On August 23, 2023 Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") reported that the U.S. Food and Drug Administration (FDA) has accepted and granted Priority Review for the companies’ supplemental New Drug Application (sNDA) for XTANDI (enzalutamide) for the treatment of patients with non-metastatic castration-sensitive prostate cancer (nmCSPC; also known as non-metastatic hormone-sensitive prostate cancer or nmHSPC) with high-risk biochemical recurrence (BCR) (Press release, Astellas Pharma, AUG 23, 2023, View Source [SID1234634642]). The FDA grants Priority Review to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) date for an anticipated FDA decision is in Q4 2023.

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"The FDA’s granting of a Priority Review designation reinforces the need to bring new treatment options for patients with high-risk biochemical recurrent nmCSPC," said Chris Boshoff, M.D., Ph.D., Chief Oncology Research and Development Officer, Executive Vice President, Pfizer. "We believe the EMBARK data demonstrate the potential of XTANDI, if approved, to help patients earlier in the course of their disease, building on XTANDI’s foundation as an existing standard of care in prostate cancer."

"Biochemical recurrence can be one of the first indicators that prostate cancer is returning or will spread, particularly among those patients that experience rapid PSA doubling times," said Ahsan Arozullah, M.D., MPH, Senior Vice President and Head of Oncology Development, Astellas. "The goal of treatment in this setting is to delay the spread of the cancer cells to other parts of the body. The addition of XTANDI to leuprolide has shown greater clinical benefit compared to placebo plus leuprolide, and we look forward to working with the FDA and other global regulatory authorities to bring XTANDI to these patients."

The sNDA is based on results from the Phase 3 EMBARK trial, which evaluated patients with nmCSPC with high-risk BCR across three study arms: XTANDI plus leuprolide (n=355), placebo plus leuprolide (n=358), or XTANDI monotherapy (n=355). The study met its primary endpoint of metastasis-free survival (MFS) for the XTANDI plus leuprolide arm, demonstrating a statistically significant 58% reduction in the risk of metastasis or death over placebo plus leuprolide (Hazard Ratio [HR]: 0.42; 95% Confidence Interval [CI], 0.30–0.61; p<0.0001). The overall safety profile was consistent with the known safety profile of each of the medicines. The most common adverse events in those treated with XTANDI plus leuprolide were fatigue, hot flush, and arthralgia and in those treated with XTANDI monotherapy were fatigue, gynecomastia, and arthralgia. Detailed results from the trial were presented as a plenary session during the 2023 American Urological Association Annual Meeting on April 29.

The sNDA for XTANDI in nmCSPC with high-risk BCR is being reviewed under the Real-Time Oncology Review (RTOR) program and Project Orbis, two initiatives of the FDA designed to bring safe and effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines by participating international partners.

The EMBARK data are being discussed with other regulatory authorities around the world to support potential additional license applications for XTANDI in this indication in 2023 and beyond.

About EMBARK
The Astellas- and Pfizer-led Phase 3, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients with nmCSPC with high-risk BCR at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. Patients who were considered to experience high-risk BCR had a prostate-specific antigen doubling time (PSA-DT) ≤ 9 months; serum testosterone ≥ 150 ng/dL (5.2 nmol/L); and screening PSA by the central laboratory ≥ 1 ng/mL if they had a radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer, or at least 2 ng/mL above the nadir if they had radiotherapy only as primary treatment for prostate cancer. Patients in the EMBARK trial were randomized to receive enzalutamide 160 mg daily plus leuprolide (n=355), enzalutamide 160 mg as a monotherapy (n=355), or placebo plus leuprolide (n=358). Leuprolide 22.5 mg was administered every 12 weeks.

The primary endpoint of the trial was MFS for enzalutamide plus leuprolide versus placebo plus leuprolide. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death due to any cause, whichever occurred first. For more information on the EMBARK trial (NCT02319837) go to www.clinicaltrials.gov.

XTANDI, either in combination with leuprolide or as a monotherapy, has not been approved by any regulatory agency for the treatment of patients with nmCSPC with high-risk BCR.

About Non-Metastatic Castration-Sensitive Prostate Cancer with High-Risk Biochemical Recurrence
In non-metastatic castration- (or hormone-) sensitive prostate cancer (nmCSPC or nmHSPC), no evidence of the cancer spreading to distant parts of the body (metastases) is detectable with conventional radiological methods (CT/MRI), and the cancer still responds to medical or surgical treatment designed to lower testosterone levels.1,2 Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a BCR within 10 years.3 About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of the recurrence.4 The EMBARK trial focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmCSPC and high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a PSA-DT ≤ 9 months. High-risk BCR patients with a PSA-DT of ≤ 9 months have a higher risk of metastases and death.5 In the U.S., it is estimated that 12,000-16,000 patients are diagnosed with nmHSPC with high-risk BCR annually.6

About XTANDI (enzalutamide)
XTANDI (enzalutamide) is an androgen receptor signaling inhibitor. XTANDI is a standard of care and has received regulatory approvals in one or more countries around the world for use in men with metastatic castration-sensitive prostate cancer (mCSPC; also known as metastatic hormone-sensitive prostate cancer or mHSPC), metastatic castration-resistant prostate cancer (mCRPC), and non-metastatic castration-resistant prostate cancer (nmCRPC). XTANDI is currently approved for one or more of these indications in more than 100 countries, including in the U.S., European Union and Japan. Over one million patients have been treated with XTANDI globally.6

U.S. Important Safety Information
XTANDI (enzalutamide) is indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space-occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity: Reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease: In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.

Embryo-Fetal Toxicity: The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI.

Adverse Reactions (ARs): In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If coadministration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for additional safety information.

On August 23, 2023 Daiichi Sankyo (TSE:4568) reported that ENHERTU (trastuzumab deruxtecan) has been approved in Japan for the treatment of adult patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) with HER2 (ERBB2) mutations that has progressed after chemotherapy (Press release, Daiichi Sankyo, AUG 23, 2023, View Source [SID1234634638]).

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Lung cancer is the second most diagnosed cancer in Japan, with more than 138,000 cases diagnosed in 2020.

1 Only 18.2% of patients with metastatic NSCLC in Japan live more than three years following diagnosis, making prognosis particularly poor for these patients.2 The approval of ENHERTU by Japan’s Ministry of Health, Labour and Welfare (MHLW) is based on results from the DESTINY-Lung02 phase 2 trial presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2022 Congress. ENHERTU previously received an Orphan Drug Designation by the Japan MHLW for this tumor type, a designation that provided priority review of the application.

In DESTINY-Lung02, a pre-specified interim analysis of patients with previously-treated HER2 mutant NSCLC showed that ENHERTU (5.4 mg/kg) demonstrated a confirmed objective response rate (ORR) of 53.8% (n=52; 95% confidence interval [CI]: 39.5-67.8) in patients with unresectable advanced or recurrent NSCLC with activating HER2 (ERBB2) mutations after prior chemotherapy as assessed by blinded independent central review (BICR).

"HER2 mutant non-small cell lung cancer is a rare but serious disease and now patients and physicians in Japan have the potential to benefit from the first HER2 directed treatment option approved specifically for this type of lung cancer," said Wataru Takasaki, PhD, Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo.

"This is the fourth indication secured for ENHERTU in Japan in just over three years and the second approval this year alone, underscoring the benefit of this medicine across a range of HER2 targetable cancers."

In DESTINY-Lung02, the safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. Treatment related adverse events (AEs) occurred in 93 patients (92.1%) treated with ENHERTU (5.4 mg/kg). The most common treatment related AEs were nausea (59.4%), decreased neutrophil count (33.7%), anemia (28.7%), decreased appetite (28.7%), fatigue (25.7%), constipation (24.8%), decreased leukocyte count (23.8%) and vomiting (22.8%). In Japanese patients, interstitial lung disease (ILD) occurred in 2.7% of patients treated with 5.4 mg/kg of ENHERTU at interim analysis.

ENHERTU is approved in Japan with a Warning for ILD. As cases of ILD, including fatal cases, have occurred in ENHERTU-treated patients, ENHERTU is to be used in close collaboration with a respiratory disease expert. Patients should be closely observed during therapy by monitoring for early signs or symptoms of ILD (such as dyspnea, cough or fever) and performing regular peripheral artery oxygen saturation (SpO2) tests, chest X-ray scans and chest CT scans. If abnormalities are observed, discontinue administration of ENHERTU and take appropriate measures, such as corticosteroid administration. Prior to initiation of ENHERTU therapy, a chest CT scan should be performed and medical history taken to confirm the absence of any comorbidity or history of ILD with the patient and carefully consider the eligibility of the patient for ENHERTU therapy. The efficacy and safety of ENHERTU as a neoadjuvant, adjuvant or first-line metastatic therapy for the treatment of patients with HER2 (ERBB2) mutant unresectable advanced or recurrent NSCLC has not been established.

ENHERTU should be administered only to patients with NSCLC with confirmed HER2 (ERBB2) mutations as detected by an approved test.

About DESTINY-Lung02

DESTINY-Lung02 is a global phase 2 trial evaluating the safety and efficacy of two doses (5.4 mg/kg or 6.4 mg/kg) of ENHERTU in patients with HER2 mutant metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomized 2:1 to receive ENHERTU 5.4 mg/kg (n=101) or ENHERTU 6.4 mg/kg (n=50) every three weeks. The primary endpoint of the study is confirmed ORR as assessed by BICR. Secondary endpoints include confirmed disease control rate, duration of response and progression free survival assessed by investigator and BICR, overall survival and safety.

DESTINY-Lung02 enrolled 151 patients at multiple sites, including Asia, Europe, Oceania and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Mutant NSCLC

Lung cancer is the second most common form of cancer globally, with more than two million cases diagnosed in 2020.

In Japan, lung cancer is the second most diagnosed cancer, with more than 138,000 cases diagnosed in 2020.1 Prognosis is particularly poor for patients with metastatic NSCLC, as only approximately 9% will live beyond five years after diagnosis.

In Japan, only 18.2% of patients with metastatic NSCLC will live more than three years following diagnosis.2 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target, and occur in approximately 2% to 4% of patients with this type of lung cancer. 4,5 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Next-generation sequencing is being utilized in the identification of HER2 (ERBB2) mutations.8 Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2 directed therapies for NSCLC in Japan prior to this approval of ENHERTU in unresectable or metastatic HER2 mutant NSCLC.

About ENHERTU

ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in more than 50 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) prior antiHER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

ENHERTU (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/in-situ hybridization (ISH)-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

ENHERTU (5.4 mg/kg) is approved in Israel, Japan and under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ENHERTU (6.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.

About the ENHERTU Clinical Development Program

A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway

On August 22, 2023 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 Interim Results (Press release, Carsgen Therapeutics, AUG 22, 2023, View Source [SID1234634637]).

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Business Highlights

Collaboration agreement for zevor-cel commercialization in mainland China with Huadong Medicine.
CT041 has achieved IND clearance from the NMPA for the postoperative adjuvant therapy of Claudin18.2 positive pancreatic cancer (PC).
CT041 Phase 2 clinical trial has been initiated in the U.S. 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.
CARsgen and Moderna have initiated a collaboration agreement to investigate CT041 in combination with Moderna’s investigational Claudin18.2 mRNA cancer vaccine.
Dr. Zonghai Li, Founder, Chairman of the Board, Chief Executive Officer, and Chief Scientific Officer of CARsgen Therapeutics Holdings Limited, said, "In the past six months, we have made significant progress in driving technological innovation, product development, and business operations. Our team has achieved remarkable accomplishments not only in the United States but also in China, continuously expanding the horizons of our scientific exploration and commercial boundaries. Looking ahead, we will persist in our commitment to innovation and strengthen international collaborations, aiming to rapidly translate cutting-edge scientific achievements into feasible treatment solutions. Our goal is to expedite the global availability of the innovative CAR T-cell therapy, benefiting cancer patients worldwide."

Zevorcabtagene Autoleucel (Zevor-cel, R&D code: 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). In October 2022, China National Medical Products Administration (NMPA) accepted the New Drug Application (NDA) and has granted the priority review for zevor-cel. Zevor-cel is expected to be approved by the NMPA for the treatment of R/R MM at the end of 2023 or the beginning of 2024. The enrollment in the Phase 2 clinical trial in the United States and Canada is underway. In January 2023, CARsgen and Huadong Medicine (Hangzhou) Co., Ltd., a wholly-owned subsidiary of Huadong Medicine Co., Ltd. (Stock Code: SZ.000963) ("Huadong Medicine") entered into a collaboration agreement for the commercialization of CARsgen’s lead drug candidate, zevor-cel, in mainland China. Since reaching the agreement, teams from CARsgen and Huadong Medicine have been working together closely to implement this collaboration and prepare for the approval and commercialization of zevor-cel in China.

CT041 is an autologous humanized CAR T-cell product candidate against Claudin18.2. Based on our information, CT041 is the world’s first CAR T-cell candidate for the treatment of solid tumors that has entered a confirmatory Phase II clinical trial. In April 2023, CT041 has achieved IND clearance from the NMPA for the postoperative adjuvant therapy of Claudin18.2 positive pancreatic cancer (PC) (CT041-ST-05, NCT05911217). In May 2023, a Phase 2 clinical trial of CT041 in the U.S. has been 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. Active CT041 trials include a Phase 1b/2 clinical trial for advanced gastric cancer (GC) and PC in the United States and Canada (CT041-ST-02, NCT04404595), a Phase Ib clinical trial for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJ) and PC (CT041-ST-01, NCT04581473), a confirmatory Phase II clinical trial for advanced GC/GEJ in China (CT041-ST-01, NCT04581473), and an investigator-initiated trial (NCT03874897). On August 21, 2023, CARsgen announced that CARsgen and Moderna, Inc. (Nasdaq: MRNA) have initiated a collaboration agreement to investigate CT041 in combination with Moderna’s investigational Claudin18.2 mRNA cancer vaccine.

On top of these existing clinical programs, CARsgen will actively explore the treatment with innovative CAR T-cell products for the earlier lines of therapies. CARsgen has also been taking efforts to develop innovative technologies and product candidates that will better address the challenges with existing cell therapy products. As of June 30, 2023, we had more than 300 patents of which 101 patents had been issued globally including China, the United States, Europe, and Japan. This status is an increase of 9 issued patents and 24 patent applications from the end of 2022. Our R&D activities would continue to generate substantial intellectual property in our areas of expertise.

We have established in-house, vertically integrated manufacturing capabilities for the three key stages of CAR T manufacturing, including the production of plasmids, lentiviral vectors, and CAR T cells. We have been expanding our global manufacturing capacity in China and the U.S. to support both clinical trials and the subsequent commercialization of our pipeline products. With the clinical manufacturing facility in Xuhui, Shanghai and commercial GMP manufacturing facility in Jinshan, Shanghai, we manufacture CAR T-cell products in-house to support clinical trials in China and manufacture the lentiviral vectors in-house to support clinical trials globally. Our Research Triangle Park (RTP) CGMP manufacturing facility in Durham, North Carolina, has commenced operations of GMP production of autologous CAR T-cell products. The RTP Manufacturing Facility will provide CARsgen additional manufacturing capacity of autologous CAR T-cell products for 700 patients annually to support clinical studies and early commercial launch in the United States, Canada, and Europe.

On August 22, 2023 Geneos Therapeutics, a clinical stage biotherapeutics company focused on the development of personalized therapeutic cancer vaccines (PTCV), reported updated data from GT-30, an ongoing single-arm open-label multi-center Phase 1b/2a study in second-line advanced hepatocellular carcinoma (HCC) (Press release, Geneos Therapeutics, AUG 22, 2023, View Source [SID1234634636]). Previously, Geneos reported three patients to have achieved a complete response (CR) and a fourth patient to be cancer-free, whose liver and lung lesions shrank to become fully responsive to surgery and radiation (secondary resectability).

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Geneos reports today that four additional patients have achieved a complete molecular response (CMR) by ultrasensitive, third-generation, circulating tumor DNA (ctDNA) analysis. The ctDNA dropped below the limit of detection in all four patients. By RECIST1.1, three of these four patients are durable partial responses (PR) and one a durable stable disease (SD). Applying mRECIST criteria as additional evaluation, each of the three PR patients is a CR and the SD patient is a PR.

Among all CR and PR patients for whom ctDNA data is available, the reductions in ctDNA level (molecular response) have preceded improvement by MRI.

To date, among 32 evaluable patients from the first 34 enrolled, by RECIST1.1 the study has achieved 3 complete responses, 7 partial responses, 9 stable disease and 13 progressive disease.

By either RECIST1.1 or by ctDNA response, 11 of 32 evaluable have achieved either a complete response, partial response, or complete molecular response.

There have been no vaccination-related serious adverse events (SAEs). Vaccination-related AEs, mostly injection site reactions, have been transient, mild, and all Grades 1 and 2.

GT-30 is evaluating the safety, immunogenicity, and efficacy of PTCV (GNOS-PV02 plus plasmid-encoded IL-12) administered in combination with the immune checkpoint inhibitor pembrolizumab, in 36 patients with unresectable or metastatic hepatocellular carcinoma (HCC) who progress on, or are intolerant to, first-line tyrosine kinase inhibitors (sorafenib or lenvatinib). HCC is characterized by a low tumor mutational burden and is resistant to immune checkpoint monotherapy in the majority of patients due to the immune-excluded tumor microenvironment. The study is fully enrolled. View Source

"As hepatologists and oncologists treating patients with HCC, we’re increasingly using ctDNA to monitor tumour response to therapy. In this study, the ctDNA improvements all preceded the MRI improvements, which shows ctDNA’s prognostic importance, especially since HCC lesions sometimes never fully resolve on MRI despite patients having no clinical evidence of residual viable cancer," said Dr Ed Gane, professor of medicine at the University of Auckland, New Zealand, hepatologist and deputy director of the New Zealand Liver Unit at Auckland City Hospital. "Historically, CRs in advanced HCC from checkpoint inhibitor treatment alone are virtually unheard of. The numerous CRs and CMRs seen here are remarkable and emphasize the role Geneos’ vaccines may have to treat seriously ill patients with late-stage HCC. I’m excited for what these vaccines may mean for these patients, who may now be able to hope, realistically, for a complete response to treatment," Dr Gane added.

"While we welcome the advances currently observed with mRNA-based cancer vaccines, they are being deployed almost exclusively in the adjuvant setting, to prevent cancer recurrence in patients who have had surgery to remove their tumor. As a result, some are even suggesting that personalized therapeutic vaccines may only be effective in the adjuvant setting and ineffective at reducing advanced, unresectable, and metastatic tumors." stated Niranjan Sardesai, PhD, president and chief executive officer of Geneos. "We feel these latest data should set the record straight. Cancer vaccines based on our DNA vaccine platform are showing complete responses in patients with late-stage, advanced cancer. We look forward to continuing to develop in the advanced setting with the goal to offer this profoundly important treatment option to patients with advanced cancer, one with a side effect profile, as seen to date, as benign as that for the typical seasonal flu shot," added Dr. Sardesai.

GT-30 Trial of Geneos’ Personalized Therapeutic Cancer Vaccines
In the GT-30 trial, DNA plasmid-encoded personalized therapeutic cancer vaccine (PTCV) together with plasmid-encoded interleukin-12 (pIL12, a T cell-stimulating cytokine) adjuvant are administered via intradermal injection followed by electroporation (EP) in combination with pembrolizumab. The potential utility of this combination was suggested by preclinical studies which demonstrate Geneos’ PTCV to rescue PD-1 in murine tumor therapeutic challenge models. Geneos’ PTCVs have been engineered to drive a strong CD8+ T cell response against the tumor. CD8 cells are the killing machines of the immune system, seeking out and destroying cancer cells, but have been difficult to induce using prior vaccine approaches. Adjuvant pIL12 and EP serve to optimize the effectiveness of peripheral vaccination, and their utility is seen by the effective CD4+/CD8+ T cell responses observed to the delivered neoantigens in the GT-30 patients. Each patient’s PTCV is designed based on their unique tumor neoantigens (abnormal mutations and genomic variations produced by cancer cells), and unlike other personalized platforms, in almost every case, Geneos’ PTCVs include all of a patient’s specific neoantigens. This removes any requirement to try to pre-select the "high value" neoantigens accurately and, instead, leaves it to nature to decide which ones will matter for triggering the desired immune response. PTCV manufacturing "needle to needle" time, i.e., from biopsy to treatment, is six to eight weeks and is in the process of being reduced to three to four weeks.

Circulating tumor DNA (ctDNA) has enabled non-invasive detection and monitoring of potentially actionable mutations and can identify therapeutic response/resistance prior to confirmation by MRI imaging. For the data announced here, the NeXT Personal platform (Personalis, Inc.) was used to longitudinally monitor molecular residual disease (MRD). NeXT Personal platform is an ultra-sensitive tumor-informed ctDNA assay that leverages whole genome sequencing of tumor/normal samples to generate personalized liquid biopsy panels. Each panel includes up to 1,800 selected variants of the highest value specific to each patient, enabling detection of ultra-low traces of residual cancer, as low as 1 – 3 parts per million (PPM).

On August 22, 2023 BerGenBio ASA (OSE: BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical needs, reported that additional clinical data of bemcentinib in combination with chemotherapy and with immunotherapy in Non-Small Cell Lung Cancer (NSCLC) have been recently published and accepted for presentation at two upcoming international oncology conferences (Press release, BerGenBio, AUG 22, 2023, View Source [SID1234634635]):

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Comprehensive results from the investigator led trial of bemcentininb + docetaxel in previously treated NSCLC patients (Study BGBIL005) were published in the August 2023 issue of Lung Cancer. "Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer." Lung Cancer 182 (2023) The trial was led by David Gerber, MD., Professor at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center.

The abstract "Bemcentinib + Pembrolizumab show promising efficacy in metastatic NSCLC harbouring mutations associated with poor prognosis: Exploratory sub-analysis from the BGBC008 trial (NCT03184571)" has been accepted for poster presentation at the SITC (Free SITC Whitepaper) 38th Annual Meeting, to be held November 3-5, 2023, in San Diego, CA (Abstract #598).

The abstract "Final top-line results of the BGBC008 phase 2, multicenter study of bemcentinib and pembrolizumab (bem+pembro) in 2nd line (2L) advanced non-squamous (NS) non-small cell lung cancer (NSCLC) (NCT03184571)" has been accepted for poster presentation at the ESMO (Free ESMO Whitepaper) Congress 2023, to be held October 20-24, 2023, in Madrid, Spain (Abstract #5343)

"The accumulating evidence supporting the potential role of bemcentinib in NSCLC aligns with our strategic focus on this disease where a large portion of patients still have very poor clinical outcome from existing therapies" said Martin Olin, Chief Executive Officer of BerGenBio. "The publication of data in a prestigious peer reviewed publication and at ESMO (Free ESMO Whitepaper) and SITC (Free SITC Whitepaper) provides us with the opportunity to share our data with a broad audience of oncologists and key opinion leaders in the field of NSCLC and the pharmaceutical industry."