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

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

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

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

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

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

Long-term results of a phase 1/1b study of ibrutinib plus umbralisib for relapsed/refractory chronic lymphocytic leukemia. (PubMed, Hemasphere) - No abstract available

Journal • P1 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Jennifer R. Brown, MD, PhD | Trial primary completion date: Dec 2023 ➔ Dec 2026

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

Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Jennifer R. Brown, MD, PhD | Trial primary completion date: Jan 2025 ➔ Dec 2023

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

Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma (SWOG-Fall 2024) - "Objectives To compare the complete response rate up to six cycles after randomization as defined by centrally read PET/CT (integral biomarker) of two targeted therapeutic regimens (obinutuzumab + TGR-1202 or obinutuzumab + lenalidomide) with obinutuzumab + chemotherapy (CHOP or bendamustine) in patients with early relapsing or refractory follicular lymphoma. One patient on the Lenalidomide + Obinutuzumab arm experienced Grade 4 haemophilus influenza (listed as "Infections/infestations-Other" and "InvestigationsOther, specify"). Twenty-seven other patients experienced Grade 3 adverse events as maximum degree."

Clinical • IO biomarker • P2 data • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hepatitis B • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Influenza • Leukopenia • Lymphoma • Neutropenia • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • Thrombocytopenia • B2M

New Agents in Marginal Zone Lymphoma (SOHO 2024) - P2 | "In a pivotal study, ibrutinib was used in 60 relapsed/refractory (R/R) MZL patients, leading to an overall response rate (ORR) of 58% with a CR rate of 10%, a median duration of response (DOR) of 27.6 months, and a median progression-free survival (PFS) of 15.7 months. The median overall survival (OS) was not reached.5 The ACE-LY-003 study evaluated acalabrutinib in 43 R/R MZL patients...The CITADEL-204 study evaluated PI3Kd inhibitor parsaclisib daily dosing in 72 R/R MZL patients.8 The ORR was 58% with a CR rate of 4.2%, a median DOR of 12.2 months, and a median PFS of 16.5 months...Umbralisib, a dual PI3Kd/casein kinase 1e inhibitor, was evaluated in 69 R/R MZL patients in the UNITY-NHL study.9 The ORR was 49% with a CR of 16%, and the median DOR and median PFS were not reached...The double-blinded, randomized, placebo-controlled phase III CHRONOS-3 trial evaluated copanlisib with rituximab vs. rituximab in CD20-positive indolent NHL (iNHL)...The Zuma-5 clinical..."

Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Marginal Zone Lymphoma • Oncology • BTK

Safety Profile of First-Line Targeted Therapies in Elderly and/or Comorbid Chronic Lymphocytic Leukaemia Patients (Unfit Subpopulation). A Systematic Review and Network Meta-Analysis. (PubMed, Crit Rev Oncol Hematol) - "This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia (CLL) patients with advanced age and/or comorbidities. In conclusion, targeted therapies are associated with variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities."

Journal • Retrospective data • Review • Cardiovascular • Chronic Lymphocytic Leukemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Post-marketing safety concern of PI3K inhibitors in the cancer therapies: an 8-year disproportionality analysis from the FDA adverse event reporting system. (PubMed, Expert Opin Drug Saf) - "Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibitingPI3Kδ) were developed to target the PI3K pathway...The safety profiles of the five PI3K inhibitorsvary concerning adverse events. These findings could guide drug selection andinform future prospective research."

Adverse events • Journal • P4 data • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Metabolic Disorders • Neutropenia • Oncology • Steven-Johnson Syndrome • PIK3CA • PIK3CD • PIK3CG

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=95 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Enrollment closed • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology • CD4

PI3K inhibitors in hematology: When one door closes…. (PubMed, Clin Cancer Res) - "Copanlisib and umbralisib received accelerated approvals, while idelalisib and duvelisib received initial accelerated approvals followed by full approvals. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3K inhibitors. Here, we review the development and current status of PI3K inhibitors in hematology, limitations to their use, and our perspective on whether there is a future for PI3K inhibitors in hematology."

Journal • Hematological Disorders • Hematological Malignancies • Oncology