On December 12, 2021 Seagen Inc. (Nasdaq:SGEN) reported promising efficacy and safety results from Part B of an open-label, phase 2 clinical trial evaluating ADCETRIS (brentuximab vedotin) in a novel combination with nivolumab, doxorubicin, and dacarbazine (AN+AD) as a frontline treatment for patients with advanced stage classical Hodgkin lymphoma (cHL) (Press release, Seagen, DEC 12, 2021, View Source [SID1234596831]). Data from this preliminary analysis were presented (Abstract #2454) as part of a poster presentation at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta.

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The preliminary results demonstrated a complete response rate of 88 percent (95% CI: 75.9, 94.8) and overall response rate of 93 percent (95% CI: 82.7, 98.0) among 56 patients who had an end of treatment assessment on or prior to the data cutoff date. Patients received up to six cycles of treatment and were evaluated after two cycles of therapy and at the end of treatment. AN+AD was well-tolerated and no new safety signals were observed.

"I am excited about this combination of brentuximab vedotin and nivolumab along with a simplified chemotherapy regimen for the frontline treatment of patients with advanced stage classical Hodgkin lymphoma," said Hun Ju Lee, M.D., Associate Professor of Medicine, Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston. "This combination demonstrated a low incidence of peripheral neuropathy and the absence of febrile neutropenia. What we are learning from our research is that the use of two active targeted agents with distinct and complementary mechanisms of action in the first-line setting shows promising activity and a tolerable safety profile."

"We are optimistic about novel combination approaches to improve outcomes in patients following a diagnosis of classical Hodgkin lymphoma, and we are encouraged by these data evaluating ADCETRIS plus nivolumab, doxorubicin and dacarbazine as a first-line therapy," said Roger Dansey, M.D., Chief Medical Officer at Seagen. "We look forward to complete results from this trial and adding to the breadth of evidence for ADCETRIS in the treatment of advanced classical Hodgkin lymphoma."

Efficacy:

Among 56 patients who had an end of treatment assessment on or prior to the data cutoff date, there was a complete response rate of 88 percent (95% CI: 75.9, 94.8) and overall response rate of 93 percent (95% CI: 82.7, 98.0).
Safety:

The most frequently reported treatment-related treatment-emergent adverse events (AEs) occurring in more than 20 percent of patients who received AN+AD included nausea (65%), fatigue (46%), peripheral sensory neuropathy (39%), alopecia (35%), diarrhea (30%) and constipation (25%).
Immune-mediated AEs were observed in 18 patients (32%) and eight patients (14%) experienced treatment-related treatment-emergent serious AEs.
Two patients (4%) experienced Grade > 3 peripheral neuropathy and no patients discontinued treatment due to peripheral neuropathy. No febrile neutropenia was observed, and there were no Grade 5 adverse events.
See ADCETRIS U.S. Important Safety Information, including Boxed Warning, below.

About the SGN35-027 Clinical Study

SGN35-027 is an ongoing open-label, multiple part, multicenter, phase 2 clinical trial evaluating two brentuximab vedotin treatment combinations in patients with advanced stage classical Hodgkin lymphoma. The trial includes three parts (Parts A, B, and C). Part A includes a combination of brentuximab vedotin and doxorubicin, vinblastine and dacarbazine (A+AVD), while Parts B and C include brentuximab vedotin in combination with nivolumab, doxorubicin, and dacarbazine (AN+AD). The primary endpoint for Part A is the proportion of patients with treatment-emergent incidence of rate of febrile neutropenia. The primary endpoint for Parts B and C is the proportion of participants with complete response at end of treatment, according to the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). Key secondary endpoints include safety, tolerability, ORR, and PFS. Incidence of adverse events is a secondary endpoint for Parts B and C.

About Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma (cHL), Hodgkin disease, or Hodgkin, is a cancer of the blood. It starts when lymphocytes, a type of white blood cell, grow out of control. People with cHL have abnormal white blood cells called Reed-Sternberg cells in their lymph nodes. These cells usually have a special protein on their surface called CD30, which is a key marker of cHL. CD30 is present in approximately 95 percent of all cases of Hodgkin lymphoma. In 2021, it is estimated that there will be 8,830 new cases of Hodgkin lymphoma and an estimated 960 people will die of this disease in the U.S.1

About ADCETRIS

ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing cells.

ADCETRIS is indicated for the treatment of adult patients with:

previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine,
cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation,
cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates,
previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone,
sALCL after failure of at least one prior multi-agent chemotherapy regimen, and
primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
ADCETRIS has received marketing authorization in more than 70 countries for certain types of relapsed or refractory Hodgkin lymphoma and sALCL.

Seagen and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) for injection U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Administer G-CSF primary prophylaxis beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Most Common (≥20% in any study) Adverse Reactions

Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

On December 12, 2021 AstraZeneca reported that Updated results from the ASCEND Phase III trial showed it’s Calquence (acalabrutinib) maintained a statistically significant progression-free survival (PFS) benefit at three years compared to investigator’s choice of rituximab combined with either idelalisib (IdR) or bendamustine (BR) in adults with relapsed or refractory chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults (Press release, AstraZeneca, DEC 12, 2021, View Source [SID1234596830]).1,2

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These data, presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, demonstrated Calquence reduced the risk of disease progression or death by 71% versus IdR/BR as assessed by investigators at three years (based on a hazard ratio [HR] of 0.29; 95% confidence interval [CI]: 0.21-0.41; p<0.0001). Similar clinical benefits were observed in an exploratory analysis comparing each regimen with Calquence. Safety and tolerability of Calquence were consistent with earlier findings, with no new safety signals identified.1

Additional safety analyses from the ELEVATE-RR Phase III trial were also presented at ASH (Free ASH Whitepaper) to further characterise adverse events (AEs) related to treatment with Bruton’s tyrosine kinase (BTK) inhibitors Calquence and ibrutinib. Overall, patients on ibrutinib experienced a 37% higher burden of AEs of any grade versus patients on Calquence.3

For any grade atrial fibrillation/flutter, a key secondary endpoint in the ELEVATE-RR trial, median time to onset was longer for Calquence versus ibrutinib (28.8 versus 16.0 months), and cumulative incidence was lower at all timepoints from six months through two years.3

Additionally, the ELEVATE-RR Phase III trial showed incidence of all-grade atrial fibrillation/flutter was lower for Calquence across subgroups of age, prior line of therapy and among patients without prior history of heart complications.3 Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure and other heart-related complications.4

John F. Seymour, MBBS PhD, Peter MacCallum Centre and the Royal Melbourne Hospital, and a lead investigator on the ELEVATE-RR trial, said: "Patients with relapsed or refractory chronic lymphocytic leukaemia face limited options to successfully manage their disease, as they are often older and dealing with significant comorbidities. The risk of cardiac adverse events is an important consideration, especially for treatment with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment. The ELEVATE-RR data provide compelling evidence that acalabrutinib is a more tolerable option with reduced cardiovascular toxicity, giving clinicians further reassurance when prescribing this medicine that fewer patients will need to cease treatment due to adverse events, thus maintaining ongoing control of their disease, even in this complex setting."

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: "These impressive new long-term data support Calquence as the preferred therapy for the most common type of leukaemia in adults, with favourable safety compared to the current standards of care. The totality of the ASCEND and ELEVATE-RR data, in addition to data introducing a new tablet formulation for patients who need alternative methods of taking Calquence, continues to reinforce the positive experience that this medicine can deliver for patients with chronic lymphocytic leukaemia."

Notes

ASCEND: Three-year follow-up data for Calquence in relapsed or refractory CLL (abstract #393)
ASCEND is a global, randomised, multicentre, open-label, Phase III trial that evaluated the efficacy and safety of Calquence (100mg twice-daily until disease progression or unacceptable toxicity) versus investigator’s choice of IdR or BR in patients with relapsed or refractory CLL.1,5 ASCEND is the first randomised trial to directly compare a BTK inhibitor as monotherapy with standard chemoimmunotherapy or idelalisib and rituximab combinations.

AEs led to treatment discontinuation in 21% of patients on Calquence, 65% of patients on IdR and 17% of patients on BR. Events of clinical interest for Calquence versus comparators included atrial fibrillation/flutter (all grade, 6% and 3%, respectively), hypertension (all grade, 7% and 4%), major haemorrhage (all grade, 3% in both arms), infections (Grade ≥3, 25% and 27%, respectively) and second primary malignancies excluding non-melanoma skin cancer (all grade, 7% and 3%, respectively). Serious AEs (any-grade) occurred in 38% of patients treated with Calquence, 63% of IdR patients and 26% of BR patients.1

ELEVATE-RR: Additional safety analyses of Calquence versus ibrutinib in relapsed or refractory CLL (abstract #3721)
Results from the ELEVATE-RR Phase III trial were first presented on 7 June 2021 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and published in the Journal of Clinical Oncology on 26 July 2021.

Additional safety data were used to characterise BTK inhibitor-related AEs, using measures of frequency, duration and drug exposure (versus incidence alone) to measure AE burden. Median treatment exposures were 38.3 months in the Calquence arm and 35.5 months in the ibrutinib arm.3

For any-grade hypertension, median time to onset was similar for Calquence and ibrutinib (8.1 months versus 7.0), but cumulative incidence was lower for Calquence at 6 months (5% versus 12%), 12 months (6% versus 16%), 18 months (8% versus 20%) and 24 months (8% versus 23%).

Hypertension also occurred less frequently with Calquence versus ibrutinib in subgroups of age, prior line of therapy and among patients without prior history.3

Among cardiovascular AEs of clinical interest, incidences of any-grade atrial fibrillation/flutter, hypertension and bleeding were statistically higher with ibrutinib versus Calquence, with higher exposure-adjusted incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exposure-adjusted time with event (2.8-, 3.7-, and 1.8-fold).3

CLL
CLL is the most common type of leukaemia in adults, with an estimated 114,000 new cases globally in 2017, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.2,6-8

In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets. This could result in anaemia, infection and bleeding.6 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

ASCEND
ASCEND (ACE-CL-309) is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy of Calquence in patients with relapsed or refractory CLL.5,9

In the trial, 310 patients were randomised (1:1) into two treatment arms. Patients in the first arm received Calquence monotherapy (100mg twice-daily until disease progression or unacceptable toxicity). Patients in the second arm received physician’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3-kinase inhibitor, or rituximab in combination with bendamustine, a chemotherapy.9

The primary endpoint at the interim analysis was PFS assessed by an Independent Review Committee (IRC), and key secondary endpoints included investigator-assessed PFS, IRC- and investigator-assessed overall response rate and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.

ASCEND is the first randomised Phase III trial to directly compare a BTK inhibitor as monotherapy to these combinations in relapsed or refractory CLL.5,9

ELEVATE-RR
ELEVATE-RR (ACE-CL-006) is a randomised, multicentre, open-label Phase III non-inferiority trial of Calquence versus ibrutinib in patients with relapsed or refractory CLL after at least one prior therapy, and at least one of the following prognostic factors: presence of 17p deletion, or presence of 11q deletion.10,11

In the trial, 533 patients were randomised (1:1) into two arms. Patients in the first arm received Calquence (100mg orally twice-daily until disease progression or unacceptable toxicity). Patients in the second arm received ibrutinib (420mg orally once-daily until disease progression or unacceptable toxicity).11

The primary endpoint for the trial was IRC-assessed PFS (non-inferiority; tested after 250 events, upper margin of 95% CI for HR<1.429). Secondary endpoints included incidence of atrial fibrillation, incidence of Grade 3 or higher infections, incidence of Richter’s transformation (a condition in which CLL changes into an aggressive form of lymphoma12) and OS.11

ELEVATE-RR is the first randomised Phase III trial to directly compare two BTK inhibitors as monotherapy in relapsed or refractory CLL.

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.13,14 In B cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.13

Calquence is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US, approved for CLL in the EU and several other countries worldwide and approved in Japan for relapsed or refractory CLL and SLL. A Phase I trial is currently underway in Japan for the treatment of front-line CLL.

In the US and several other countries, Calquence is also approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Calquence is not currently approved for the treatment of MCL in Europe or Japan.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in more than 20 company-sponsored clinical trials. Calquence is being evaluated for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, follicular lymphoma and other haematologic malignancies.

AstraZeneca in haematology
AstraZeneca is pushing the boundaries of science to redefine care in haematology. Applying our deep understanding of blood cancers and leveraging our strength in solid tumour oncology, we are driving the development of novel therapies designed to target underlying drivers of disease across six scientific platforms.

By addressing blood cancers with high unmet medical needs, our aim is to deliver innovative medicines and approaches to healthcare services that have a meaningful impact on patients and caregivers, transforming the haematologic cancer care experience.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On December 12, 2021 Imago BioSciences, Inc. ("Imago") (Nasdaq: IMGO), a clinical stage biopharmaceutical company discovering new medicines for the treatment of myeloproliferative neoplasms (MPNs), reported that positive data from its ongoing global Phase 2 clinical study evaluating bomedemstat in patients with essential thrombocythemia (ET) (Press release, Imago BioSciences, DEC 12, 2021, View Source [SID1234596827]). The data were presented in an oral session during the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place December 11-14, 2021. Previously, a Phase 2 data set with a cut-off date of May 18, 2021 was presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress.

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Updated Highlights (as of November 1, 2021 cutoff):

Of the 29 patients treated with bomedemstat for more than 6 weeks:
100% (29/29) of patients experienced platelet count reduction to within normal ranges (150 – 400 x 109/L).
90% (26/29) of patients achieved a platelet count of less than 400 x 109/L without thromboembolic events, the primary composite endpoint of this study.
Of the 17 evaluable patients at 24 weeks:
71% (12/17) showed a decrease in Total Symptom Score (TSS).
53% (9/17) showed a ≥50% decrease in TSS.
Patients with all genotypes identified in the study (CALR, JAK2V617F, Triple Negative) responded to bomedemstat.
"As of the most recent data cut-off in this Phase 2 trial, bomedemstat as a monotherapy in a 2nd line ET population demonstrated significant and durable hematologic control and symptom improvement while maintaining normal hemoglobin levels. I am delighted with the progress we are making with this study and would like to take this opportunity to thank all of the investigators and patients involved," said Hugh Young Rienhoff, Jr., M.D., CEO, Imago BioSciences. "Even with only 36 of the up-to 60 patients we plan to enroll, we have commenced planning for a registrational clinical trial for ET. We expect an End-of-Phase 2 meeting and discussion of the Phase 3 Protocol in the second half of 2022."

Safety & Tolerability

Bomedemstat was generally well-tolerated.
The most common AEs (>20%) were dysgeusia (altered taste), constipation, arthralgia, and fatigue.
4 patients have discontinued due to AEs.
"We are pleased with the safety and tolerability of Bomedemstat in this trial in a patient population, most of whom were intolerant or resistant to hydroxyurea," said Wan-Jen Hong, M.D., CMO, Imago BioSciences. "In addition, the data presented provide evidence of continued durability of the response."

Details on Imago’s ASH (Free ASH Whitepaper) Presentation

Oral Presentation Title: A Phase 2 Study of the LSD1 Inhibitor IMG-7289 (Bomedemstat) for the Treatment of Essential Thrombocythemia (ET)
Session: Myeloproliferative Syndromes: Clinical and Epidemiological: Non-JAK inhibitor Therapies for Myelofibrosis
Presenter: Francesca Palandri, M.D., Ph.D., Institute of Hematology "L. & A. Seràgnoli," Sant’Orsola-Malpighi University Hospital, Bologna, Italy
Date and Time: Sunday, December 12, 2021, at 9:45 AM ET

For further details, please see the ASH (Free ASH Whitepaper) 2021 abstract and presentation on the Imago website here.

About Imago’s Phase 2 Essential Thrombocythemia Program

Essential thrombocythemia (ET) is a rare blood cancer resulting from the overproduction of platelets, which increases the risk of blood clots and bleeding. It is one of the myeloproliferative neoplasms (MPN) family of rare bone marrow diseases, and affects approximately 80,000 – 100,000 patients in the U.S. Imago BioSciences is developing bomedemstat (IMG-7289), an orally administered LSD1 inhibitor, as a potential therapy for patients with ET.

This Phase 2b multi-center, open-label study is designed to assess the safety, efficacy, and pharmacodynamics of bomedemstat, an oral inhibitor of the epigenetic enzyme lysine-specific demethylase 1 (LSD1) (www.clinicaltrials.gov Identifier NCT04254978). Eligible patients aged 18 or older with ET who have failed at least one standard therapy and require treatment in order to lower their platelet count will be considered for participation in this study. Exploratory assessments include the serial measurement of mutant allele frequencies and changing plasma cytokine profiles. The trial is being conducted in the United States, the United Kingdom, Europe, New Zealand, and Australia. Imago BioSciences announced first patient dosed on October 1, 2020. As of November 1, 2021, the trial has enrolled 36 of up to 60 planned study participants.

On December 12, 2021 Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (NYSE: LLY), reported updated clinical data from the pirtobrutinib global Phase 1/2 BRUIN clinical trial in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) (Press release, Eli Lilly, DEC 12, 2021, View Source [SID1234596826]). Pirtobrutinib is an investigational, highly selective, non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor. These data are being presented in oral presentations at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstracts 391 and 381).

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"BRUIN is now the largest clinical trial conducted to date that has enrolled CLL/SLL patients previously treated with modern standards of care including BTK and BCL2 inhibitors. In this real-world population of relapsed/refractory patients, pirtobrutinib continues to demonstrate robust activity with a safety profile amenable to chronic administration. Now with the longer follow-up that this analysis affords, we are encouraged by evidence of durable disease control in this very heavily pretreated CLL/SLL population," said Anthony Mato, M.D., MSCE, director of the CLL Program at Memorial Sloan Kettering Cancer Center and a presenting author. "As recently detailed by a global panel of experts in Clinical Cancer Research, there are currently no evidence-based treatment options for patients following covalent BTK and BCL2 inhibitor therapy. Pirtobrutinib has the potential to offer a meaningful new approach for these CLL/SLL patients, as well as those patients who are less heavily pretreated."

"I’m pleased to share the pirtobrutinib data in MCL patients with the hematology community at ASH (Free ASH Whitepaper)", said Michael Wang, M.D., Puddin Clarke Endowed Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center and a presenting author. "Since our last analysis of these data, we have doubled the number of evaluable BTK pretreated patients and observed a nearly-identical response rate. New treatment options following covalent BTK therapy represent an area of urgent unmet need and the durable response rate observed with pirtobrutinib demonstrates its potential to provide a significant clinical advancement for patients with MCL following covalent BTK therapy."

Key Data Presented at ASH (Free ASH Whitepaper)
As of July 16, 2021, 618 patients were enrolled in the study, including 296 with CLL/SLL, 134 with MCL, and 188 with other B-cell malignancies. The efficacy data presented at ASH (Free ASH Whitepaper) are based on investigator response assessments. Patients were considered efficacy-evaluable if they had at least one post-baseline response assessment or if they discontinued treatment prior to their first post-baseline response assessment.

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
Among the 296 CLL/SLL patients enrolled, 261 were previously treated with a BTK inhibitor and are the subject of this analysis. The median number of prior lines of therapy was three with 100% receiving a prior BTK inhibitor, 88% an anti-CD20 antibody, 79% chemotherapy, 41% venetoclax, 20% a PI3K inhibitor, 6% CAR-T therapy and 2% stem cell transplant.

In 252 efficacy-evaluable patients (an additional nine patients ongoing prior to first restaging), 171 responded including two complete responses (CR), 137 partial responses (PR), 32 partial responses with ongoing lymphocytosis (PR-L), and 62 stable disease (SD), resulting in an overall response rate (ORR) of 68% (95% CI: 62-74). Responses continue to deepen over time, with the ORR rising to 73% (88/119) for those followed 12 months or more, and ORR remains consistent regardless of reason for prior BTK discontinuation, type or number of prior therapies or BTK C481 or PCLG2 mutational status.

Pirtobrutinib demonstrated evidence of durable activity with a median progression-free survival (PFS) not reached in patients who had received at least a prior BTK inhibitor (lower limit of 95% confidence interval of 17.0 months, median of three prior lines of therapy). In patients who had received at least a BTK inhibitor and BCL2 inhibitor (median of five lines of prior therapy), the estimated median PFS was 18 months, although these data remain immature and unstable due to the small percentage of patients with progression. As of the data cut-off, 74% (194/261) of BTK pre-treated patients remained on pirtobrutinib. Median follow-up for all BTK pre-treated patients was 9.4 months (range 0.3-27.4 months).

In an exploratory analysis in patients with prior progression on a BTK inhibitor, the PFS with pirtobrutinib was similar in patients with BTK C481-mutated and BTK C481-wildtype CLL and SLL.

Mantle cell lymphoma (MCL)
The 134 patients with MCL received a median of three prior lines of therapy, with 90% receiving a prior BTK inhibitor, 97% an anti-CD20 antibody, 91% chemotherapy, 22% stem cell transplant, 17% immunomodulatory (IMiD) drugs, 15% venetoclax, 13% proteasome inhibitor, 5% CAR-T cell therapy, and 4% PI3K inhibitor.

Of the 100 efficacy-evaluable patients with BTK pre-treated MCL (an additional 23 patients ongoing prior to first restaging, 11 patients had not received a prior BTK inhibitor), 51 responded including 25 CRs and 26 PRs resulting in an ORR of 51% (95% CI: 41-61). Among 11 BTK naïve MCL patients, nine responded including two CRs and seven PRs resulting in an ORR of 82% (95% CI: 48-98). Responses in MCL were observed in patients who received prior stem cell transplant and prior CAR-T therapy.

Median duration of response was 18 months (lower limit of 95% confidence interval of 4.6 months). Median follow-up for all responding MCL patients was 8.2 months (range of 1.0-27.9 months) with 60% (36/60) of responses ongoing as of the data cut-off.

Safety data were presented for the entire enrolled BRUIN population. Across all 618 patients enrolled in the study, the most commonly reported adverse events, regardless of attribution, were fatigue (23%), diarrhea (19%), neutropenia (18%) and contusion (17%). In addition, adverse events commonly associated with covalent BTK inhibitors occurred at a low rate, with the majority being Grade 1 or 2. During the Phase 1 dose escalation, no dose limiting toxicities were reported and a maximum tolerated dose (MTD) was not reached. Permanent discontinuations for drug-related adverse events were observed in 1% (n=6) of patients.

"As the pirtobrutinib data continue to mature we remain extremely excited by its potential to meaningfully improve the treatment landscape for patients with CLL, SLL and MCL", said David Hyman, M.D., chief medical officer, oncology at Lilly. "We have initiated a robust Phase 3 program for pirtobrutinib and look forward to further exploring its potential as monotherapy, in combination, and in earlier lines of therapy."

Real-world evidence studies
A real-world evidence database study on outcomes for patients with CLL previously treated with a covalent BTK inhibitor and a BCL2 inhibitor will be presented in a poster presentation on Monday, December 13 from 6-8 p.m. ET (abstract 3743). Additionally, a study on outcomes for patients with MCL following covalent BTK inhibitor therapy was published as an online-only abstract (abstract 4523).

Loxo Oncology at Lilly is studying pirtobrutinib in multiple Phase 3 studies. Details on the trials can be found in Trials in Progress posters (abstracts 2422, 3732, 3736 and 3742) and on lillyloxooncologypipeline.com.

About Pirtobrutinib (LOXO-305)
Pirtobrutinib is an investigational, highly selective, non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma. Currently available covalent BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies can be limited by acquired resistance, most commonly through BTK C481 mutations. In rapidly growing tumors with inherently high rates of BTK turnover, resistance to covalent BTK therapies may be the result of incomplete target inhibition. Pirtobrutinib was designed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. Interested patients and physicians can contact the Loxo Oncology at Lilly Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email [email protected].

About the BRUIN Phase 1/2 Trial
This first-in-human, global, multi-center Phase 1/2 trial evaluates pirtobrutinib as a single agent in patients with previously treated chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin’s lymphomas (NHL). The trial includes a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The Phase 1 dose escalation enrolls patients with CLL/SLL or NHL who have received at least two prior lines of therapy and have progressed or are intolerant to standard of care. The dose escalation phase followed a "3+3" design with pirtobrutinib dosed orally in 28-day cycles. As dose cohorts were cleared, additional patients could enroll in cleared cohorts and intra-patient dose escalation was permitted. The primary objective of the Phase 1 portion of the trial is to determine the maximum tolerated dose and recommended Phase 2 dose. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Overall Response Rate (ORR) and Duration of Response, as determined by appropriate histology-specific response criteria). In the Phase 2 dose expansion, patients are enrolled across various cohorts, depending on disease type and prior therapy. The primary endpoint for Phase 2 is ORR. Secondary endpoints include duration of response (DOR), overall survival (OS), safety, and pharmacokinetics (PK).

About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.

On December 12, 2021 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that updated initial safety and efficacy findings from the Phase 1b/2 study of IMGN632 in combination with Vidaza (azacitidine) and Venclexta (venetoclax) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were presented in an oral session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, ImmunoGen, DEC 12, 2021, View Source [SID1234596824]). Data for IMGN632 in frontline patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) were also presented in a poster session at the conference.

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"The unmet need in AML remains large, as patients typically have low survival rates despite initial response," said Naval Daver, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "Together, the observed anti-leukemia activity and tolerability of IMGN632 in the relapsed/refractory setting are compelling and support the continued evaluation of this triplet in AML patients. I look forward to the next steps for IMGN632 in combination with azacitidine and venetoclax, with preparations for Phase 2 expansion cohorts already underway in both the relapsed and frontline AML settings."

IMGN632 TRIPLET DATA IN AML

Title (Abstract #372): "Safety and Efficacy from a Phase 1b/2 Study of IMGN632 in Combination with Azacitidine and Venetoclax for Patients with CD123-Positive Acute Myeloid Leukemia"
Oral Session: 616
Session Date: Sunday, December 12, 2021
Session Time: 9:30 am – 11:00 am

Updated key findings from the Phase 1b/2 study of IMGN632 in combination with azacitidine and venetoclax include:

Safety

IMGN632 was administered to 51 patients at 15 mcg/kg or 45 mcg/kg, azacitidine at 50-75 mg/m2 for 7 days, and venetoclax at 400 mg daily for 8-21 days per 28-day cycle.
IMGN632 continued to display a manageable safety profile in R/R AML patients.
The most common treatment emergent adverse events all grades [grade 3+ events] seen in >20% of patients were infusion-related reactions (33% [2%]), febrile neutropenia (31% [26%]), dyspnea (28% [8%]), fatigue (28% [0%]), hypophosphatemia (26% [2%]), diarrhea (22% [0%]), hypokalemia (22% [2%]), nausea (22% [0%]), vomiting (22% [0%]), and pneumonia (20% [16%]).
No tumor lysis syndrome, veno-occlusive disease, capillary leak, or cytokine release were reported.
Efficacy

Responses were seen across all cohorts/doses and schedules (efficacy evaluable population, n=46). The objective response rate (ORR) was 48%, with a composite complete remission (CCR) rate of 30% (4 CR, 8 CRh, 1 CRp, 1 CRi).
Higher intensity cohorts (n=29) were associated with higher response rates including an ORR of 59% and a CCR rate of 38% (4 CR, 6 CRh, 1 CRp).
Significant activity was also observed in the FLT3 mutant subset (n=9), with ORR and CCR rates of 89% and 78%, respectively.
Enrollment continues at the putative recommended Phase 2 dose (IMGN632 45 mcg/kg IV on day 7, azacitidine 50 or 75 mg/m2 on days 1-7, and venetoclax 400 mg on days 1-14).
"These data reinforce the potential of IMGN632 as a new therapy for patients with relapsed/refractory AML. We are very encouraged by the manageable safety profile and 38% composite complete remission rate seen in the higher intensity cohorts," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "We look forward to further exploring the safety and efficacy of this triplet in Phase 2 expansion cohorts planned for next year. We believe IMGN632 also has the potential to become a best-in-class monotherapy treatment option for patients with BPDCN. Based on the results seen in three frontline patients, we continue to enroll patients in our pivotal study, CADENZA, and look forward to sharing top-line data in the second half of 2022."

IMGN632 MONOTHERAPY IN FRONTLINE BPDCN

Poster Presentation, Abstract #1284

IMGN632, administered as a brief outpatient infusion, was evaluated as monotherapy in frontline BPDCN patients. Three patients received IMGN632 prior to commencement of the enrolling pivotal cohort and achieved a clinical complete remission (CRc). IMGN632 in these three frontline BPDCN patients was associated with a favorable safety profile and limited grade 3+ TEAEs. Enrollment continues in the pivotal frontline and R/R cohorts.

Additional information can be found at www.hematology.org, including abstracts.

ABOUT IMGN632

IMGN632 is a CD123-targeting ADC in clinical development for hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), and other CD123+ hematologic malignancies. IMGN632 is currently being evaluated in multiple cohorts, including monotherapy for patients with BPDCN and minimal residual disease positive (MRD+) AML and in combinations with Vidaza (azacitidine) and Venclexta (venetoclax) for patients with relapsed/refractory AML. IMGN632 uses one of ImmunoGen’s novel indolinobenzodiazepine (IGN) payloads, which alkylate DNA and cause single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. The FDA granted IMGN632 Breakthrough Therapy Designation in relapsed/refractory BPDCN.

ABOUT ACUTE MYELOID LEUKEMIA (AML)

AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia. It is estimated that, in the U.S. alone, more than 20,000 people will be diagnosed with AML this year and more than 11,000 will die from the disease.

ABOUT BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN)

BPDCN is a rare form of blood cancer that has features of both leukemia and lymphoma, with characteristic skin lesions, lymph node involvement, and frequent spread to the bone marrow. This aggressive cancer requires intense treatment often followed by stem cell transplant. Despite the approval of a CD123-targeting therapy, the unmet need remains high for patients, both in the frontline and in the relapsed/refractory setting.

ABOUT CD123

CD123, the interleukin-3 alpha chain, is expressed on multiple myeloid and lymphoid cancers including AML, BPDCN, ALL, chronic myeloid leukemia, and myeloproliferative neoplasms. With limited expression on normal hematopoietic cells, rapid internalization, and expression on AML leukemia stem cells, CD123 is a validated therapeutic target, with the approval of a CD123-targeting therapy for BPDCN.