- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku
P1 data, P3 data, PK/PD data, Clinical Trial,Phase I, Journal: Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. (Pubmed Central) - Jul 28, 2022
P1, P3
PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL.
- |||||||||| Next Questions: Mantle Cell Lymphoma (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_279;
P2, P3
Chimeric antigen receptor (CAR) T cell therapy is available to patients who progress after second-line therapy and are candidates for this approach with one currently available product (brexucabtagene autoleucel (brexicel))...The OASIS-2 trial is evaluating time-limited “chemo-free” treatment randomizing patients to obinutuzumab + ibrutinib vs obinutuzumab + ibrutinib + the BCL-2 inhibitor venetoclax...The role of BTKi is being evaluated in more intensive combination regimens in both EA4181, a randomized phase II trial evaluating BR + HiDAC vs BR + HiDAC + acalabrutinib vs BR + acalabrutinib (NCT04115631) and TRIANGLE, a randomized phase III trial evaluating alternating R-CHOP/R-DHAP (dexamethasone, cisplatin, cytarabine) followed by ASCT vs the addition of ibrutinib to this regimen followed by ASCT + 2 years of maintenance ibrutinib vs the addition of ibrutinib to this regimen without ASCT but followed by 2 years of maintenance ibrutinib with MR given for up to 3 years in all arms (NCT02858258)...The future role of BTKi in relapse will likely be impacted by its more frequent use in frontline combinations, although data on the non-covalent BTKi pirtobrutinib has shown this agent to have activity in patients who have disease progression on covalent BTKi suggesting a role for BTKi in succession.8 Brexi-cel was the fi rst autologous CD19-directed cellular therapy approved in r/r with an ORR of 93% including 67% CR, a median PFS 25.8 months and OS 47.4 months.9-10 This product has demonstrated similar activity among patients with high-risk disease features including TP53 mutations, blastoid morphology, and high risk MIPI, leading to trials evaluating it in earlier lines of therapy in these patient populations...Lisocabtagene maraleucel is a second autologous CD19-directed cellular therapy that has shown similar effi cacy in a smaller patient population, but with improved toxicity profi le,11 leaving the potential for “safer” products...This provides an “off the shelf ” treatment option with overall lower grade toxicity than reported with CAR products, which may make it more accessible to a larger number of patients and combination will likely emerge. Immunotherapy approaches with antibody drug conjugates (ADC) have shown promise with zilovertamab vedotin13 targeting ROR-1 and loncantuximab tesirine14 targeting CD19 reported to be active in r/r MCL, with plans for further evaluation.
- |||||||||| Next Questions: Chronic Lymphocytic Leukemia (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_274;
Another BET inhibitor, JQ1, increases venetoclax induced apoptosis...Longer follow up is warranted to evaluate if the current combinations are the best way to benefi t from the effi cacy of BTK and Bcl2 inhibitors, and we have to integrate more biological data to propose more personalized therapies. We should keep in mind that CLL treatment is not a sprint, but a long distance race.
- |||||||||| Emerging Treatment Options for Mantle Cell Lymphoma (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_234;
P1/2, P2,
Novel Agent Combinations for High-Risk Disease Six non-chemotherapy options, namely bortezomib, lenalidomide, BTK inhibitors including ibrutinib, acalabrutinib, zanubrutinib, as well as CAR-T cell therapy (brexucabtagene autoleucel) have been approved by the United States FDA for the treatment of MCL...Examples include phase 1/2 study data on ibrutinib + novel agent combinations, in partnership with BH3-mimetic venetoclax, immunomodulatory agent lenalidomide, CDK4/6 inhibitor palbociclib, and PI3K inhibitors, etc. Exploratory analyses were performed in some of these studies to evaluate predictive biomarkers for response and survival, such as Ki-67 index, MIPI scores and TP53 status...Newer combinations under investigation include ibrutinib-venetoclax-obinutuzumab (OAsIs, NCT02558816), acalabrutinib-rituximab (ALTAMIRA, NCT05214183), acalabrutinib-lenalidomide-rituximab (NCT03863184), zanubrutinib-obinutuzumab-venetoclax (BOVen, NCT03824483), and acalabrutinib-venetoclaxrituximab, amongst others...The advancement of BTK inhibitors and other targeted agents to earlier lines of treatment is reshaping the treatment landscape for MCL patients. Research efforts are underway to develop new sequence and combinations to overcome treatment resistance and extend survival.
- |||||||||| Immunotherapeutic Options for Patients with MCL Who Progress on BTK Inhibitors (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_232;
The overall response rate was 81%, and 67% of patients achieved a complete response.11 Epcoritamab, which can be administered subcutaneously, is also active in this setting, and other bispecifi c antibodies continue to be investigated.12 It remains to be seen whether this class will supplant CAR-T or be used as an additional therapy option for patients before or after CAR-T treatment...Future studies will explore the role of immunotherapy earlier in the treatment course, especially for highrisk patients, and proper sequencing of BTK inhibitors, cellular therapies, novel antibodies, and bispecifi c antibodies will need to be determined through additional investigation. Evaluation of combination therapies which incorporate BTK inhibitors and other targeted agents with immunotherapies may induce deeper, longlasting remissions, which further improve OS for all patients.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku
First Prospective Data on Minimal Residual Disease Outcomes After Fixed-Duration Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for First-Line Treatment of CLL in Older Adult or Unfit Patients: The GLOW Study (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_166;
P3
Evaluation of combination therapies which incorporate BTK inhibitors and other targeted agents with immunotherapies may induce deeper, longlasting remissions, which further improve OS for all patients. All-oral, once-daily, fi xed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment versus Clb+O in older adult or unfi t patients with previously untreated CLL.
- |||||||||| Debate: Sequencing Small Molecules Is the Way to Go (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_160;
Toxicity of ibrutinib leading to discontinuation is a major problem2 which the next generation covalent BTK inhibitors acalabrutinib and zanubrutinib have substantially improved, with each drug demonstrating similar effi cacy with improved tolerability in head-to-head comparison trials in the relapsed setting3,4...In matching adjusted indirect treatment comparisons of fi rst-line acalabrutinib obinutuzumab to either ibrutinib or venetoclax obinutuzumab, fi rst-line acalabrutinib obinutuzumab improved PFS and OS against even those excellent comparators6, suggesting very durable long-term remissions...Venetoclax-rituximab for two years as studied in MURANO had a 54-month median PFS, with demonstrated high response rates upon subsequent re-treatment8...Recent clinical trial data with non-covalent BTK inhibitors such as pirtobrutinib support the possibility that the non-covalent inhibitors may further extend the duration of benefi t from therapies based on BTK inhibition12...The majority of patients treated on CAPTIVATE remain on therapy, suggesting that their disease will be refractory at time of progression, making salvage more complicated15. Discussion Sequencing small molecules is proven effective therapy that will control CLL for the expected lifespan of the great majority of CLL patients.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku
The Value to Society of Advancing the Care of Patients with Fixed Treatment Duration in Chronic Lymphocytic Leukemia () - Jul 24, 2022 - Abstract #PPLC2022PPLC_178;
The societal value associated with VenO treatment is largely realized by patients and far surpasses the costs of treatment while the manufacturer portion of societal value is negligible due to relatively low drug costs over the course of treatment. This study suggests that a fixed-duration venetoclax regimen offering patients treatment-free remission may provide greater value to patients with CLL than longer-term therapies.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku, Calquence (acalabrutinib) / AstraZeneca
MAJIC: A Phase 3 Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma () - Jul 24, 2022 - Abstract #PPLC2022PPLC_148;
Preclinical data support combining BTKis and BCL-2is, and recent studies with the first-generation BTKi ibrutinib plus venetoclax have demonstrated deep/durable responses with uMRD rates similar to VO in treatment-naive (TN) pts with CLL; however, toxicities of this regimen (eg, cardiac events, neutropenia, etc) may be challenging, particularly in older pts and those with comorbidities. This trial in progress is to inform the choice of which of these doublet therapy approaches might be most appropriate for pts with TN CLL/SLL without restriction by genetic background or age.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku, Rituxan (rituximab) / Roche
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: Pembrolizumab With Rituximab or Obinutuzumab in Treating Patients With Relapsed or Refractory Follicular Lymphoma or Diffuse Large B Cell Lymphoma (clinicaltrials.gov) - Jul 23, 2022
P2, N=18, Active, not recruiting,
This trial in progress is to inform the choice of which of these doublet therapy approaches might be most appropriate for pts with TN CLL/SLL without restriction by genetic background or age. Recruiting --> Active, not recruiting | N=62 --> 18 | Trial completion date: Feb 2023 --> Jul 2024 | Trial primary completion date: Feb 2023 --> Jan 2024
- |||||||||| obexelimab (ZB012) / Zenas BioPharma, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku, Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
Review, Journal: Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies. (Pubmed Central) - Jul 23, 2022
Controlled trials are needed in IgG4-ND not only with rituximab but also with the other anti-B cell agents that target CD19/20, especially those like obexelimab and obinutuzumab, that concurrently activate the inhibitory FcγRIIb receptors which have low binding affinity to IgG4, exerting a more prolonged anti-B cell action affecting also antigen presentation and cytotoxic T cells. Antibody therapies targeting FcRn, testing those anti-FcRn inhibitors that effectively catabolize the IgG4 antibody subclass, may be especially promising.
- |||||||||| Review, Journal: Therapeutic Monoclonal Antibody Therapies in Chronic Autoimmune Demyelinating Neuropathies. (Pubmed Central) - Jul 23, 2022
However, none of the abovementioned monoclonal antibodies is currently approved for treatment of any immune-mediated neuropathies. While more specific and individualized therapies are being developed, the possibility of combined treatments targeting different pathogenic mechanisms deserves consideration as well.
- |||||||||| Arzerra (ofatumumab) / Novartis, Genmab, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku
Journal: The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura. (Pubmed Central) - Jul 20, 2022
There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku, Imbruvica (ibrutinib) / AbbVie, J&J
Enrollment closed: A041702: Testing The Addition of a New Anti-cancer Drug, Venetoclax, to the Usual Treatment (Ibrutinib and Obinutuzumab) in Untreated, Older Patients With Chronic Lymphocytic Leukemia (clinicaltrials.gov) - Jul 19, 2022
P3, N=454, Active, not recruiting,
doi: 10.1111/bjh.18192.. Suspended --> Active, not recruiting
- |||||||||| Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku, Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
Journal: KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity. (Pubmed Central) - Jul 16, 2022
We developed a novel single-cell RNA-sequencing technique to identify KIR2DS2 NK cells, and this confirmed that KIR2DS2 is associated with enhanced NK cell-mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anticancer activity and indicates that KIR2DS2 is an attractive target for NK-based therapeutic strategies.
- |||||||||| Arzerra (ofatumumab) / Novartis, Genmab, Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku, Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
Understanding how epitope binding influences antibody dependent complement engagement for therapy of B-cell malignancies () - Jul 8, 2022 - Abstract #ITOC2022ITOC_19;
Conclusions Taken together this implies that bivalent target engagement helps cluster CD20 on the cell surface leading to beneficial arrangement of IgG Fc for stable C1q capture through optimization of avidity effects, which translates to efficient activation of the complement cascade. These findings are strongly supported by recent structural data in the field and add to the understanding on how the binding mechanism influences immune activation for CD20 mAbs.
- |||||||||| Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku, Imbruvica (ibrutinib) / AbbVie, J&J
Trial completion date, Trial primary completion date, Combination therapy: Ibrutinib in Combination With GA101 (Obinutuzumab) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients. (clinicaltrials.gov) - Jul 5, 2022
P1/2, N=32, Active, not recruiting,
No abstract available Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: Nov 2022 --> Nov 2023
- |||||||||| Gazyva (obinutuzumab) / Roche, Biogen, Nippon Shinyaku
Trial completion, Enrollment change, Trial completion date, Trial primary completion date: Obinutuzumab, High Dose Methylprednisolone (HDMP), and Lenalidomide for the Treatment of Patients With Richter's Syndrome (clinicaltrials.gov) - Jul 5, 2022
P1, N=4, Completed,
Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: Nov 2022 --> Nov 2023 Active, not recruiting --> Completed | N=10 --> 4 | Trial completion date: Aug 2022 --> May 2022 | Trial primary completion date: Aug 2022 --> May 2022
- |||||||||| REGEN-COV (casirivimab/imdevimab) / Regeneron, Roche
Journal: Casirivimab/imdevimab for active COVID-19 pneumonia persisted for nine months in a patient with follicular lymphoma during anti-CD20 therapy. (Pubmed Central) - Jul 1, 2022
This patient had persistent RT-PCR positivity and live virus isolation for nine months despite treatment with remdesivir and other potential antiviral therapies...His antibody titer of SARS-CoV-2 was negative throughout the illness, even after two doses of BNT162b2 mRNA vaccine given in the seventh month...Therapeutic administration of anti-SARS-CoV-2 monoclonal antibodies is essential for immunocompromised patients. Measures to prevent resistance against these key drugs are in dire need.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Review, Journal: Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia. (Pubmed Central) - Jun 28, 2022
Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine, is also approved in the United States for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy...It is therefore essential to provide information on the appropriate management of venetoclax-associated side effects. This article discusses the efficacy and safety of venetoclax administration and presents strategies specifically for the management of neutropenia and certain nonhematologic adverse events in patients receiving venetoclax for the treatment of AML and CLL.
- |||||||||| FT596 / Fate Therap
Enrollment change, Combination therapy, Monotherapy: FT596 as a Monotherapy and in Combination With Anti-CD20 Monoclonal Antibodies (clinicaltrials.gov) - Jun 27, 2022
P1, N=552, Recruiting,
This article discusses the efficacy and safety of venetoclax administration and presents strategies specifically for the management of neutropenia and certain nonhematologic adverse events in patients receiving venetoclax for the treatment of AML and CLL. N=285 --> 552
- |||||||||| Review, Journal, IO biomarker: SOHO State of the Art Updates and Next Questions | Management of Most Difficult Cases of Chronic Lymphocytic Leukemia: Relapse After Both BTK and BCL2 Inhibition and Richter Transformation. (Pubmed Central) - Jun 22, 2022
In the second case, a patient with CLL and del 17p develops a Richter transformation to diffuse large B-cell lymphoma after treatment with obinutuzumab, chlorambucil, ibrutinib, venetoclax, and idelalisib...The literature pertaining to these two scenarios is reviewed, including the role of available targeted therapies, chemoimmunotherapy, and hematopoietic cell transplantation. Emerging novel therapies, including reversible BTK inhibitors and CAR T cell therapy, are discussed.
- |||||||||| Journal: Epidermal necrolysis in the context of immuno-oncologic medication as well as kinase inhibitors and biologics. (Pubmed Central) - Jun 22, 2022
Fourteen cases were EN-like reactions: six bullous lichenoid drug eruptions (DE) to pembrolizumab (2), obinutuzumab, nivolumab, rituximab, infliximab/nivolumab, and eight multiforme-like DE to rituximab (2), adalimumab, ramucirumab, bevacizumab, vemurafenib, sorafenib (2)...A correct diagnosis is highly relevant in terms of prognosis and use of these drugs in malignoma treatment. Re-exposure is contraindicated in EN, but possible in other DE after rigorous risk-benefit evaluation.
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