On June 4, 2022 MEI Pharma, Inc. (NASDAQ: MEIP), a latestage pharmaceutical company focused on advancing new therapies for cancer, and Kyowa Kirin Co., Ltd. (Kyowa Kirin, TSE: 4151), a global specialty pharmaceutical company creating innovative medical solutions utilizing the latest biotechnology, reported data from the ongoing Phase 2 TIDAL study evaluating the intermittent dosing of zandelisib, an orally administered investigational phosphatidylinositol 3-kinase delta ("PI3Kδ") inhibitor in clinical development for the treatment of B-cell malignancies, is highlighted in a poster and oral discussion session at the of American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting(Press release, Kyowa Hakko Kirin, JUN 4, 2022, View Source [SID1234615564]).

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"The Phase 2 TIDAL data generated to date continue to highlight zandelisib’s therapeutic profile and the potential to benefit patients, supporting our commitment to advancing the program and our already ongoing randomized Phase 3 COASTAL study with our partner, Kyowa Kirin," said Richard Ghalie, M.D., chief medical officer of MEI Pharma. "In light of the promising results from TIDAL to date, we remain committed to the zandelisib program with our primary focus being on COASTAL, our ongoing Phase 3, randomized, study evaluating zandelisib in combination with rituximab in follicular and marginal zone lymphoma patients with at least one prior line of therapy."

"We are very pleased to present data from Phase 2 TIDAL study in ASCO (Free ASCO Whitepaper) meeting," said Yoshifumi Torii, Ph.D., Executive Officer, Vice President, Head of R&D Division of Kyowa Kirin. We continue to see favorable profile of zandelisib that balances efficacy and safety. We remain committed to maximizing the value of zandelisib in B-cell malignancies with our partner MEI Pharma."

Clinical Data from the Phase 2 TIDAL Study Evaluating Zandelisib in Patients with Relapsed or Refractory Follicular Lymphoma
• Presentation Title: Efficacy and safety of zandelisib administered by intermittent dosing (ID) in patients with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the global phase 2 study TIDAL
• Session Title: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
• Presenter: Andrew David Zelenetz, Ph.D., M.D.
• Date and Time: Saturday, June 4, 2022, at 3:00 Central Time
• Poster ID: 7511 / 165

Study Details The ongoing TIDAL study (NCT03768505) is a global, open-label Phase 2 trial evaluating zandelisib as a single agent in two disease cohorts: one in relapsed or refractory (r/r) follicular lymphoma (FL) and one for r/r marginal zone lymphoma (MZL), in both cases after failure of at least two prior systemic therapies, including chemotherapy and an anti-CD20 antibody. Patients were administered zandelisib once daily for two 28-day cycles as response induction therapy, followed thereafter by once daily dosing for the first seven days of each subsequent 28-day cycle, a schedule called Intermittent Dosing (ID). Enrollment in the FL cohort is complete; enrollment in the MZL cohort is ongoing.

The FL cohort enrolled a total of 121 patients, with the first 91 consisting of the primary efficacy population (PEP) for the evaluation of overall response rate (ORR) and duration of response (DOR).

The median age of patients enrolled with FL was 64 years old. Enrolled patients were generally heavily pretreated; the median number of prior therapies was 3 (range 2-8) and 96% of patients had received prior chemoimmunotherapy. Further, 28 patients (23%) received prior stem cell transplant, 50 patients (41%) were refractory to last therapy, 41 patients (34%) had tumors ≥5 cm, and 68 patients (56%) were POD24 (progression of disease within 24 months of prior chemoimmunotherapy). The primary efficacy endpoint is ORR as assessed by independent review committee (IRC) using a modified Lugano criteria. The data cutoff date is September 30, 2021, approximately 6 months after the last patient in the PEP received their first dose of zandelisib. Data from the enrolling MZL cohort is not reported.

Efficacy The primary endpoint of ORR of zandelisib as a single agent in the PEP was 70.3% (N=64), 95% CI=59.8, 79.5, as assessed by IRC; the complete response rate was 35.2% (N=32), 95% CI=25.4, 45.9. Responses across sub-groups (i.e. response to last treatment, number of prior therapies and POD24) were all >63%. Response Rates by Independent Review Committee in All PEP Patients and by Subgroup Response to Last Treatment Number of Prior Therapies POD24 n(%) Efficacy Population (n=91) Relapsed (n=49) Refractory (n=42) 2 (n=42) >2 (n=49) Yes (n=51) No (n=40) ORR (CR or PR) 64 (70.3) 37 (75.5) 27 (64.3) 33 (78.6) 31 (63.3) 34 (66.7) 30 (75.0) CR 32 (35.2) 20 (40.8) 12 (28.6) 18 (42.9) 14 (28.6) 16 (31.4) 16 (40.0) CR, complete response; PEP, primary efficacy population; POD24 progression of disease within 24 months; PR, partial response. Responses were first observed in the first two cycles of therapy in 87.5% of all responses (N=56) and 75% of all CRs (N=24) were observed in the first four cycles. As of the data cutoff date, the data are not sufficiently mature to accurately estimate the final DOR in the PEP.

Safety and Tolerability With a median follow-up of 9.4 months (range 0.8-24) in the safety population of 121 patients, 9.9% (N=12) of patients had discontinued therapy due to any drug-related adverse event. Grade 3 adverse events of special interest (AESI) were diarrhea in 5% (N=6), colitis in 1.7% (N=2), cutaneous rash in 3.3% (N=4), stomatitis in 2.5% (N=3), and 0.8% (N=1) each for AST and ALT elevation, and non-infectious pneumonitis. Grade 3 AESIs primarily (83%, 15 of 18) occurred in cycles 1-3, with only 3 cases reported on ID in Cycles ≥4. No Grade 4 or Grade 5 AESI were recorded. Cumulative Incidence of Time to First Occurrence of Grade 3 AESI Treatment-emergent COVID-19 infections were reported in 8.3% (N=10) of patients, and 8.3% (N=10) of patients reported other Grade 3 infections. Four COVID infections were fatal, as were 1 case each of pneumonia and Tumor Lysis Syndrome About Zandelisib Zandelisib, a selective PI3Kδ inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, treatment for patients with B-cell malignancies. Clinical trials are investigating the efficacy and safety of zandelisib as a single agent and in combination with other modalities while administered on an Intermittent Dosing Regimen (ID) and in a timelimited manner when dosed in combination. The ID leverages molecular and biologic properties specific to zandelisib. In November 2021, MEI Pharma and Kyowa Kirin announced topline data from ongoing Phase 2 TIDAL study (NCT03768505) evaluating zandelisib as a single agent for follicular lymphoma (FL) patients who received at least two prior systemic therapies. Zandelisib demonstrated a 70.3% objective response rate (ORR) as determined by an Independent Review Committee (IRC) assessment in the primary efficacy population (n=91). In addition, 35.2% of patients achieved a complete response. At the time of the data cutoff, the data were insufficiently mature to accurately estimate duration of response (DOR). In line with previously reported data from the Phase 1B study, zandelisib was generally well tolerated. With 9.4 months (range: 0.8-24) median duration of follow-up in the total study population (n=121), interim data demonstrated a discontinuation rate due to any drug related adverse event of 9.9%.

Patients enrolled in the study will continue to be followed for safety and DOR. Ongoing zandelisib studies include the cohort in TIDAL evaluating patients with r/r marginal zone lymphoma (MZL) and continuing evaluation of the cohort of patients in the study with r/r FL. Also ongoing is the Phase 3 COASTAL study (NCT04745832), comparing zandelisib plus rituximab to standard of care chemotherapy plus rituximab in patients with r/r FL or MZL who received more than one prior line of therapy, which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide. COASTAL, which is also evaluating timelimited intermittent administration of zandelisib, is intended to support marketing applications in the U.S. and globally. Other ongoing studies include a Phase 2 pivotal study in Japan (NCT04533581) in patients with indolent B-cell non-Hodgkin’s lymphoma (iB-NHL) without small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and Waldenström’s macroglobulinemia (WM) conducted by Kyowa Kirin. In March 2020, the FDA granted zandelisib Fast Track designation for the treatment of adult patients with r/r follicular lymphoma who have received at least two prior systemic therapies. In November 2021, the FDA granted zandelisib Orphan Drug designation for the treatment of patients with follicular lymphoma. In April 2020, MEI and Kyowa Kirin entered a global license, development, and commercialization agreement to further develop and commercialize zandelisib. MEI and Kyowa Kirin will co-develop and co-promote zandelisib in the U.S., with MEI booking all revenue from the U.S. sales. Kyowa Kirin has exclusive commercialization rights outside of the U.S. About Follicular Lymphoma Follicular lymphoma (FL) is the most common indolent lymphoma, comprising about 20-30% of all non-Hodgkin lymphomas (NHL).

The disease also develops in B lymphocytes, is chronic in most cases and tends to progress slowly. Most people diagnosed with FL are over 65 years of age. Sometimes follicular lymphomas can transform into a more aggressive form of large B-cell lymphoma, a fast-growing (aggressive) type of NHL.

On June 4, 2022 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported the presentation of encouraging clinical data from both the TakeAim Lymphoma and TakeAim Leukemia studies at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting currently taking place in Chicago and online until June 7, 2022 (Press release, Curis, JUN 4, 2022, View Source [SID1234615562]).

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"We are excited to share data with the oncology community from our TakeAim Lymphoma and TakeAim Leukemia studies at ASCO (Free ASCO Whitepaper), including the first release of clinical data investigating the use of emavusertib in combination with ibrutinib in patients with Non-Hodgkin’s Lymphoma," said James Dentzer, President and Chief Executive Officer of Curis. "These data demonstrate encouraging signs of anti-cancer activity, including a complete response in a primary CNS lymphoma patient who had prior treatment with ibrutinib. We also presented a poster with data from the TakeAim Leukemia study, previously disclosed in a January 2022 press release, demonstrating emavusertib’s encouraging monotherapy activity in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS)."

"In addition to the data from Curis’s studies, there are presentations at the meeting this year by our collaborators at Washington University and the University of Florida, which help more fully explore emavusertib’s use in tumor types outside of the company’s current focus in hematologic malignancies," said Robert Martell, M.D., Ph.D., Head of Research and Development.

TakeAim Lymphoma:
The TakeAim Lymphoma study is a Phase 1/2 open-label, dose escalation, dose expansion clinical trial investigating emavusertib as monotherapy and in combination with ibrutinib in patients with R/R hematologic malignancies, such as non-Hodgkins’s lymphoma and other B cell malignancies. The poster presentation (#7575) made by Dr. Grzegorz Nowakowski, Division of Hematology, Mayo Clinic-Minnesota, today at ASCO (Free ASCO Whitepaper) includes clinical data from a May 6, 2022 data cutoff, on 13 patients who received the combination, 9 of whom had post-baseline response assessments and were evaluable for response.

Key findings in patients treated with the combination included:

The combination appeared to be well tolerated
No dose-limiting toxicities (DLTs) at 200mg of emavusertib; 2 DLTs observed at 300mg (stomatitis and syncope)
8 of 9 evaluable patients experienced reduction in tumor burden, including:
2 complete responses (CR) (primary CNS lymphoma and mantle cell lymphoma)
2 partial responses (PR) (chronic lymphocytic leukemia and mantle cell lymphoma)
One of the CRs was in a patient who had received prior treatment with ibrutinib, suggesting that the combination may be able to overcome ibrutinib resistance
Next steps for the TakeAim Lymphoma study include further dose expansion in order to determine the Recommended Phase 2 Dose for the combination.

TakeAim Leukemia:
The TakeAim Leukemia study is a Phase 1/2 dose escalation and dose expansion study examining emavusertib use as both monotherapy and in combination with azacitidine or venetoclax in patients with R/R AML or high risk MDS. The poster presentation (#7016) made by Dr. Guillermo Garcia-Manero, Chief of the Section of Myelodysplastic Syndromes within the Department of Leukemia at The University of Texas MD Anderson Cancer Center, today at ASCO (Free ASCO Whitepaper), include clinical data from a December 16, 2021 data cutoff for the 49 patients who had been treated with emavusertib in monotherapy as of that date.

Key safety findings included:

Emavusertib was well-tolerated across multiple dose levels, including at the Recommended Phase 2 Dose of 300 mg BID
No dose-limiting myelosuppression observed
No cumulative toxicities observed
These attributes of emavusertib’s emerging safety profile may provide an advantage compared to current standard of care therapies in monotherapy and may also make emavusertib an attractive candidate for addition to combination therapy regimens.

Key tumor assessment findings included:

Collaborator Studies:
In patients with spliceosome-mutated R/R AML:
CR/CRh rate of 40% (2 out of 5 patients) (CRh=complete response with partial hematologic recovery)
Both patients who achieved CR/CRh have been on study > 6 months and achieved negative MRD (minimal residual disease) status
Consistent tumor burden reduction observed, 4 out of 5 patients achieved blast reduction, 3 of whom by ≥ 50%
In patients with spliceosome-mutated R/R MDS:
Objective response rate of 57% (4 out of 7 patients)
One of the patients who achieved a marrow CR (mCR) proceeded to stem cell transplant after 1 cycle
Consistent tumor burden reduction observed, with 4 out of 6 patients with elevated baseline blast counts achieving ≥ 50% reduction in blast counts
In patients with FLT3-mutated R/R AML:
CR rate of 33% (1 out of 3 patients)
2 out of 3 patients showed eradication of FLT3 mutation following treatment, indicating potential for disease modification with emavusertib
Consistent tumor burden reduction observed with 2 out of 3 patients with elevated blast counts achieving ≥ 50% reduction in blast counts
Being presented today (#TPS4168) is work in gastric cancer by Dr. Kian-Huat Lim’s team at Washington University School of Medicine. Based on compelling preclinical work, Dr. Lim and his team have developed a clinical study exploring combination of emavusertib (CA-4948) in combination with FOLFOX chemotherapy plus nivolumab or pembrolizumab. Preclinically, it has been established that chemotherapy resistance can be driven by TLR9 activation and IRAK4 dependent activation of pro-survival NF-kB signaling. Inhibition of IRAK4 has been shown to block this signaling, and to reduce tumor desmoplasia along with revitalization of intratumoral T-cells, setting the stage for combination with immune checkpoint inhibitors. This study is active, but not yet recruiting.

Being presented tomorrow (#2011), June 5, is preclinical work from Dr. Duane Mitchell’s team at the University of Florida, which investigated emavusertib (CA-4948) in melanoma brain metastasis where IRAK4-dependent signaling is known to be high. Emavusertib exposure in the brain and in brain tumors achieved therapeutically relevant levels, resulted in substantial reduction of B16.F10 tumor volume and prolonged survival of the mice.

About Emavusertib (CA-4948)
Emavusertib is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with cancer. TLRs and the IL-1R family signal through the adaptor protein MYD88, which results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the NF-κB protein complex. Additionally, third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutation such as SF3B1 and U2AF1. In addition to inhibiting IRAK4, emavusertib was also designed to inhibit FLT3, a known oncologic driver, which may provide additional benefit in patients with AML and MDS.

On June 4, 2022 AstraZeneca it’s Updated results from the ELEVATE-TN Phase III trial showed Calquence (acalabrutinib) maintained a statistically significant progression-free survival (PFS) benefit versus chlorambucil plus obinutuzumab and a safety and tolerability profile consistent with the known profile for Calquence at a median follow up of approximately five years in combination and as a monotherapy in chronic lymphocytic leukaemia (CLL) (Press release, AstraZeneca, JUN 4, 2022, View Source [SID1234615559]).1

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Results also showed longer overall survival (OS) for Calquence combined with obinutuzumab compared with chlorambucil combined with obinutuzumab in previously untreated adults with CLL.1 CLL is the most prevalent type of leukaemia in adults, with over 100,000 patients diagnosed globally in 2019.2

At a median follow-up of 58.2 months, Calquence plus obinutuzumab reduced the risk of disease progression or death by 89% (based on a hazard ratio [HR] of 0.11, 95% confidence interval [CI] 0.07-0.16) and as a monotherapy by 79% (based on a HR of 0.21, 95% CI 0.15-0.30), compared with chlorambucil plus obinutuzumab.1 OS data are immature, and medians were not yet reached in any treatment arm.1 The relative risk for death was 45% lower in the Calquence plus obinutuzumab arm (based on a HR of 0.55, 95% CI 0.30-0.99).1 An estimated 90% of patients treated with the Calquence combination were alive at five years versus 84% for Calquence alone and 82% for chlorambucil plus obinutuzumab.1

Separately, follow-up data from the ASCEND Phase III trial showed Calquence demonstrated a sustained PFS benefit at four years based on investigator assessment compared with investigator’s choice of rituximab combined with either idelalisib (IdR) or bendamustine (BR) in adults with relapsed or refractory CLL.3 At 42 months, an estimated 62% of patients treated with Calquence were alive and had not progressed in comparison with 19% of patients treated with IdR/BR.3 The median follow-up was 46.5 months for Calquence and 45.3 months for IdR/BR.3

The safety and tolerability of Calquence in the ELEVATE-TN and ASCEND trials were consistent with earlier findings, with no new safety signals identified.1,3

Jeff P. Sharman, MD, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for the US Oncology Network, and a lead investigator of the ELEVATE-TN trial, said: "These data from ELEVATE-TN, with nearly five years of follow-up, support what I have seen in clinical practice and provide clinicians with further reassurance when prescribing this therapy. Patients with chronic lymphocytic leukaemia often remain on therapy for many years, so long-term efficacy and tolerability are critical factors that physicians consider when deciding on a treatment plan. These data show that acalabrutinib combined with obinutuzumab helped previously untreated patients live longer compared with chlorambucil plus obinutuzumab and was generally well-tolerated."

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: "We are committed to bringing efficacious and safe treatments to patients with haematological diseases. With chronic lymphocytic leukaemia, these two factors are particularly important due to the chronic nature of the disease and the likelihood of patients having comorbidities. The totality of our longer-term data at ASCO (Free ASCO Whitepaper) show Calquence’s efficacy benefits and sustained safety profile in key treatment settings, providing more options for patients and their physicians."
The results were presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on 4 June 2022.

NR, not reached; ORR, overall response rate
*Investigator-assessed
†P-values are descriptive and not adjusted for multiplicity

Treatment is ongoing in 65% of patients on Calquence plus obinutuzumab and 60% of patients on Calquence monotherapy.1 The most common reasons for treatment discontinuation were adverse events (AEs) (17%, 16% and 14% for Calquence plus obinutuzumab, Calquence monotherapy and chlorambucil plus obinutuzumab, respectively) and progressive disease (6%, 10% and 2%, respectively).1

Median treatment exposures were 58.1 months and 5.5 months, respectively, for Calquence and obinutuzumab in the Calquence combination arm; 58.0 months for Calquence in the monotherapy arm; and 5.5 months and 5.6 months, respectively, for chlorambucil and obinutuzumab in the chlorambucil plus obinutuzumab arm.1 Selected AEs of interest of any grade in the Calquence combination arm, Calquence monotherapy arm and chlorambucil plus obinutuzumab arm included bleeding (49.4%, 43.6% and 11.8%, respectively), hypertension (9.6%, 8.9% and 3.6%, respectively) and atrial fibrillation (6.2%, 7.3% and 0.6%, respectively).1 Common AEs (any grade, greater than or equal to 30% of patients) observed with Calquence with or without obinutuzumab included diarrhoea, headache, arthralgia and neutropenia.1

INV-assessed ORR inc. PR with lymphocytosis, %

*Investigator-assessed

Median treatment exposures were 44.2 months for Calquence; 11.5 months and 5.5 months, respectively, for idelalisib and rituximab in the IdR arm; and 5.6 months and 5.5 months, respectively, for bendamustine and rituximab in the BR arm.3 AEs led to treatment discontinuation in 23% of patients in the Calquence arm, 67% of patients in the IdR arm and 17% of patients in the BR arm.3 Events of clinical interest for Calquence versus comparators included atrial fibrillation/flutter (all grade, 8% and 3%, respectively), hypertension (all grade, 8% and 5%, respectively), major haemorrhage (all grade, 3% in both arms) and infections (greater than or equal to grade 3, 29% in both arms).3 Common AEs (any grade, greater than or equal to 15% of patients; or grade 3 or higher, greater than or equal to 5% of patients) observed with Calquence included neutropenia, headache, diarrhoea and upper respiratory tract infection.3

Notes

CLL
CLL is the most prevalent type of leukaemia in adults, with over 100,000 new cases globally in 2019 and an estimated 20,160 new cases in the US in 2022.2,4 Although some people with CLL may not experience any symptoms at diagnosis, others may experience symptoms, such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes and abdominal pain.5

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

ELEVATE-TN
ELEVATE-TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence alone or in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL. In the trial, 535 patients were randomised (1:1:1) into three arms.7 Patients in the first arm received chlorambucil in combination with obinutuzumab.7 Patients in the second arm received Calquence (100mg twice daily until disease progression) in combination with obinutuzumab.7 Patients in the third arm received Calquence monotherapy (100mg twice daily until disease progression).7

The primary endpoint was PFS in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint was IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm.7 Other secondary endpoints included overall response rate, time to next treatment, OS and investigator assessed PFS.7 After interim analysis, assessments were by investigator only.7,8

Initial results from the ELEVATE-TN Phase III trial were presented in December 2019 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exhibition.9 The trial met its primary endpoint (IRC-assessed PFS with Calquence plus obinutuzumab versus chlorambucil plus obinutuzumab) at the data cut-off for the interim analysis after a median follow-up of 28.3 months.8 The findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, supported the approvals of Calquence by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by the European Medicines Agency (EMA) and Health Canada 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.10

In the trial, 310 patients were randomised (1:1) into two treatment arms.10 Patients in the first arm received Calquence monotherapy (100mg twice-daily until disease progression or unacceptable toxicity).10 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.10

The primary endpoint at the interim analysis was PFS assessed by an 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.10,11

ASCEND is the first randomised Phase III trial to directly compare a BTK inhibitor as monotherapy to these combinations in relapsed or refractory CLL.11

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.12,13 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 SLL in the US, approved for CLL in the EU and many 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, marginal zone lymphoma and other haematologic malignancies.

AstraZeneca in haematology
AstraZeneca is pushing the boundaries of science to redefine care in haematology. We have expanded our commitment to patients with haematologic conditions, not only in oncology but also in rare diseases with the acquisition of Alexion, allowing us to reach more patients with the greatest unmet needs. By applying our deep understanding of blood cancers, leveraging our strength in solid tumour oncology and delivering on Alexion’s pioneering legacy in complement science to provide transformative medicines for rare diseases, we are pursuing the end-to-end development of novel therapies designed to target underlying drivers of disease.

By targeting haematological conditions with high unmet medical needs, we aim to deliver innovative medicines and approaches to improve patient outcomes. Our goal is to transform the lives of patients living with malignant, rare and other related haematologic diseases, shaped by insights from patients, caregivers and physicians to have the most meaningful impact.

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 June 3, 2022 Novartis reported results of an exploratory retrospective biomarker analysis finding that different genetic mutation profiles in tumors harboring PIK3CA mutation did not affect treatment benefit with Piqray (alpelisib) plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer following progression on or after an endocrine-based regimen (Press release, Novartis, JUN 3, 2022, View Source [SID1234634694]). Selected as an oral presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #1006), the retrospective analysis of data from the Phase III SOLAR-1 study found that the clinical benefit of the Piqray and fulvestrant combination was maintained regardless of genetic alterations in most biomarkers, including ESR1 and genes implicated in resistance to CDK4/6 inhibitors1.

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"This analysis evaluating alpelisib and fulvestrant across HR+/HER2- advanced breast cancer tumors with different genetic alterations confirms the importance of using alpelisib to selectively target PIK3CA as a major oncogenic driver in these tumors," said Dejan Juric, MD, Director, Termeer Center for Target Therapies, Mass General Cancer Center in Boston.

"PIK3CA mutations affect approximately 40% of those with the HR+/HER2- subtype and are known oncogenic drivers of metastatic breast cancer, associated with endocrine resistance and an overall worse prognosis—so it’s critical for physicians to test and treat with Piqray for patients with PIK3CA mutations upfront consistent with ASCO (Free ASCO Whitepaper) and NCCN guidelines," said Reshema Kemps-Polanco, Executive Vice President, US Oncology at Novartis.

Highlights from the SOLAR-1 biomarker retrospective analysis at ASCO (Free ASCO Whitepaper)

Patients with ESR1 gene alterations achieved 12.0 months of median progression-free survival (mPFS) when treated with Piqray and fulvestrant compared to 6.5 months for those treated with fulvestrant alone1.
Even patients with FGFR1 and FGFR2 gene alterations, which have been associated with resistance to CDK4/6 inhibitors, had benefit when treated with Piqray plus fulvestrant (12.7 months and 9.6 months mPFS, respectively), compared to those treated with fulvestrant alone (3.8 months and 2.8 months mPFS, respectively)1.
The benefit seen with the Piqray and fulvestrant combination was independent of additional genetic alterations, including TP53, CCND1, MAP3K1 and ARID1A; genes in the MAPK pathway, genes implicated in CDK4/6 inhibitor resistance such as RB11.
Real-world evidence supports effectiveness of Piqray in tumors with PIK3CA mutation
A real-world retrospective analysis (Abstract #1055) showed clinical benefit for 157 patients with HR+/HER2- advanced or metastatic breast cancer with PIK3CA genetic mutation following treatment with Piqray plus fulvestrant, even when exposed to prior treatment with fulvestrant, confirming the oncogenic dependence of the tumor on the PIK3CA mutation2. In the analysis, prior fulvestrant treatment included CDK4/6 inhibior plus fulvestrant (74.5%), fulvestrant alone (33.8%), and non-CDK4/6 inhibitor plus fulvestrant (21.0%)2.

About PIK3CA-mutated Breast Cancer
An estimated 361,826 people are diagnosed with metastatic breast cancer worldwide each year, and approximately 40% of those with HR+/HER2- subtype have tumors that harbor a PIK3CA mutation, which is associated with a poor prognosis6-7.

About Piqray (alpelisib)
Piqray is a kinase inhibitor developed for use in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR+/HER2-, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after endocrine-based regimen3. Piqray is approved in over 70 countries, including the US6. In the European member states, Piqray plus fulvestrant is approved after disease progression following endocrine therapy as monotherapy8.

Novartis is continuing to reimagine cancer with additional trials of Piqray. To complement the SOLAR-1 study, EPIK-B5, a large Phase III clinical trial is conducted with Piqray in combination with fulvestrant following treatment with a CDK4/6 inhibitor and aromatase inhibitor9. Novartis is also studying the potential of Piqray in triple-negative breast cancer (TNBC) in the EPIK-B3 Phase III clinical trial, in advanced HER2+ breast cancer in the EPIK-B2 Phase III clinical trial and in ovarian cancer in the EPIK-O Phase III clinical trial10-12.

On June 3, 2022 Helix BioPharma Corp. (TSX: "HBP") ("Helix" or the "Company"), a clinical-stage biopharmaceutical company developing unique therapies in the field of immuno-oncology, based on its proprietary technological platform DOS47, reported that it has successfully closed its Early Warrant Exercise Incentive Program (the "Incentive Program") and Extension of Warrant Exercise Period ("Warrant Extension"), previously announced on March 11, 2022 and April 13, 2022 (Press release, Helix BioPharma, JUN 3, 2022, View Source [SID1234615761]). The Company has received gross proceeds of $3,210,204 from the exercise of 12,346,938 share purchase warrants at $0.26 per share.

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The balance of the warrants not exercised under this Incentive Program and Warrant Extension will remain outstanding and continue to be exercisable for common shares of the Company on their original terms.

The proceeds from the Incentive Program and Warrant Extension will be used for working capital purposes and advancing the Company’s L-DOS47 drug development program.

Artur Gabor, CEO of Helix, stated "We are extremely grateful for the support and belief in the Company from the warrant holders that participated in our Early Warrant Exercise Incentive Program and Warrant Extension. This is significant as it demonstrates their belief in the Company and the technology. With the capital raised, we are financially well situated for operations for our development programs."