Calquence plus obinutuzumab demonstrated sustained survival benefit in 1st-line chronic lymphocytic leukaemia with 90% of patients surviving five years in ELEVATE-TN trial

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.

New Novartis data show Piqray® effectiveness across key biomarkers in patients with HR+/HER2- metastatic breast cancer

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.

Helix Biopharma Corp. Announces Closure of Early Warrant Exercise Incentive Program | Raises Aggregate $3.21 Million

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."

Caris Life Sciences Introduces the Caris Assure™ Liquid Biopsy Assay at ASCO 2022

On June 3, 2022 Caris Life Sciences (Caris), the leading molecular science and technology company actively developing and delivering innovative solutions to revolutionize healthcare, reported its Caris Assure liquid biopsy assay at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Booth #22081) (Press release, Caris Life Sciences, JUN 3, 2022, View Source [SID1234615604]).

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"Caris Assure establishes a new standard for liquid biopsy testing," said David D. Halbert, Chairman, Founder and CEO of Caris Life Sciences. "Current liquid biopsy offerings examine smaller panels of genes, which lack the versatility for the identification of novel predictive markers and signatures that are only possible through the whole exome and whole transcriptome approach unique to Caris. With Caris Assure, we have created the most extensive sequencing assay available to ensure we leave no stone unturned in properly guiding treatment selection and ongoing cancer care management."

Caris Assure is a blood-based molecular profiling assay that uses a novel circulating nucleic acids sequencing (cNAS) approach to analyze the Whole Exome (cfDNA) and Whole Transcriptome (cfRNA) of 22,000 genes, including Loss of Heterozygosity (LOH), Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) from a simple blood sample. This unique assay includes characterization of somatic tumor alterations, somatic Clonal Hematopoiesis of Indeterminate Potential (CHIP) alterations and identification of incidental germline findings. The assay further enables minimally invasive serial monitoring for detection of tumor heterogeneity and emergence of resistance mutations.

"We have applied the same industry leading, multi-cancer profiling technology used in our tissue assay to blood," said David Spetzler, M.S., Ph.D., MBA, President and Chief Scientific Officer of Caris. "Our broad, 22,000 gene WES and WTS analysis ensures we render the most accurate results and findings for physicians seeking to properly diagnose, treat and monitor cancer patients. We are excited to bring this assay to the market and provide physicians with a new and comprehensive multi-cancer blood assay to add to their cancer diagnoses and treatment strategies."

Caris Assure sequences the largest panel of genes across both cfDNA (Whole Exome) and cfRNA (Whole Transcriptome), which helps overcome many of the shedding problems that plague cfDNA-only assays. By including DNA and RNA coverage across somatic tumor, somatic CHIP and germline alterations, Caris Assure captures more tumor-informed material, leading to improved performance and comprehensive molecular profiling results for the physician and patient. The approach also results in fewer missed mutations due to more tumor derived material inputs and concordance to tissue, as well as fewer false positives due to the analysis of CHIP mutations.

In an initial performance validation study of this first-of-its-kind whole exome, whole transcriptome (22,000 gene) blood assay, Caris Assure demonstrated more than 95 percent sensitivity for variant frequencies greater than 0.5 percent, while maintaining greater than 99.99 percent specificity. Additional validation data will be released in the coming months.

Caris Assure will be commercially available in the second half of calendar year 2022, with limited availability in the third quarter and expanding availability in Q4 and 2023.

Cure Brain Cancer Foundation Research Grant

On June 3, 2022 Patrys reported that share news that the Telethon Kids Institute has been awarded significant funding from the Cure Brain Cancer Foundation to support research for Patrys’ PAT-DX1 and PAT-DX3 programs (Press release, Patrys, JUN 3, 2022, View Source [SID1234615602]).

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The grant will be used to investigate Patrys’ deoxymab assets PAT-DX1 and PAT-DX3 in both in vitro and in vivo studies of high grade glioma (HGG), by combining with standard of care (SOC) treatments such as radiotherapy and temozolomide to determine efficacy.

Based within the Perth Children’s Hospital, the Telethon Kids Institute conducts translational research focused on improving treatments for the health and wellbeing of children. The research will be led by Professor Terrance Johns, who is at the forefront of Australian brain cancer research.

Patrys CEO and Managing Director, Dr James Campbell, said:

"This is one of our most exciting collaborations to date. Professor Terrance Johns and his team are pivotal in the brain cancer space in Australia. We gratefully acknowledge the Cure Brain Cancer Foundation Clinical Accelerator grant scheme for providing funding for therapeutic products with the potential to improve the pathway to the clinic."