payments after announcement of negative confirmatory study results. Industry payments for oncology drugs with accelerated approvals mostly decreased after announcement of negative confirmatory trial results; however, there was evidence of continued promotion for certain drugs until a request for voluntary withdrawal was made by FDA. This suggests that regulatory..."

Oncology

Investigating Overlapping Immune-related Genetic Markers in Cholangiocarcinoma and Inflammatory Bowel Disease for Predictive Prognosis. (PubMed, J Immunother) - "This study also predicted potential small molecule drugs that might be effective for the treatment of CHOL, such as Umbralisib and Tamoxifen. In conclusion, this study provides new biomarkers and potential targets for diagnosis, prognosis assessment, and treatment of CHOL and IBD."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Oncology • Solid Tumor • CCR7 • OSMR • PIK3R3 • S100P • SPP1

A chemotherapy-free regimen of acalabrutinib, umbralisib and ublituximab achieved high response rates and undetectable minimal residual disease in patients with untreated mantle cell lymphoma. (PubMed, Br J Haematol) - No abstract available

Journal • Minimal residual disease • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

Protein profiles predict treatment responses to the PI3K inhibitor umbralisib in patients with chronic lymphocytic leukemia. (PubMed, Clin Cancer Res) - P2 | "Functional phenotyping reveals differential cellular responses to umbralisib treatment in responders and non-responders; predicts treatment response of individual CLL patients; and suggests alternative treatment options for the non-responders."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Targeting PI3K in Cancer Treatment: A Comprehensive Review with Insights from Clinical Outcomes. (PubMed, Eur J Pharmacol) - "Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and haematologic malignancies. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance."

Clinical data • Journal • Review • Breast Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • PTEN

Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (clinicaltrials.gov) - P2 | N=29 | Active, not recruiting | Sponsor: Jennifer R. Brown, MD, PhD | N=60 ➔ 29 | Trial completion date: Jan 2030 ➔ Jan 2028

Enrollment change • Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Treatment of Relapsed/Refractory CLL Patients With PI3Kδ Inhibitor and Anti-CD20 Antibody Rapidly Decreases Tumor Burden but Could Induce Resistance. (PubMed, Am J Hematol) - "The clinical trial utilized 1)a therapeutic anti-CD20 monoclonal antibody (mAb), ublituximab, which destroys CLL cells by an antibody-dependent cellular phagocytosis (ADCP) mechanism; 2)a B cell receptor (BCR) signaling inhibitor, umbralisib, which blocks PI3Kẟ; 3)and an anti-apoptosis inhibitor, venetoclax, which blocks cell survival promoted by BCL-2 that stops mitochondria from initiating apoptosis. Standard high dose (375 mg/m2) anti-CD20 antibody treatment significantly decreased CLL surface CD20 levels, potentially limiting treatment efficacy. Anti-CD20 antibody plus B cell receptor signaling inhibition reduced CLL cell counts and lymph node tumors, enabling BCL-2 inhibitor treatment to avoid tumor lysis syndrome."

Journal • Hematological Malignancies • Leukemia • Lymphoma • Oncology • PIK3CD