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 CuraCell reported the company has signed a partnership agreement with the German Clinical Research Organisation, IKF, located in Frankfurt, Germany. IKF will support CuraCell in the preparation of the upcoming phase 1/2a trial and coordinate clinical operations throughout the trial.

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IKF is specialized in investigator-initiated and industry-academia collaborative cancer research. Founded by oncologists, with more the 20 years of operations, the company has been involved in oncology trials across 300 centers world-wide.

(Press release, CuraCell, AUG 22, 2023, View Source [SID1234661185])

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."