On December 11, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that new analyses illustrating responses that first-line treatment with DARZALEX▼ (daratumumab)-based regimens may be able to achieve, including a potential survival benefit for daratumumab in combination with lenalidomide and dexamethasone (Rd).1,2 Updated data from the randomised Phase 2 GRIFFIN study in transplant-eligible patients and real-world evidence in transplant-ineligible patients were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting (Press release, Johnson & Johnson, DEC 11, 2021, View Source [SID1234596850]). Data from the GRIFFIN study will also be featured in the Highlights of ASH (Free ASH Whitepaper) programme.

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"Despite treatment advances, multiple myeloma remains a complex, currently incurable blood cancer. The latest clinical trial data and real-world evidence presented for daratumumab at ASH (Free ASH Whitepaper) shines a light on the potential of daratumumab-based combinations and sequencing approaches in the first-line, to tackle this complexity and improve patient outcomes," said Edmond Chan MBChB M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "At Janssen, we are committed to developing transformative treatment regimens that address individual patient needs and offer physicians options which they have not had before, as we work towards our longer-term goal of curing multiple myeloma."

Updated Phase 2 GRIFFIN data of investigational daratumumab quadruple regimen for newly diagnosed transplant-eligible patients1

Updated results from the GRIFFIN study, now with a median follow-up of 38.6 months, were presented in an oral session (Abstract #79). The data show improved outcomes with the addition of daratumumab to bortezomib (VELCADE), lenalidomide (Revlimid) and dexamethasone (VRd), followed by daratumumab plus lenalidomide (R) maintenance therapy, in transplant-eligible patients.1 Key findings included:

The rate of stringent complete response (sCR) favoured daratumumab-VRd compared to VRd alone (66 percent versus 47.4 percent; p=0.0096).1,3
Minimal residual disease (MRD) negativity rates at a threshold of 10-5 remained significantly higher in patients treated with daratumumab-VRd versus VRd alone (64.4 percent versus 30.1 percent; p<0.0001).1, 3
Whilst this study was not powered for progression-free survival (PFS), at 36 months, the PFS rate trended toward favouring daratumumab-VRd compared to VRd alone (88.9 percent versus 81.2 percent).1
At the median follow-up of 38.6 months, median progression-free survival (mPFS) had not been reached in either arm.1
No new safety concerns were observed with longer-term follow up.1
"These updated findings from the GRIFFIN study are promising when adding daratumumab to VRd in the treatment of newly diagnosed, transplant-eligible multiple myeloma," said Jacob Laubach†, M.D., M.P.P, Clinical Director of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and GRIFFIN study investigator.

Additional analyses of daratumumab-based regimens for the treatment of transplant-ineligible newly diagnosed multiple myeloma2

Research shows that 50 percent of transplant-ineligible patients will not receive a second line of therapy.2 An oral presentation at ASH (Free ASH Whitepaper) 2021 highlighted clinical sequencing scenarios in patients with newly diagnosed transplant-ineligible multiple myeloma, utilising data from the Phase 3 MAIA study, including attrition rates, and real-world evidence from the Flatiron Health electronic health record-derived de-identified database* (Abstract 118).2 Researchers explored survival outcomes based on clinical sequencing scenarios using daratumumab first in combination with Rd, compared to when bortezomib was administered first in combination with Rd.2 Results from this modelled analysis suggest a potential for a survival benefit when patients received daratumumab in first-line treatment versus saving it for later.2 Future research is required to generate clinical data to confirm these results.2

A second presentation of real-world evidence data provided additional insights on sequencing, based on results from a retrospective, observational cohort study evaluating patients from the Flatiron database who received first-line daratumumab-Rd (Abstract #1979).4 The analysis indicated that the real-world patient population was similar to that of the MAIA study population, with an early trend of PFS similar to that observed in the MAIA study.4

A post-hoc analysis of the Phase 3 MAIA study, focusing on patients with renal impairment, was highlighted in a poster presentation (Abstract #1646).5 Research shows that approximately 20 to 50 percent of patients with multiple myeloma have baseline renal impairment that can impact their choice of treatment and efficacy.5 The exploratory analyses presented at ASH (Free ASH Whitepaper) showed that PFS and overall survival (OS) benefits were observed in these patients who were treated with daratumumab-Rd compared to Rd alone, regardless of the lenalidomide starting dose.5 OS data from the MAIA study were recently published in The Lancet Oncology.

"The clinical data presented at ASH (Free ASH Whitepaper) support daratumumab as a foundational therapy for patients with newly diagnosed multiple myeloma in transplant-ineligible populations," said Imran Khan, M.D., Ph.D., U.S. Vice President, Medical Affairs, Hematology, Janssen Scientific Affairs, LLC. "Real-world evidence about efficacy, safety and adherence is becoming increasingly important for clinicians in optimising treatment approaches for patients with multiple myeloma. We will continue to advance research that can provide important insights about daratumumab as part of a standard of care regimen in the frontline setting."

#ENDS#

About the GRIFFIN Study1,6

The Phase 2 GRIFFIN (NCT02874742) study evaluated the investigational regimen of daratumumab in combination with VRd and enrolled and treated more than 200 adults aged 18–70 years with newly diagnosed multiple myeloma (NDMM) and who were eligible for high-dose therapy/autologous stem cell therapy (ASCT).6

In the safety run-in cohort, patients received 25 mg of lenalidomide orally on Days 1–14; 1.3 mg/m2 of bortezomib subcutaneously on Days 1, 4, 8 and 11; and 20 mg of dexamethasone on Days 1, 2, 8, 9, 15 and 16, every 21 days during the induction and consolidation phases (Cycles 1–6).1 Daratumumab 16 mg/kg IV was given on days 1, 8 and 15 of Cycles 1–4 and on day 1 of Cycles 5–6.1

During the maintenance phase (Cycles 7–32), patients received 10 mg daily of lenalidomide (15 mg beginning at Cycle 10 if tolerated) on days 1–21 every 28 days and daratumumab 16 mg/kg IV every 56 days; this was amended to every 28 days based upon emerging clinical pharmacokinetic data demonstrating improved target saturation with every four-week maintenance dosing.1 Maintenance therapy with lenalidomide may be continued beyond Cycle 32 in both arms, per local standard of care.1

In the subsequent randomised Phase 2 portion of the study, 207 patients were randomised and received treatment with VRd induction and consolidation, ASCT, and maintenance therapy with lenalidomide; or daratumumab and VRd, ASCT, and maintenance therapy with daratumumab and lenalidomide.1

About the MAIA Study7

The randomised, open-label, multicentre Phase 3 MAIA study (NCT02252172) included 737 newly diagnosed patients with multiple myeloma ineligible for high-dose chemotherapy and ASCT, aged 45–90 years (median age of 73).7 Patients were randomised to receive either daratumumab-Rd or Rd alone in 28-day cycles. In the daratumumab-Rd arm, patients received daratumumab 16 mg/kg IV weekly for Cycles 1–2, every two weeks for Cycles 3–6 and every four weeks for Cycle 7 and thereafter.7 Patients in both treatment arms received 25 mg of lenalidomide on Days 1–21 of each 28-day cycle, and dexamethasone at 40 mg once a week.7 Patients in both treatment arms continued until disease progression or unacceptable toxicity.7

Earlier results from the MAIA study supported the European Commission (EC) approval of daratumumab in combination with Rd, marking the first approval of a CD38 monoclonal antibody for patients with transplant-ineligible NDMM. These data were also published in The New England Journal of Medicine in 2019.

Modelling and Real-World Data Limitations

Modelling and real-world data have the potential to supplement randomised controlled trial data by providing additional information about how a medicine performs across all available Phase 2 and 3 clinical trials and in routine clinical practice. There are limitations, however, and these data cannot be used as stand-alone evidence to validate the efficacy or safety of a treatment.

*The Flatiron Health database is a longitudinal database comprising de-identified, patient-level structured and unstructured data curated via technology-enabled abstraction.

About daratumumab

Janssen is committed to exploring the potential of daratumumab for patients with multiple myeloma across the spectrum of the disease. Daratumumab has been approved in eight indications for multiple myeloma, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.8

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. Since launch, daratumumab has become a foundational therapy in the treatment of multiple myeloma, having been used in the treatment of more than 227,000 patients worldwide.9 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. Daratumumab subcutaneous (SC) formulation is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.10

CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.8 Daratumumab binds to CD38 and inhibits tumour cell growth causing myeloma cell death.8 Daratumumab may also have an effect on normal cells.8 Data across eight Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in PFS and/or OS.11,12,13,14,15,16,17,18

For further information on daratumumab, please see the Summary of Product Characteristics at: View Source

About Multiple Myeloma

Multiple myeloma is currently an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.19 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow.20 In Europe, more than 50,900 people were diagnosed with multiple myeloma in 2020, and more than 32,500 patients died.20 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.21

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 Incyte (Nasdaq:INCY) reported data from three ongoing Phase 2 studies evaluating parsaclisib, an investigational novel potent, highly selective, next-generation oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), for the treatment of patients with relapsed or refractory follicular lymphoma (FL) (CITADEL-203), marginal zone lymphoma (MZL) (CITADEL-204) and mantle cell lymphoma (MCL) (CITADEL-205) (Press release, Incyte, DEC 11, 2021, View Source [SID1234596807]). These data were accepted as oral presentations at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH 2021), held December 11–14, 2021 in Atlanta, Georgia and virtually.

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The primary endpoint for the CITADEL-203, -204 and -205 studies is objective response rate (ORR). Key secondary endpoints include complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and tolerability. All radiology-based endpoints are based on independent review committee (IRC) assessment.

Building on previous findings presented at ASH (Free ASH Whitepaper) 2020, these updated data from the primary analysis continue to show treatment with parsaclisib resulted in a rapid and durable response with an acceptable safety profile, and supported the New Drug Application (NDA) for parsaclisib, recently accepted by the U.S. Food and Drug Administration (FDA).

Key results from the CITADEL studies include:

ORR (95% CI), %

CRR (95% CI), months

mDOR (95% CI), months

mPFS (95% CI), months

mOS (95% CI), months

CITADEL-203: R/R Follicular Lymphoma

DG (N=103)

77.7 (68.4–85.3)

19.4 (12.3-28.4)

14.7 (10.4-NE)

15.8 (11.0-NE)

NR (NE-NE)

All (N=126)

75.4 (66.9-82.6)

18.3 (11.9-26.1)

14.7 (12.0-20.3)

14.0 (11.3-19.6)

NR (NE-NE)

CITADEL-204: R/R Marginal Zone Lymphoma

DG (N=72)

58.3 (46.1-69.8)

4.2 (0.9-11.7)

12.2 (8.1-17.5)

16.5 (11.5-20.6)

NR (NE-NE)

All (N=100)

58.0 (47.7-67.8)

6.0 (2.2-12.6)

12.2 (8.1-17.5)

16.5 (13.5-19.6)

NR (NE-NE)

CITADEL-205: R/R Mantle Cell Lymphoma (BTK Inhibitor Treatment Naive)

DG (N=77)

70.1 (58.6-80.0)

15.6 (8.3-25.6)

12.1 (9.0-NE)

13.6 (10.0-16.9)

NR (NE-NE)

All (N=108)

68.5 (58.9-77.1)

17.6 (10.9-26.1)

13.7 (9.0-19.9)

11.99 (8.3-16.9)

NR (NE-NE)

R/R: relapsed or refractory; ORR: objective response rate; CRR: complete response rate; mDOR: median duration of response (reported for responders); mPFS: median progression-free survival; mOS: median overall survival; DG: daily dosing group; NE: not estimable; NR: not reached.

Parsaclisib was generally well tolerated in all studies with a manageable safety profile.

"We are pleased to share these updated results from the CITADEL studies with the oncology community," said Peter Langmuir, M.D., Group Vice President, Oncology Targeted Therapies, Incyte. "The promising data add to the body of evidence that support parsaclisib, which has the potential to become a meaningful treatment for patients with relapsed or refractory follicular, marginal zone or mantle cell lymphomas, and we look forward to working with the FDA as we strive to bring this therapy to patients."

"Non-Hodgkin lymphoma is composed of varying subtypes and is one of the most common cancers in the United States. Given the fact that a significant subset of those afflicted will not be cured with current options, we need new treatment options," said Tycel Phillips, M.D., Primary Investigator, CITADEL-204 and Associate Professor, Division of Hematology and Oncology, Rogel Cancer Center, University of Michigan. "I am encouraged to see parsaclisib result in rapid and durable responses with a manageable safety profile in patients with a variety of non-Hodgkin lymphomas. The results observed across several key endpoints of the CITADEL studies suggest that parsaclisib may be a favorable treatment option for patients."

Presentations can be accessed via the ASH (Free ASH Whitepaper) website at View Source; #813 (Oral presentation, CITADEL-203), #44 (Oral presentation, CITADEL-204), #382 (Oral presentation, CITADEL-205).

About Follicular, Marginal Zone and Mantle Cell Lymphomas
Non-Hodgkin lymphoma (NHL) is a type of cancer that starts in the lymphocytes, a type of white blood cell. Follicular lymphoma (FL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL) are forms of B-Cell NHLs. FL and MZL are indolent or slow growing lymphomas; MCL is an aggressive or rapidly developing form. There is an unmet medical need for treatment options for patients who are relapsed or refractory to initial therapies.

About CITADEL
The CITADEL (Clinical Investigation of TArgeted PI3K-DELta Inhibition in Lymphomas) clinical trial program is evaluating parsaclisib in several ongoing studies as a treatment for adult patients with lymphomas, including:

CITADEL-203 (NCT03126019) is evaluating patients with relapsed or refractory follicular lymphoma (FL) Grade 1, 2 or 3a who received at least two prior systemic therapies, had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and were ineligible for hematopoietic stem cell transplantation (HSCT).
CITADEL-204 (NCT03144674) is evaluating patients with relapsed or refractory marginal zone lymphoma (MZL) who received at least one prior systemic therapy and were Bruton’s tyrosine kinase (BTK) inhibitor treatment naive. Patients with prior ibrutinib treatment were initially allowed to enroll; however, the cohort was terminated due to slow enrollment. Eligible patients had radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (or histologically confirmed bone marrow infiltration in cases of splenic MZL), and an ECOG PS ≤2.
CITADEL-205 (NCT03235544) is evaluating patients with relapsed or refractory mantle cell lymphoma (MCL), who received one to three prior systemic therapies and were either naive to or were previously treated with a BTK inhibitor. Eligible patients had an ECOG PS ≤2, and radiologically measurable lymphadenopathy or extranodal lymphoid malignancy.
Patients eligible for each trial were allocated to receive parsaclisib 20 mg once daily for eight weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg once daily (daily-dosing group [DG]). Subsequently, daily dosing was selected as the preferred regimen and the WG patients were allowed to switch to DG. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required.

About Parsaclisib
Parsaclisib is a potent, highly selective, next-generation investigational novel oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ). It is currently under evaluation as a monotherapy in several ongoing Phase 2 trials as a treatment for non-Hodgkin lymphomas (follicular, marginal zone and mantle cell); and autoimmune hemolytic anemia. Pivotal trials of parsaclisib in combination with ruxolitinib for the treatment of patients with myelofibrosis are underway; and there are plans to initiate trials to evaluate parsaclisib in combination with tafasitamab, including a pivotal trial in B-cell malignancies.

In December 2018, Innovent and Incyte entered into a strategic collaboration for three clinical-stage product candidates, including parsaclisib. Under the terms of the agreement, Innovent has received the rights to develop and commercialize parsaclisib and two other assets in Mainland China, Hong Kong, Macau and Taiwan.

On December 11, 2021 Orca Bio, a clinical-stage biotechnology company developing purified, high-precision cell therapies for the treatment of cancer, autoimmune diseases and genetic blood disorders, reported positive clinical data on its lead investigational cell therapy, Orca-T, were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Orca Bio, DEC 11, 2021, View Source [SID1234596852]). The data presented on 109 patients with at least 90 days of follow-up in combined data from the Phase 1b and Phase 2 trials showed significantly higher graft-versus-host disease-free, relapse-free survival (GRFS) rates compared to patients who received standard of care.

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"The lower rates of graft versus host disease and improved relapse-free survival suggest Orca-T has the potential to become a safer and more effective treatment option for patients living with serious blood cancers," said Ivan Dimov, Ph.D., cofounder and chief executive officer of Orca Bio. "We are further encouraged by the validation of our platform as we advance Orca-T into our pivotal Phase 3 trial, a significant step toward potential commercialization and, most importantly, to helping more patients in need."

Findings presented today in an oral presentation included pooled results from the single-center Phase 2 and multi-center Phase 1b trials from 109 patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, myelofibrosis and other hematological malignancies. Median follow-up for these patients was 617 days (single-center) and 209 days (multi-center). For comparison purposes, a contemporary, propensity-matched cohort of 95 matched patients undergoing standard of care allogeneic hematopoietic stem cell transplant (alloHSCT) served as the standard of care cohort ("SOC cohort"). Results demonstrated that:

Patients who received Orca-T had a GRFS of 74%. When comparing this non-randomized data to the SOC cohort, the difference was significant (74% vs. 34%; p<0.0001).
Orca-T showed the potential for lower rates of moderate-to-severe chronic graft versus host disease (GvHD) at 1 year post-transplant (3% vs. 43%; p<0.0005).
Overall survival rates with Orca-T (90% vs. 78%; p<0.03) and rates of chronic-GvHD-free survival (87% vs. 45%; p<0.0001) were improved.
Orca-T was manufactured reliably and delivered with vein-to-vein times of 72 hours or less across the continental U.S.
In a poster presentation at ASH (Free ASH Whitepaper), Orca Bio also shared an analysis of treatment impact in patients with myelofibrosis. The analysis compared eight patients with myelofibrosis who were treated with Orca-T with six patients who underwent standard of care (SOC) alloHSCT. Regression of marrow fibrosis to myelofibrosis grade 0 or 1 was observed by Day 100 post-transplant in all eight Orca-T recipients, but was observed in only one of the six SOC patients. Additionally, Orca-T recipients had lower incidence of acute and chronic GvHD.

Along with the positive Phase 1b/2 results, Orca Bio announced that it has completed a successful end of Phase 2 meeting with the U.S. Food and Drug Administration and plans to commence a Phase 3 trial for Orca-T in early 2022.

The full presentation is available on www.orcabio.com.

About Orca-T
Orca-T is an investigational high-precision allogeneic cellular therapy consisting of infusions containing regulatory T-cells, conventional T-cells and CD34+ stem cells derived from peripheral blood from either related or unrelated matched donors. Orca-T has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration and is being studied to treat multiple hematologic malignancies.

On December 11, 2021 Servier, a growing leader in oncology committed to bringing the promise of tomorrow to the patients we serve, reported Phase 3 data demonstrating that TIBSOVO (ivosidenib tablets) in combination with the chemotherapy azacitidine significantly improved event-free survival (EFS) and overall survival (OS) compared to azacitidine plus placebo in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (Press release, Servier, DEC 11, 2021, View Source [SID1234596887]). These data from the global AGILE study will be presented in an oral session on Monday, December 13, 2021 from 2:45 – 4:15 PM ET, Abstract #697 and featured in the official press program during the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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Treatment with TIBSOVO in combination with azacitidine demonstrated a statistically significant improvement in EFS (hazard ratio [HR] = 0.33, 95% CI 0.16, 0.69, 1-sided P = 0.0011 1,2). In addition, the combination of TIBSOVO with azacitidine showed a statistically significant improvement in OS (HR = 0.44 [95% CI 0.27, 0.73]; 1-sided P = 0.0005), with a median OS of 24.0 months in the ivosidenib + azacitidine arm vs 7.9 months in the placebo + azacitidine arm.

"These significant findings from the AGILE Phase 3 study for TIBSOVO bolster our growing body of evidence supporting the rationale to target IDH1 mutations early in blood cancers like acute myeloid leukemia," said Susan Pandya, M.D., Vice President Clinical Development & Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier Pharmaceuticals. "Up to 10 percent of patients with AML have mutations in the IDH1 enzyme, and current treatment options are limited, especially for those who are newly diagnosed and are not eligible for intensive chemotherapy."

Additional Study Results
Investigators reported on results of key secondary endpoints of the AGILE trial including:

Complete remission (CR) rate was 47.2% (n=34/72) for TIBSOVO in combination with azacitidine vs. 14.9% (n=11/74) for placebo plus azacitidine (p < 0.0001).
CR + complete remission with partial hematologic recovery rate (CR + CRh rate) was 52.8% (n=38/72) for TIBSOVO in combination with azacitidine vs. 17.6% (n=13/74) for placebo plus azacitidine (p < 0.0001).
Objective response rate (ORR) was 62.5% (n=45/72) for TIBSOVO in combination with azacitidine vs. 18.9% (n=14/74) for placebo plus azacitidine (p < 0.0001).
"We are excited about the potential to bring a new treatment option to patients with previously untreated IDH1-mutated AML. This further extends the significant clinical benefit for patients with acute myeloid leukemia and IDH1 mutations," said Patrick Therasse, M.D., Ph.D., Vice President, Head of Late Stage and Life Cycle Management in Oncology and Immuno-Oncology Therapeutic Area, Servier Group.

Acute myeloid leukemia is a rapidly progressing type of cancer, and the prognosis is often poor," said Stephane De Botton, M.D. Ph.D., Principle Investigator and Head of Multidisciplinary Hematology Committee at the Institut Gustave Roussy, Villejuif, France. "Our goal with treatment is to prolong overall survival, and the impressive clinical benefit following treatment with TIBSOVO in combination with azacitidine is incredibly promising for these patients with previously untreated IDH1-mutated acute myeloid leukemia."

Common all-grade adverse events (AEs) occurring in more than 20 percent of patients receiving TIBSOVO in combination with azacitidine vs. placebo plus azacitidine were nausea (42.3% vs. 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), neutropenia (28.2% vs 16.4%), constipation (26.8% vs 52.1%) and pneumonia (23.9% vs 31.5%).

The AGILE study has halted further enrollment due to compelling efficacy data for TIBSOVO.

Servier is in discussions with regulatory health authorities regarding submissions to expand the currently approved indications for TIBSOVO.

TIBSOVO[*] is currently approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML), and for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Recently, TIBSOVO was approved as a first and only targeted therapy for patients with previously treated IDH1-mutated cholangiocarcinoma.

About NCT03173248 AGILE Phase 3 AML Trial
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 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.

Other key secondary endpoints included complete remission rate (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) is a cancer of the blood and bone marrow marked by rapid disease progression and 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 year3,4. The majority of patients with AML eventually relapse. Relapsed or refractory AML has a poor prognosis5. The five-year survival rate is approximately 27%3. For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia6.