Tag: Non-Hodgkin Lymphoma

FDA Approves LYMPHIR® for Relapsed and Refractory Cutaneous T-Cell Lymphoma

RR

SUMMARY: The FDA on August 7, 2024 approved LYMPHIR® (Denileukin diftitox-cxdl), a novel immunotherapy for the treatment of relaped/refractory Cutaneous T-Cell Lymphoma (CTCL) after at least one prior systemic therapy.

Primary Cutaneous T Cell Lymphoma is a type of Non Hodgkin Lymphoma and includes a spectrum of diseases that primarily involve the skin, but may ultimately involve lymph nodes, blood and visceral organs such as spleen, liver and lungs. CTCL initially presents as red, scaly, itchy patches on the skin and is often misdiagnosed as eczema. Approximately 3,000 new cases are reported in the United States every year, with an estimated 30,000 – 40,000 individuals living with the disease. The incidence is higher in blacks than Caucasians or Asians. It is more common in men, and is typically first diagnosed in patients between the ages of 50 and 60 years of age. Mycosis Fungoides/Sezary Syndrome is the most common type of CTCL. There is currently no curative therapy for advanced CTCL other than Allogeneic Stem Cell Transplantation. Patients often receive several skin-directed therapies as well as systemic therapies to achieve effective disease control, but the disease eventually becomes refractory. There is therefore an unmet clinical need for novel therapies.

Denileukin diftitox is a recombinant fusion protein composed of Interleukin-2 (IL-2) receptor binding domain and diphtheria toxin fragments. It selectively targets IL-2 receptor-expressing cells, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis, leading to apoptosis. Its unique mechanism of action targets both malignant T-cells and immunosuppressive regulatory T-cells (Tregs). Transiently eliminating Tregs has the potential of unleashing potent immune responses by the immune system of the patient against their tumors. This agent was approved and marketed as ONTAK® in the US from 1999-2014 for the treatment of relapsed/refractory CTCL. However, the product was withdrawn from the market in 2014 because of manufacturing issues related to its bacterial expression. Manufacturing improvements to decrease the presence of misfolded and aggregated proteins resulted in a new and more purified bioactive formulation LYMPHIR®, that has 1.5-2 times greater specific bioactivity in non-clinical assays compared with ONTAK®. It is considered a new drug by the FDA, requiring a new registrational clinical trial.

The efficacy and safety of LYMPHIR® was assessed in a multicenter, open-label, Phase III Pivotal Study 302 of CTCL patients, who had previously received at least one systemic treatment. This analysis included 69 patients (N=69) with Stage I-III CTCL who had CD25 expression on at least 20% of biopsied malignant cells per immunohistochemistry and had received a median four prior therapies. The median age was 64 years, 65% were men, 73% were White and 19% were African American, 66 patients had Mycosis fungoides and 3 had Sezary syndrome. Approximately 30% had Stage I disease, 48% had Stage II disease and 22% had Stage III disease. Patients received LYMPHIR® 9 mcg/kg/day for 5 days, every 21 days for up to 8 cycles. The Primary efficacy outcome measure was Objective Response Rate (ORR), as assessed by an Independent Review Committee (IRC).

The Objective Response Rate was 36.2%, with 8.7% achieving a Complete Response. The median time to response was 1.41 months, with 70% of responders seeing results after 1-2 cycles of treatment. Duration of response was at least 6 months for 52% of the patients and 84% (54/64) of skin evaluable patients had a decrease in skin tumor burden, and 12.5% (8/64) saw complete clearing of skin disease. Pruritis was evaluated as an exploratory endpoint with 31.7% of patients demonstrating clinically significant pruritus improvement. Importantly, no cumulative toxicity was observed in patients receiving LYMPHIR®.

The safety profile of LYMPHIR® was consistent with the known safety profile for Denileukin diftitox. Across three studies of 119 CTCL patients receiving 9 μg dose of Denileukin diftitox, the most common (20% or more) adverse reactions including laboratory abnormalities were, infusion reactions, increased transaminases, decreased albumin, nausea, edema, anemia, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, blurred vision and Capillary Leak Syndrome (CLS). Infusion reactions, CLS, and visual impairment were mostly Grade 1/2 and effectively managed.

In conclusion, LYMPHIR® represents a significant advancement in treating Cutaneous T-Cell Lymphoma, especially for patients who have not responded well to previous treatments. As the first systemic option in years targeting the IL-2 receptor on malignant T-cells and Tregs, LYMPHIR® provides new hope for managing the long-term challenges of CTCL, such as severe skin symptoms and secondary infections. This development moves us closer to addressing the needs of CTCL patients who struggle with ongoing disease despite prior therapies.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761312s000lbl.pdf

What is the Real-World Evidence for the Effectiveness of Mogamulizumab in Patients with Mycosis Fungoides and Sézary Syndrome?

RR

Written by: Francine Foss, MD
Professor of Medicine (Hematology) and Dermatology
Director, Multidisciplinary T cell Lymphoma Program, Hematology; Scientific Leader, Lymphoma CRT
Yale Cancer Center
Content sponsored by Kyowa Kirin, Inc.
Dr. Foss is a paid consultant for Kyowa Kirin and was compensated for her contribution in drafting this article.

POTELIGEO® (mogamulizumab–kpkc), indicated for the treatment of adult patients with relapsed or refractory Mycosis Fungoides (MF) or Sézary Syndrome (SS) after at least one prior systemic therapy, is a first-in-class humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4), a protein consistently expressed on cancerous cells seen in both MF and SS.1-3

POTELIGEO received FDA approval based on results of the MAVORIC trial, a randomized, open-label, phase 3 trial that compared its efficacy with that of an active comparator, vorinostat, in previously treated patients with relapsed or refractory MF or SS. In MAVORIC, patients receiving mogamulizumab (n=186) demonstrated efficacy superior to those receiving vorinostat (n=186) in the prespecified primary endpoint, with significantly longer progression-free survival (PFS) (7.6 vs 3.1 months; hazard ratio: 0.53, 95% CI [0.41, 0.69], P<0.001). For the secondary endpoint, overall response rate (ORR), significantly more patients achieved a response to mogamulizumab vs the comparator (28% vs 5%, P<0.001). When evaluated by disease compartment, response rates were higher with mogamulizumab compared with vorinostat in the blood (67% vs 18%), skin (42% vs 16%), and lymph nodes (15% vs 4%). The most common adverse reactions (reported in ≥20% of patients) were rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infection.4

The OMEGA study was a retrospective analysis of real-world patients receiving mogamulizumab in 14 centers throughout France. The full study-report article can be accessed at https://doi.org/10.1111/jdv.19134. A total of 122 patients were reviewed, 53 with MF and 69 with SS. All had been treated with mogamulizumab from February 2014 until March 2020.5 The OMEGA study contains information that is not included in the FDA-approved labeling for POTELIGEO; the study included 2 patients with SS in whom mogamulizumab was administered as a first-line therapy. OMEGA also reported a serious adverse reaction, vitiligo (3 patients [2.4%]), that was not captured in the MAVORIC trial. It is not known if there were variations from the FDA-approved labeling in the dosing schedule for any patients included in the study. Also, OMEGA differed from MAVORIC by defining treatment responses as complete or partial response (CR or PR) that occurred at any time, and for no prespecified duration post-initiation of mogamulizumab. In MAVORIC, by definition, treatment responses were required to be confirmed CR or PR at 2 or more consecutive assessments spaced at least 8 weeks apart.5

In the OMEGA study, key outcome measures were:
Primary endpoint: Best overall response rate (bORR)a
Secondary endpoints: bORR by compartment (skin, blood, lymph nodes, viscera)b and safety
Exploratory endpoint: PFS

a Percentage of patients achieving a global overall response (CR or PR) at any time and for no prespecified duration.
b Percentage of patients achieving a CR or PR in the specified compartment at any time and for no prespecified duration.

As shown in Figure 1, in the entire patient population, bORR was 58.7% (12.8% CR; 45.9% PR). In patients with SS, bORR was 69.5% (16.9% CR; 52.5% PR), and in patients with MF, bORR was 46.0% (8.0% CR; 38.0% PR). The median time to response under treatment (CR or PR) was similar according to disease subtype (3.1 months for patients with SS and MF; respective ranges: 01–25.0, and 0.3–44.3 months).5

Best-ORR-Primary-Endpoint

Responses were seen across all involved disease compartments, as seen in Table 1.5

Best-Responses-Blood-Skin-LN-Viscera-Secondary-Endpoint

As seen in Figure 2, in the overall analysis population (n=122), the median PFS was estimated at 15.0 months (95% CI [9.0–50.8]). It was longer in patients with SS than in patients with MF (20.3 months [11.7–not reached] vs. 8.8 months [4.6–43.0]) but no significant difference between disease subtypes was shown (P= 0.0542).5

Progression-Free-Survival

The percentage of patients who experienced a serious adverse reaction (AR) was consistent with MAVORIC (18.5% vs 20% in MAVORIC).1,2 Discontinuations of mogamulizumab due to ARs occurred in 15 patients (12.1%) rash was the most common reason for permanent discontinuation (9 patients; 7.3%). One patient discontinued due to thrombopenia and one patient discontinued due to an infusion-related reaction (0.8% each).5 The most common ARs can be seen in Table 2.

Adverse-Drug-Reactions

Limitations of the OMEGA study include its non-interventional and retrospective design, a patient population less selective than those in clinical trials, and overlap of 20 patients that were also part of the MAVORIC trial. The results are in line with efficacy and safety data demonstrated in the global clinical trial MAVORIC, and supports the effectiveness of mogamulizumab in real-world clinical practices.

INDICATION
POTELIGEO injection for intravenous infusion is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.

IMPORTANT SAFETY INFORMATION
Warnings and Precautions
• Dermatologic toxicity: Monitor patients for rash throughout the course of treatment. For patients who experienced dermatologic toxicity in Trial 1, the median time to onset was 15 weeks, with 25% of cases occurring after 31 weeks. Interrupt POTELIGEO for moderate or severe rash (Grades 2 or 3). Permanently discontinue POTELIGEO for life-threatening (Grade 4) rash or for any Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).
• Infusion reactions: Most infusion reactions occur during or shortly after the first infusion. Infusion reactions can also occur with subsequent infusions. Monitor patients closely for signs and symptoms of infusion reactions and interrupt the infusion for any grade reaction and treat promptly. Permanently discontinue POTELIGEO for any life-threatening (Grade 4) infusion reaction.
• Infections: Monitor patients for signs and symptoms of infection and treat promptly.
• Autoimmune complications: Interrupt or permanently discontinue POTELIGEO as appropriate for suspected immune-mediated adverse reactions. Consider the benefit/risk of POTELIGEO in patients with a history of autoimmune disease.
• Complications of allogeneic HSCT after POTELIGEO: Increased risks of transplant complications have been reported in patients who received allogeneic HSCT after POTELIGEO. Follow patients closely for early evidence of transplant-related complications

Adverse Reactions
• The most common adverse reactions (reported in ≥10% of patients) with POTELIGEO in the clinical trial were rash, including drug eruption (35%), infusion reaction (33%), fatigue (31%), diarrhea (28%), drug eruption (24%), upper respiratory tract infection (22%), musculoskeletal pain (22%), skin infection (19%), pyrexia (17%), edema (16%), nausea (16%), headache (14%), thrombocytopenia (14%), constipation (13%), anemia (12%), mucositis (12%), cough (11%), and hypertension (10%).

Please see the full Prescribing Information for POTELIGEO at www.poteligeohcp.com for additional information.

You are encouraged to report suspected adverse reactions to Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References:
1. Ferenczi K, et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol. 2002;119(6):1405-1410.
2. Yoshie O, et al. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood. 2002;99(5):1505-1511.
3. Ishida T, et al. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res. 2003;9(10 Pt 1):3625-3634.
4. POTELIGEO [package insert]. Kyowa Kirin Inc., Princeton, NJ USA.
5. Beylot-Barry M, Quereux G, Nardin C, et al. Effectiveness of mogamulizumab in patients with mycosis fungoides or Sézary syndrome: a multicentre, retrospective, real-world French study. J Eur Acad Dermatol Venereol. 2023;37(9):1777-1784.

POTELIGEO is a registered trademark of Kyowa Kirin Co., Ltd.
© 2024 Kyowa Kirin, Inc. All rights reserved.
510 Carnegie Center Dr. Princeton, NJ 08540 USA

COMM-US-POT-0274 May 2024

Late Breaking Abstract – ASCO 2024: ADCETRIS® Combination Improves Overall Survival in Relapsed and Refractory Diffuse Large B-Cell Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and more than 25,000 cases of DLBCL are diagnosed each year in the United States, accounting for more than 25 percent of all lymphoma cases. The incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL can develop spontaneously or as a result of Richters transformation of low grade diseases such as Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Follicular Lymphoma, or Marginal Zone Lymphoma.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless of molecular subtype, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL. Approximately 30-40% of patients experience disease progression or relapse during the first 2 years, and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor. There is a critical unmet need for this patient group.

Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. Preclinical data and early phase studies provided the rationale for combining Brentuximab vedotin, Lenalidomide and Rituximab for the treatment of Relapsed/Refractory DLBCL.

ECHELON-3 is an ongoing, global, randomized, double-blind, multicenter Phase III study, designed to evaluate the efficacy and safety of Brentuximab vedotin in combination with Lenalidomide and Rituximab, compared to Lenalidomide and Rituximab plus placebo, in adult patients with Relapsed/Refractory DLBCL, regardless of CD30 expression, who have received two or more prior lines of therapy and were ineligible for or had previously failed Hematopoietic Stem Cell Transplant (HSCT) or Chimeric Antigen Receptor (CAR) T-cell therapy.

In this global study, 230 patients were randomized 1:1 to receive either Brentuximab vedotin plus Lenalidomide and Rituximab (BV+R2) – N=112, with Brentuximab vedotin administered at 1.2 mg/kg IV every 3 weeks, Lenalidomide at 20 mg orally daily, and Rituximab at 375 mg/m² IV every 3 weeks, or Placebo plus Lenalidomide and Rituximab (placebo+R2) – N=118. Placebo for Brentuximab vedotin with Lenalidomide and Rituximab was administered in the same manner. Treatment continued until disease progression or unacceptable toxicity. The median age was 71 years, 56% were male, median prior lines of therapy was 3, 29% had prior CAR T-cell therapy, approximately 15% of patients had prior bispecific antibody exposure, and 68% were CD30 negative with CD30 tumor expression of less than 1%. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Objective Response Rate (ORR) and Complete Response (CR) Rate.

At the interim analysis, with a median follow-up of 16.4 months, BV+R2 regimen demonstrated a median OS of 13.8 months compared to 8.5 months with placebo+R2, representing a 37% reduction in the risk of death (HR=0.63; P=0.0085). The median PFS was 4.2 months in the BV+R2 arm versus 2.6 months in the placebo+R2 arm (HR=0.53; P<0.0001). The ORR was 64.3% with BV+R2 compared to 41.5% with placebo+R2 (P=0.0006). The CR rate was 40.2% with BV+R2 versus 18.6% with placebo+R2. The efficacy benefits of BV+R2 were consistent across key subgroups, including patients with CD30-positive and CD30-negative disease, highlighting the broad applicability of the regimen.

Grade 3 or higher adverse events were more frequent in the BV+R2 arm compared to placebo+R2 (88% versus 77%), and the most common Grade 3 or higher adverse events included neutropenia, anemia and diarrhea. Peripheral Neuropathy was higher with BV+R2 compared to placebo+R2, although generally manageable.

In conclusion, the ECHELON-3 study demonstrated that the addition of Brentuximab vedotin to Lenalidomide and Rituximab significantly improved Overall Survival, Progression-Free Survival, and Response Rates in patients with Relapsed/Refractory DLBCL, compared to Lenalidomide and Rituximab alone. This regimen offers a promising new treatment option for patients who have exhausted standard therapies, or are ineligible for intensive treatments like CAR-T cell therapy or HSCT. The results underscore the potential of targeted therapies in reshaping the management of DLBCL, providing renewed hope for improved outcomes in this challenging disease setting. As the study continues to follow patients for long-term outcomes, ongoing research will further elucidate the durability of responses and additional safety data, thereby informing future clinical practice guidelines and optimizing patient care strategies.

Brentuximab vedotin in combination with lenalidomide and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma: Results from the phase 3 ECHELON-3 study. Kim JA, Hahn U, Kim W-S, et al. Journal of Clinical Oncology. Volume 42, Number 17_suppl. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA7005

FDA Approves BREYANZI® for Relapsed/Refractory Follicular Lymphoma

RR

SUMMARY: The FDA on May 15, 2024, granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel) for adults with Relapsed or Refractory Follicular Lymphoma who have received two or more prior lines of systemic therapy. The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Despite advances in treatment for Follicular Lymphoma, there remains an unmet need for additional options that offer treatment-free intervals with durable, complete responses.

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the body of patients and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.

Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process, is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody, produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.

BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® contains a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. BREYANZI® was previously approved in the US for the treatment of Relapsed or Refractory Large B-Cell Lymphoma (LBCL) after at least one prior line of therapy, and also received accelerated approval for the treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma after at least two prior lines of therapy.

TRANSCEND-FL is a global, multicenter, open-label, single-arm Phase II trial which included patients with Relapsed or Refractory Follicular Lymphoma after two or more lines of systemic therapy including an anti-CD20 antibody and an alkylating agent. This study included 94 eligible patients (N=94) and these patients also needed to have an ECOG PS of 1 or less, as well as adequate bone marrow function to receive lymphodepleting chemotherapy. Eligible patients had PET-positive disease at baseline or after bridging therapy and had at least 9 months of follow up from first response. Patients were excluded if they had evidence or a history of composite Diffuse Large B-Cell Lymphoma and Follicular Lymphoma, or transformed Follicular Lymphoma, a WHO subclassification of duodenal-type Follicular Lymphoma, CNS-only involvement by malignancy, or prior CAR T-cell therapy or other genetically modified cell therapy. Following apheresis and collection of T cells, patients received lymphodepleting chemotherapy consisting of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV daily for 3 days. Patients could receive bridging therapy for disease control following apheresis and prior to lymphodepletion and subsequent administration of BREYANZI®. Patients received a single dose of BREYANZI® 2-7 days, following the completion of lymphodepleting chemotherapy at a target dose of 100 x 106 CAR-positive T cells.

The Primary efficacy endpoint was the Overall Response Rate (ORR), defined as the percentage of patients achieving a Partial or Complete Response per Lugano criteria as assessed by an Independent Review Committee (IRC). Secondary endpoints included Complete Response (CR) rate, Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and Safety. Responses were evaluated using PET scans, providing a comprehensive assessment of treatment efficacy.

The study demonstrated impressive efficacy outcomes, with an ORR of 95.7% and a CR rate of 73.4% in the primary analysis set. Responses were rapid, with a median time to response of one month. After a median follow up of 16.8 months, the median Duration of Response was Not Reached. Approximately 81% of responders remained in response at 12 months, and 77% of responders remained in response at 18 months, underscoring the potential of this therapy to induce long-lasting remissions. The most common non-laboratory adverse reactions were Cytokine Release Syndrome (CRS), headache, musculoskeletal pain, fatigue, constipation, and fever.

In this largest primary analysis assessing CAR T-cell therapy for Relapsed or Refractory Follicular Lymphoma, a treatment option with a one-time infusion of BREYANZI® with the potential for lasting remission, addresses the unmet need of these patients, heralding a new era in the management of this challenging disease.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma

Minimal Residual Disease Status Predicts Outcome in Patients with Previously Untreated Follicular Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years.

GAZYVA® (Obinutuzumab) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells (natural killer cells, macrophages and neutrophils), Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis are significantly enhanced but induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® which is a first-generation type I, chimeric, anti-CD20 targeted monoclonal antibody that kills lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.

GALLIUM is a randomized, Phase III trial, which included 1,202 patients with newly diagnosed Follicular Lymphoma, who had Grade I-IIIa tumors and had an ECOG PS of 2 or less. Patients were randomly assigned to receive either GAZYVA® plus chemotherapy, followed by GAZYVA® maintenance (N=601), or RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance (N=601). The chemotherapy regimens used were CHOP, CVP or Bendamustine, based on the discretion of the treating physician. Patients received either RITUXAN® 375mg/m2 IV on day 1 of each cycle or GAZYVA® 1000 mg IV on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (CHOP and CVP) or six 28-day cycles (Bendamustine). Patients who achieved a Complete Response (CR) or Partial Response (PR) at the end of induction therapy, received maintenance therapy with RITUXAN® or GAZYVA® every 2 months for 2 years or until disease progression. The median age was 59 years and 57.1% of patients received Bendamustine, 33.1% received CHOP, and 9.8% received CVP. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Response Rate, Overall Survival (OS), Disease Free Survival and safety. After a median follow up of 34.5 months, upon recommendations from the Independent Monitoring Committee, the study was unblinded after a preplanned interim efficacy analysis. The estimated 3-year rate of Progression Free Survival in the GAZYVA® group was 80% compared with 73.3% in the RITUXAN® group, with a 34% reduction in the risk of progression or death noted in the GAZYVA® group (HR=0.66; P=0.001).

The researchers conducted a preplanned analysis of the Phase III Gallium study and explored the role of Minimal Residual Disease (MRD) as a predictor of outcome after GAZYVA® or RITUXAN® based treatment, in these previously untreated patients with Follicular Lymphoma. MRD status was assessed at predefined time points (Mid-Induction-Day 85 for all treatment groups, End of Induction, and at 4-6 monthly intervals during maintenance and follow-up) and the study objectives were to evaluate the depth and kinetics of MRD response to first-line GAZYVA® plus chemotherapy or RITUXAN® plus chemotherapy, and explore the prognostic role of MRD-status prospectively, to evaluate the use of MRD as a dynamic parameter for treatment modification. Patients with evaluable biomarker data at diagnosis were included in the survival analysis.

MRD analysis was performed at the central reference laboratory and was assessed by nested and quantitative PCR for clonal immunoglobulin gene rearrangement and the t(14;18) translocation. MRD status was classified as positive if both quantitative PCR and nested PCR were positive and were detectable at or above 104 sensitivity. Both peripheral blood and bone marrow samples were collected and MRD status was evaluated at Mid-Induction, End of Induction, during maintenance treatment and follow up. MRD status at End of Induction was determined as positive if at least one sample (PB or BM) was positive. Assessments during maintenance were conducted every 4 months during the first year, every 6 months thereafter, and at the final termination/discontinuation visit. Assessments were conducted every 6 months during follow-up. Patients who progressed during induction were excluded from the corresponding MRD analysis. Of the 1064 patients enrolled for MRD evaluation, 249 patients (23%) had no clonal PCR marker detected or had samples that did not meet MRD evaluability criteria.

At a median follow up of 59 months, MRD positivity at the Mid-Induction or End of Induction was significantly associated with inferior Progression Free Survival compared with MRD negativity. (PFS for those with detectable MRD at the Middle of Induction-HR=3.03, P<0.0001) and at the End of Induction- HR= 2.25, P<0.0001).

MRD response was higher after GAZYVA® plus chemotherapy versus RITUXAN® plus chemotherapy at the Middle of Induction (94.2% vs 88.9%, P=0.013) and at the End of Induction (93.1% vs 86.7%, P=0.0077), respectively.

Late responders with detectable MRD at the Middle of Induction and undetectable MRD at the End of Induction had significantly poorer PFS versus early responders who had undetectable MRD at both the Middle of induction and the End of Induction (HR=3.11, P=0.00011).

MRD positivity at the Middle of Induction was observed in a smaller proportion of patients receiving Bendamustine than CHOP (4.8% versus 16.0%; P<0.0001).

GAZYVA® appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the GAZYVA® plus chemotherapy groups.

During maintenance, more patients treated with RITUXAN® had detectable MRD compared to GAZYVA®, and throughout maintenance treatment, MRD positivity was associated with clinical relapse.

The researchers concluded that based on this analysis, early and continuous MRD negativity after immunochemotherapy is the most important prognostic factor for long-term disease control and outcomes, following first line treatment in Follicular Lymphoma. Further, this analysis has also suggested that the higher MRD responses after GAZYVA®, compared to RITUXAN® based chemotherapy, confirm more effective tumor cell clearance with GAZYVA® based chemotherapy regimens.

Minimal Residual Disease Status Predicts Outcome in Patients with Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study. Pott C, Jurinovic V, Trotman J, et al. J Clin Oncol. 2024;42:550-561.

FDA Approves BREYANZI®, First CAR-T Cell Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

RR

SUMMARY: The FDA on March 14, 2024 granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel, Liso-cel), a CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy, for the treatment of adults with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have received at least two prior lines of therapy (including a Brutons Tyrosine Kinase-BTK inhibitor and a B-Cell Lymphoma 2-BCL2 inhibitor).

The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitors such as Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®), time limited therapy with BCL2 inhibitor Venetoclax, given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy. Patients have few options and poor outcomes upon progression on these therapies, and there is an unmet need for novel therapies.

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patients body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.

BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® was previously approved by the FDA for treatment of adults with relapsed or refractory Large B-cell lymphoma, who received at least one prior therapy. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process, is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody, produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.

TRANSCEND CLL 004 is an open-label, single-arm, multicenter Phase1/2 study, conducted in the United States, to evaluate the efficacy and safety of BREYANZI® in adult patients with relapsed or refractory CLL/SLL. This study included 117 eligible patients who underwent leukapheresis between January 2018 and June 2022, at 27 sites in the United States. Patients received a single intravenous infusion of BREYANZI® at one of two target dose levels: 50×10⁶ (Dose Level 1) or 100×10⁶ (Dose Level 2) Chimeric Antigen Receptor-positive T cells. The median age was 65 years, 68% were men, 44% had bulky lymphadenopathy, and 83% had high-risk cytogenetics. All patients had previously received and failed treatment with a BTK inhibitor and 80% had received prior Venetoclax. Among these patients, 60% had progressed on BTK inhibitors and had Venetoclax failure. Patients had a median of five prior lines of therapy. The Primary endpoint was Complete Response or Remission (including with incomplete marrow recovery), assessed by Independent Review in efficacy-evaluable patients with previous BTK inhibitor progression and Venetoclax failure at Dose Level 2 (100×10⁶). The total efficacy analysis included 89 patients treated at a dose level of 100×10⁶ CAR-positive T cells, with 49 patients evaluable.

In the Primary efficacy analysis set treated at a dose level of 100×10⁶ (N=49), the Complete Response or Remission rate (including with incomplete marrow recovery) was statistically significant at 18% (P=0.0006). The Overall Response Rate was 45%, and the median Duration of Response was 35.3 months. The median Duration of Response in the Complete Responders was Not Reached at the time of data cutoff and Minimal Residual Disease negativity rates were 100% in blood and 92.3% in bone marrow among Complete Responders. The median time to first response was 1.2 months, and for Complete Response or Remission was 3.0 months, respectively.

Among 89 patients in the study treated with BREYANZI®, Cytokine Release Syndrome (CRS) and neurologic events were mostly low-grade. CRS of any grade occurred in 83% of patients, with grade 3 CRS reported in 9% of patients, and with no grade 4 or 5 events reported. Any-grade neurologic events were reported in 46% of patients, with grade 3 neurologic events reported in 20% of patients, and one grade 4 neurologic event reported. No deaths due to either toxicity were reported.

It was concluded that a single infusion of BREYANZI® induced Complete Response or Remission in patients with relapsed or refractory CLL/SLL, including those with previous treatment failure on both BTK inhibitors and Venetoclax. It is the first CAR T-cell therapy approved in this setting and the safety profile was deemed manageable, offering a potential breakthrough in the treatment paradigm for these challenging diseases. Further confirmatory trials will be required to validate these findings and support continued approval of BREYANZI® for this indication.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Siddiqi T, Maloney DG, Kenderian SS, et al. The Lancet. 2023;402:641-654.

Late Breaking Abstract – ASH 2023: Oral Ibrutinib-Venetoclax Combination Improved Outcomes in Mantle Cell Lymphoma

RR

SUMMARY: It is estimated that approximately 3,300 new cases of Mantle Cell Lymphoma (MCL) are diagnosed in the US each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.

Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation. The four BTK inhibitors presently approved by the FDA for MCL include IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, BRUKINSA® (Zanubrutinib) approved in 2019 and JAYPIRCA® (Pirtobrutinib) approved in 2023.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation, and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Single agent Ibrutinib is presently approved by the FDA for the treatment of MCL patients who have received at least one prior therapy. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. By virtue of their unique and complementary mechanism of action, Ibrutinib in combination with Venetoclax demonstrated promising clinical activity in early phase MCL studies (N Engl J Med 2018; 378:1211-1223).

The Sympatico trial, is a multinational, randomized, double-blind, phase III study conducted to compare the combination of Ibrutinib and Venetoclax with Ibrutinib plus placebo, in patients with relapsed or refractory Mantle Cell Lymphoma (MCL). In this study, a total of 267 adult patients (N=267) with relapsed or refractory MCL who had previously received at least one prior line of therapy were randomly assigned in a 1:1 ratio to receive Ibrutinib 560 mg orally once daily concurrently with, either oral Venetoclax given at a standard 5-week ramp-up dose to a target dose of 400 mg once daily (N=134), or Placebo (N=133) for 2 years, followed by single-agent Ibrutinib until progressive disease (PD) or unacceptable toxicity. The median age was 68 years, 96% of patients had an ECOG PS of 0-1, 17% had 3 or more prior lines of therapy, and 22% were at increased risk for Tumor Lysis Syndrome (TLS). Both treatment groups were well balanced, and randomization was stratified based on ECOG PS, prior lines of therapy, and TLS risk based on tumor burden and Creatinine Clearance. The study evaluated the efficacy of the combination therapy across various subgroups, including those with high-risk features such as blastoid variant or TP53-mutated MCL. The Primary endpoint was investigator assessed Progression Free Survival (PFS) using Lugano criteria, and key Secondary endpoints included Complete Response (CR) rate, Time To Next Treatment (TTNT), Overall Survival (OS), and Overall Response Rate (ORR) by investigator assessment.

With a median follow up of 51.2 months, the median PFS was significantly longer with the Ibrutinib-Venetoclax combination, compared with the Placebo group (31.9 months versus 22.1 months; HR=0.65; P=0.0052). These PFS benefits were consistent across patient subgroups, including those with blastoid-variant or TP53-mutated MCL. In the combination group, 54% of patients achieved a Complete Remission, compared to 32% in the Placebo group (P=0.0004). The Time to Next Treatment in the combination group was median Not Reached (NR) versus 35.4 months in the Placebo group. At the time of this primary analysis, the median OS was 44.9 months with the Ibrutinib-Venetoclax combination versus 38.6 months with Ibrutinib plus Placebo, but the difference was not statistically significant. Adverse events were more common among patients who received the combination therapy, and included cytopenias and pneumonia.

It was concluded that a combination of Ibrutinib and Venetoclax was synergistic and demonstrated efficacy and safety, for the treatment of relapsed or refractory Mantle Cell Lymphoma, providing a potential new standard of care for this patient population. This chemo-free treatment option represents a milestone achievement in Mantle Cell Lymphoma treatment.

Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study. Wang M, Jurczak W, Trněný M, et al. Presented at the 2023 ASH Annual Meeting & Exposition December 9-12, 2023. LBA-2.

FDA Approves JAYPIRCA® for Chronic Lymphocytic Leukemia

RR

SUMMARY: The FDA on December 1, 2023, granted accelerated approval to Pirtobrutinib (JAYPIRCA®) for adults with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL), who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. The American Cancer Society estimates that for 2023, about 18,740 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4490 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors presently approved by the FDA for CLL/SLL include IMBRUVICA® (Ibrutinib), CALQUENCE® (Acalabrutinib), and BRUKINSA® (Zanubrutinib). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a highly selective, reversible (non-covalent) BTK inhibitor, developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated promising efficacy in patients with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTK inhibitors (Mato et al. Lancet, 2021).

The present FDA approval was based on BRUIN trial, which is an open-label, international, single-arm, multicohort, Phase I-II trial, conducted to evaluate the efficacy of Pirtobrutinib in patients with Relapsed or Refractory B-cell cancers. The trial involved patients receiving Pirtobrutinib monotherapy in either the Phase I or Phase II portion. In the Phase I portion, patients received Pirtobrutinib at doses ranging from 25 to 300 mg once daily in 28-day cycles. In the Phase II portion, patients received the recommended dose of 200 mg once daily. Majority of patients (85%) received the recommended dose of 200 mg once daily. Treatment was continued until disease progression or unacceptable toxicities. This analysis included 247 patients (N=247) with CLL or SLL, who had previously received a BTK inhibitor, among who the median number of previous lines of therapy was 3, and 100 patients (40.5%) had also received a B-Cell Lymphoma 2 (BCL2) inhibitor such as Venetoclax. This efficacy cohort (N=247) consisted of 86 patients from the Phase I portion and 161 patients from the Phase II portion. The median age was 69 years and in addition to previous BTK inhibitor therapy and BCL2 inhibitors, patients had also received anti-CD20 antibody (87.9%), chemotherapy (78.9%), PI3K inhibitors (18.2%), Chimeric Antigen Receptor (CAR) T-cell therapy (5.7%), and Allogeneic Stem-Cell Transplantation (2.4%). In those who received previous BTK inhibitor therapy, treatment was discontinued due to disease progression in 77% of patients and 23% discontinued due to toxicities or other reasons. High-risk molecular features were common in this patient group, and when present included the presence of a del(17p) or TP53 mutation or both (46.6%), complex karyotype (42%), and unmutated IGHV (84.8%). The Primary endpoint was Overall Response Rate (ORR), and Secondary endpoints included Progression Free Survival and Safety.

Among the patients who had previously received a BTK inhibitor, the ORR with Pirtobrutinib was 73.3% which were mostly Partial Responses. In the subset of patients who had previously received both a BTK inhibitor and a BCL2 inhibitor, the ORR was 70%. In the overall efficacy cohort, the median Progression Free Survival (PFS) at a median follow up of 19.4 months was 19.6 months. The median PFS was 22.1 months among patients who had received a BTK inhibitor but not a BCL2 inhibitor, and the median PFS was 16.8 months in the subset of patients who had previously received both a BTK inhibitor and a BCL2 inhibitor. The most common adverse events were infections, bleeding and neutropenia, and some adverse events that are typically associated with BTK inhibitors such as hypertension, atrial fibrillation or flutter and major hemorrhage occurred less frequently, and only 2.8% discontinued Pirtobrutinib due to a treatment-related adverse event.

It was concluded that Pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL and these data continue to reinforce the ability of Pirtobrutinib to extend the benefit of BTK inhibition for patients with CLL or SLL, following treatment with a covalent BTK inhibitor.

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. Mato AR, Woyach JA, Brown JR, et al. N Engl J Med 2023;389:33-44.