On September 10, 2023 Astrazeneca and Daiichi Sankyo reported that Initial results from the TROPION-Lung04 Phase Ib trial showed datopotamab deruxtecan (Dato-DXd) in combination with Imfinzi (durvalumab), an anti-PD-L1 therapy, with or without carboplatin demonstrated encouraging responses and no new safety signals in patients with previously untreated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (Press release, AstraZeneca, SEP 10, 2023, View Source [SID1234635045]).

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These data were presented today in a late-breaking oral presentation (#OA05.06) at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC).

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

More than one million people worldwide are diagnosed with advanced NSCLC each year.1,2 While 1st-line treatment with immune checkpoint inhibitors with or without chemotherapy has improved outcomes for patients with NSCLC without actionable genomic alterations, like EGFR or ALK, most patients eventually experience disease progression.3-5 TROP2 is a protein broadly expressed in a large majority of NSCLC tumours.6 There are currently no TROP2-directed ADCs approved for the treatment of patients with lung cancer.7,8

In previously untreated patients, datopotamab deruxtecan plus durvalumab (doublet; n=14) demonstrated an objective response rate (ORR) of 50.0%, including 7 partial responses (PR), and a disease control rate (DCR) of 92.9%. Response rates were higher in patients receiving datopotamab deruxtecan plus durvalumab and carboplatin (triplet; n=13) which demonstrated an ORR of 76.9%, including 10 PRs, and a DCR of 92.3%. Responses were observed across PD-L1 expression levels.

Saiama Waqar, MD, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, and investigator in the trial, said: "Most patients with advanced non-small cell lung cancer experience disease progression after initial treatment, underscoring the need for more effective first-line treatment options. The TROPION-Lung04 results offer preliminary evidence for the efficacy of datopotamab deruxtecan in combination with durvalumab and chemotherapy in first-line advanced non-small cell lung cancer with no new safety signals. We eagerly await enrolment and results from the Phase III programme evaluating various datopotamab deruxtecan and immune checkpoint inhibitor combinations in this setting."

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "Following the positive high-level results of TROPION-Lung01, these initial TROPION-Lung04 results in the first-line setting reinforce our confidence in datopotamab deruxtecan as a potential treatment option for patients with advanced non-small cell lung cancer. Through our robust clinical programme we are eager to continue evaluating this TROP2-directed antibody drug conjugate in lung cancer across treatment settings, alone and in novel combinations."

Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo, said: "These early trial results further demonstrate the potential for datopotamab deruxtecan to enhance response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer and without actionable genomic alterations. We look forward to continuing to evaluate this promising TROP2-directed antibody drug conjugate in multiple ongoing Phase III trials to address what has long been an unmet need for the lung cancer community across treatment settings."

In both previously treated and untreated patients, the safety profiles of datopotamab deruxtecan and Imfinzi with and without carboplatin were consistent with other clinical trials and with the known safety profile of each agent. Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 42.1% of patients receiving doublet therapy and 71.4% of patients receiving triplet therapy. In patients receiving triplet therapy, the most common Grade 3 or greater TEAEs (occurring in more than 15% of patients) were anaemia (36%) and thrombocytopenia (21%). No Grade 3 or greater TEAE occurred in more than 15% of patients receiving doublet therapy. Across treatment cohorts, there were four interstitial lung disease (ILD) events adjudicated as drug-related by an independent committee including one Grade 1 event, two Grade 2 events and one Grade 4 event. No Grade 5 ILD events were observed.

Summary of TROPION-Lung04 Efficacy Results

Responses in Previously Untreated Patients

Doublet Therapy

(Cohort 2; n=14)

Triplet Therapy

(Cohort 4; n=13)

ORR (confirmed and pending), %i (95% CI)

50.0% (23.0-77.0; n=7)

76.9% (46.2-95.0; n=10)

CR, %

0%

0%

PR, %

50.0% (n=7)

76.9% (n=10) ii

SD, %

42.9% (n=6)

15.4% (n=2)

PD, %

7.1% (n=1)

7.7% (n=1)

DCR, % iii

92.9% (66.1-99.8; n=13)

92.3% (64.0-99.8; n=12)

CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PR, partial response; PD, progressive disease; SD, stable disease
i ORR is CR + PR
ii One of the 10 partial responses in Cohort 4 was confirmed after data cut-off
ii iDCR is best overall response of confirmed CR + confirmed PR + SD

In the doublet cohort, 73.7% (n=14 of 19) of patients were previously untreated. In the triplet cohort, 92.9% (n=13 of 14) of patients were previously untreated. Both the doublet and triplet cohorts included patients with PD-L1 expression levels ranging from less than 1% (n=6, 6), 1-49% (n=6, 3) and 50% or greater (n=7, 5). As of the 6 March 2023 data cut-off, median study duration was six months for both cohorts and treatment was ongoing in 31.6% and 50.0% of patients in the doublet and triplet cohorts, respectively.

AstraZeneca and Daiichi Sankyo have three Phase III trials evaluating datopotamab deruxtecan-based combinations as potential 1st-line treatment options for patients with advanced or metastatic NSCLC without actionable genomic alterations compared to the respective standard of care for the patient population of each study.

AVANZAR is evaluating datopotamab deruxtecan plus Imfinzi and carboplatin in patients regardless of PD-L1 expression or tumour histology.
TROPION-Lung07 is evaluating datopotamab deruxtecan plus pembrolizumab with or without chemotherapy in patients with non-squamous disease and PD-L1 expression less than 50%.
TROPION-Lung08 is evaluating datopotamab deruxtecan plus pembrolizumab in patients with PD-L1 expression of 50% or greater.
Notes

Non-small cell lung cancer
More than one million people worldwide are diagnosed with advanced NSCLC each year.1,2 While targeted therapies and immune checkpoint inhibitors have improved patient outcomes, advanced NSCLC has a poor prognosis and is associated with worsening outcomes after each line of subsequent therapy.3-5

Most patients with NSCLC have tumours that do not express a known actionable genomic alteration (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET).9-11 The current 1st-line standard of care for these patients is immune checkpoint inhibitors with or without platinum-based chemotherapy. Approximately 40-60% of tumours will not respond to this initial treatment and while these therapies may improve survival for patients whose tumours do respond, most will experience disease progression.5,7

TROP2, a transmembrane glycoprotein, is broadly expressed in a large majority of NSCLC tumours.6 There are currently no TROP2-directed ADCs approved for the treatment of lung cancer.

TROPION-Lung04
TROPION-Lung04 is an ongoing global, open-label, 11-cohort Phase Ib trial evaluating the efficacy and safety of datopotamab deruxtecan (4 mg/kg or 6 mg/kg) in combination with immunotherapy (Imfinzi, AZD2936 or MEDI5752) with or without up to four cycles of carboplatin in patients with advanced or metastatic NSCLC without actionable genomic alterations. Patients enrolled in the cohorts evaluating Imfinzi were previously untreated or had received one or fewer lines of systemic chemotherapy without concomitant immunotherapy. The primary endpoints of TROPION-Lung04 are safety and tolerability. Secondary endpoints include ORR, DCR, duration of response and progression-free survival as assessed by investigator. TROPION-Lung04 will enrol approximately 230 patients globally.

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 five lead 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 humanized 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 development programme is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple TROP2-targetable tumours, including NSCLC, triple-negative breast cancer and hormone receptor-positive, HER2-negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials. AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage SCLC based on the CASPIAN Phase III trial. In an exploratory analysis in 2021, updated results from the CASPIAN trial showed Imfinzi plus chemotherapy tripled patient survival at three years versus chemotherapy alone. Additionally, Imfinzi is approved in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indications in lung cancer, Imfinzi is also approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer in the US, EU, Japan and several other countries; in combination with Imjudo in unresectable hepatocellular carcinoma in the US, EU and Japan; and in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 200,000 patients have been treated with Imfinzi.

AstraZeneca has several ongoing registrational trials focused on testing Imfinzi in earlier stages of lung cancer, including in resectable NSCLC (ADJUVANT BR.31) and unresectable NSCLC (PACIFIC-2, 4, 5, 8 and 9), and in limited-stage SCLC (ADRIATIC).

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer and other solid tumours.

On September 10, 2023 Allist Pharmaceuticals Co., Ltd. ("Allist") and ArriVent Biopharma, Inc. ("ArriVent") reported that interim results from the Phase Ib, randomized, open-label, multi-center clinical study (FAVOUR), evaluating the efficacy and safety of furmonertinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, were presented by Professor Baohui Han from Shanghai Chest Hospital during an oral session on September 10, 2023 at the 2023 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer (IASLC) (Press release, ArriVent Biopharma, SEP 10, 2023, https://arrivent.com/allist-and-arrivent-announce-interim-results-from-ongoing-phase-1b-trial-with-furmonertinib-at-the-2023-world-conference-on-lung-cancer/?utm_source=rss&utm_medium=rss&utm_campaign=allist-and-arrivent-announce-interim-results-from-ongoing-phase-1b-trial-with-furmonertinib-at-the-2023-world-conference-on-lung-cancer [SID1234635042]).

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Key Results
As of the data cutoff date of June 15, 2023, a total of 86 patients were enrolled in the FAVOUR study and were included in the safety analysis; 80 evaluable patients were analyzed for efficacy. Based on IRC assessments, the confirmed objective response rate (cORR) was 78.6% in the treatment-naïve patients who received furmonertinib at 240 mg daily dose, 46.2% in previously treated patients who received furmonertinib at 240 mg daily dose, and 38.5% in previously treated patients who received furmonertinib at 160 mg daily dose. The median duration of response were 15.2 months, 13.1 months, and 9.7 months in the treatment-naïve 240 mg, previously treated 240 mg, and previously treated 160 mg patient groups, respectively. Anti-tumor responses were observed across near-loop, far-loop and helical EGFR exon 20 insertion mutations.

A well-tolerated safety profile has been observed to-date in the FAVOUR study. Most of the treatment-related adverse events (TRAEs) were Grades 1 and 2. TRAEs leading to treatment discontinuation occurred in 0%, 4%, and 4% of patients in the 240 mg treatment-naïve, 240 mg previously treated, and 160 mg previously treated patient groups, respectively. The safety profile of furmonertinib in the FAVOUR study is overall consistent with that of approved dosage (80 mg) of furmonertinib in China for patients with advanced NSCLC with classical EGFR mutations with no new safety findings. The most common treatment related adverse events include diarrhea, anemia, and liver enzyme elevation.

Based on the FAVOUR study results, furmonertinib has shown promising anti-tumor activity as a single agent, good tolerability, and a manageable safety profile in treatment naïve and previously treated patients with advanced NSCLC who have EGFR exon 20 insertion mutations. Allist and ArriVent are currently collaborating on a global registrational Phase III study to compare furmonertinib to platinum-based chemotherapy for patients with locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations (FURVENT, NCT05607550 / CTR20231409). The trial is currently enrolling patient in the US, China and other countries.

About Furmonertinib
Furmonertinib is a novel, oral, highly brain-penetrant, EGFR kinase inhibitor designed for broad activity and selectivity across EGFR mutations.

Furmonertinib targets both classical (exon 19 deletion and L858R) and uncommon EGFR mutations, including exon 20 insertion mutations as well as HER2 exon 20 insertion mutations. Furmonertinib is approved in China as an anticancer therapy for first-line treatment for classical EGFR mutant NSCLC patients and EGFR T790M NSCLC patients. Furmonertinib is being developed in China by Allist Pharmaceuticals and in the rest of the world by ArriVent Biopharma.

On September 10, 2023 Amgen (NASDAQ:AMGN) reported exciting data from a study arm of the CodeBreaK 101 clinical trial, a Phase 1b study evaluating LUMAKRAS (sotorasib) with carboplatin and pemetrexed in adult patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) (Press release, Amgen, SEP 10, 2023, View Source [SID1234635041]). These results were featured in an oral presentation at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC) in Singapore on Sunday, September 10.

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In patients treated in the first-line setting (n=20), the confirmed objective response rate (ORR) was 65%, with a 100% disease control rate (DCR) (95% CI: 83.2, 100). In assessable patients in the second-line setting (n=13), the ORR was 54%, with a DCR of 85% (95% CI: 54.6, 98.1). Among patients with protein ligand-1 (PD-L1) expression less than 1%, the ORR was 62% in the first-line setting and 50% in the second-line setting. With a median follow-up of 3.0 months, preliminary rapid and durable responses were observed. Progression-free survival (PFS) and overall survival (OS) were immature.

"We are delighted to see the positive data from the global CodeBreaK 101 trial further validate our approach to move LUMAKRAS earlier within the treatment paradigm through novel therapeutic combinations," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "Notably, these results follow and further expand upon the Phase 2 investigator-led data demonstrating favorable efficacy and safety of LUMAKRAS plus carboplatin and pemetrexed in the first-line treatment of patients with KRAS G12C-mutated NSCLC."

The LUMAKRAS plus chemotherapy combination reported treatment-related adverse events (TRAEs) consistent with LUMAKRAS and other platinum doublet-based approaches. The most common TRAEs were neutropenia/neutrophil count decrease (53%), anemia (39%) and thrombocytopenia/platelet count decrease (37%). No fatal adverse events occurred.

"Combination treatment is an important approach to prevent or delay the onset of drug resistance and improve the depth and durability of targeted response in KRAS G12C­­-mutated NSCLC," said Jeffrey M. Clarke, M.D., oncologist and associate professor of medicine, Duke Cancer Institute at Duke University. "The CodeBreaK 101 results show exciting efficacy with sotorasib plus chemotherapy and, importantly for a combination treatment, a safety profile consistent with the individual therapies. These data warrant continued investigation in larger trials."

Based on these results, Amgen has initiated a Phase 3 study of LUMAKRAS plus carboplatin and pemetrexed in first-line KRAS G12C-mutant and negative for programmed cell death PD-L1 advanced NSCLC (CodeBreaK 202; NCT05920356), with enrollment expected to start before the end of 2023.

About CodeBreaK 101

CodeBreaK 101 (NCT04185883) is a global Phase 1b/2 clinical trial evaluating the safety, tolerability, pharmacokinetics, and efficacy of sotorasib in combination with other anticancer therapies in patients with advanced solid tumors and the KRAS G12C mutation. Subprotocol F of the Phase 1b trial is assessing the safety, tolerability, pharmacokinetics, and efficacy of sotorasib in combination with carboplatin and pemetrexed with or without pembrolizumab maintenance, with docetaxel, or with carboplatin and paclitaxel in patients with KRAS G12C-mutated NSCLC.1

About LUMAKRAS/LUMYKRAS (sotorasib)

Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.2 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep, and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.3

Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, with clinical trial sites spanning five continents. To date, over 6,500 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.

In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the European Union, Japan, United Arab Emirates, South Korea, Hong Kong, Switzerland, Taiwan, Turkey, Thailand, Qatar, Australia, Argentina, Brazil, Canada, Great Britain, Kuwait, Macao, Singapore, Mexico, Israel, Bulgaria, Hungary, Romania, and Russia. Additionally, Amgen has submitted MAAs in Colombia, Malaysia and Saudi Arabia.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.4

About Advanced Non-Small Cell Lung Cancer and the KRAS G12C Mutation

Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer combined.5 Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease, and 5-year survival is only 9% for those with metastatic disease.6

KRAS G12C is the most common KRAS mutation in NSCLC.7 About 13% of patients with non-squamous NSCLC harbor the KRAS G12C mutation.8 Unmet medical need remains high and treatment options are limited for NSCLC patients with the KRAS G12C mutation whose first-line treatment has failed to work or has stopped working. The outcomes with other approved therapies are suboptimal, with a median progression-free survival of approximately four months following second-line treatment of KRAS G12C-mutated NSCLC.9

LUMAKRAS (sotorasib) U.S. Indication

LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (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 overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

LUMAKRAS (sotorasib) Important U.S. Safety Information

Hepatotoxicity

LUMAKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
Among 357 patients who received LUMAKRAS in CodeBreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.
Monitor liver function tests (ALT, AST and total bilirubin) prior to the start of LUMAKRAS every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations.
Withhold, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis

LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions

The most common adverse reactions occurring in ≥ 20% were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and cough.
Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products.
Inform patients to avoid proton pump inhibitors and H2 receptor antagonists while taking LUMAKRAS.
If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid.
Please see LUMAKRAS full Prescribing Information.

On September 9th, 2023, Biosyngen Pte Ltd (hereafter as "Biosyngen") reported that the U.S. FDA has cleared the Investigational New Drug (IND) application for Phase I/II clinical trial of BRL03 for the treatment of lung cancer, gastric cancer and other advanced solid tumors (Press release, BioSyngen, SEP 9, 2023, View Source [SID1234635079]). The approval granted to BRL03, the company’s third first-in-class therapy, marks another breakthrough Biosyngen made in the CGT field.

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Notably, BRL03 is also the first TCR-T product developed by Biosyngen to enter clinical trials. This significant achievement is attributed to the company’s cutting-edge technology and extensive accumulation of capabilities and resources over the years.

IDENTIFIER, independently developed technology platform by Biosyngen, provides solid support for discovery and identification of antigen, antibody and TCR. Currently, utilizing the TCR and tumor proteome databases of thousands of individuals, Biosyngen can go from screening to optimization in two weeks to discover the optimal development for different therapeutic needs. With IDENTIFIER, Biosyngen selected TCRs with high specificity and affinity for a wide range of solid tumors, targeting a broad patient base. In addition, the company’s MSE-T technology platform allows T cells to be less easily depleted in the microenvironment in solid tumors and to exert tumor suppressing effects more persistently through additional functional module components.

Looking back, in December 2022, BRG01, an EBV-targeted CAR-T cell therapy developed by Biosyngen for nasopharyngeal cancer, received IND approval from NMPA. In February 2023, BRG01 obtained U.S. FDA approval for the same indication to commence Phase I/II clinical trials. It is expected that the Phase I clinical trial of BRG01 will be completed by the end of 2023.

The IND application of BRG01 for the treatment of EBV-positive lymphoma has also been approved by NMPA and U.S. FDA earlier this year in April.

The successful filing of BRL03 marks a significant milestone for the company’s strategy featuring diverse pipelines. Alongside CAR-T therapies, BRL03 will become Biosyngen’s flagship asset in the TCR-T field, with ongoing progress in clinical studies and regulatory consultation.

Biosyngen is currently in the process of filing the IND application for BST02, its fourth in the company’s pipeline. With the addition of this TIL therapy, the company solidifies its position as a promising biopharmaceutical company with global ambitions, boasting assets in all three major T-cell therapy types, namely, CAR-T, TCR-T, and TIL.

Biosyngen remains committed to its mission of addressing unmet clinical needs of patients and pursuing its goal to be a global leader in the development of innovation drugs.

About BRL03

Lung cancer is the leading cause of cancer deaths worldwide, with 2.21 million new cases and 1.8 million deaths in 2020. As a heterogeneous disease, lung cancer is categorized into two main groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Gastric cancer has about 1.27 million new cases and 957,000 deaths globally every year, accounting for the 3rd most deadly of all malignant tumors. Gastric cancer is also one of the more common malignant solid tumors in China, with incidence and deaths accounting for 42.6% and 45.0% worldwide.

BRL03 developed by Biosyngen is an engineered T cell therapy, also known as a type of adoptive immune cell therapy for lung cancer, gastric cancer and other solid tumors. Patients’ T cells were isolated and genetically modified in a GMP-compliant facility to enhance their ability to recognize and attack specific antigens on cancer cells. The modified T cells are expanded ex vivo and infused back into the patient. The infused T cells would bind to specific antigen on the cancer cells to mediate tumor killing. The preliminary safety and efficacy of BRL03 have been demonstrated in data from exploratory clinical trials.

On September 9, 2023 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a commercial stage research and development, biotechnology company, reported two-year follow-up data from a pooled analysis of the Phase 1/1b Cohort and Phase 2 Cohort A for the KRYSTAL-1 study evaluating adagrasib (KRAZATI) in patients with non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation (Press release, Mirati, SEP 9, 2023, View Source [SID1234635043]).

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In the pooled analysis, adagrasib demonstrated durable efficacy with a median overall survival (OS) of 14.1 months and a 2-year OS rate of 31% in patients with previously treated KRASG12C-mutated NSCLC. Exploratory analyses suggested clinical benefit in patients with treated, stable central nervous system (CNS) metastases at baseline with clinical benefit noted across most baseline co-mutations.

In the study, adagrasib demonstrated a manageable long-term safety profile with low grade treatment-related adverse events (TRAEs). Hepatotoxicity was not observed in any patients who received adagrasib within 30 days of prior immunotherapy and, overall, there was a low rate of grade >3 hepatoxicity.

A confirmatory Phase 3 study, KRYSTAL-12, is ongoing, evaluating adagrasib vs. docetaxel in previously treated patients with KRASG12C-mutated NSCLC.

"This data reinforces the ability of adagrasib to positively impact patients as a potential best in class option," said Alan Sandler, M.D., chief medical officer, Mirati Therapeutics, Inc. "Adagrasib offers a differentiated option for KRASG12C-mutated NSCLC as evidenced by its clinical activity in the CNS and ability to sequence adagrasib immediately after prior immunotherapy. We look forward to continuing to advance adagrasib across lines of therapy in a range of tumor types for the benefit of patients living with KRASG12C-mutated cancer."

"These data continue to reinforce the benefit of adagrasib for patients living with KRASG12C-mutated NSCLC who are in need for better options than the historical standard of care chemotherapy," Shirish M. Gadgeel, MD, head, the Division of Hematology/Oncology, associate director, Patient Experience and Clinical Care, the Henry Ford Cancer Institute. "The long term overall survival for adagrasib is meaningful for patients."

In December of 2022, adagrasib was added to the National Comprehensive Center Network (NCCN) Guidelines for patients living with previously treated KRASG12C-mutant NSCLC. Following, adagrasib was added the NCCN guidelines for CNS Cancers for patients living with previously treated KRASG12C-mutant NSCLC and CNS metastases.

About KRAZATI (adagrasib)

In the U.S., KRAZATI was approved by the FDA for Accelerated Approval (Subpart H), which allows for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. KRAZATI was reviewed under the FDA Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible. Mirati submitted a Marketing Authorization Application (MAA) in the EU in May 2022. In 2021, adagrasib achieved Breakthrough Therapy Designation in the U.S. as a potential treatment for patients with NSCLC harboring the KRASG12C mutation who have received at least one prior systemic therapy. For Prescribing Information, visit Mirati.com/KRAZATI_USPI.

Adagrasib continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science.

KRAZATI (adagrasib) U.S. Indication

KRAZATI is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (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).

KRAZATI (adagrasib) Important Safety Information

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in 1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in 0.5% of patients, including 0.5% grade 3, and colitis in 0.3%, including 0.3% grade 3. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of KRAZATI in 0.3%
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity
QTc Interval Prolongation

KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death
In the pooled safety population, 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms, and 11% of patients had an increase from baseline of QTc >60 msec. KRAZATI causes concentration-dependent increases in the QTc interval
Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation
Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are taking medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity
Hepatotoxicity

KRAZATI can cause hepatotoxicity
In the pooled safety population, hepatotoxicity occurred in 37%, and 7% were grade 3 or 4. A total of 32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in 11% of patients. KRAZATI was discontinued due to increased ALT/AST in 0.5% of patients
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity
Interstitial Lung Disease /Pneumonitis

KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. In the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients, 1.4% were grade 3 or 4, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was discontinued due to ILD/pneumonitis in 0.8% of patients
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified
Adverse Reactions

The most common adverse reactions (≥25%) are nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite
Females and Males of Reproductive Potential

Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential
Please see Full Prescribing Information.