On March 27, 2024 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, reported its 2023 Annual Results (Press release, Carsgen Therapeutics, MAR 27, 2024, View Source [SID1234641517]).

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Business Highlights

Zevorcabtagene autoleucel (CT053) NDA was approved by the NMPA.

Satricabtagene autoleucel (CT041) IND was approved by the NMPA for the postoperative adjuvant therapy of Claudin18.2 positive pancreatic cancer.

CT011 IND was approved by the NMPA for GPC3-positive stage IIIa hepatocellular carcinoma at high risk of recurrence after surgical resection.
Two hepatocellular carcinoma patients treated with a combination of local therapy and GPC3 CAR-T cells achieved disease-free survival exceeding 7 years.
CT071 IND was cleared by the FDA for relapsed/refractory multiple myeloma and relapsed/refractory primary plasma cell leukemia.
Developed a proprietary CARcelerateTM platform, shortening the manufacturing time to around 30 hours. The platform has been utilized for CT071.
CARsgen and Huadong Medicine entered into a collaboration agreement for the commercialization of zevorcabtagene autoleucel in mainland China.
CARsgen and Moderna initiated a collaboration agreement to investigate satricabtagene autoleucel in combination with an mRNA cancer vaccine.
Dr. Zonghai Li, Founder, Chairman of the Board, Chief Executive Officer, and Chief Scientific Officer of CARsgen Therapeutics, said, "In 2023, CARsgen remained dedicated to our vision, ‘Making Cancer Curable’ and were committed to reinforcing our team and improving operational efficiency. We made substantial progresses in the regulatory and clinical development of our innovative products and the advancement of new technology platforms. Multiple important milestones for different product candidates across clinical, regulatory, and business development were achieved. We are optimistic that we will navigate and overcome the challenges ahead with resilience and determination, advancing our innovative cell therapies."

Zevorcabtagene autoleucel (CT053) is an autologous fully human CAR T-cell product candidate against B-cell maturation antigen (BCMA) for the treatment of relapsed/refractory multiple myeloma (R/R MM). As informed by the NMPA on March 1, 2024, zevorcabtagene autoleucel was granted conditional approval on February 23, 2024 for the treatment of adult patients with relapsed or refractory multiple myeloma who have progressed after at least 3 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory agent). An update from the Phase I study in China (NCT03975907) with 3-year follow-up was presented as a poster at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting in December 2023.

Satricabtagene autoleucel (CT041) is an autologous humanized CAR T-cell product candidate against Claudin18.2 (CLDN18.2), a membrane protein highly expressed in certain cancers. As of the date of the announcement, satricabtagene autoleucel, based on our information, is the world’s first CAR T-cell candidate for the treatment of solid tumors entering a Phase II clinical trial. In April 2023, satricabtagene autoleucel IND was approved by the National Medical Products Administration (NMPA) for the postoperative adjuvant therapy of Claudin18.2 positive pancreatic cancer (PC) (CT041-ST-05, NCT05911217). In May 2023, the Phase 2 part of the Phase 1b/2 clinical trial (NCT04404595) in the U.S. and Canada was initiated for the treatment of Claudin18.2 positive advanced gastric cancer/gastroesophageal junction cancer (GC/GEJ) in patients who have failed at least 2 prior lines of systemic therapies. Updates from the Phase 1b study in the U.S. (NCT04404595) were presented as a poster at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium ("ASCO GI").

CT011 is an autologous CAR T-cell product candidate against Glypican-3 (GPC3). In January 2024, CT011 IND was approved by the NMPA for GPC3-positive stage IIIa hepatocellular carcinoma at high risk of recurrence after surgical resection.

In July 2023, an article titled "Combined local therapy and CAR-GPC3 T-cell therapy in advanced hepatocellular carcinoma: a proof-of-concept treatment strategy" was published in Cancer Communication (London, England) demonstrating patients who received local therapy followed by sequential infusions of CAR-GPC3 T-cells achieved more than 7-year disease-free survival.

CT071 is an autologous fully human CAR T-cell therapy candidate against G protein-coupled receptor class C group 5 member D (GPRC5D) developed utilizing CARsgen’s proprietary CARcelerateTM platform for the treatment of R/R MM and relapsed/refractory primary plasma cell leukemia (R/R pPCL). The IND was cleared by the FDA on November 30, 2023 for R/R MM and R/R pPCL. An investigator-initiated trial (IIT) is ongoing in China to assess the safety and efficacy of CT071 in treating R/R MM and relapsed/refractory plasma cell leukemia (R/R PCL) (NCT05838131).

In January 2023, CARsgen and Huadong Medicine (Hangzhou) Co., Ltd., a wholly-owned subsidiary of Huadong Medicine Co., Ltd. (SZ. 000963) entered into a collaboration agreement for the commercialization of zevorcabtagene autoleucel, in mainland China.

In August 2023, CARsgen and Moderna, Inc. (Nasdaq: MRNA, "Moderna") have initiated a collaboration agreement to investigate satricabtagene autoleucel in combination with Moderna’s investigational Claudin18.2 mRNA cancer vaccine.

On March 27, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported its annual results for the full year 2023 (Press release, Ascentage Pharma, MAR 27, 2024, View Source [SID1234641516]). During the reporting period, Ascentage Pharma made further strides in revenue generation through its commercialized product, achieved rapid progress with its patient-centric global innovation strategy, and delivered numerous milestones in clinical development and global expansion.

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Newly approved indication of olverembatinib expands the drug’s addressable market

In 2023, Ascentage Pharma recorded a revenue of RMB222 million, most of which was attributable to product sales and milestone payments, including a revenue of RMB194 million from product sales. For the first time, the company achieved commercial breakeven through topline growth while keeping selling and distribution expenses at a manageable level and significantly improving the efficiency of marketing activities.

Developed internally by Ascentage Pharma, olverembatinib is the first and only approved third-generation BCR-ABL inhibitor in China. In January 2023, as a Model Product of China-Developed Innovative Drugs, olverembatinib was included into the 2022 National Reimbursement Drug List (NRDL), a major step-forward that drastically improved the drug’s accessibility and paved the way for accelerated volume growth. Since its approval till December 31, 2023, olverembatinib generated an accumulated sales revenue of RMB362 million (audited, inclusive of value-added tax).

Meanwhile, Ascentage Pharma continued to strengthen its ability to drive revenue growth through product commercialization. On November 17, 2023, olverembatinib was approved for adult patients with chronic-phase chronic myeloid leukemia (CML-CP) resistant and/or intolerant of first-and second-generation tyrosine kinase inhibitors (TKIs). The indication expansion will allow a broader population of patients with CML to benefit from the drug and offer a new treatment option to drug-resistant patients, which will further olverembatinib’s commercial success. During the reporting period, the sales volume of olverembatinib increased 259%, the number of listed hospitals increased 567%, the total number of patients on treatment increased 123%. Looking ahead in 2024, with the approval of the new indication of olverembatinib, compounded by accelerated hospital listings, a growing number of patients on treatment, and ever longer duration of treatment, more patients will benefit from olverembatinib, driving the sales of the product.

Obtained clearances for five global registrational Phase III trials as the global innovation strategy began to bear fruit

Led by its global innovation strategy, Ascentage Pharma has delivered multiple milestones in clinical development as it effectively advanced global clinical development programs. Since the beginning of 2023, olverembatinib and the Bcl-2 inhibitor lisaftoclax (APG-2575) have been cleared to commence five global registrational Phase III studies, bolstering the company’s moat in the field of hematologic malignancies.

In February 2024, the US Food and Drug Administration (FDA) cleared a global registrational Phase III trial of olverembatinib in previously treated adult patients with CML-CP. This is the first global registrational Phase III trial of olverembatinib cleared by the US FDA and represents another step in Ascentage Phara’s growing presence in the global hematology arena. In January 2024, as a global best-in-class innovative drug from China, olverembatinib was included in the National Comprehensive Cancer Network (NCCN)’s latest guidelines for the management of CML. This inclusion highlights the therapeutic utility of olverembatinib and marks another major recognition from the global oncology community.

In addition to CML, olverembatinib has also made significant progress with its clinical development for the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). In July 2023, the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) granted the clearance for the global registrational Phase III trial of olverembatinib in combination with chemotherapy versus imatinib in combination with chemotherapy for the treatment of newly diagnosed patients with Ph+ ALL, paving the way for olverembatinib to potentially become the first China-approved TKI for the treatment of patients with Ph+ ALL in the first-line setting.

Lisaftoclax obtained clearances for three global registrational Phase III studies. In August 2023, the US FDA cleared a global registrational Phase III study of lisaftoclax in previously treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This regulatory clearance marked a major step-forward in the global clinical development of lisaftoclax as it can potentially accelerate the drug’s journey to market as the world’s second approved Bcl-2 inhibitor competing in the global market. Shortly after receiving this clearance, lisaftoclax was approved by the China CDE to enter a global registrational Phase III study of lisaftoclax combined with acalabrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, versus immunochemotherapy for the first-line treatment of patients with CLL/SLL. In December 2023, the China CDE approved another global registrational Phase III study of lisaftoclax for the first-line treatment of newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML).

Promising clinical results underscore strong competitiveness in the field of hematologic malignancies

Pursuing its mission of addressing unmet clinical needs in China and around the world, Ascentage Pharma has built a rich pipeline composed of promising drug candidates with first-in-class and/or best-in-class potentials, and is conducting more than 40 clinical studies in China, the US, Australia, Europe, and Canada. The company’s innovative and clinical development capabilities have received growing recognition from the global research community as it continued to explore and validate the therapeutic potential of its drug candidates and frequently showcased new clinical data at major international congresses.

At the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) (ASH 2023), Ascentage Pharma presented the latest results from multiple studies of olverembatinib and lisaftoclax, demonstrating the clinical advantages of these products.

Among those studies, two studies of olverembatinib were selected for Oral Presentations, making 2023 the sixth consecutive year in which data of olverembatinib were selected for Oral Presentations at the ASH (Free ASH Whitepaper) Annual Meeting. One of these Oral Presentations featured a registrational Phase II study evaluating the efficacy and safety of olverembatinib versus the best available therapy (BAT) in patients with CML-CP resistant and/or intolerant to prior treatment with TKIs. Results of the study showed that compared to the BAT, olverembatinib significantly improved the prognosis of patients with CML. The other Oral Presentation featured the preliminary results from a Phase II study of olverembatinib. Selected for "Highlights of ASH (Free ASH Whitepaper)", these results showed encouraging clinical benefit and favorable tolerability of an olverembatinib regimen that could potentially usher in an era of chemotherapy-free treatment for Ph+ ALL.

After releasing preliminary results from the US study of olverembatinib in an Oral Report at the ASH (Free ASH Whitepaper) Annual Meeting in 2022, at ASH (Free ASH Whitepaper) 2023, Ascentage Pharma presented updated data from a larger patient sample that showed the favorable clinical benefit and tolerability of olverembatinib, as a monotherapy and in combinations, in heavily pretreated patients with CML or Ph+ ALL, particularly those who have failed prior treatment with the third-generation TKI ponatinib or the allosteric STAMP inhibitor asciminib. These results suggest that olverembatinib has global best-in-class potential as an effective new therapy for patients with CML or Ph+ ALL.

Also at the 2023 ASH (Free ASH Whitepaper) Annual Meeting, Ascentage Pharma released results from three clinical studies of lisaftoclax, for the treatment of CLL, AML, and multiple myeloma (MM), separately. Among them, the study in patients with relapsed/refractory (R/R) CLL once again showed the favorable tolerability and significant efficacy of lisaftoclax. In particular, the company released the first dataset of lisaftoclax in MM and AML that reaffirmed the global best-in-class potential and unique therapeutic utility of lisaftoclax and provided strong evidence of the drug’s therapeutic applications to indications beyond CLL.

Prior to that, Ascentage Pharma presented updated clinical data of olverembatinib, lisaftoclax, the MDM2-p53 inhibitor alrizomadlin (APG-115), and the FAK/ALK/ROS1 inhibitor APG-2449, four of the company’s lead drug candidates, at the 59th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO 2023). In particular, the data of olverembatinib showed promising clinical benefit and favorable tolerability in patients with TKI-resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST), thus indicating a potential breakthrough for an indication that currently has no effective treatment. Also in 2023, olverembatinib was granted a Breakthrough Therapy Designation (BTD) by the China CDE for the treatment of patients with SDH-deficient GIST who had received first-line treatment.

Building vertically integrated industrialization capabilities to further accelerate global expansion

Upholding its global innovation strategy, Ascentage Pharma is committed to building a large portfolio of global intellectual property rights. As of December 31, 2023, Ascentage Pharma holds 498 issued patents globally, among which 352 patents were issued overseas.

In addition, Ascentage Pharma received a zero-deficiency report from the Good Manufacturing Practice (GMP) compliance audit by a Qualified Person (QP) of the European Union (EU) in April 2023, which indicates that the company’s Global Manufacturing Center and its quality management system are now fully compliant with the GMP standards of the EU, generating extra tailwind to Ascentage Pharma’s ongoing transition towards a global biopharmaceutical company.

"In 2023, Ascentage Pharma has achieved multiple milestones across product commercialization, global clinical development, and corporate development, while continuing to showcase its prowess in global innovation," said Dr. Dajun Yang, Chairman and CEO of Ascentage Pharma. "The NRDL inclusion and newly approved indication of olverembatinib has further boosted the company’s commercialization capabilities. Meanwhile, olverembatinib, supported by its excellent efficacy and safety, was reaffirmed as a best-in-class drug and begun to show encouraging therapeutic value in additional indications that currently have no treatment options."

Dr. Yang continued, "In the past year, we accelerated our global clinical development programs and have in the process obtained clearances, including two from FDA, for five global registrational Phase III trials of olverembatinib and lisaftoclax. At the same time, our lead drug candidates continued to show clinical potential in additional indications, thus further strengthening our position in the field of hematologic malignancies."

In conclusion, Dr. Yang said, "Implementing our global innovation strategy with a patient-centric approach, we have built a rich pipeline that holds enormous clinical potential, particularly in hematologic malignancies. Moving forward, we will further enhance our commercialization and clinical development capabilities, and accelerate our global clinical development programs. Fulfilling the mission of addressing unmet clinical needs in China and around the world, we aim to bring our innovative drugs to the global market in the future for the benefit more patients around the world and create greater value for our communities and shareholders."

On March 27, 2024 Medigene AG (Medigene or the "Company", FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported financial results for the fiscal year ended December 31, 2023, and provided a corporate update (Press release, MediGene, MAR 27, 2024, View Source [SID1234641515]).

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Select FY 2023 financial results

Revenues amounted to EUR 6.0 million, a decrease of 81% (or EUR 25.2 million) compared to EUR 31.2 million in 2022. Higher revenues in 2022 were due to the comprehensive TCR-T and technology partnership with BioNTech concluded in February 2022, resulting in EUR 20.9 million in product revenues. In addition, revenues from the partnerships with 2seventy bio and Hongsheng Sciences were generated in 2022.

Selling expenses decreased from EUR 2.2 million in 2022 to EUR 20 thousand in 2023. This decrease is due to the above-mentioned partnership with BioNTech and the related costs incurred in the first half of 2022 as part of the preparation process leading up to the agreement.

General and administrative (G&A) expenses were EUR 9.3 million in 2023 compared to EUR 7.7 million in the year prior. This 21% increase was mainly due to higher personnel and consulting expenses as the Company supported its strategic efforts to advance all scientific and partnering activities.

Research and development (R&D) expenses decreased by 59% to EUR 11.5 million (2022: EUR 28.5 million) and reflect the work associated with the development of T cells for the treatment of solid tumors and pre-clinical development activities. The significant decrease in 2023 is mainly due to depreciation related to the full impairment of the drug candidate RhuDex, out-licensed to Dr. Falk Pharma GmbH for the amount of EUR 20.4 million in 2022. R&D expenses incurred in the collaborations with partner companies are reimbursed by the companies. The reimbursements are recognized as R&D payments in immunotherapies revenue.

Net loss for fiscal 2023 increased to EUR 16.2 million compared to EUR 8.3 million in 2022. The increase is due to the described partnership with BioNTech in February 2022 and the associated revenues.

Cash and cash equivalents amounted to EUR 8.7 million and time deposits for EUR 8 million, totaling EUR 16.7 million on Dec 31, 2023 (Dec 31, 2022: EUR 33.2 million), with a cash runway extended into April 2025 (previously Q1 2025).

"2023 was a highly productive year for Medigene. We have made significant progress in broadening our pipeline into TCR-T therapies targeting KRAS mutations, which represent one of the most frequent neoantigens in solid cancers. We significantly advanced our End-to-End (E2E) Platform, adding new technologies such as the CD40L-CD28 costimulatory switch protein, and with a focus on improving our drug product composition to enable better efficacy, safety and durability. This was reflected by an increase in the size and scope of our patent portfolio," said Selwyn Ho, Chief Executive Officer of Medigene. "Importantly, we advanced our lead program MDG1015 towards a first-in-human clinical trial, which is expected by the end of 2024 subject to financing. This first-in-human trial will target patients with gastric cancer, ovarian cancer, myxoid/round cell liposarcoma and synovial sarcoma as the initial clinical indications."

"In 2024, we will continue to advance our differentiated TCR-T therapies for the treatment of solid tumors. Using our core expertise and ability to generate optimal TCRs, we will also aim to apply these to new TCR-based modalities beyond TCR-T cell therapies, such as off-the shelf T cell engagers and allogeneic TCR-Natural Killer cells, where further value could be created for patients and our shareholders. We believe that these additional potential therapeutic options represent highly promising commercial opportunities for Medigene."

Financial Guidance 2024

The 2024 financial projections include potential future milestone payments from existing partnerships that are highly likely to materialize in the amount of USD 1 million and EUR 2 million, respectively. They do not include potential milestone payments from or future/new partnerships or new transactions as the occurrence of such payments or their timing and size largely depend on third parties and cannot be controlled or influenced by Medigene.

As such, the 2024 financial guidance reflects the Company’s focus and progress in its core immunotherapies business.

Based on the above assumptions, Medigene expects revenue in 2024 to be between EUR 9 and 11 million. The Company expects R&D costs to range from EUR 11 to 13 million. And as already mentioned, based on current planning, the Company is funded into April 2025.

Program development highlights

MDG1015: MDG1015 is a first-in-class, third generation T cell receptor engineered T cell (TCR-T) therapy targeting NY-ESO-1/LAGE-1a (New York esophageal squamous cell carcinoma 1 / L Antigen Family Member-1a), armored and enhanced by the costimulatory switch protein PD1-41BB and targeting HLA-A*02 (HLA, human leukocyte antigen). Preclinical data presented in 2023 at the AACR (Free AACR Whitepaper) and ESMO (Free ESMO Whitepaper) conferences demonstrated the clear potential of MDG1015 to improve clinical outcomes in solid tumors.

Following recent positive EU and US preliminary regulatory interactions, the Company remains on track for an IND/CTA approval in the second half of 2024. Subject to financing, the Company expects to initiate a first in-human trial for MDG1015 by the end of 2024.

MDG2011: MDG2011 is a potential best-in-class third generation TCR-T therapy targeting KRAS G12V (HLA-A*11), further armored and enhanced by the PD1-41BB costimulatory switch protein. First pre-clinical data on MDG2011 was presented at the ESMO (Free ESMO Whitepaper) Congress 2023 and the SITC (Free SITC Whitepaper) Annual Meeting 2023. Lead selection for MDG2011 was announced in the third quarter 2023.

MDG2021 and MDG2012: MDG2021 is our second candidate within the KRAS library targeting KRAS G12D (HLA-A*11) with lead selection expected in the first half of 2024. The lead selection for the Company’s third announced KRAS-targeted program MDG2012, KRAS G12V (HLA-A*03), is expected in 2025.

Corporate development highlights

To support the development of our research projects, we have established a partnership network with both, well-known biotechs and renowned academic bodies.

In April 2023, Medigene entered into a joint collaboration with the US National Cancer Institute to assess the potential of Medigene’s proprietary TCRs for use in new cell constructs in the treatment of solid tumors.

The Company’s existing partnerships with BioNTech and 2seventy bio are progressing well.

In January 2023, Medigene received a USD 3 million milestone payment from its partner 2seventy bio triggered by 2seventy bio’s initiation of a strategic partnership with JW Therapeutics in December 2022.

Expansion of patent portfolio

The advancement of its E2E Platform allowed the Company to extend and strengthen its patent portfolio with new technologies as well as to expand existing patents into additional jurisdictions, such as the costimulatory switch proteins for use in multiple cell types and their geographical coverage. As of Dec 31, 2023, Medigene’s IP portfolio consisted of 112 issued and 131 pending patents across 28 patent families.

Conference Call and Webcast

The Company will host a conference call and webcast today at 3 pm CET / 10 am ET. A Q&A session will follow the management’s formal presentation.

Full details for the conference call and webcast are as follows:

Date March 28, 2024
Time 3:00 p.m. CET (10 a.m. ET)
Conference ID: 20240088
Registration Conference Call: Registration Conference Call here
Webcast: Join the live webcast here
Participants may pre-register and will receive dedicated dial-in details to easily and quickly access the call with the above registration link for the conference call.

Please dial in 10 minutes ahead of time to ensure a timely start of the conference call.

Following the call, an archived webcast will be accessible on the Investors & Media section of the Medigene website: View Source

On March 27, 2024 Adaptimmune Therapeutics plc (NASDAQ: ADAP), a company redefining the treatment of solid tumor cancers with cell therapy, reported that The Lancet published the company’s pivotal Phase 2 data with afami-cel (Press release, Adaptimmune, MAR 27, 2024, View Source [SID1234641514]). The article, titled "SPEARHEAD-1: a single-arm phase 2 trial of afamitresgene autoleucel (afami-cel) in advanced synovial sarcoma and myxoid/round cell liposarcoma," details clinical and translational results from afami-cel’s SPEARHEAD-1 trial (NCT04044768).

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Dennis Williams, PharmD., Senior Vice President, Late-Stage Development, Adaptimmune: "It is exciting to see the Lancet share the afami-cel SPEARHEAD-1 trial results in advanced sarcomas with the broader clinical and research communities. The study further demonstrates the ability of engineered T-cell therapies to effectively target solid tumors and we are eager to introduce the first engineered T-cell therapy, afami-cel, to more patients later this year."

Dr. Sandra D’Angelo, M.D., Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, lead author of the publication: "The reported findings are clinically impactful, considering the current standard of care and limited therapies available in advanced sarcomas. Treatment with afami-cel resulted in 39% overall response rate in synovial sarcoma with durable responses. These results suggest that a one-time treatment with afami-cel has the potential to extend life while allowing responders to go off chemotherapy. The publication of this data further validates the potential of afami-cel to offer a new tool to address the unmet needs of people diagnosed with these often-devastating diseases."

About Afami-cel (afamitresgene autoleucel): On January 31, 2024, Adaptimmune announced that the U.S. Food and Drug Administration (FDA) has accepted for priority review its Biologics License Application (BLA) for afami-cel, an investigational engineered T-cell therapy for advanced synovial sarcoma. The application has a Prescription Drug User Fee Act (PDUFA) target action date of August 4, 2024.

In the SPEARHEAD-1 trial, 44 patients with advanced synovial sarcoma were treated with a single dose of afami-cel after undergoing lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Safety findings were overall consistent with those previously observed in advanced cancer patients undergoing lymphodepleting chemotherapy and cell therapy. Haematologic toxicities were the most common adverse events. Low grade cytokine release syndrome occurred in most patients and was managed with standard treatments.

About Synovial Sarcoma: There are more than 50 different types of soft tissue sarcomas which are categorised by tumors that appear in fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues.1 Synovial sarcoma accounts for approximately 5% to 10% of all soft tissue sarcomas (there are approximately 13,400 new soft tissue cases in the U.S. each year).2 One third of patients with synovial sarcoma will be diagnosed under the age of 30.2 The five-year survival rate for people with metastatic disease is just 20% and most people undergoing standard of care treatment for advanced disease experience recurrence and go through multiple lines of therapy, often exhausting all options.3

View Source
Synovial Sarcoma – NCI (cancer.gov).
Aytekin MN, et al. J Orthop Surg (Hong Kong). 2020;28(2).

On March 27, 2024 AstraZeneca reported that Truqap (capivasertib) in combination with Faslodex (fulvestrant) has been approved in Japan for the treatment of adult patients with unresectable or recurrent PIK3CA, AKT1, or PTEN-altered hormone receptor (HR)-positive, HER2-negative breast cancer following progression after treatment with endocrine therapy (Press release, AstraZeneca, MAR 27, 2024, View Source [SID1234641513]).

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The approval by the Japanese Ministry of Health, Labour, and Welfare (MHLW) was based on the results from the CAPItello-291 Phase III trial published in The New England Journal of Medicine.1 In the trial, Truqap in combination with Faslodex reduced the risk of disease progression or death by 50% versus Faslodex alone in patients with tumours harbouring PI3K/AKT pathway biomarker alterations (based on hazard ratio of 0.50, 95% confidence interval 0.38-0.65; p=<0.001; median progression-free survival (PFS) 7.3 versus 3.1 months).1

In Japan, more than 90,000 women were diagnosed with breast cancer in 2022, and more than 17,000 patients died from the disease in the same year.2 Globally, HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common breast cancer subtype, with more than 65% of tumours considered HR-positive and HER2-low or HER2-negative.3 Collectively, mutations in PIK3CA, AKT1 and alterations in PTEN occur frequently, affecting approximately 50% of patients with advanced HR-positive breast cancer.4-6 Endocrine therapies are widely used in this setting, often in combination with cyclin-dependent kinase (CDK) 4/6 inhibitors, but some tumours develop resistance to these therapies, underscoring the need for additional combination approaches with endocrine therapy to extend time before the initiation of chemotherapy.7

Masakazu Toi, MD, PHD, Director of Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Japan said: "The approval of capivasertib and fulvestrant signifies a new era of care in advanced hormone receptor-positive breast cancer in Japan, providing a much-needed new treatment option for approximately half of patients in this setting who have tumours harbouring mutations in PIK3CA, AKT1 or alterations in PTEN. It is important for us to detect these specific tumour biomarker alterations in each patient we see, so that they are potentially able to benefit from this important combination to extend the effectiveness of endocrine-based treatment and delay disease progression."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said:
"Breast cancer is the most common cancer among women in Japan, and innovative, new treatment options are urgently needed. Today’s approval of Truqap, a first-in-class AKT-inhibitor, represents a significant step forward for HR-positive breast cancer treatment and an important new option for approximately fifty per cent of patients who have tumours with these specific mutations or alterations."

In the CAPItello-291 trial, the safety profile of Truqap plus Faslodex was similar to that observed in previous trials evaluating this combination.1

The MHLW have also approved a companion diagnostic test to detect the relevant alterations (PIK3CA, AKT1 and PTEN).

Regulatory applications are currently under review in China, the European Union, and several other countries, and this indication for Truqap in combination with Faslodex is already approved in the US and several other countries based on results from the CAPItello-291 trial.

Financial considerations
Following this approval in Japan, Astex Therapeutics is eligible to receive a milestone payment from AstraZeneca on first commercial sale of the drug in Japan as well as royalties on future sales in line with the agreement between the two companies.

Notes

HR-positive breast cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related death worldwide.8 More than two million patients were diagnosed with breast cancer in 2022, with more than 665,000 deaths globally.8

HR-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with more than 65% of tumours considered HR-positive and HER2-low or HER2-negative.3

The growth of HR-positive breast cancer cells is often driven by estrogen receptors (ER), and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with CDK4/6 inhibitors.7,9,10 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.9 Once this occurs, treatment options are limited – with chemotherapy being the current standard of care – and survival rates are low with approximately 30% of patients anticipated to live beyond five years after diagnosis.3,9,11

The optimisation of endocrine therapy and overcoming resistance to enable patients to continue benefiting from these treatments, as well as identifying new therapies for those who are less likely to benefit, are active areas of focus for breast cancer research.

CAPItello-291
CAPItello-291 is a Phase III, double-blind, randomised trial evaluating the efficacy of Truqap in combination with Faslodex versus placebo plus Faslodex for the treatment of locally advanced (inoperable) or metastatic HR-positive, HER2-low or negative (immunohistochemistry (IHC) 0 or 1+, or IHC 2+/in-situ hybridisation (ISH)-negative) breast cancer.

The global trial enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The trial has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumours have qualifying alterations in the PI3K/AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumours had these alterations and approximately 70% of patients received a prior CDK4/6 inhibitor.

Truqap
Truqap is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

Truqap in combination with Faslodex is approved in the US, Japan and several other countries for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) based on the results from the CAPItello-291 trial. Eligible patients will have progressed on at least one endocrine-based regimen in the metastatic setting or experienced recurrence on or within 12 months of completing adjuvant therapy.

Truqap is currently being evaluated in Phase III trials for the treatment of multiple subtypes of breast cancer and in other tumour types in combination with established treatments. The ongoing clinical research programme is focused on tumours reliant on signalling via the PI3K/AKT pathway, and in tumours harbouring biomarker alterations in this pathway.

Truqap was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

Faslodex
Faslodex is an endocrine therapy indicated for the treatment of estrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy, or with disease relapse on or after adjuvant anti-estrogen therapy, or disease progression on anti-estrogen therapy.

In the US, EU and Japan, Faslodex is also approved in combination with CDK4/6 inhibitors for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, whose cancer has progressed after endocrine medicine. Faslodex represents a hormonal treatment approach that helps to slow tumour growth by blocking and degrading the estrogen receptor – a key driver of disease progression.

Faslodex is approved as monotherapy or in combination with medicines from various drug classes including CDK4/6, PI3K and AKT inhibitors for the treatment of patients with HR-positive advanced breast cancer and is being evaluated in combination with medicines from other drug classes.