On April 2, 2024 AstraZeneca and Daiichi Sankyo reported that Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd) has been accepted in the US for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior systemic therapy for unresectable or metastatic disease (Press release, AstraZeneca, APR 2, 2024, View Source [SID1234641671]). The Prescription Drug User Fee Act date, the US Food and Drug Administration (FDA) action date for its regulatory decision, is during the first quarter of 2025.

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The BLA is based on results from the pivotal TROPION-Breast01 Phase III trial in which datopotamab deruxtecan demonstrated a statistically significant and clinically meaningful improvement for the dual primary endpoint of progression-free survival (PFS) compared to investigator’s choice of chemotherapy in patients with unresectable or metastatic HR-positive, HER2-negative breast cancer previously treated with endocrine-based therapy and at least one systemic therapy. For the dual primary endpoint of overall survival (OS), interim results numerically favoured datopotamab deruxtecan over chemotherapy but were not mature at the time of data cut-off. The trial is ongoing and OS will be assessed at future analyses.

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by AstraZeneca and Daiichi Sankyo.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Despite marked progress in the treatment of HR-positive, HER2-negative breast cancer, most patients with advanced disease develop endocrine resistance and face the prospect of one or several lines of chemotherapy. If approved, datopotamab deruxtecan has the potential to provide these patients an efficacious and better tolerated alternative to conventional chemotherapy."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "The FDA’s acceptance of the BLA brings us closer to providing patients with previously treated HR-positive, HER2-negative breast cancer an alternative option to conventional chemotherapy earlier in the metastatic setting. Following our recently accepted application for advanced nonsquamous non-small cell lung cancer in the US, along with additional regulatory reviews underway in China, the EU, Japan and other regions, we are working swiftly to bring datopotamab deruxtecan as a potential new treatment option to patients around the world."

Results from TROPION-Breast01 were presented during a Presidential Symposium at the 2023 European Society for Medical Oncology Congress and in an oral presentation at the 2023 San Antonio Breast Cancer Symposium.

The safety profile of datopotamab deruxtecan was consistent with that observed in other ongoing trials with no new safety concerns identified.

An additional BLA for datopotamab deruxtecan based on results from the pivotal TROPION-Lung01 Phase III trial is under review in the US for the treatment of adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have received prior systemic therapy. Additional regulatory submissions for datopotamab deruxtecan in lung and breast cancer are underway globally.

Notes

HR-positive breast cancer
More than 275,000 breast cancer cases were diagnosed in the US in 2022.1 HR-positive, HER2-negative breast cancer is the most common subtype, accounting for more than 65% of diagnosed cases.2 Breast cancer is considered HR-positive, HER2-negative when tumours test positive for oestrogen and/or progesterone hormone receptors and negative for HER2 (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-).2,3 Standard initial treatment for this subtype of breast cancer is endocrine therapy but most patients with advanced disease will develop resistance, underscoring the need for additional options.4,5

TROP2 is a protein broadly expressed in HR-positive, HER2-negative breast cancer and is associated with increased tumour progression and poor survival.6,7

TROPION-Breast01
TROPION-Breast01 is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have progressed on and are not suitable for endocrine therapy per investigator assessment and have received at least one additional systemic therapy for unresectable or metastatic disease.

The dual primary endpoints of TROPION-Breast01 are PFS as assessed by blinded independent central review and OS. Key secondary endpoints include objective response rate, duration of response, investigator-assessed PFS, disease control rate, time to first subsequent therapy and safety. TROPION-Breast01 enrolled more than 700 patients in Africa, Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanised anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive global clinical development programme is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer (TNBC) and HR-positive, HER2-negative breast cancer.

On April 1, 2024 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) and Innovent Biologics, Inc. ("Innovent") (HKEX:1801) reported that the New Drug Application ("NDA") for the combination of fruquintinib and sintilimab for the treatment of patients with advanced endometrial cancer with pMMR1 or non-MSI-H2 tumors that have failed prior systemic therapy but are not candidates for curative surgery or radiation has been accepted and granted priority review by the China National Medical Products Administration ("NMPA") (Press release, Hutchison China MediTech, APR 2, 2024, View Source [SID1234641668]).

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The NDA is supported by data from FRUSICA-1, the endometrial cancer registration cohort of a multi-center, open-label Phase II study investigating fruquintinib in combination with sintilimab in endometrial cancer patients who experienced disease recurrence, disease progression or intolerable toxicity with treatment on platinum-based doublet chemotherapy. The primary endpoint was independent review committee (IRC) assessed objective response rate (ORR), with secondary endpoints including disease control rate (DCR), duration of response (DoR), progression free survival (PFS), overall survival (OS), as well as pharmacokinetic (PK) assessments. Data from FRUSICA-1 will be submitted for presentation at an upcoming medical conference. Additional details may be found at clinicaltrials.gov, using identifier NCT03903705.

"This is the first regulatory filing for the combination of fruquintinib and the immune checkpoint inhibitor sintilimab. It also represents an important step closer to reshaping the treatment landscape for this challenging disease in China," said Dr. Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED. "Endometrial cancer remains one of the most common gynecological malignancies. We look forward to bringing this much-awaited treatment advancement to endometrial cancer patients to improve their treatment outcome."

"TYVYT (sintilimab injection), as a backbone therapy in immuno-oncology, in combination with an anti-angiogenetic drug, may improve the prognosis for endometrial cancer patients in China," said Dr. Hui Zhou, Senior Vice President of Innovent. "We are excited about the NDA acceptance and priority review designation, which increases our potential to bring a new treatment option to endometrial cancer patients, and concurrently strengthens the leadership position of TYVYT in China."

The NMPA granted Breakthrough Therapy designation to the combination of fruquintinib and sintilimab for this potential indication in July 2023. The NMPA granted this designation to this combination as a new treatment that could target a serious condition for which there are no effective treatment options, and where clinical evidence demonstrates substantial advantages over existing therapies.

About Endometrial Cancer
Endometrial cancer is a type of cancer that begins in the uterus. Globally, an estimated 417,000 people were diagnosed with endometrial cancer and it caused approximately 97,000 deaths in 2020.3 Іn China, an estimated 82,000 people were diagnosed with endometrial cancer, causing approximately 17,000 deaths in 2020.4 Although early-stage endometrial cancer can be surgically resected, recurrent and/or metastatic endometrial cancer remains an area of high unmet need with poor outcomes and limited treatment options.5,6,7

About Fruquintinib
Fruquintinib is a selective oral inhibitor of vascular endothelial growth factor receptor ("VEGFR")-1, -2 and -3. VEGFR inhibitors play a pivotal role in inhibiting tumor angiogenesis. Fruquintinib was designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for its potential use as part of a combination therapy. Fruquintinib has demonstrated a manageable safety profile and is being investigated in combinations with other anti-cancer therapies.

About Fruquintinib Approval in China
Fruquintinib is approved for marketing for the treatment of patients with metastatic colorectal cancer who have previously received fluoropyrimidine, oxaliplatin and irinotecan-based chemotherapy, and those who have previously received or are not suitable for receiving anti-vascular endothelial growth factor ("VEGF") therapy or anti-epidermal growth factor receptor ("EGFR") therapy (RAS wild-type) in China, where it is co-developed and co-marketed by HUTCHMED and Eli Lilly and Company under the brand name ELUNATE. It was included in the China National Reimbursement Drug List ("NRDL") in January 2020. The approval was based on data from the FRESCO study, a Phase III pivotal registration trial of fruquintinib in 416 patients with metastatic colorectal cancer in China, which were published in The Journal of the American Medical Association, JAMA. Since its launch in China and as of mid-2023, fruquintinib has benefited more than 80,000 colorectal cancer patients.

About Fruquintinib Approval in the United States
Fruquintinib received approval for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine, oxaliplatin, and irinotecan‑based chemotherapy, an anti‑VEGF therapy, and, if RAS wild‑type and medically appropriate, an anti-EGFR therapy in the United States in November 2023, where it is marketed by Takeda under the brand name FRUZAQLA. The approval was based on data from two large Phase III trials: the multi-regional FRESCO-2 trial, data from which were published in The Lancet, along with the FRESCO trial conducted in China. The trials investigated fruquintinib plus best supportive care versus placebo plus best supportive care in patients with previously treated metastatic colorectal cancer. Both FRESCO and FRESCO-2 met their primary and key secondary efficacy endpoints and showed consistent benefit among a total of 734 patients treated with fruquintinib. Safety profiles were consistent across trials. Takeda has the exclusive worldwide license to further develop, commercialize, and manufacture fruquintinib outside of mainland China, Hong Kong and Macau.

About Sintilimab
Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody co-developed by Innovent and Eli Lilly and Company. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells.8

In China, sintilimab has been approved and included in the NRDL for seven indications. The updated NRDL reimbursement scope for TYVYT (sintilimab injection) includes:

For the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy;
For the first-line treatment of unresectable locally advanced or metastatic non-squamous non-small cell lung cancer lacking EGFR or ALK driver gene mutations;
For the treatment of patients with EGFR-mutated locally advanced or metastatic non-squamous non-small cell lung cancer who progressed after EGFR-TKI therapy;
For the first-line treatment of unresectable locally advanced or metastatic squamous non-small cell lung cancer;
For the first-line treatment of unresectable or metastatic hepatocellular carcinoma with no prior systematic treatment;
For the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma;
For the first-line treatment of unresectable locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma.

Besides, the combination of sintilimab and fruquintinib for the treatment of patients with advanced endometrial cancer with pMMR or non-MSI-H tumors that have failed prior systemic therapy but are not candidates for curative surgery or radiation has been accepted and granted priority review by the NMPA.

In addition, two clinical studies of sintilimab have met their primary endpoints:

Phase II study of sintilimab monotherapy as second-line treatment of esophageal squamous cell carcinoma;
Phase III study of sintilimab monotherapy as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.

Statement: Innovent does not recommend the use of any unapproved drug(s)/indication(s).

On April 1, 2024 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company working to develop the world’s most potent vaccines, reported the pricing of an approximately $32.5 million underwritten public offering of its common stock (or pre-funded warrants to purchase common stock in lieu thereof) and accompanying common warrants to purchase common stock (or pre-funded warrants to purchase common stock in lieu thereof), before deducting underwriting discounts and commissions and offering expenses (Press release, Gritstone Bio, APR 1, 2024, View Source [SID1234641695]).

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The offering consists of (i) 8,333,333 shares of common stock and accompanying common warrants to purchase up to 8,333,333 shares of common stock at a per share exercise price of $1.65 (provided, however, that the purchaser may elect to exercise the common warrants for pre-funded warrants in lieu of shares of common stock at an exercise price of $1.65 minus $0.0001, the exercise price of each pre-funded warrant), at a combined public offering price of $1.50 per share and accompanying common warrant and (ii) to a certain investor in lieu of common stock, pre-funded warrants to purchase up to 13,334,222 shares of common stock at a per share exercise price of $0.0001 and accompanying common warrants to purchase up to 13,334,222 shares of common stock at a per share exercise price of $1.65 (provided, however, that the purchaser may elect to exercise the common warrants for pre-funded warrants in lieu of shares of common stock at an exercise price of $1.65 minus $0.0001, the exercise price of each pre-funded warrant) at a combined public offering price of $1.4999 per pre-funded warrant and accompanying common warrant, which represents the per share combined purchase price for the common stock and accompanying common warrants less the $0.0001 per share exercise price for each such pre-funded warrant. The accompanying common warrants will be immediately exercisable for shares of common stock or pre-funded warrants in lieu thereof, and will expire on the twelve-month anniversary of the date of issuance. All of the shares of common stock, accompanying common warrants and pre-funded warrants are being offered by Gritstone bio. The offering is expected to close on or about April 4, 2024, subject to the satisfaction of customary closing conditions.

TD Cowen and Evercore ISI are acting as the joint book-running managers for the offering.

The securities are being offered by Gritstone bio pursuant to a registration statement on Form S-3 (File No. 333-263455) previously filed and declared effective by the Securities and Exchange Commission ("SEC"). A final prospectus supplement and accompanying base prospectus relating to and describing the terms of the proposed offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Copies of the final prospectus supplement and accompanying base prospectus may also be obtained, when available, from: TD Securities (USA) LLC, 1 Vanderbilt Avenue, New York, NY 10017, by telephone at (855) 495-9846 or by email at [email protected]; or Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, New York 10055, by telephone at (888) 474-0200, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation, or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On April 1, 2024 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) partner Bristol Myers Squibb (NYSE: BMY) reported the pivotal Phase 3 KRYSTAL-12 study, evaluating KRAZATI (adagrasib) as a monotherapy in patients with pretreated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation, met the primary endpoint of progression-free survival (PFS) and the key secondary endpoint of overall response rate (ORR) as assessed by Blinded Independent Central Review (BICR) at final analysis for these endpoints (Press release, Zai Laboratory, APR 1, 2024, View Source; [SID1234641684]). The study remains ongoing to assess the additional key secondary endpoint of overall survival. Results of the confirmatory trial showed that KRAZATI demonstrated a statistically significant and clinically meaningful benefit in PFS and ORR compared to standard-of-care chemotherapy as a second-line or later treatment for these patients. KRAZATI had no new safety signals and the safety data was consistent with the known safety profile.

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"We are delighted to see these data underscoring the potential of adagrasib as a therapy for patients with KRASG12C mutated NSCLC in second or later line treatment," said Rafael G. Amado, M.D., President, Head of Global Oncology Research and Development, Zai Lab. "Lung cancer is the most common cancer in China, and adagrasib is one of several important products in Zai Lab’s growing lung cancer pipeline. We are proud to have contributed to the KRYSTAL-12 study and are looking forward to bringing adagrasib to patients in need in China."

Bristol Myers Squibb will complete a full evaluation of the available data and will share the results with the scientific community at an upcoming medical conference as well as discuss the results with health authorities.

Zai Lab expects to submit the New Drug Application (NDA) for adagrasib to the National Medical Products Association (NMPA) for KRASG12C mutated NSCLC in second or later line treatment in China this year.

In addition to KRASG12C-mutated NSCLC, KRAZATI and KRAZATI-based combinations have shown encouraging meaningful benefit in Phase 2 clinical trials across several tumors, including advanced colorectal cancer, pancreatic cancer and other solid tumors. In February, the U.S. FDA accepted for priority review the supplemental new drug application (sNDA) for KRAZATI in combination with cetuximab for the treatment of patients with previously treated KRASG12C-mutated locally advanced or metastatic colorectal cancer (CRC). The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.

Zai Lab thanks the patients and investigators involved in the KRYSTAL-12 clinical trial.

About NSCLC in China
According to the World Health Organization, the incidence of lung cancer in China in 2020 was 815,563 cases, with 714,699 deaths. Lung cancer consists of NSCLC in approximately 85% of cases and small cell lung cancer (SCLC) in approximately 15% of cases. KRASG12C is the most common KRAS mutation in NSCLC. The mutation is a biomarker of poor prognosis in Chinese patients with NSCLC.

ABOUT KRAZATI (adagrasib)
KRAZATI (adagrasib) is highly selective and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRAS protein regenerates every 24-48 hours. In China, it is estimated that there are around 42,000 patients each year with KRASG12C-mutated NSCLC and colorectal cancer indications alone.

In 2022, KRAZATI was granted accelerated approval for treatment of adult patients with KRASG12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

In 2023, Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization for KRAZATI as a targeted treatment option for adult patients with KRASG12C-mutated advanced non-small cell lung cancer and disease progression after at least one prior systemic therapy followed by the European Commission (EC) in 2024.

KRAZATI continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including non-small cell lung cancer and colorectal cancer.

In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab in patients with KRASG12C-mutated advanced colorectal cancer whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.

For U.S. Prescribing Information, visit KRAZATI.

About KRYSTAL-12
KRYSTAL-12 is an open-label, multicenter, randomized Phase 3 study evaluating KRAZATI compared to standard-of-care chemotherapy alone, in patients with KRASG12C-mutated non-small cell lung cancer. The primary endpoint of the study is PFS as assessed by BICR. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), and safety.

On April 1, 2024 GeneCentric Therapeutics, a company making precision medicine more precise through RNA-based diagnostics, reported upcoming presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 being held in San Diego, California from April 5-10 (Press release, GeneCentric Therapeutics, APR 1, 2024, View Source [SID1234641683]). Presentations will include a poster describing a new colorectal cancer predictive response signature (MSS-PRS) that selects tumors not identified with conventional MSI testing but have molecular characteristics consistent with microsatellite instability, making them a potential target for immune checkpoint inhibition. A second poster presentation describes ongoing clinical validation for PurISTSM, a novel RNA-expression test developed in collaboration with Tempus. PurIST identifies patients with the classical subtype of pancreatic ductal adenocarcinoma (PDAC) that are likely to experience longer overall survival with standard of care FOLFIRINOX than patients with the basal subtype of PDAC.

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Details of the AACR (Free AACR Whitepaper) presentations are as follows:

Title: Development of a novel RNA-based microsatellite stable predictive response signature (MSS-PRS) to identify MSS colorectal cancer (CRC) patients with a microsatellite instability-high (MSI-H) molecular phenotype
Session: PO.CL01.01 – Diagnostic Biomarkers 1, Section 42
Date: April 7, 2024, 1:30pm – 5:00pm PT
Abstract/Poster Number: 040 / 20

Title: Real-world validation of the PurIST classifier demonstrates enhanced therapy selection for pancreatic ductal adenocarcinoma (PDAC) patients
Session: PO.CL10.01 – Real-World Biomarkers, Section 45
Date: April 8, 2024, 9:00am – 12:30pm PT
Abstract/Poster Number: 2542 / 2

The posters will be accessible under the News & Events section of the Company’s website following the conference.