On December 10, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new four-year follow-up results from the Phase 3 GLOW study (Abstract #93), which showed investigational, fixed-duration treatment with IMBRUVICA + venetoclax (I+V) reduced the risk of progression or death by 79 percent among older and/or unfit patients with previously untreated chronic lymphocytic leukemia (CLL) compared to patients treated with chemoimmunotherapy (Press release, Janssen Biotech, DEC 10, 2022, View Source [SID1234625042]).1 These results were highlighted in an oral presentation during the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.1

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CLL is the most common form of leukemia in adults in the U.S. and currently has no cure.2 While the treatment landscape has evolved significantly since the emergence of targeted agents, there is still significant unmet need for novel treatment options, including fixed-duration regimens.

"The GLOW study results demonstrate the potential of fixed-duration I+V to become an additional treatment option for older, unfit patients with CLL in the first-line setting, and this fixed-dose combination may offer a flexible regimen for patients seeking a time-limited treatment approach," said study investigator Carsten Niemann,† M.D., Ph.D., Clinical Associate Professor and Principal Investigator at Rigshospitalet, Copenhagen, Denmark. "This first all-oral, fixed-duration novel combination demonstrates an OS advantage in the first-line treatment of CLL and is an innovative option for patients."

In the study, fixed-duration I+V therapy exhibited robust efficacy in older and/or unfit adults with previously untreated CLL, with a superior and sustained benefit in progression-free survival (PFS) with four years of follow-up.1 Seventy-five percent of patients treated with the combination were alive and progression-free at 3.5 years.1 I+V also demonstrated an OS advantage versus chlorambucil plus obinutuzumab (Clb+O) at this latest study follow-up.1 Exploratory analyses showed that post-treatment PFS rates were higher for I+V (n=106) than Clb+O (n=105), regardless of minimal residual disease (MRD) status post-treatment.1

GLOW Results

With a median 46 months of follow-up, I+V reduced the risk of disease progression or death by 79 percent versus Clb+O (Hazard Ratio (HR) 0.214; [95 percent Confidence Interval (CI), 0.138-0.334]; p<0.0001).1
I+V is the first fixed-duration novel combination to demonstrate an OS advantage compared to Clb+O in the first-line treatment of CLL (HR 0.487; [95 percent CI, 0.262-0.907]; nominal p=0.0205).1
An estimated 74.6 percent of previously untreated older and/or comorbid patients were alive and progression-free at 3.5 years with all-oral, once-daily, fixed-duration I+V treatment compared to an estimated 24.8 percent of patients in the Clb+O cohort.1
PFS at 3.5 years was higher for patients in the I+V arm compared to the Clb+O arm for both unmutated IGHV (uIGHV) and mutated IGHV (mIGHV) CLL.1
PFS was better sustained in the I+V arm compared to the Clb+O arm, regardless of MRD (≥10-4) status, measured at three months following end of treatment.1
Two years after end of treatment, estimated PFS was ≥ 90 percent for patients with mIGHV CLL, independent of MRD status, and for the 60 percent of patients with uIGHV CLL who achieved undetectable MRD (uMRD).1
Updated data for both studies showed the safety profile of the I+V regimen was consistent with known safety profiles of IMBRUVICA and venetoclax.1

"IMBRUVICA has helped change the standard of care for adults living with CLL and other B-cell malignancies, and this study adds to the extensive body of evidence supporting its potential to provide improved survival for patients with CLL. These results highlight the potential for front-line CLL patients to be treated with an all-oral, fixed-duration treatment," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Janssen Research & Development, LLC. "At Janssen, we are committed to addressing the unmet needs of patients with CLL through continued investment in our IMBRUVICA clinical development program."

In addition to the GLOW results, data from the Phase 2 CAPTIVATE study of the MRD cohort (PCYC-1142) (Abstract #92), which utilized the same I+V schedule for the first 15 cycles as in the GLOW study, were also presented in an oral session at ASH (Free ASH Whitepaper).3 After the first 15 cycles, patients with confirmed uMRD (n=86) were randomized to IMBRUVICA or placebo.3 Disease-free survival at three years post-randomization was 93 percent for IMBRUVICA and 85 percent for placebo. PFS rates at four years from start of treatment were 95 percent and 88 percent, respectively, and OS rates were 98 percent and 100 percent.3

During the three-year post-randomization period, no new atrial fibrillation events occurred in the placebo arm, and no new grade three or higher hemorrhage events occurred in either arm.3 The incidences of hypertension, arthralgia, neutropenia and diarrhea were generally infrequent in the placebo arm during this time period.3 No deaths occurred in either arm during the last 12 months of follow-up.3

About GLOW
The GLOW study (NCT03462719) is a randomized, open-label, Phase 3 trial that evaluated the efficacy and safety of first-line, fixed-duration I+V versus Clb+O in elderly patients (≥65 years of age) with CLL/SLL, or patients ages 18-64 with a cumulative illness rating scale (CIRS) score of greater than six or creatinine clearance less than 70 mL/min, who had active disease requiring treatment per the International Workshop on CLL (iwCLL) criteria.4 Patients with del(17p) or known TP53 mutations were excluded.4 There were 211 patients randomly assigned in a 1:1 ratio to receive either I+V (n=106) and or Clb+O (n=105) and the median age was 71 years.4 Patients assigned to I+V received treatment for 15 cycles (1 cycle is 28 days), starting with three cycles of IMBRUVICA monotherapy lead-in followed by the combination of I+V for 12 cycles.4 Patients assigned to Clb+O were treated for six cycles.4

Among patients with partial response or better, MRD in peripheral blood (PB) was evaluated using next-generation sequencing (NGS) via clonoSEQ on-treatment and at 3-6 month intervals post-treatment.4 ClonoSEQ data was used as part of CLL clonal testing.4

The primary endpoint was PFS up to two years and 10 months.4 Secondary endpoints of the study include MRD negative rate, compete response rate, overall response rate, OS, duration of response and time-to-next treatment.4

About CAPTIVATE

The Phase 2 CAPTIVATE study (NCT02910583) evaluated previously untreated adult patients with CLL who were 70 years or younger, including patients with high-risk disease, in two cohorts: an MRD-guided cohort (n=164; median age, 58 years) and a fixed-duration cohort (n=159; median age, 60 years). Patients received three cycles of IMBRUVICA lead-in followed by 12 cycles of I+V (oral IMBRUVICA [420 mg/d]; oral venetoclax [five-week ramp-up to 400 mg/d]) and the primary endpoint was one-year disease-free survival.5 In this MRD cohort, after completion of I+V, patients with confirmed uMRD were randomly assigned to double-blind treatment with placebo (i.e., a fixed-duration regimen), or continuous IMBRUVICA.5

About IMBRUVICA
IMB­RUVICA (ibrutinib) is a once-daily oral medication that is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company. IMBRUVICA blocks the Bruton’s tyrosine kinase (BTK) protein, which is needed by normal and abnormal B cells, including specific cancer cells, to multiply and spread. By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments and inhibits their proliferation.6,7,8

IMBRUVICA is approved in more than 100 countries and has been used to treat more than 270,000 patients worldwide. There are more than 50 company-sponsored clinical trials, including 18 Phase 3 studies, more than 11 years evaluating the efficacy and safety of IMBRUVICA.

IMBRUVICA was first approved by the U.S. Food and Drug Administration (FDA) in November 2013 and today is indicated for adult patients in six disease areas, including five hematologic cancers. These include indications to treat adults with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) with or without 17p deletion (del17p); adults with Waldenström’s macroglobulinemia (WM); adult patients with previously treated mantle cell lymphoma (MCL)*; adult patients with previously treated marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy*; and adult and pediatric patients aged one year and older with previously treated chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.9

*Accelerated approval was granted for MCL and MZL based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

For more information, visit www.IMBRUVICA.com.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA, respectively.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients who received IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.

Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events.

Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved monotherapy or combination regimens. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections.

Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued IMBRUVICA treatment.

Hypertension: Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months). Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension.

Cytopenias: In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements. Monitor complete blood counts monthly.

Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients who received IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥30%) in adult patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (54.5%)*, diarrhea (43.8%), fatigue (39.1%), musculoskeletal pain (38.8%), neutropenia (38.6%)*, rash (35.8%), anemia (35.0%)*, and bruising (32.0%).

The most common Grade ≥ 3 adverse reactions (≥5%) in adult patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (20.7%)*, thrombocytopenia (13.6%)*, pneumonia (8.2%), and hypertension (8.0%).

Approximately 9% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of adult patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in adult or pediatric patients with cGVHD were fatigue (57%), anemia (49%)*, bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, musculoskeletal pain (30%), pyrexia (30%), muscle spasms (29%), stomatitis (29%), hemorrhage (26%), nausea (26%), abdominal pain (23%), pneumonia (23%), and headache (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in adult or pediatric patients with cGVHD were pneumonia (14%), anemia (13%)*, fatigue (12%), pyrexia (11%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), osteonecrosis (9%), stomatitis (9%), hypokalemia (7%), headache (5%), and musculoskeletal pain (5%).

Discontinuation of IMBRUVICA treatment due to an adverse reaction occurred in 24% of adult patients and 23% of pediatric patients. Adverse reactions leading to dose reduction occurred in 26% of adult patients and 19% of pediatric patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of IMBRUVICA are recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or moderate inhibitors of CYP3A. See dose modification guidelines in USPI sections 2.3 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Pediatric Use: The safety and effectiveness of IMBRUVICA have not been established for the treatment of cGVHD after failure of one or more lines of therapy in pediatric patients less than 1 year of age. The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in MCL, CLL/SLL, CLL/SLL with 17p deletion, WM, MZL or in patients with mature B-cell non-Hodgkin lymphoma.

In the randomized population from a study that included 35 patients (26 pediatric patients age 5 to less than 17 years) with previously treated mature B-cell non-Hodgkin lymphoma, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.

Hepatic Impairment:

Adult Patients with B-cell Malignancies: Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA dose and monitor more frequently for adverse reactions of IMBRUVICA.

Patients with cGVHD: Avoid use of IMBRUVICA in patients with total bilirubin level > 3x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering IMBRUVICA to patients with total bilirubin level > 1.5 to 3x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).

On December 10, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported updated results from the Phase 1/2 MonumenTAL-1 study of talquetamab, an investigational, off-the-shelf (ready to use), bispecific T-cell engager antibody (Press release, Janssen Biotech, DEC 10, 2022, View Source [SID1234625041]). Talquetamab targets both GPRC5D, a novel target on multiple myeloma cells, and CD3 on T cells, activating the body’s immune system to fight this blood cancer .1 Results from the study suggest patients with relapsed or refractory multiple myeloma who received a median of five prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, achieved overall response rates (ORR) of 74.1 percent and 73.1 percent with subcutaneously (SC) administered recommended Phase 2 doses (RP2Ds) of 0.4 mg/kg weekly and 0.8 mg/kg every two weeks, respectively, with a median duration of response (DOR) of nine months or longer.2 Data from this investigational trial were featured during the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting as an oral presentation and highlighted in an ASH (Free ASH Whitepaper) press briefing on Saturday, December 10, 2022 (Abstract #157).2

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"The responses observed in the MonumenTAL-1 study suggest the clinical potential of talquetamab in the treatment of many patients who are triple-class refractory," said Ajai Chari, M.D., Professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai, and principal study investigator.† "The results of this study indicate the potential of this treatment for heavily pretreated patients who have exhausted currently approved therapies."

Results from the Phase 1 portion of the MonumenTAL-1 study were also published in The New England Journal of Medicine on December 10, 2022.

The ORR to talquetamab treatment was similar across both dose schedules.2 With a median follow-up of 14.9 months (range 0.5+ to 29.0), 74.1 percent of patients treated at the SC 0.4 mg/kg dose administered weekly (QW) achieved a response, 59.4 percent achieved a very good partial response (VGPR) or better, 33.6 percent achieved a complete response (CR) or better and 23.8 percent achieved a stringent complete response (sCR).2 The median progression free survival (PFS) was 7.5 months (95 percent CI, 5.7–9.4) at the 0.4 mg/kg QW dose.2 At the SC 0.8 mg/kg dose administered every two weeks (Q2W), 73.1 percent of patients achieved a response, 57.2 percent achieved a VGPR or better, 32.4 percent achieved a CR or better, and 20 percent achieved a sCR at a median follow-up of 8.6 months (range 0.2 to 22.5).2 Due to shorter follow-up in the 0.8 mg/kg Q2W dose cohort, the median PFS is not yet mature.2 Median DOR was nine months or longer in all groups, and longer DOR was observed in those patients who achieved a CR or better.2 There were no significant differences in ORR in subgroup analysis including prior lines of therapy, refractoriness to prior therapy and cytogenetic risk at baseline.

"These data represent the importance of engaging T cells via CD3 and targeting GPRC5D – a tumor associated antigen which is overexpressed in multiple myeloma cells – for the treatment of patients with relapsed or refractory disease," said Sen Zhuang, M.D., Ph.D., Vice President, Clinical Research and Development, Janssen Research & Development, LLC. "Following our recent Biologics License Application submission to the U.S. FDA, we look forward to working with the agency to make this available as a treatment option in the short term and continuing our longer-term investigations of talquetamab as we aim to develop additional options for patients with this complex blood cancer."

An additional cohort was studied to determine response to talquetamab at either dose schedule after previous T-cell redirection therapy, either a CAR-T or CD3 bispecific antibody. Patients in this cohort were younger, had a higher prevalence of high-risk cytogenetics, and had received a median of six prior lines of therapy (range, 3 to 15).2 Among these patients, 70.6 percent received prior CAR-T-cell therapy and 35.3 percent received prior bispecific antibody therapy.2 At a median follow-up of 11.8 months (range 1 to 25.4), 62.7 percent of patients with prior T-cell redirection therapy achieved a response. An ORR of 72.2 percent (95 percent CI, 54.8–85.8) was observed in patients with prior CAR-T-cell therapy and 44.4 percent (95 percent CI, 21.5-69.2) in patients with prior bispecific antibody treatment.2 The safety profile was comparable in patients with and without prior T-cell redirection therapy.2

No new safety signals were identified with longer follow-up in Phase 1 or Phase 2 of the MonumenTAL-1 study.2 The most common adverse events (AEs) at the SC 0.4 mg/kg QW dose were cytokine release syndrome (CRS) (79 percent; 2.1 percent grade 3/4), skin-related AEs (55.9 percent; all grade 1/2) and nail-related AEs (51.7 percent; all grade 1/2).2 The most common AEs at the SC 0.8 mg/kg Q2W dose were CRS (72.4 percent; 0.7 percent grade 3/4), skin-related AEs (67.6 percent; 0.7 percent grade 3/4) and dysgeusia (46.2 percent; not applicable).2 CRS incidents were mostly grade 1/2 and largely confined to the step-up doses and first full dose.2 The incidence of infection was 57.3 percent at the SC 0.4 mg/kg QW dose and 50.3 percent at the SC 0.8 mg/kg Q2W dose, with 16.8 percent and 11.7 percent grade 3 or higher, respectively.2 One patient in each dose cohort died due to COVID-19 infection.2

Most high-grade hematologic AEs were cytopenias, which were generally limited to the first few cycles of treatment.2 Neutropenia was observed in 34.3 percent of patients treated at the SC 0.4 mg/kg QW dose (30.8 percent grade 3/4) and 28.3 percent of patients treated at the SC 0.8 mg/kg Q2W dose (22.1 percent grade 3/4).2 Thrombocytopenia was observed in 27.3 percent of patients treated at the SC 0.4 mg/kg QW dose (20.3 percent grade 3/4) and 26.9 percent of patients treated at the SC 0.8 mg/kg Q2W dose (16.6 percent grade 3/4).2 At the SC 0.4 mg/kg QW dose, 4.9 percent of patients discontinued treatment due to AEs; 8.4 percent had dose delays and 14.7 percent had dose reductions.2 At the SC 0.8 mg/kg Q2W dose, 6.2 percent of patients discontinued treatment due to AEs; 13.8 percent had dose delays and 6.2 percent had dose reductions.2

About Talquetamab

Talquetamab is a first-in-class, off-the-shelf (ready to use), investigational bispecific T-cell engager antibody targeting both GPRC5D, a novel multiple myeloma target, and CD3, a primary component of the T-cell receptor.2 CD3 is involved in activating T cells, and GPRC5D is highly expressed on multiple myeloma cells.3,4

Talquetamab, which is given by subcutaneous injection, is currently being evaluated in the Phase 1/2 MonumenTAL-1 clinical study for the treatment of relapsed or refractory multiple myeloma (NCT03399799), and in combination studies RedirecTT-1 (NCT04586426), TRIMM-2 (NCT04108195), TRIMM-3 (NCT05338775), MonumenTAL-2 (NCT05050097) and MonumenTAL-3 (NCT05455320).

On December 9, 2022, Janssen submitted a Biologics License Application to the U.S. Food and Drug Administration (FDA) for talquetamab for the treatment of patients with relapsed or refractory multiple myeloma. Talquetamab received Breakthrough Therapy designation from the U.S. FDA in June 2022 for the treatment of adult patients with relapsed or refractory multiple myeloma, who have previously received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. In May 2021 and August 2021, talquetamab was granted Orphan Drug designation for the treatment of multiple myeloma by the U.S. FDA and the European Commission, respectively. In January 2021, talquetamab received a PRIME designation by the European Commission.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.5 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.6 In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.7 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.

On December 10, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new results from a cohort of the Phase 1b MajesTEC-2 study of TECVAYLI (teclistamab-cqyv), a first-in-class, BCMAxCD3 bispecific T-cell engager antibody, in combination with DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) and lenalidomide (Press release, Janssen Biotech, DEC 10, 2022, View Source [SID1234625040]). According to the results, the immune-based triplet therapy regimen had a manageable safety profile with no unexpected safety signals observed. A very good partial response (VGPR) or better was achieved by 90.3 percent of patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, with responses deepening over time.1 These data were presented during the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #160).

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"These results show the potential of the combination of the bispecific BCMA-directed antibody teclistamab with the anti-CD38 antibody daratumumab and lenalidomide in the treatment of patients with relapsed or refractory multiple myeloma," said Emma Searle, M.D., Ph.D., Consultant Hematologist and Honorary Senior Lecturer, The Christie Hospital and University of Manchester, England, and study investigator.† "This is the first presentation of data from a teclistamab-based triplet regimen and we are eager to better understand how this combination may benefit patients through ongoing clinical studies."

At a median follow-up of 8.4 months (range, 1.1 to 12.9), the overall response rate (ORR) was 93.5 percent.1 Among all patients in the trial, VGPRs or better were achieved by 90.3 percent of patients, and 54.8 percent of patients achieved a complete response (CR) or better.1 Median time to response was one month, and responses deepened.1 The median time to CR or better was three months (range, 1 to 10.4).1 At data cut-off, 80.6 percent of patients remained progression-free and on treatment.1 Responses deepened over time, and median duration of response had not been reached.1

"Following the recent regulatory approvals of TECVAYLI in the U.S. and EU, as well as its inclusion in the NCCN Clinical Practice Guidelines in Oncology as a recommended treatment option for certain patients with multiple myeloma, we are encouraged by its potential to improve outcomes in combination regimens and for earlier lines of treatment," said Sen Zhuang, M.D., Ph.D., Vice President, Clinical Research and Development, Janssen Research & Development, LLC. "We remain committed to addressing the unmet needs of patients with multiple myeloma through off-the-shelf immunotherapies like TECVAYLI and where we can bring together novel therapeutic approaches in the treatment of complex blood cancers."

The primary objective of this cohort of the MajesTEC-2 study (NCT04722146) was to understand if the immunomodulatory effects of daratumumab and lenalidomide could enhance the function of TECVAYLI, resulting in enhanced antimyeloma activity in a broader population of patients.1 The MajesTEC-7 study (NCT05552222) will examine the potential of this combination in patients newly diagnosed with multiple myeloma.

The most frequent hematological adverse events (AEs) observed in the study included neutropenia (84.4 percent any grade, 78.1 percent grade 3/4) and thrombocytopenia (25 percent any grade, 15.6 percent grade 3/4).1 The most frequent non-hematological AE was cytokine release syndrome (CRS) (81.3 percent, all grade 1/2); 97 percent of CRS events occurred during cycle 1.1

Other common non-hematological AEs included fatigue (46.9 percent any grade, 6.3 percent grade 3/4); diarrhea (46.9 percent any grade, none grade 3/4); cough (40.6 percent any grade, 3.1 percent grade 3/4); COVID-19 (37.5 percent any grade, 12.5 percent grade 3/4); insomnia (37.5 percent any grade, 3.1 percent grade 3/4); hypophosphatemia (31.3 percent any grade, 6.3 percent grade 3/4); pyrexia (31.3 percent any grade, 3.1 percent grade 3/4); upper respiratory tract infection (31.3 percent any grade, none grade 3/4); increased alanine aminotransferase (ALT) (28.1 percent any grade, 9.4 percent grade 3/4) and pneumonia (25 percent any grade, 15.6 percent grade 3/4).1 Two patients discontinued therapy due to an AE (COVID-19), considered to be unrelated to the study by investigator assessment.1 Infections were common among patients in the study and the majority were low grade (90.6 percent any grade, 37.5 percent grade 3/4).1

New Data from the Phase 1/2 MajesTEC-1 Study Evaluating TECVAYLI in Relapsed or Refractory Multiple Myeloma Patients
New correlative analyses were also presented from the MajesTEC-1 study (NCT04557098). Data from these analyses may be used to help better understand baseline immune and tumor correlatives associated with outcomes in patients treated with TECVAYLI.2 The data were presented during an oral abstract session (Abstract #97). Additional pharmacokinetic data evaluating potential drug interactions with TECVAYLI were presented during a separate poster session (Abstract #3228), as well as analyses of serum teclistamab-cqyv concentrations after intravenous and subcutaneous administration (Abstract #1911), to improve understanding of the clinical pharmacological profile of TECVAYLI.3,4

About the MajesTEC-2 Study
MajesTEC-2 (NCT04722146); is Phase 1b multicohort study evaluating the safety and efficacy of TECVAYLI in combination with other anticancer therapies in patients with relapsed or refractory multiple myeloma who received at least one prior line of therapy.1 Patients were eligible for treatment if they had received 1-3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug.1

In the presented study cohort, 32 patients received weekly doses of TECVAYLI (0.72 mg/kg or 1.5 mg/kg, with step-up dosing) plus the approved schedules of DARZALEX FASPRO 1800 mg and lenalidomide 25 mg.1 Responses were investigator assessed using International Myeloma Working Group criteria, and AEs were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0, except for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), which were graded per American Society for Transplantation and Cellular Therapy (ASTCT) guidelines.1

About TECVAYLI
TECVAYLI (teclistamab-cqyv) received approval from the U.S. Food and Drug Administration in October 2022 as an off-the-shelf (or ready to use) bispecific antibody that is administered as a subcutaneous treatment for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.5 In August 2022, TECVAYLI received approval from the European Commission as an off-the-shelf bispecific antibody administered as a subcutaneous treatment for adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.6 Teclistamab-cqyv (TECVAYLI) was recently recommended by the National Comprehensive Cancer Network (NCCN) as a treatment option for these patients. TECVAYLI is a first-in-class, bispecific T-cell engager antibody therapy which uses innovative science to activate the immune system by binding to the CD3 receptor expressed on the surface of T cells and to the B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells.7

About DARZALEX FASPRO
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for eight indications in multiple myeloma (MM), three of which are for frontline treatment in newly diagnosed patients who are transplant eligible or ineligible.8 It is the only subcutaneous CD38-directed antibody approved to treat patients with MM. DARZALEX FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.9 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.10 In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.11 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.12

TECVAYLI IMPORTANT SAFETY INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TECVAYLI. Initiate treatment with TECVAYLI step-up dosing schedule to reduce risk of CRS.
Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and serious and life-threatening reactions, can occur in patients receiving TECVAYLI. Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment and treat promptly.
TECVAYLI is available only through a restricted program called the TECVAYLI Risk Evaluation and Mitigation Strategy (REMS).
WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome: TECVAYLI can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 72% of patients who received TECVAYLI at the recommended dose, with Grade 1 CRS occurring in 50% of patients, Grade 2 in 21%, and Grade 3 in 0.6%. Recurrent CRS occurred in 33% of patients. Most patients experienced CRS following step-up dose 1 (42%), step-up dose 2 (35%), or the initial treatment dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI. The median time to onset of CRS was 2 (range: 1 to 6) days after the most recent dose with a median duration of 2 (range: 1 to 9) days. Clinical signs and symptoms of CRS included, but were not limited to, fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation).

Initiate therapy according to TECVAYLI step-up dosing schedule to reduce risk of CRS. Administer pretreatment medications to reduce risk of CRS and monitor patients following administration of TECVAYLI accordingly. At the first sign of CRS, immediately evaluate patient for hospitalization, manage per consensus guidelines, and administer supportive care based on severity; withhold or permanently discontinue TECVAYLI based on severity.

TECVAYLI is available only through a restricted program under a REMS.

Neurologic Toxicity including ICANS: TECVAYLI can cause serious or life-threatening neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

In the clinical trial, neurologic toxicity occurred in 57% of patients who received TECVAYLI at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients. The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%). With longer follow-up, Grade 4 seizure and fatal Guillain-Barré syndrome (one patient each) occurred in patients who received TECVAYLI.

In the clinical trial, ICANS was reported in 6% of patients who received TECVAYLI at the recommended dose [see Adverse Reactions (6.1)]. Recurrent ICANS occurred in 1.8% of patients. Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%). Less than 3% of patients developed first occurrence of ICANS following subsequent doses of TECVAYLI. The median time to onset of ICANS was 4 (range: 2 to 8) days after the most recent dose with a median duration of 3 (range: 1 to 20) days. The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity; withhold or permanently discontinue TECVAYLI based on severity and follow management recommendations.

Due to the potential for neurologic toxicity, patients are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves.

TECVAYLI is available only through a restricted program under a REMS.

TECVAYLI REMS: TECVAYLI is available only through a restricted program under a REMS called the TECVAYLI REMS because of the risks of CRS and neurologic toxicity, including ICANS.

Hepatotoxicity: TECVAYLI can cause hepatoxicity, including fatalities. In patients who received TECVAYLI at the recommended dose in the clinical trial, there was one fatal case of hepatic failure. Elevated aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%. Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity.

Infections: TECVAYLI can cause severe, life-threatening, or fatal infections. In patients who received TECVAYLI at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 30% of patients, with Grade 3 or 4 infections in 35%, and fatal infections in 4.2%. Monitor patients for signs and symptoms of infection prior to and during treatment with TECVAYLI and treat appropriately. Administer prophylactic antimicrobials according to guidelines. Withhold TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity.

Monitor immunoglobulin levels during treatment with TECVAYLI and treat according to guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Neutropenia: TECVAYLI can cause neutropenia and febrile neutropenia. In patients who received TECVAYLI at the recommended dose in the clinical trial, decreased neutrophils occurred in 84% of patients, with Grade 3 or 4 decreased neutrophils in 56%. Febrile neutropenia occurred in 3% of patients.

Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines.

Monitor patients with neutropenia for signs of infection.

Withhold TECVAYLI based on severity [see Dosage and Administration (2.4)].

Hypersensitivity and Other Administration Reactions: TECVAYLI can cause both systemic administration-related and local injection-site reactions. Systemic Reactions – In patients who received TECVAYLI at the recommended dose in the clinical trial, 1.2% of patients experienced systemic-administration reactions, which included Grade 1 recurrent pyrexia and Grade 1 swollen tongue. Local Reactions – In patients who received TECVAYLI at the recommended dose in the clinical trial, injection-site reactions occurred in 35% of patients with Grade 1 injection-site reactions in 30% and Grade 2 in 4.8%. Withhold TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity.

Embryo-Fetal Toxicity: Based on its mechanism of action, TECVAYLI may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECVAYLI and for 5 months after the last dose.

Adverse Reactions: The most common adverse reactions (≥20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin and decreased platelets.

Please read full Prescribing Information including Boxed Warning for TECVAYLI.

DARZALEX FASPRO IMPORTANT SAFETY INFORMATION
INDICATIONS
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor
In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent
CONTRAINDICATIONS
DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Hypersensitivity and Other Administration Reactions
Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO.

Systemic Reactions

In a pooled safety population of 898 patients with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or in combination, 9% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related reactions occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 140 systemic administration-related reactions that occurred in 77 patients, 121 (86%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension and tachycardia. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

Local Reactions

In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.

Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis
Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone. Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

Neutropenia
Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia were observed.

Thrombocytopenia
Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets.

Embryo-Fetal Toxicity
Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose.

The combination of DARZALEX FASPRO with lenalidomide is contraindicated in pregnant women, because lenalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.

Interference with Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO.

Interference with Determination of Complete Response
Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.

ADVERSE REACTIONS
The most common adverse reaction (≥20%) with DARZALEX FASPRO monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, pyrexia, cough, muscle spasms, back pain, vomiting, upper respiratory tract infection, peripheral sensory neuropathy, constipation, pneumonia, and peripheral edema.

The most common adverse reactions (≥20%) in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.

The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

Please see full Prescribing Information for DARZALEX FASPRO.

On December 10, 2022 Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, reported new data at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) characterizing clonal evolution and relapse mechanisms in patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) who are 75 years of age or older or have comorbidities that preclude use of intensive induction chemotherapy treated with TIBSOVO in combination with azacitidine (Press release, Servier, DEC 10, 2022, View Source [SID1234625039]).

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Results from the study reinforce that TIBSOVO in combination with azacitidine leads to deep, durable remissions associated with clearance of IDH1-mutated AML, with no second-site IDH1 mutations observed to date amongst the patients enrolled in the TIBSOVO plus azacitidine study arm with both baseline and longitudinal DNA sequencing available (46/72 patients). Amongst patients who relapsed (n=22), mutations in other genes, including IDH2, can emerge and provide an opportunity for relapse. Further study is needed to better characterize mechanisms of relapse for patients treated with TIBSOVO plus azacitidine combination therapy.

"Combination therapy consisting of TIBSOVO in combination with azacitidine for newly-diagnosed patients with acute myeloid leukemia and an IDH1 mutation has shown significant clinical effectiveness, but it’s important that we analyze patient response throughout their treatment to better understand mechanisms of resistance," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "We are committed to our exploratory translational efforts and will continue to update the data, as available, to contribute to a better understanding of how to improve outcomes for patients living with this aggressive hematologic malignancy."

These data presented today at ASH (Free ASH Whitepaper) 2022 represent continued clinical evidence on the effectiveness of TIBSOVO amongst newly-diagnosed AML patients with an IDH1 mutation who are 75 years of age or older or have comorbidities that preclude use of intensive induction chemotherapy, and follows the expanded approval of TIBSOVO in AML supported by data from the AGILE study. Data from the global Phase 3 AGILE study showed TIBSOVO as the first IDH1 mutation-specific targeted therapy to demonstrate improved event-free survival (EFS) and overall survival (OS) in combination with azacitidine compared to azacitidine plus placebo.

"These new data reinforce the original results from the AGILE trial, showing TIBSOVO in combination with azacitidine as an effective, first-of-its kind combination treatment option for patients with newly-diagnosed, IDH1-mutated acute myeloid leukemia," said Eytan Stein, M.D., Chief of the Leukemia Service in the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center (MSKCC). "Given the rapid progression of acute myeloid leukemia, it’s important to have a targeted therapeutic option that provides significant event-free survival and overall survival alongside a favorable safety profile, and that’s what we’ve seen clinically with TIBSOVO plus azacitadine."

About the NCT03173248 AGILE Phase 3 AML Triali

The AGILE trial is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of TIBSOVO in combination with azacitidine compared with placebo in combination with azacitidine, in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy). The study’s primary endpoint is event-free survival (EFS), defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission (CR) by Week 24.

Key secondary endpoints include CR rate, defined as the proportion of participants who achieve a CR; overall survival (OS), defined as the time from date of randomization to the date of death due to any cause; CR and complete remission with partial hematologic recovery (CRh) rate, defined as the proportion of participants who achieve a CR or CRh; and objective response rate (ORR), defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS).

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults, with approximately 20,000 new cases in the U.S., and 43,000 cases in Europe each year.ii,iii AML incidence significantly increases with age, and the median age of diagnosis is 68.ii The five-year survival rate is approximately 30.5%.iv For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia.v

About TIBSOVO (ivosidenib tablets)

TIBSOVO (ivosidenib tablets) is approved in the U.S. in combination with azacitidine for the treatment of patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) in adults 75 years of age or older, or who have comorbidities that preclude use of intensive induction chemotherapy. TIBSOVO is the first therapy targeting cancer metabolism approved in combination with azacitidine for patients with newly-diagnosed IDH1-mutated AML.

TIBSOVO is also approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML, and for adults with newly-diagnosed IDH1-mutated AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Last year, TIBSOVO garnered its first approval in a non-hematologic malignancy for patients with previously treated IDH1-mutated cholangiocarcinoma.

Please see the TIBSOVO indications and Important Safety Information with a link to the full Prescribing Information below.

On December 10, 2022 Sumitomo Pharma Oncology, Inc., a clinical-stage company focused on novel cancer therapeutics, reported new data from the ongoing Phase 1/2 study evaluating TP-3654, an investigational selective oral PIM1 kinase inhibitor, in patients with myelofibrosis (MF) previously treated with or ineligible for JAK inhibitor therapy (Press release, Sumitomo Pharmaceuticals, DEC 10, 2022, View Source;exposition-301699788.html [SID1234625038]). These results were presented during an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, being held Dec 10-13, 2022, in New Orleans, LA.

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Preliminary findings from the Phase 1 dose escalation study indicated TP-3654 is well tolerated with limited myelosuppressive adverse events. TP-3654, as a single agent, showed preliminary signs of clinical activity in the study, including spleen volume reduction, symptom improvement, and broad cytokine reduction, in patients previously treated with JAK inhibitors.1

"We are pleased by these preliminary clinical data and are encouraged by the safety and tolerability data seen in the ongoing TP-3654 dose escalation study. We remain committed to progressing this program, including expanding our clinical sites, and contributing to the advancement of possible treatment options which may improve outcomes for patients with myelofibrosis," said Patricia S. Andrews, Chief Executive Officer and Global Head of Oncology, Sumitomo Pharma Oncology, Inc.

The dose escalation portion of the study has enrolled 9 patients at the time of the analysis. To date, five dose levels of TP-3654 were evaluated, including once-daily and twice-daily regiments. No dose-limitation or related serious adverse event was observed up to the time of the analysis.

The data showed an early signal of clinical activity with spleen volume reduction (SVR). Six of 8 evaluable patients on treatment for at least 12 weeks experienced SVR, including 2 of 8 patients having at least 35% SVR. Additionally, a reduction in the symptom burden, measured by change in treatment score symptom (TSS), was experienced by 7 of the 8 evaluable patients, with 5 out of 8 patients having greater than 50% reduction. TP-3654 treatment was associated with reduced levels of cytokines associated with MF as early as 4 weeks, with cytokine reductions correlating with improved TSS.

Overall, TP-3654 appears to be well tolerated with no dose limiting toxicity (DLT) to date. The most common adverse events are Grade 1 gastrointestinal toxicities, which resolved in 1-2 weeks. Additionally, patients showed stable blood counts and no cytopenia with extended time on treatment. Currently, there are no discontinuations due to adverse events.

"These preliminary data presented at ASH (Free ASH Whitepaper) 2022 Annual Meeting & Exhibition are encouraging as we learn more about how TP-3654’s inhibition of PIM1 kinase may lead to reductions in bone marrow fibrosis and splenomegaly, and improved overall survival in patients with myelofibrosis," said Jatin J. Shah, M.D., Chief Medical Officer and Global Head of Development, Sumitomo Pharma Oncology (SMP Oncology). "We look forward to continuing to advance this study to evaluate the potential role of TP-3654 as a monotherapy, in addition to exploring combination opportunities with JAK inhibitors, for patients with myelofibrosis." Below are the details for the SMP Oncology presentation:

Abstract Title

Details

Presenter

Preliminary Data From the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients With Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Presentation #240 Saturday, December 10 at 3:15 p.m. CST
Oral Podium Presentation

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

To view the full presentation, please visit to our website here.

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