On December 11, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new data from two studies evaluating the efficacy and safety of IMBRUVICA (ibrutinib) plus venetoclax (I+V) as a potential fixed-duration treatment in adult patients with previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, Johnson & Johnson, DEC 11, 2021, View Source [SID1234596886]). These data were both featured today during the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting. New secondary endpoint data from the Phase 3 GLOW study (NCT03462719) showed that fixed-duration treatment with I+V resulted in undetectable minimal residual disease (uMRD) responses that were deeper compared to patients treated with chlorambucil plus obinutuzumab (Clb+O), and an additional analysis showed that uMRD responses were better sustained during the first year post-treatment.1

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Updated results from the Phase 2 CAPTIVATE study (NCT02910583) of the same investigational regimen, now with a median 38 months of follow-up, further demonstrated sustained uMRD and disease-free survival (DFS). There were no new MRD relapses, clinical progressions or deaths with an additional year of study follow-up in patients with confirmed uMRD following 12 cycles of combined I+V who were randomized to placebo or continued IMBRUVICA.2

"GLOW and CAPTIVATE are part of a comprehensive development program continuing to evaluate the potential of IMBRUVICA-based therapy in patients with previously untreated CLL with various needs and risk factors, including those with high-risk disease," said Craig Tendler, M.D., Global Head of Late Development, Diagnostics and Medical Affairs, Hematology & Oncology, Janssen Research & Development, LLC. "With data from these two studies showing patients can achieve deep responses with this novel IMBRUVICA plus venetoclax combination, we believe this all-oral, once-daily, fixed-duration regimen offers patients the potential for treatment-free remissions and physicians the flexibility to use IMBRUVICA alone or as a combination therapy to meet the different goals and needs of patients."

Data on MRD Outcomes After Fixed-Duration IMBRUVICA Plus Venetoclax from the GLOW Study (Abstract #70)

The Phase 3 GLOW study is a randomized, open-label trial which evaluated the efficacy and safety of first-line, fixed-duration I+V vs. 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, without del(17p) or known TP53 mutations.1 Patients in the study were randomized to receive either I+V (n= 106) or Clb+O (n=105).1 Previously reported data were presented at the 2021 European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress and showed that the study met its primary endpoint of progression-free survival (PFS) as measured by an independent review committee (IRC).3

The prespecified secondary endpoint was rate of uMRD (uMRD < 10-4). MRD was evaluated via next-generation sequencing (NGS) and reported with cutoffs of < 10-4 and < 10-5.1 Rate of uMRD was reported at three and 12 months after end of treatment in both study arms.1

The data presented at ASH (Free ASH Whitepaper) demonstrated deeper responses at end of treatment and better sustained uMRD responses during the first year post-treatment with all-oral, once-daily fixed-duration I+V vs. Clb+O.1 Further, responses were proportionally deeper at the level of < 10-5 in the I+V arm vs. Clb+O arm in both peripheral blood (PB) and bone marrow (BM).1

"The GLOW study combines two highly active blood cancer treatments that act in a synergistic fashion by complementary mechanisms to deliver superior progression-free survival in the first-line treatment of CLL," said Arnon Kater†, M.D., Ph.D., Deputy Head of Hematology, Amsterdam University Medical Centers, University of Amsterdam and Chairman of the HOVON CLL Working Group, the Netherlands and principal study investigator. "These latest results show the potential to provide treatment-free remissions for patients through robust disease clearance in lymphoid tissue, blood and bone marrow, and early sustainability of those responses after stopping treatment."

GLOW Results:

With updated median follow-up of 34.1 months, the 30-month PFS was 80.5 percent with I+V vs. 35.8 percent for Clb+O.1
Rates of uMRD < 10-5 were higher with I+V vs. Clb+O in BM (40.6 percent vs. 7.6 percent) and in PB (43.4 percent vs. 18.1 percent).1
With I+V, deep responses < 10-5 were seen in patients with unmutated IGHV CLL, and depth of response was mirrored in PB (49.1 percent) and BM (45.5 percent).1
An additional analysis evaluated sustainability of uMRD response between three and 12 months following end of treatment; 80.4 percent of patients with I+V had sustained uMRD < 10-5 vs. 26.3 percent with Clb+O.1
PFS rate during the first-year post-treatment was sustained >90 percent with I+V, independent of BM or PB MRD status three months after end of treatment.1
Additional follow-up is warranted to confirm the long-term impact of MRD status on PFS.1
Data from the MRD Cohort of the Phase 2 CAPTIVATE (PCYC-1142) Study (Abstract #68)

The Phase 2 CAPTIVATE trial evaluated adult patients younger than 70 years, including patients with high-risk disease, in two cohorts: an MRD-guided cohort where treatment duration is guided by the patient’s MRD status after 12 cycles of combination I+V therapy; and a fixed-duration cohort where all patients stop therapy after 12 cycles of the combination, regardless of MRD status.2 The primary endpoints of the study included MRD negative response rate, DFS, and complete response rate. Data from the primary analysis from both the fixed-duration and MRD-guided cohorts were previously reported.4,5 Patients with high-risk disease included unmutated IGHV (60 percent of patients), del(17p)/TP53 mutation (20 percent), complex karyotype (19 percent), and del(11q) without del(17p) (17 percent). Patients in the MRD-guided cohort (n=164; median age, 58 years) who achieved uMRD [defined as having uMRD (<10–4 by 8-color flow cytometry) serially over at least three cycles and uMRD in both PB and BM with combination therapy], were randomized in a double-blinded fashion to continue treatment with IMBRUVICA monotherapy or placebo until disease progression.2 Patients in the MRD-guided cohort who did not achieve uMRD following 12 cycles of combination I+V therapy were randomized to continue IMBRUVICA monotherapy or the combination.2

DFS was defined as freedom from MRD relapse (≥10–2 confirmed on two separate occasions) and without progressive disease or death starting from randomization after 15 cycles of treatment. The two-year DFS rates post-randomization with time-limited treatment (randomized to placebo) was maintained at 95 percent with an additional year of study follow-up.2 There were no new MRD relapses, disease progressions, or deaths in patients with confirmed uMRD treated with placebo or IMBRUVICA.2 Early data suggest that patients who progress after time-limited treatment with I+V have the potential to be successfully retreated with single-agent IMBRUVICA.2

Additionally, the estimated 36-month PFS rates were 95.3 percent with placebo and 100 percent with IMBRUVICA (95 percent Confidence Interval [CI], 4.7 percent difference, -1.6–10.9, overall log-rank P=0.1573); placebo 82.7–98.8, IMBRUVICA 100–100).2 Ultimately, these results in patients randomized to placebo following an initial 12 cycles of the I+V combination support the potential for treatment-free remission with first-line, fixed-duration I+V, an all-oral, once-daily regimen. Among 12 patients who progressed after fixed-duration treatment, nine patients with available responses all had a partial response to single-agent IMBRUVICA with limited follow-up; three have pending responses.2

With a median study follow-up of 38 months, the safety profile of the I+V regimen in CAPTIVATE was consistent with known safety profiles of IMBRUVICA and venetoclax.2 The most common AEs of any Grade 13-24 months post-randomization were arthralgia (29 percent I+V; 22 percent IMBRUVICA monotherapy) and upper respiratory tract infection (20 percent I+V; 15 percent IMBRUVICA monotherapy).2 Grade ≥3 adverse events (AEs) were infrequent across randomized arms with the exception of neutropenia.2

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 250,000 patients worldwide. There are more than 50 company-sponsored clinical trials, including 18 Phase 3 studies, over 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 CLL/SLL with or without 17p deletion (del17p), and adults with Waldenström’s macroglobulinemia (WM), and adult patients with previously treated mantle cell lymphoma (MCL)*, as well as to treat 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 patients 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.

Since 2019, the National Comprehensive Cancer Network (NCCN), recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and has Category 1 treatment status for treatment-naïve patients without deletion 17p/TP53 mutation and as a preferred treatment for treatment-naïve patients with deletion 17p/TP53 mutation. The NCCN Guidelines also recommend IMBRUVICA, with or without rituximab, as a preferred regimen for the treatment of relapsed/refractory MCL, as a Category 1 preferred regimen for both untreated and previously treated WM patients, and as a preferred regimen for relapsed/refractory MZL.10

For more information, visit www.IMBRUVICA.com.

IMBRUVICA 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 postprocedural hemorrhage) occurred in 4% 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.

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 3%, based on laboratory measurements.

Monitor complete blood counts monthly.

Cardiac Arrhythmias and Cardiac Failure: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4%, and Grade 3 or greater cardiac failure occurred in 1% of 1,476 patients who received IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

At baseline and then periodically, monitor patients clinically for cardiac arrhythmias and cardiac failure. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias and cardiac failure appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

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 and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (4%), 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 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 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 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 patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

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

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of 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. Dose modifications of IMBRUVICA may be 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). See dose modification guidelines in USPI sections 2.3 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

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.

Please click here to see the full Prescribing Information.

On December 11, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported updated results from the MonumenTAL-1 Phase 1 first-in-human dose-escalation study of talquetamab (NCT03399799). Talquetamab is the only investigational off-the-shelf T cell redirecting bispecific antibody in clinical development targeting both GPRC5D, a novel multiple myeloma target, and CD3 on T cells (Press release, Johnson & Johnson, DEC 11, 2021, View Source [SID1234596884]).1 Results from the study show that no new safety signals were observed with longer follow-up.1 Heavily pretreated patients with multiple myeloma treated with talquetamab at the recommended subcutaneous (SC) Phase 2 doses (RP2D) administered weekly (QW) and every two weeks (Q2W) achieved high overall responses that deepened over time.1 These data were featured during the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting as an oral presentation (Abstract #158).1

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No new safety signals were identified with longer follow-up of either dose cohort.1 The most common adverse events (AEs) at the SC 405 µg/kg QW dose were cytokine release syndrome (CRS – 77 percent; three percent grade 3), neutropenia (67 percent; 60 percent grade 3/4) and dysgeusia (60 percent).1 Dysgeusia was generally mild with few dose adjustments required. The most common AEs at the SC 800 µg/kg Q2W dose were CRS (72 percent; all grade 1/2), neutropenia (44 percent; 36 percent grade 3/4), and dry mouth (40 percent; all grade 1/2).1 Cytopenias were mostly confined to step-up doses and cycles one and two and were reversible, including neutropenias which generally resolved within a week. Infections occurred in 33 percent of patients and there was a low rate of high-grade infections (five percent grade 3/4).1 Skin-related and nail disorder AEs occurred in 75 percent of patients, most commonly exfoliation (37 percent at SC 405 µg/kg QW; 36 percent at 800 µg/kg Q2W, all grade 1/2), which did not lead to treatment modification.1 Injection site reactions occurred in 16 percent of patients and were all grade 1/2.1

Pre-treatment medications (including glucocorticoid, antihistamine, and antipyretic treatments) were only required at the step-up and first full doses, and no steroid treatment was required after the first full dose.

"New treatment options are needed for patients with multiple myeloma," said Amita Krishnan, M.D., Chief, Division of Multiple Myeloma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California, and principal study investigator.† "The continued observation of a tolerable safety profile and durable responses seen in these updated data suggest that in both doses, talquetamab may offer a new treatment option for heavily pretreated patients."

With a median follow-up of nine months (range 0.9-17.1), 70 percent (21/30) of response-evaluable patients treated with the SC 405 µg/kg QW dose achieved a response, 53 percent achieved a very good partial response (VGPR) or better, 13 percent achieved a complete response (CR) or better, and 10 percent achieved a stringent complete response (sCR).1 With a median follow-up of 4.8 months (range 0.4-11.1), 67 percent (14/21) of response-evaluable patients treated with the SC 800 µg/kg Q2W dose achieved a response, 52 percent achieved a VGPR or better, 19 percent achieved a CR or better, and 10 percent achieved an sCR.1 The median duration of response (DOR) was not reached for either dose.1

Among response-evaluable patients who were triple-class refractory, a response was achieved by 65 percent (15/23) of patients treated with the SC 405 µg/kg QW dose and 67 percent (12/18) of patients treated with the SC 800 µg/kg Q2W dose.1 In patients who were penta-drug refractory, 83 percent (5/6) of patients responded in both dose groups.1

"These new data provide important insights into the potential safety, efficacy and tolerability of talquetamab for relapsed and refractory patients," said Sen Zhuang, M.D., Ph.D., Vice President, Clinical Research and Development, Janssen Research & Development, LLC. "We look forward to fully evaluating this novel bispecific antibody as both a monotherapy and in combination immunotherapy regimens."

The primary objectives of the MonumenTAL-1 study were to identify the recommended subcutaneous Phase 2 dose(s) (part 1) and assess the safety and tolerability of talquetamab at the recommended dose (part 2).1 As of September 2021, 102 patients with multiple myeloma who had relapsed or become refractory or intolerant to established therapies have received SC talquetamab in the study.1 For part 2, 30 patients received the weekly RP2D of SC 405 µg/kg QW dosing schedule with step-up doses; 100 percent were triple-class exposed, 80 percent were penta-drug exposed, 77 percent were triple-class refractory, 20 percent were penta-drug refractory and 27 percent had prior B-cell maturation antigen (BCMA)-directed therapy.1 Twenty-five patients received the SC RP2D of 800 µg/kg Q2W; 92 percent were triple-class exposed; 68 percent were penta­drug exposed; 76 percent were triple-class refractory, 24 percent were penta-drug refractory, and 16 percent had prior BCMA-­directed therapy.1

Data from the Phase 2 TRiMM-2 Study Evaluating Talquetamab in Combination with DARZALEX FASPRO (Abstract #161)
Additional data for talquetamab will be highlighted in an oral presentation at ASH (Free ASH Whitepaper) on Saturday, December 11 (Abstract #161).2 The Phase 1b TRIMM-2 investigational study (NCT04108195) evaluated talquetamab in combination with DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) – the CD38-directed monoclonal antibody approved to be given subcutaneously for the treatment of patients with multiple myeloma. Results suggest that the combination is tolerable in patients with relapsed or refractory multiple myeloma who had received a median of six prior lines of therapy (range 2-18), with a safety profile comparable to each agent as a monotherapy at each of three doses evaluated in the study.2

Patients received step-up doses of talquetamab of SC 400 µg/kg QW (n=9); SC 400 µg/kg Q2W (n=5); or SC 800 µg/kg Q2W (n=15), in combination with DARZALEX FASPRO at the approved dosing schedule.2 At a median follow-up of 4.2 months, 86 percent (6/7) of response-evaluable patients treated with the SC 400 µg/kg QW achieved a response, and 80 percent (4/5) of patients treated with the SC 400 µg/kg Q2W dose achieved a response. At the SC 800 µg/kg Q2W dose of talquetamab 78 percent (7/9) of patients achieved a response.2

The safety profile of the combination appeared consistent with each agent as a monotherapy.2 At all doses, the most common AE was cytokine release syndrome (CRS), observed in 55 percent (16/29) of patients.2 All CRS events were grade 1/2 and all but one event occurred with step-up doses of talquetamab.2 CRS resolved in all patients, and no patients discontinued treatment due to CRS.2 Other AEs included dysgeusia (48 percent; all grade 1/2) and dry mouth (35 percent; all grade 1/2).2 Skin-related and nail disorders were reported in 65 percent of patients (all grade 1/2); the most commonly reported skin or nail event was skin exfoliation (28 percent, all grade 1/2).2 One patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS), including one grade 3 event and one grade 1 event, both of which resolved yet resulted in discontinuation of talquetamab.2

The primary objectives of the TRiMM-2 study were to identify the Phase 2 dose (RP2D) for each component of the treatment combination (Part One); characterize the safety of the treatment combination at the RP2D (Part 2); and assess antitumor activity, pharmacokinetics and pharmacodynamics for the combination treatment (Part 3).2 Patients in the study (n=29) all had multiple myeloma and had received a minimum three prior lines of therapy or were double refractory to a proteasome inhibitor (PI) and an immunomodulatory agent; patients who had been exposed or refractory to an anti-CD38 therapy more than ninety days prior to the start of the trial were also included, as well as those refractory to anti-CD38 therapy.2

About Talquetamab
Talquetamab is a first-in-class, investigational T-cell redirecting bispecific antibody targeting both GPRC5D, a novel multiple myeloma target, and CD3, a T-cell receptor.3 CD3 is involved in activating T-cells, and GPRC5D is highly expressed on multiple myeloma cells.4,5 Results from preclinical studies in mouse models demonstrate that talquetamab induces T-cell-mediated killing of GPRC5D-expressing multiple myeloma cells through the recruitment and activation of CD3-positive T-cells and inhibits tumor formation and growth.6

Talquetamab is currently being evaluated in a Phase 1/2 clinical study for the treatment of relapsed or refractory multiple myeloma (NCT03399799) and is also being explored in combination studies (NCT04586426). In January 2021, talquetamab was granted PRIority MEdicines (PRIME) designation by the European Commission.

About DARZALEX FASPRO
In August 2012, Janssen Biotech, Inc. and Genmab A/S entered into a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. DARZALEX FASPRO is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma and now light chain (AL) amyloidosis. DARZALEX FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

DARZALEX FASPRO 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 bortezomib and dexamethasone in patients who have received at least one prior therapy
in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of 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
DARZALEX FASPRO in combination with bortezomib, cyclophosphamide, and dexamethasone is indicated for the treatment of adult patients with newly diagnosed AL amyloidosis. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Limitations of Use
DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with AL amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.

Full prescribing information for DARZALEX FASPRO is available here.

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.6,7 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow.7,8 In 2021, it is estimated that nearly 35,000 people will be diagnosed and more than 12,000 will die from the disease in the U.S. While some patients 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.8

DARZALEX FASPRO IMPORTANT SAFETY INFORMATION
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.

On December 11, 2021 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported initial positive results from a Phase 2/3 trial of intramuscular (IM) administration of Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) in adult and pediatric patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) who have developed hypersensitivity or silent inactivation to an E. coli-derived asparaginase (Press release, Jazz Pharmaceuticals, DEC 11, 2021, View Source [SID1234596882]). The study was developed and conducted in close collaboration with the Children’s Oncology Group (COG). These initial results will be presented for the first time today at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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Three cohorts with unique, IM administration dosing schedules were evaluated in the trial, demonstrating a safety profile consistent with other asparaginases. In Cohort 1c, a dosing regimen of Rylaze administered 25 mg/m2 on Monday and Wednesday and 50 mg/m2 on Friday demonstrated a positive benefit-to-risk profile, showing that Rylaze maintains a clinically meaningful level of nadir serum asparaginase activity (NSAA) ≥0.1 IU/mL at both 48 and 72 hours. Rylaze was approved by the U.S. Food and Drug Administration (FDA) on June 30, 2021 under the Real-Time Oncology Review (RTOR) program for use as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL or LBL in adult and pediatric patients one month and older who have developed hypersensitivity to E. coli-derived asparaginase. Rylaze was approved at the dosing schedule of 25 mg/m2 every 48 hours based on data from Cohort 1a, in conjunction with data produced by a preliminary population pharmacokinetic (PPK) model.

These data will support additional regulatory filings for Rylaze, including a supplemental Biologics Licensing Application (sBLA) in early 2022 for a Monday/Wednesday/Friday (M/W/F) IM dosing schedule that will be reviewed under the FDA RTOR program. These data will also support regulatory submissions in Europe in mid-2022, with potential for approval in 2023.

"Asparaginase is an integral part of ALL therapy that is associated with improvement in survival rates. Following FDA approval earlier this year, Rylaze is already providing patients who have developed hypersensitivity to E. coli-derived asparaginase with a much-needed, effective therapeutic option with reliable supply and consistently high quality," said Rob Iannone, M.D., M.S.C.E., executive vice president, research and development and chief medical officer of Jazz Pharmaceuticals. "Rylaze is proof of Jazz’s ability to take medicines from concept through development, approval and launch, and we look forward to working with the FDA through the sBLA submission with these additional data in early 2022 in support of a label expansion for M/W/F dosing."

"The results from the Phase 2/3 study for Rylaze help to expand our knowledge of its dosing and safety profile, and support Monday/Wednesday/Friday dosing, which is more in line with clinical practice," said primary study investigator Dr. Luke Maese, associate professor at the University of Utah, Primary Children’s Hospital and Huntsman Cancer Institute. "The accelerated development and approval of Rylaze ensured that many patients with LBL and ALL – most of whom are children – who cannot tolerate E. coli-derived asparaginases have a new treatment option that maintains therapeutic levels of asparaginase activity throughout duration of treatment."

Interim Trial Results
Data presented at ASH (Free ASH Whitepaper) 2021 include initial analyses from an ongoing Phase 2/3 open-label, multicenter, dose confirmation and pharmacokinetic (PK) study of Rylaze (also known as JZP458) in patients with ALL/LBL who developed hypersensitivity or silent inactivation to a long-acting E. coli-derived asparaginase. Preliminary data are from Part A of the study, which investigated three Cohorts via IM administration:

Cohort 1a (n=33): studied a dose of 25 mg/m2 Monday/Wednesday/Friday
Cohort 1b (n=53): studied a dose of 37.5 mg/m2 Monday/Wednesday/Friday
Cohort 1c (n=52): studied a dose of 25 mg/m2 on Monday and Wednesday and 50 mg/m2 on Friday
Part B of the Phase 2/3 study remains active to further confirm the dose and schedule of the intravenous (IV) route of administration for Rylaze.

Efficacy Findings
The primary efficacy endpoints of the trial were the proportion of patients with a last 72-hour (from Friday to Monday) NSAA levels of ≥0.1 IU/mL during the first treatment course, in addition to safety and tolerability of Rylaze in patients with ALL/LBL.

The key secondary endpoint included the proportion of patients achieving the last 48-hour NSAA ≥0.1 IU/mL during the first treatment course.

The proportion of patients with observed NSAA levels ≥0.1 IU/mL with a 95% CI during Course 1 from these initial results is as follows (primary and key secondary endpoints):

Cohort 1a

Cohort 1b

Cohort 1c

At 48 hours

97% (CI: 91%, 100%)

98% (CI: 95%, 100%)

96% (CI: 90%, 100%)

At 72 hours

66% (CI: 48%, 83%)

80% (CI: 70%, 91%)

90% (CI:81%, 98%)

Based on a PPK modeling and simulation analysis versus observed data for Cohort 1c, the proportion of patients predicted to achieve NSAA levels ≥0.1 IU/mL with a 95% CI from these initial results is as follows:

Observed

Model Prediction

At 48 hours

96% (CI: 90%, 100%)

93% (CI: 92%, 94%)

At 72 hours

90% (CI:81%, 98%)

91% (CI: 90%, 92%)

The mean serum asparaginase activity (SAA) levels were also determined: mean SAA levels (95% CIs) from the initial data in Cohorts 1a, 1b and 1c at 48 hrs were 0.45 IU/mL (0.37, 0.53), 0.84 IU/mL (0.68, 0.99), and 0.66 IU/mL (0.54, 0.77); and at 72 hrs were 0.15 IU/mL (0.12, 0.19), 0.30IU/mL (0.23, 0.37), and 0.46 IU/mL (0.34, 0.58), respectively. These results reflect the higher dose on Friday from Cohort 1c.

Safety Findings
Grade 3/4 treatment-emergent adverse events (TEAEs), regardless of causality, occurred in 78/137 (57%) patients. There were no treatment-related TEAEs leading to death. The most commonly reported non-hematologic TEAEs (in ≥20% in any cohort) regardless of causality included: vomiting, nausea, fatigue, decreased appetite, pyrexia, abdominal pain, alanine aminotransferase (ALT) increased, febrile neutropenia, back pain, headache, sinus tachycardia, stomatitits, pain in extremity, aspartate aminotransferase (AST) increased and hyperglycemia. Treatment-related TEAEs leading to study drug discontinuation occurred in 6/137 (4%) of patients.

Overall, the safety profile of Rylaze was consistent with the reported safety information for patients with ALL/LBL receiving asparaginase with combination chemotherapy.

Further study analyses (including PK and safety analyses) are ongoing, and full study results will be reported at a later date.

About Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn)
Rylaze, also known as JZP458, is approved in the U.S. for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients one month or older who have developed hypersensitivity to E. coli-derived asparaginase. Rylaze has orphan drug designation for the treatment of ALL/LBL in the United States. Rylaze is a recombinant erwinia asparaginase that uses a novel Pseudomonas fluorescens expression platform. JZP458 was granted Fast Track designation by the U.S. Food and Drug Administration (FDA) in October 2019 for the treatment of this patient population. Rylaze was approved as part of the Real-Time Oncology Review (RTOR) program, an initiative of the FDA’s Oncology Center of Excellence designed for efficient delivery of safe and effective cancer treatments to patients.

The full U.S. Prescribing Information for Rylaze is available at: View Source

Important Safety Information

RYLAZE should not be given to people who have had:

Serious allergic reactions to RYLAZE
Serious swelling of the pancreas (stomach pain), serious blood clots, or serious bleeding during previous asparaginase treatment
RYLAZE may cause serious side effects, including:

Allergic reactions (a feeling of tightness in your throat, unusual swelling/redness in your throat and/or tongue, or trouble breathing), some of which may be life-threatening
Swelling of the pancreas (stomach pain)
Blood clots (may have a headache or pain in leg, arm, or chest)
Bleeding
Liver problems
Contact your doctor immediately if any of these side effects occur.

Some of the most common side effects with RYLAZE include: liver problems, nausea, bone and muscle pain, tiredness, infection, headache, fever, allergic reactions, fever with low white blood cell count, decreased appetite, mouth swelling (sometimes with sores), bleeding, and too much sugar in the blood.

RYLAZE can harm your unborn baby. Inform your doctor if you are pregnant, planning to become pregnant, or nursing. Females of reproductive potential should use effective contraception (other than oral contraceptives) during treatment and for 3 months following the final dose. Do not breastfeed while receiving RYLAZE and for 1 week after the final dose.

Tell your healthcare provider if there are any side effects that are bothersome or that do not go away.

These are not all the possible side effects of RYLAZE. For more information, ask your healthcare provider.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088 (1-800-332-1088).

About Acute Lymphoblastic Leukemia (ALL)
ALL is a cancer of the blood and bone marrow that can progress quickly if not treated.1 Leukemia is the most common cancer in children, and about three out of four of these cases are ALL.2 Although it is one of the most common cancers in children, ALL is among the most curable of the pediatric malignancies due to recent advancements in treatment.3,4 Adults can also develop ALL, and about four of every 10 cases of ALL diagnosed are in adults.4 The American Cancer Society estimates that almost 6,000 new cases of ALL will be diagnosed in the United States in 2021.4 Asparaginase is a core component of multi-agent chemotherapeutic regimens in ALL.5 However, asparaginase treatments derived from E. coli are associated with the potential for development of hypersensitivity reactions.6

About Lymphoblastic Lymphoma (LBL)
LBL is a rare, fast-growing, aggressive subtype of Non-Hodgkin’s lymphoma, most often seen in teenagers and young adults.6 LBL is a very aggressive lymphoma – also called high-grade lymphoma – which means the lymphoma grows quickly with early spread to different parts of the body.[7],[8]

On December 11, 2021 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that the Phase II pivotal study (the APG2575CC201 study) of the company’s novel Bcl-2 selective inhibitor, lisaftoclax (APG-2575), for the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL) has been approved by the Center for Drug Evaluation (CDE) in China (Press release, Ascentage Pharma, DEC 11, 2021, View Source [SID1234596878]).

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APG2575CC201 is a single-arm, open-label, Phase II pivotal study designed to evaluate the efficacy and safety of lisaftoclax, with objective response rate (ORR) as the primary endpoint. Based on existing safety and efficacy data of lisaftoclax, the CDE has agreed that results from the APG2575CC201 study can be used to support the future New Drug Application for the indication of R/R CLL/SLL.

Lisaftoclax is a novel, orally administered Bcl-2 selective inhibitor being developed by Ascentage Pharma. Lisaftoclax is designed to treat a variety of malignancies by selectively blocking Bcl-2 to restore the normal apoptosis process in cancer cells. It is the first China-developed Bcl-2 inhibitor entering clinical development in China. Lisaftoclax is being studied in multiple clinical studies in countries and regions including the U.S., China, Australia, and the European Union, for a range of hematologic malignancies and solid tumors such as CLL/SLL. At the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, data of China studies of lisaftoclax in the treatment of hematologic malignancies were released for the first time. These data demonstrated lisaftoclax’s favorable tolerability and enormous therapeutic potential, without evidence of any tumor lysis syndrome (TLS). The six patients with CLL who received lisaftoclax at 200 mg or higher doses achieved an ORR of 100% and one case of complete response (CR).

Globally, there are significant unmet medical needs in the treatment of CLL/SLL. Patients with R/R CLL/SLL, especially those who are refractory or resistant to immunotherapies, chemotherapies, and Bruton Tyrosine Kinase (BTK) inhibitors, commonly experience rapid disease progression and currently lack any effective treatment, thus represents an urgent need for an effective novel therapy.

"Lisaftoclax is a key candidate in our apoptosis-targeted pipeline. In earlier studies, it has demonstrated promising efficacy and safety implicating great best-in-class potential. The approval for this Phase II pivotal study makes us even more confident in the developmental and regulatory pathway of lisaftoclax," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "There are urgent unmet medical needs in patients with R/R CLL/SLL who currently lack effective salvage therapies. We will actively advance this Phase II pivotal study of lisaftoclax to hopefully offer a new treatment option to patients around the world, and let more patients with CLL/SLL who now lack any effective treatment benefit from this novel therapeutic as soon as possible."

About Lisaftoclax (APG-2575)
Lisaftoclax is a novel, orally administered small-molecule Bcl-2‒selective inhibitor being developed by Ascentage Pharma to treat hematologic malignancies and solid tumors by selectively blocking antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first China-developed Bcl-2 inhibitor entering clinical development in China.

Lisaftoclax is being studied in multiple clinical studies in countries and regions including the U.S., China, Australia, and the European Union, for a range of hematologic malignancies and solid tumors such as chronic lymphocytic leukemia, acute myeloid leukemia, and breast cancer. Lisaftoclax has been granted Orphan Drug Designations for five indications including Waldenström macroglobulinemia, chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia, and follicular lymphoma.

On December 11, 2021 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that valemetostat, a potential first-in-class dual inhibitor of EZH1 and EZH2, demonstrated promising response rates in a pivotal phase 2 study in Japanese patients with relapsed/refractory adult T-cell leukemia/lymphoma (ATL) (Press release, Daiichi Sankyo, DEC 11, 2021, View Source [SID1234596865]). The results were reported today in an oral presentation (#303) at the 63rd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (#ASH21).

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While ATL is a rare disease, it occurs with greater frequency in parts of Japan and other regions.1 Currently, there are no optimal standard treatment options for ATL.1 Nearly 90% of patients relapse after completing intensive first-line treatment, at which point there are few options available.1,2

The phase 2 study of valemetostat met its primary endpoint, demonstrating an objective response rate (ORR) of 48% (90% CI: 30.5%-65.9%) in 25 patients with relapsed/refractory ATL, as evaluated by an independent efficacy assessment committee. Five complete remissions, seven partial remissions and 10 cases of stable disease were reported. The median duration of response (DOR) was not reached (95% CI: 1.87 months-NR) at a median follow-up of 6.5 months. Eight patients remained on treatment at the time of data cut-off on April 24, 2021.

The safety profile of valemetostat in the study was consistent with the phase 1 trial in patients with several types of non-Hodgkin lymphoma including peripheral T-cell lymphoma (PTCL) and ATL.3 Grade 3 or higher treatment emergent adverse events (TEAEs) occurred in 15 of 25 patients (60%), the most common of which (occurring in ≥30% of patients) were platelet count decrease (80%), anemia (48%), alopecia (40%) and dysgeusia (36%). Dose interruptions or reductions due to TEAEs occurred in 20% (n=5) and 8% (n=2) of patients, respectively. Two patients (8%) discontinued treatment due to TEAEs.

Based on these data, valemetostat was granted Orphan Drug designation by the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of relapsed/refractory ATL. Therapies receiving Orphan Drug designation from the Japan MHLW are those being developed for serious, difficult-to-treat diseases that affect fewer than 50,000 patients in Japan, and they qualify for several measures intended to support development including, but not limited to, guidance and subsidies for research and development activities, priority consultation for clinical development and priority review of applications.

"The phase 2 trial of valemetostat demonstrated encouraging response rates in Japanese patients with a history of mogamulizumab therapy for relapsed/refractory ATL," said Makoto Yoshimitsu, MD, PhD, Associate Professor, Kagoshima University Hospital, Japan. "For patients in Japan with aggressive ATL subtypes, median overall survival is about 12 months even with intensive chemotherapy regimens, and potential new options such as valemetostat are greatly needed to improve outcomes, particularly in the relapsed/refractory setting."4

"Based on these pivotal data for valemetostat, dual targeting of EZH1 and EZH2, which play important roles in the pathophysiology of T-cell lymphomas, appears to be a promising therapeutic approach for patients with relapsed/refractory ATL, a type of PTCL with particularly poor prognosis," said Ken Takeshita, MD, Global Head of R&D, Daiichi Sankyo. "We are working to deliver valemetostat to ATL patients in Japan as soon as possible while continuing global development in T-cell and B-cell lymphomas."

The study also showed a trend towards a decrease in measurable lesions across all disease sites assessed, including nodal, extranodal, skin and peripheral blood.

The trial included patients with three aggressive subtypes of ATL who received a median of three prior lines of therapy (range, 1-8). Twenty-four of 25 patients had received prior treatment with mogamulizumab.

Summary of Phase 2 Results

Efficacy Measure*

All Patients

(n=25)

Acute

(n=16)

Lymphoma

(n=6)

Unfavorable chronic

(n=3)

ORR, n (%)

12 (48.0)

10 (62.5)

1 (16.7)

1 (33.3)

CR

5 (20.0)

5 (31.3)

0

0

CRu

0

0

0

0

PR

7 (28.0)

5 (31.3)

1 (16.7)

1 (33.3)

SD

10 (40.0)

4 (25.0)

5 (83.3)

1 (33.3)

RD/PD

3 (12.0)

2 (12.5)

0

1 (33.3)

Median time to first response (months)

1.43

(range 1.0-5.6)

n/a

n/a

n/a

Median DOR (months)

NR

(95% CI: 1.87-NR)

n/a

n/a

n/a

*CR, complete remission; CRu, complete remission unconfirmed; DOR, duration of response; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; RD, relapsed disease; SD, stable disease

About Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a rare and aggressive type of peripheral T-cell lymphoma (PTCL) that is caused by human T-cell lymphotropic virus type 1 (HTLV-1).1 More than 3,000 new cases of ATL are diagnosed each year worldwide.5 While ATL is rare, it occurs with greater frequency in some regions including parts of Japan, the Caribbean, South America and Australia.5 In Japan, there are approximately 1,000 new ATL cases and over 1,000 deaths due to ATL annually.6

ATL continues to have a dismal prognosis with current therapies.7 The five-year overall survival rate for patients with ATL is about 14%.8 A median survival time of approximately eight months (252 days) was reported for patients in Japan with the most common acute ATL subtype.5

Treatment of ATL is based on subtype and consists primarily of intensive multi-drug chemotherapy regimens.7 Nearly 90% of patients relapse after completing intensive first-line treatment, at which point there are few options available.1,2 Additional therapies are needed to improve the prognosis of ATL in Japan and worldwide.1,7

About EZH1 and EZH2

EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes are part of polycomb protein complexes and act through histone methylation to regulate expression of genes involved in maintaining hematopoietic stem cells.9 EZH1 and EZH2 are recurrently highly expressed or mutated in many hematologic malignancies including T-cell lymphomas.10 Research has demonstrated that both EZH1 and EZH2 enzymes have a role in hematologic cancer progression and that simultaneous inhibition would be effective in targeting the cancers.11 There are no dual inhibitors of EZH1 and EZH2 approved for cancer treatment.

About the Phase 2 Study

The pivotal, open-label, multi-center, single-arm phase 2 study evaluated efficacy and safety of valemetostat (200 mg dose daily) as monotherapy in patients with relapsed/refractory ATL who were previously treated with mogamulizumab or at least one systemic chemotherapy in case of intolerance/contraindication for mogamulizumab and with no history of allogenic hematopoietic stem cell transplant.

The primary endpoint is ORR assessed by independent efficacy assessment committee. Secondary endpoints include investigator-assessed ORR, best response in tumor lesions, complete remission rate, tumor control rate, time to response, duration of response, progression-free survival, overall survival and safety. A total of 25 patients were enrolled in the study in Japan. For more information, visit ClinicalTrials.gov.

About Valemetostat

Valemetostat is a potential first-in-class dual inhibitor of EZH1 and EZH2 currently in clinical development in the Alpha portfolio of Daiichi Sankyo. A potent and selective small molecule inhibitor, valemetostat is designed to counter epigenetic dysregulation by targeting both the EZH1 and EZH2 enzymes.12

The valemetostat development program includes VALENTINE-PTCL01, a global pivotal phase 2 trial in patients with relapsed/refractory PTCL and ATL; a pivotal phase 2 trial in patients with relapsed or refractory ATL in Japan; and, a phase 1 study in patients with relapsed/refractory NHL in the U.S. and Japan. Valemetostat received Orphan Drug Designation (ODD) from the U.S. Food & Drug Administration for the treatment of PTCL in December 2021, ODD from the Japan MHLW for the treatment of relapsed/refractory ATL in November 2021 and SAKIGAKE Designation from the Japan MHLW for the treatment of adult patients with relapsed/refractory PTCL in April 2019.

Valemetostat is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Oncology

The oncology portfolio of Daiichi Sankyo is powered by our team of world-class scientists that push beyond traditional thinking to create transformative medicines for people with cancer. Anchored by our DXd antibody drug conjugate (ADC) technology, our research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in the U.S. We also work alongside leading academic and business collaborators to further advance the understanding of cancer as Daiichi Sankyo builds towards our ambitious goal of becoming a global leader in oncology by 2025.