On September 11, 2023 Astrazeneca and Daiichi Sankyo reported Results from the primary analysis of the DESTINY-Lung02 Phase II trial showed Enhertu (trastuzumab deruxtecan) continued to demonstrate strong and durable tumour responses in previously treated patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC).

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These results, along with the first report on progression-free survival (PFS) and overall survival (OS), were presented today at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC) (abstract #MA13.10) and simultaneously published in the Journal of Clinical Oncology.

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

At the primary analysis, a confirmed objective response rate (ORR) of 49.0% and 56.0% was seen in the 5.4mg/kg arm and 6.4mg/kg arm respectively, as assessed by blinded independent central review (BICR). The safety profile for both doses was consistent with the overall safety profile of Enhertu, with the 5.4mg/kg dose demonstrating a favourable safety profile in this patient population.

Secondary endpoint data were also encouraging, with Enhertu demonstrating a median PFS of 9.9 months and 15.4 months in the 5.4mg/kg and 6.4mg/kg arms respectively, as assessed by BICR. A median OS of 19.5 months was achieved in the 5.4mg/kg arm and not reached in the 6.4mg/kg arm at time of analysis.

Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, US, said: "The primary results from DESTINY-Lung02 demonstrate that Enhertu continues to show strong and durable tumour responses for patients treated at either dose. The favourable safety profile seen at the 5.4mg/kg dose continues to support the use of Enhertu in the treatment of patients with HER2-mutant non-small cell lung cancer, a particularly aggressive form of the disease where patients face a poor prognosis and have historically had few options."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These results from DESTINY-Lung02 highlight that HER2 is an actionable target in lung cancer and reinforce the importance of testing for predictive biomarkers, including HER2 alterations, at the time of diagnosis to accurately identify patients who may be able to benefit from a targeted treatment. The data also reaffirm our belief in Enhertu as a potential new targeted treatment option for patients who have historically had limited options."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "The disease control achieved by more than 90% of patients with previously treated HER2-mutant non-small cell lung cancer in the primary analysis of DESTINY-Lung02 reinforces the efficacy we have already seen with Enhertu in this hard-to-treat disease. These results, along with encouraging progression-free survival and overall survival findings reported for the first time, demonstrate the potential role of Enhertu as an important treatment option for this patient population."

Summary of results: DESTINY-Lung02 Primary analysis

Efficacy Measure

Enhertu (5.4mg/kg)

n=102

Enhertu (6.4mg/kg)

n=50

Confirmed ORR (%)

(95% CI)i

49.0% (39.0-59.1)

56.0% (41.3-70.0)

Complete Response (%)

1.0%

4.0%

Partial Response (%)

48.0%

52.0%

Stable Disease (%)

44.1%

36.0%

Progressive Disease (%)

3.9%

4.0%

Not Evaluable (%)ii

2.9%

4.0%

DCR (95% CI) iii

93.1% (86.4-97.2)

92.0% (80.8-97.8)

Median DoR (months)

(95% CI)iv,v

16.8 (6.4-NE)

NE (8.3-NE)

Median TTIR (months)

(95% CI)iv

1.8 (1.2-7.0)

1.6 (1.2-11.2)

Median PFS (months)

(95% CI)iv,vi

9.9 (7.4-NE)

15.4 (8.3-NE)

Median OS (months)

(95% CI)vii

19.5 (13.6-NE)

NE (12.1-NE)

CI, confidence interval; DCR, disease control rate; DoR, duration of response; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression free survival; TTIR, time to initial response
Data cutoff: As of 23 December 2022
i Proportion of patients with confirmed CR or PR assessed by BICR per RECIST v1.1
ii Three patients were NE at 5.4mg/kg (one patient never received treatment due to COVID-19; two patients discontinued before first tumour assessment); two patients were NE at 6.4mg/kg (discontinued due to adverse event before first tumour assessment).
iii Proportion of patients with confirmed CR, PR, or SD assessed by BICR
iv Assessed by BICR
v 60.0% and 75.0% of patients in the 5.4 mg/kg and 6.4 mg/kg arms were censored
vi 56.9% and 60.0% of patients in the 5.4 mg/kg and 6.4 mg/kg arms were censored
vii 63.7% and 72.0% of patients in the 5.4 mg/kg and 6.4 mg/kg arms were censored

In DESTINY-Lung02, no new safety signals were observed at either dose of Enhertu. Grade 3 or higher treatment-related treatment emergent adverse events (TEAEs) were lower with Enhertu 5.4mg/kg versus 6.4mg/kg, occurring in 38.6% and 58.0% of all patients, respectively. The most common Grade 3 or higher TEAEs were neutropenia (18.8% (5.4mg/kg); 36.0% (6.4mg/kg)) and anaemia (10.9% (5.4mg/kg); 16.0% (6.4mg/kg)).

There were 27 cases (12.9% in the 5.4mg/kg arm and 28% in the 6.4mg/kg arm) of treatment-related interstitial lung disease (ILD) or pneumonitis reported as determined by an independent adjudication committee. In the 5.4mg/kg arm, the majority of ILD cases were low Grade (Grade 1 or 2) (10.9%) with one Grade 3 event (1.0%), no Grade 4 events and one Grade 5 event (1.0%) observed. In the 6.4mg/kg arm, the majority of ILD cases were also low Grade (26.0%) with no Grade 3 or 4 events and one Grade 5 event (2.0%) reported.

Notes

HER2m NSCLC
Lung cancer is the second most common form of cancer globally, with more than two million patients diagnosed in 2020.1 Prognosis is particularly poor for patients with metastatic NSCLC, as only approximately 9% will live beyond five years after diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, 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 2-4% of patients with this type of lung cancer.3,4 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.5 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.6 Next-generation sequencing has been utilised in the identification of HER2 (ERBB2) mutations.7,8

Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2-directed therapies in NSCLC prior to the approvals of Enhertu by the Israel Ministry of Health (MOH) Pharmaceutical Division, the Japan Ministry of Health, Labour and Welfare and the accelerated US Food and Drug Administration (FDA) approval of Enhertu in unresectable or metastatic HER2 mutant NSCLC.9

DESTINY-Lung02
DESTINY-Lung02 is a global, randomised Phase II trial evaluating the safety and efficacy of Enhertu in patients with HER2m unresectable and/or 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 randomised 2:1 to receive Enhertu 5.4mg/kg (n=102) or Enhertu 6.4mg/kg (n=50).

The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include confirmed DCR, DoR and PFS assessed by investigator and BICR, OS and safety.

DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu 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 programme 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 (5.4mg/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 anti-HER2-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 (5.4mg/kg) is approved in more than 40 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/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 (5.4mg/kg) is approved in Israel, Japan and under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours 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 for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/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 (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.

Enhertu development programme
A comprehensive clinical development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

On September 11, 2023 PDS Biotechnology reported its corporate presentation (Presentation, PDS Biotechnology, SEP 11, 2023, View Source [SID1234635071]).

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On September 11, 2023 Marker Therapeutics, Inc. (Nasdaq: MRKR) is a clinical-stage immuno-oncology company focusing on developing next-generation T cell-based immunotherapies for the treatment of hematological malignancies and solid tumor indications, reported the preliminary results of the first participant treated with MT-601, its multi-tumor associated antigen (multiTAA)-specific T cell product targeting 6 TAAs, in the Phase 1 multicenter APOLLO clinical trial (Press release, Marker Therapeutics, SEP 11, 2023, View Source [SID1234635070]). The APOLLO trial is investigating the safety and efficacy of MT-601 for the treatment of patients with lymphoma who have either failed or are ineligible to receive anti-CD19 CAR T cell therapy.

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This first APOLLO study participant had diffuse large B cell lymphoma (DLBCL) and was enrolled into the Phase 1 dose escalation stage of the trial (Press Release, June 12, 2023) after failing 4 prior lines of therapy, including anti-CD19 CAR T cell therapy.

After relapse following anti-CD19 CAR T cell therapy, the participant was treated with 2 doses of MT-601 at the 200 million cell dose level without prior lymphodepletion. MT-601 treatment was well tolerated with no reports of higher than Grade 1 treatment-related adverse events. The tolerability at this initial dose level is consistent with the favorable clinical safety profile and tolerability previously reported for other multiTAA-specific T cell products. Eight weeks after the 2nd infusion of MT-601, the participant demonstrated complete metabolic response based on PET-CT scans.

Marker previously reported non-clinical proof-of-concept data that showed that MT-601 has the potential to eliminate lymphoma cells that are resistant to anti-CD19 CAR T cells, highlighting the therapeutic potential of MT-601 in vitro (Press Release, May 31, 2023).

"We are delighted to announce that the first study participant treated in the APOLLO trial achieved a complete response after treatment with MT-601," said Monic Stuart, M.D., Chief Medical Officer of Marker Therapeutics. "This is a significant initial step forward in our Phase 1 clinical trial and highlights the potential benefit of MT-601 in patients who have relapsed after anti-CD19 CAR T cell therapy. The patient will remain under close observation as we continue to monitor long-term treatment effects and the durability of response."

"The complete response we have observed in this CAR T relapsed patient with lymphoma marks a remarkable milestone for Marker and our technology," said Juan F. Vera, M.D., President and Chief Executive Officer of Marker Therapeutics. "Our APOLLO trial is an important area for MT-601 assessment, as up to 60% of patients treated with anti-CD19 CAR T therapies relapse within one year. While a complete response in our first patient treated with MT-601 is certainly encouraging, the focus of the APOLLO study is to continue to treat and evaluate additional participants in this Phase 1 study."

About MT-601

MT-601 utilizes a novel non-genetically modified approach that specifically targets six different tumor antigens upregulated in lymphoma cells (Survivin, PRAME, WT-1, NY-ESO-1, SSX-2, MAGEA-4). Marker is currently investigating MT-601 in the Company-sponsored Phase 1 APOLLO trial (clinicaltrials.gov identifier: NCT05798897) for the treatment of lymphoma patients who are relapsed/refractory after or ineligible to anti-CD19 CAR T cell therapies.

About APOLLO

The APOLLO trial (clinicaltrials.gov Identifier: NCT05798897) is a Phase 1, multicenter, open-label study designed to evaluate the safety and efficacy of MT-601 in participants with relapsed or refractory lymphoma who either received anti-CD19 chimeric antigen receptor (CAR) T cell therapy or are ineligible for anti-CD19 CAR T cell therapy. The primary objective of this exploratory Phase 1 clinical trial is to evaluate the optimum dose, safety, and preliminary efficacy of MT-601 in participants with various lymphoma subtypes. Under the APOLLO trial, eight clinical sites across the United States will cumulatively enroll up to approximately 30 participants during the dose escalation phase.

About multiTAA-specific T cells

The multi-tumor associated antigen (multiTAA)-specific T cell platform is a novel, non-genetically modified cell therapy approach that selectively expands tumor-specific T cells from a patient’s/donor’s blood capable of recognizing a broad range of tumor antigens. Clinical trials that enrolled more than 180 patients with various hematological malignancies and solid tumors showed that autologous and allogeneic multiTAA-specific T cell products were well tolerated and demonstrated durable clinical responses, and consistent epitope spreading. The latter is typically not observed with other T cell therapies and enables the potential contribution to a lasting anti-tumor effect.

On September 11, 2023 Cellares, the first Integrated Development and Manufacturing Organization (IDMO) dedicated to clinical and industrial-scale cell therapy manufacturing, and Lyell Immunopharma (NASDAQ: LYEL), a clinical‑stage T-cell reprogramming company advancing a diverse pipeline of cell therapies for patients with solid tumors, reported Lyell will evaluate Cellares’ automated manufacturing platform, the Cell Shuttle, through Cellares’ Technology Adoption Partnership (TAP) program (Press release, Lyell Immunopharma, SEP 11, 2023, View Source [SID1234635069]). As part of the collaboration, the companies have agreed on a proof-of-concept technology transfer process for the manufacture of Lyell’s LYL797 CAR T-cell therapy, using the Cell Shuttle.

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CAR T-cell therapy is a personalized immunotherapy that takes a patient’s own T cells and modifies them to recognize and kill cancer cells that have a specific biomarker. LYL797 is an investigational CAR T-cell therapy in development for the treatment of solid tumors that express ROR1, a protein present on the surface of various solid tumors. LYL797 is enhanced with Lyell’s novel genetic and epigenetic reprogramming technologies designed to generate highly tumor-reactive, longer-lasting functional T cells. Lyell is enrolling patients with triple-negative breast cancer and non-small cell lung cancer in a Phase 1 clinical trial evaluating LYL797.

"We are excited to work with Cellares to evaluate their innovative automated manufacturing processes as part of our overall manufacturing strategy to efficiently, rapidly, and cost-effectively scale manufacturing capacity for our CAR T-cell product candidates for future clinical trials and potential commercialization," said Stephen Hill, Chief Operating Officer of Lyell. "We are impressed with the progress Cellares has made with their manufacturing capabilities, and the commitment and vision of the Cellares team to apply these technologies to help deliver new and potentially transformative therapies to patients."

Cellares’ TAP program offers cell therapy developers a swift and low-risk pathway to embrace the company’s automated manufacturing technology for their pipeline products. Lyell is utilizing this program to assess the automated manufacturing process and generate data that validates the Cell Shuttle’s viability as a manufacturing option for CAR T-cell therapies. Cellares partners with prominent cell therapy developers through its TAP program to integrate the Cell Shuttle as a GMP manufacturing solution in both clinical and commercial stages at their IDMO Smart Factories.

"By integrating LYL797 into our TAP program, we seek to demonstrate the ability to seamlessly adapt Lyell’s CAR T-cell manufacturing process to our Cell Shuttle platform," said Fabian Gerlinghaus, CEO of Cellares. "This collaboration represents a significant step towards fulfilling our vision of accelerating access to life-saving cell therapies, reducing process failure rates, and meeting total patient demand through the efficient utilization of the Cell Shuttle platform at global scale."

Cellares’ innovative manufacturing technology transforms autologous and allogeneic cell therapy processes, covering nearly 90% of cell therapy modalities. Through their TAP program, Cellares can facilitate the automation and tech transfer of manual processes onto the Cell Shuttle manufacturing platform in just six months. This program allows cell therapy developers to seamlessly integrate their processes onto a Cell Shuttle at any stage of development – from pre-clinical to post-regulatory approval. With automation, standardization, and software-defined manufacturing (SDM), subsequent tech transfers become instant to any other Cell Shuttle into any IDMO Smart Factory worldwide.

Please visit cellares.com/partnering/ to learn more about the TAP program and request a meeting with a business development representative.

On September 11, 2023 Laminar Pharma reported that the U.S. Food & Drug Administration (FDA) has granted Rare Pediatric Disease (RPD) Designation to LAM561 (idroxioleic acid, sodium) an investigational drug candidate for patients with Pediatric-Type Diffuse High Grade Glioma (pdHGG) (Press release, Laminar Pharma, SEP 11, 2023, View Source [SID1234635068]).

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"Pediatric patients who develop Pediatric-Type Diffuse High Grade Glioma face a significant unmet need with limited treatment options, presenting differential characteristics from adult patients with high grade glioma that need to be considered during their treatment" said Dr. Victoria Llado, Chief Scientific Officer of the US subsidiary, Laminar Pharma Inc. "The Rare Pediatric Disease Designation highlights the serious and life-threatening manifestations of this rare disease in the pediatric population and supports our mission to provide LAM561 as a potential new treatment option for patients suffering from Pediatric-Type Diffuse High Grade Glioma."

The RPD program is intended to encourage the development of new drugs for the treatment of rare pediatric diseases. RPD Designation is granted by the FDA for serious or life-threatening diseases which affect fewer than 200,000 people in the United States and in which the serious or life-threatening manifestations primarily affect individuals less than 18 years of age. If, in the future, a New Drug Application (NDA) for LAM561 for the treatment of pdHGG is approved by the FDA, Laminar Pharma might be eligible to receive a Priority Review Voucher (PRV) that could be redeemed to receive a priority review for any subsequent marketing application.

LAM561 is a synthetic fatty acid which has previously been granted with the designation of Orphan Drug/Medicinal Product for the treatment of malignant glioma in adult and pediatric patients by the FDA and the European of Medicines Agency (EMA), It also received Fast Track designation from the FDA in October 2022 for the treatment of glioblastoma. The clinical development of LAM561 includes two successfully completed studies to determine its safety and tolerability in adult patients (a Phase I/IIa in patients with advanced solid tumors and a Phase Ib study in patients with newly diagnosed glioblastoma in combination with the standard of care) and other two clinical trials that are being currently conducted: A Phase IIb/III clinical study for the treatment of adult patients with newly diagnosed glioblastoma in combination with standard of care in Europe; and a Phase I/IIa study to determine the safety, tolerability and potential clinical activity in pediatric patients with advanced solid tumors (including malignant glioma) in the US, as part of a pediatric program initiated by Laminar in accordance with its commitment with this population.