On June 13, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that clinical data of IBI363 (first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein) in advanced solid tumors are presented at the 2024 ESMO (Free ESMO Whitepaper) Virtual Plenary (ClinicalTrials.gov, NCT04085185) (Press release, Innovent Biologics, JUN 13, 2024, View Source [SID1234644315]).

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Dr. Hui Zhou, Senior Vice President of Innovent, stated: "IBI363, as a first-in-class molecule, represents Innovent’s continuous innovation and advancement in the immunotherapy field. Starting from molecular design, the unique approach of α bias with β and γ attenuated were creatively adopted, which greatly improved the therapeutic window of IL-2. Meanwhile, through the specific traction of PD-1, tumor-specific T cells expressing both PD-1 and CD25 can be selectively stimulated and amplified, thus exerting anti-tumor effects. IBI363 has demonstrated excellent druggability with antibody-like pharmacokinetics (IgG-like PK) and low immunogenicity. On top of the preliminary data reported at ASCO (Free ASCO Whitepaper), we presented more informative data at the ESMO (Free ESMO Whitepaper) virtual plenary. Especially in the IO-treated squamous NSCLC, IBI363 has demonstrated strong anti-tumor effects, which could potentially be the next breakthrough in this area. Moreover, a promising efficacy signal was shown in IO-naïve mucosal melanoma, a relatively ‘cold’ tumor, which brings us great confidence in the next step to expand the IO-naïve population, and also indicates the broad application potential of IBI363."

First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein IBI363 in patients with advanced solid tumors: Results from Phase 1 study

This Phase 1a/1b Study was conducted to evaluate the safety, tolerability and preliminary efficacy of IBI363 in subjects with advanced solid tumors.

Over 300 subjects received IBI363 monotherapy treatment, unprecedented dosing level compared with traditional IL-2 therapy, with good tolerability and safety

As of the data cutoff date (Apr 16, 2024), 347 subjects with advanced solid tumors received IBI363 monotherapy (0.2μg/kg QW~3mg/kg Q3W). The tumor types included NSCLC (N=100), melanoma (N=89), colorectal cancer (N=102) and others (N=56). 81.8% of subjects had 2 or more lines of prior systemic therapy. In patients with solid tumors other than CRC (N=245), 84.1% received prior immunotherapy.
As for safety, the most common treatment related adverse events (TRAEs) were arthralgia, anaemia, hyperthyroidism and hypothyroidism. The total incidence of TRAEs ≥ grade 3 was 23.9%. Immune related adverse events (irAEs) ≥ grade 3 occurred in 10.4% of subjects. In the 38 subjects of 3mg/kg Q3W dose group, 13.2% had TRAEs ≥ grade 3, the safety profile was similar to that of the total population, and no new safety signals were identified.
Broad anti-tumor activity and applicability across tumor types, dose-dependent efficacy observed as dose reached 3mg/kg

As for efficacy, 300 subjects received IBI363 ≥0.1mg/kg and had at least one post-baseline tumor assessment. 3 subjects achieved complete response (CR) and 49 subjects had partial response (PR). As of the data cutoff date, 38 responders are still free of disease progression (PD). The duration of response (DoR) was immature. In 204 IO-treated subjects, the ORR was 17.6%.
In 15 subjects who received IBI363 3mg/kg and had at least one post-baseline tumor assessment, the ORR was 46.7% and DCR was 80.0%.
Promising efficacy signals in driver gene wild-type non-small cell lung cancer

– 70 subjects received IBI363 ≥0.3mg/kg and had at least one post-baseline tumor assessment. 77% of them had 2 or more lines of prior systemic therapy, and only 1 subject was IO-naïve. The overall ORR was 27.1%, and DCR was 72.9%.

– In the 37 subjects with squamous cell carcinoma (36 received prior PD-(L)1 treatment, 1 received prior TCE treatment), 13 achieved PR. The ORR was 35.1%, and DCR was 75.7%. As of the data cutoff date, the median follow up time was 5.7 months and the median PFS was 5.5 months (95% CI, 3.2-6.9). 11 of 13 responders are free of disease progression.

– A total of 9 NSCLC subjects (8 received prior PD-(L)1 treatment, 1 received prior TCE treatment) received IBI363 at 3mg/kg Q3W and had at least one post-baseline tumor assessment, including 6 squamous and 3 driver gene wild-type adeno NSCLC. All of the 6 patients with squamous NSCLC and 1 patient with adeno NSCLC achieved PR. The ORR was 100% and 33.3%, respectively, and the DCR were both 100%.

Promising efficacy signals in IO-treated melanoma and IO-naïve mucosal melanoma

– 37 IO-treated melanoma subjects received IBI363 1mg/kg and had at least one post-baseline tumor assessment. There were 11 responders, including 1 CR and 10 PR. The ORR and DCR was 29.7% and 73.0%, respectively.

– In 8 IO-naïve mucosal melanoma subjects, 1 patient achieved CR and 5 patients had PR. The ORR was 75.0%, and DCR was 100%.

As IBI363 has shown encouraging efficacy signals and good tolerability, this study is continuing to further explore the anti-tumor activity of IBI363 in NSCLC, melanoma and other tumors. Relevant data and analysis results will be updated in future academic conferences or journals.

Professor Xueli Bai, The First Affiliated Hospital, School of Medicine, Zhejiang University, stated: "Lung cancer is the leading cause of cancer death worldwide, of which non-small cell lung cancer accounts for about 80%[1]. In recent years, PD-1/PD-L1 inhibitors have shown promising efficacy in non-small cell lung cancer. However, most patients developed primary or secondary resistance to immune checkpoint inhibitors after treatment. IO-failed patients with NSCLC always suffer from a lack of effective treatment, and chemotherapy such as docetaxel elicits an ORR of only about 10% and a median PFS of less than 4 months[2]. As an important cytokine activating tumor-specific CD8+T cells, IL-2 is complementary to immune checkpoint inhibitors in MOA. The combination of PD-1 and IL-2 may reverse the exhaustion of tumor-specific CD8+ T cells, thereby overcoming immune resistance. As a PD-1/IL-2α-bias bispecific molecule, IBI363 showed promising antitumor activity in IO-resistant driver gene wild-type NSCLC, and clinical benefits were demonstrated by both ORR and PFS. At the same time, the safety is manageable, without new safety signals at high dose level, which gives us more confidence."

Professor Yu Chen, Fujian cancer hospital, stated: "Melanoma is a rare tumor in China, and the majority of patients are acral or mucosal subtypes (about 60%-70%[3]), which are not sensitive to immunotherapy. IL-2, as an important cytokine that activates tumor-specific CD8+ T cells and mechanistically complementary to immune checkpoint inhibitors, has long become a well-established target in melanoma. As a novel PD-1/IL-2α-bias bispecific molecule, IBI363 demonstrates significantly higher response rate than the current standard of care in IO-failed melanoma, and the response is durable. Encouraging high ORR and DCR have been observed in mucosal melanoma, a subtype known to be insensitive to immunotherapy. IBI363 is well tolerated, and the toxicity is manageable. The current safety profile is similar to that of previous anti-PD-1 monoclonal antibodies. The clinical data suggest that IBI363 has great development potential in melanoma population. Clinical trials are ongoing for further confirming the clinical benefits of IBI363 in melanoma population."

About IBI363 (First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein)

IBI363 is a First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein independently developed by Innovent Biologics, which has two functions: blocking the PD-1/PD-L1 pathway and activating the IL-2 pathway. The IL-2 arm of IBI363 was modified to retain its affinity for IL-2Rα, but weakened its binding ability to IL-2Rβ and IL-2Rγ, thereby reducing toxicity. The PD-1 binding arm can simultaneously block PD-1 and selectively deliver IL-2. Since the newly activated tumor specific T cells express both PD-1 and IL-2α, this differential strategy allows for more precise and effective targeting and activation of this T cell subpopulation. IBI363 not only showed good antitumor activity in a variety of tumor-bearing pharmacological models, but also showed outstanding efficacy in PD-1 resistance and metastasis models. Starting from the urgent clinical needs, Innovent Biologics is conducting clinical studies in China, the United States and Australia to explore the efficacy and safety of IBI363 in advanced tumors.

On June 13, 2024 LG Chem and AVEO Oncology, an LG Chem company, reported that it has enrolled the first patient in the United States for a Phase 1 clinical study of LB-LR1109 (NCT06332755; LG project code LR19155), LG Chem’s first proprietary anti-cancer investigational drug candidate (Press release, LG Chem, JUN 13, 2024, View Source [SID1234644316]). LG Chem will be collaborating closely with AVEO Oncology, its wholly owned subsidiary, that specializes in oncology development and commercialization, to advance strategies for late-stage clinical development and regulatory approval.

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This is a Phase 1, multi-center, open-label, non-randomized, dose escalation study designed to determine the recommended Phase 2 dose of LB-LR1109 and to evaluate safety, tolerability, preliminary efficacy, pharmacokinetics, immunogenicity, and pharmacodynamics of LB-LR1109, and its potential impact on quality of life. The study is evaluating participants with unresectable and metastatic non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, urothelial carcinoma, or malignant melanoma who have progressed on standard of care treatment options.

In preclinical studies of LB-LR1109, LG Chem observed dose-dependent anti-cancer effects. Subsequently, the company received approval for an Investigational New Drug application from the U.S. Food and Drug Administration (FDA) in December last year.

Leukocyte Immunoglobulin Like Receptor B-1 (LILRB1), a protein released by cancer cells to prevent immune cell attacks, is commonly expressed on the surfaces of several immune cells, including T cells, natural killer cells (NK cells), and macrophages (phagocytic cells). This mechanism is believed to work by activating the tumor-eradicating cells such as T cells, NK cells, and macrophages simultaneously.i This simultaneous activation of overall immune cell functions may differentiate it from existing therapies that focus on single immune cells like T cells.

"We are excited to partner with LG Chem on their first proprietary anti-cancer compound," said Dr. Alex Spira, Director of Next Oncology of Virginia Cancer Specialists Research Institute and the Phase 1 Trial Program. "There is a high unmet need for patients that have progressed on standard of care treatment which necessitates the need to explore novel immune checkpoint inhibitors such as LB-LR1109."

Jeewoong Son, MD, President of LG Chem Life Sciences Company, stated, "We are focusing all our capabilities to provide innovative treatments that will be recognized by medical professionals and patients, as we aim to improve the lives of patients with cancer. While this is the first oncology compound from LG Chem, we are developing a robust pipeline that target novel oncology targets. We will continue to offer differentiated treatment options in the oncology field, where there is the greatest unmet medical need."

The advancement of this program into the clinic brings LG Chem and AVEO Oncology one step closer to realizing our vision of becoming one of the world’s leading oncology companies with a robust clinical pipeline of innovative therapies.

On June 13, 2024 Sirnaomics Ltd. (the "Company"; together with its subsidiaries, "Sirnaomics" or the "Group"; stock code: 2257), a leading biopharmaceutical company in discovery and development of RNAi therapeutics, reported that the Group has published a major advancement of its novel Oligonucleotide-Chemodrug Conjugate (ODC) agent (Press release, Sirnaomics, JUN 13, 2024, View Source [SID1234644317]). The ODC demonstrated potent antitumor activity in multiple tumor cell lines and a pancreatic tumor model in mice. The work was published in the latest issue of Journal of Oncology Research and Therapy (06, 2024: p1-16, Volume 9, issue 02). This groundbreaking work creates a solid foundation for the Company’s RNAi-based cancer therapeutic program using a proprietary Antibody-Oligonucleotide-Chemodrug Conjugate (AODC) modality.

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The published results are the extension of prior work (NAR Cancer, 2020, Vol. 2, No. 3. p1-12) using a proprietary anticancer ODC agent comprising a double-stranded siRNA targeting CHK1 mRNA incorporating gemcitabine into its Sense Strand in place of Cytidines. Gemcitabine (a small molecule anticancer drug) is synergistic with CHK1 inhibition increasing the IC50 of the combination about 100-fold in different cell lines. In the latest work, the ODC construct contained chemically modified bases to improve stability and this construct improved potency and efficacy against CHK1 gene expression. In vitro tests have shown potent antitumor activities of gemcitabine containing CHK1 specific siRNA validated using Pancreatic, NSCLC, TNBC and Ovarian cell culture models. The construct also provides efficacy against a pancreatic tumor in a xenograft model in mice, ablating the tumor upon Intravenous administration using Sirnaomics proprietary polypeptide nanoparticle formulation.

"Antibody Drug Conjugates (ADCs) have demonstrated exceptional specificity and efficacy for cancer treatment. Sirnaomics expects to harness similar benefits with its ODC constructs, to improve potency or duration of effect of small molecule therapeutics. Many small molecule drugs show efficacy initially but encounter drug resistance later due to upregulation of certain protein expression by tumor cells. Identifying those proteins and designing specific siRNAs against these targets provides a powerful approach to overcome these chemodrug induced resistances." Dr. David Evans, Head of Discovery Research of Sirnaomics and the corresponding author of the publication, indicated, "Building an oligonucleotide-drug conjugate (ODC) construct will minimize resistance and potentiate chemodrug efficacy, while reducing systemic toxicity of the chemodrug. Together with an antibody derived targeting property, this will provide a novel drug modality Antibody Oligonucleotide Drug Conjugate (AODC) for improvement of cancer treatment."

Dr. Patrick Lu, the founder, Chairman and CEO of Sirnaomics, comments, "The latest advancement of Sirnaomics proprietary ODC agent demonstrates the Company’s continuing innovative effort for novel cancer RNAi therapeutics, while pushing our clinical studies of STP705 for the treatment of skin cancer, STP707 for the treatment of solid tumors and STP122G for anticoagulation therapy. We expect Sirnaomics’ AODC agents will provide an alternative approach to treat various cancers based on tremendous success of ADCs and bring broad partnership opportunities."

About STP888

An example of an Oligonucleotide-Drug Conjugate (ODC) – CHK1 siRNA duplex containing Gemcitabine (STP888) targets the gene CHK1 which has been shown to synergize with the small molecule Gemcitabine in inducing anticancer efficacy. Upon binding, the mRNA is degraded and eventually the protein level of CHK1 is reduced. The Sense strand is degraded, releasing the gemcitabine and allowing the synergistic effect to be observed. The chemically stabilized construct will allow direct targeting to tumor cells (leaving adjacent normal cells) which will improve efficacy and reduce toxicity. Sirnaomics will pursue delivery using this construct coupled to an antibody against markers upregulated in the tumor but not in normal cells. This will be the foundation of Antibody Oligonucleotide-Drug Conjugates (AODC).

On June 13, 2024 Remix Therapeutics (Remix), a clinical-stage biotechnology company developing small molecule therapies to modulate RNA processing and address underlying drivers of disease, reported that it will deliver a poster presentation demonstrating the therapeutic potential of REM-422, a potent, selective, oral small molecule MYB mRNA degrader for the treatment of acute myeloid leukemia (AML), at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Hybrid Congress in Madrid, Spain (Press release, Remix Therapeutics, JUN 13, 2024, View Source [SID1234644319]).

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The poster presentation will include preclinical data from MYB-dependent AML cell lines and human leukemia xenograft models showing REM-422 is broadly active across various AML models. Furthermore, REM-422 induces tumor regressions in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of AML at well-tolerated doses. In vitro and in vivo studies show that REM-422 functions by inducing incorporation of a poison exon into the MYB mRNA transcript resulting in mRNA degradation and inhibition of MYB protein expression.

"We’ve built a robust package of preclinical data across various models that reinforces the therapeutic potential of REM-422 for the treatment of AML and other MYB-dysregulated cancers," said Peter Smith, Ph.D., Co-Founder and Chief Executive Officer of Remix Therapeutics. "The ability to successfully target a previously undruggable transcription factor is encouraging as we continue to investigate REM-422 in our ongoing clinical trials."

The dysregulation of MYB, an oncogenic transcription factor, has been linked to numerous cancers including AML, myelodysplastic syndromes (MDS) and lymphoma. REM-422 is a potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and subsequent protein expression, resulting in antitumor activity in MYB-dependent human tumor models.

REM-422 is currently being investigated as a potential treatment for AML/HR-MDS and adenoid cystic carcinoma (ACC) in two, phase 1 clinical trials.

Details for the poster presentation are as follows:

Title: REM-422, a potent, selective, oral small molecule mRNA degrader of the MYB oncogene, demonstrates anti-tumor activity in mouse xenograft models of AML
Abstract Number: P531
Session Date and Time: June 14 at 6:00 PM CEST
Session Location: Poster Hall

About REM-422

REM-422 is a first-in-class, potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and subsequent protein expression. REM-422 functions by facilitating the incorporation of poison exons within the mRNA transcript, leading to nonsense-mediated decay (NMD) of the transcript. REM-422 addresses MYB dysregulation, a driver of oncogenesis, upstream of protein expression.

About ACC

Adenoid cystic carcinoma (ACC) is a rare cancer that commonly develops in glandular tissues in the head and neck. It is caused by genetic mutations, likely developed over a patient’s lifetime, with the majority of ACC cases linked to an overexpression of the MYB protein. Depending on the location of the tumor, symptoms may include numbness of the face, difficulties swallowing, changes in vision, or difficulty breathing, among others. Current treatment solutions include surgery, radiation therapy, and chemotherapy.

About AML/HR-MDS

Acute myeloid leukemia (AML), a rare cancer of the blood and bone marrow, is the most common type of acute leukemia in adults. AML is caused by genetic mutations within bone marrow cells, which in turn causes the production of leukemic white blood cells that crowd out healthy blood cells. This may cause problems with bleeding, infection, and anemia. Myelodysplastic Syndromes (MDS) are disorders of blood-forming units in the bone marrow. High-risk (HR)-MDS patients have a higher percentage of blast cells in the bone marrow and that, in many cases, progresses to AML. There are several approved agents to treat AML, however, many patients relapse after achieving a response, underscoring the need for new therapies.

On June 13, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Augtyro (repotrectinib) for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy (Press release, Bristol-Myers Squibb, JUN 13, 2024, View Source [SID1234644303]). The approval is based on results from the Phase 1/2 TRIDENT-1 study, which evaluated Augtyro in adult patients with NTRK-positive solid tumors.1 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.1

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"NTRK fusion-positive tumors can present challenges in the clinical setting, which is why it is important that we have additional treatment options for these patients," said Alexander Drilon, MD, TRIDENT-1 global trial lead and Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center.2,3 "The FDA approval of repotrectinib adds an important tool to our toolbox, offering oncologists a next-generation TKI that can be used across a broad range of NTRK fusion-positive solid tumors for both TKI-naïve and TKI-pretreated patients."1

The TRIDENT-1 trial included both TKI-naïve (n=40) and TKI-pretreated (n=48) patients with NTRK-positive locally advanced/metastatic solid tumors collectively representing 15 different types of cancer.1 In TKI-naïve patients, with a median follow up of 17.8 months, 58% (95% CI: 41 to 73) had a confirmed objective response rate (cORR); of those, 43% experienced partial responses (PR) and 15% had complete responses (CR).1,4 Of the TKI-naïve responding patients, 83% were still in response at one year with Augtyro. The median duration of response (mDOR) was not yet reached. In TKI-pretreated patients, with a median follow up of 20.1 months, the cORR was 50% (95% CI: 35 to 65); of those, 50% experienced PR and no patients achieved CR.1,4 Additionally, 42% of TKI-pretreated responding patients were still in response at one year with Augtyro.1 The mDOR was 9.9 months (95% CI: 7.4 to 13.0).1 Among those who had measurable central nervous system (CNS) metastases at baseline, intracranial response was observed in 2 out of 2 TKI-naïve patients and in 3 out of 3 TKI-pretreated patients.1

Augtyro is associated with the following Warnings & Precautions: central nervous system (CNS) effects, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.1 Please see Important Safety Information below.

"Today’s FDA approval of Augtyro for patients with NTRK-positive tumors adds to its indication in ROS1-positive NSCLC, showing its clinical value for more people across multiple genetic markers," said Nick Botwood, senior vice president of Medical Oncology at Bristol Myers Squibb.1 "Previously, there was not an FDA approved treatment option for NTRK-positive cancers that was studied in both TKI-naïve and TKI-pretreated patients across solid tumors. This milestone helps address this area of unmet need and builds on Bristol Myers Squibb’s longstanding legacy of bringing innovations to individuals who are facing cancer and urgently seeking new treatment options."

"Cancer can be frightening regardless of the type, but having a rare gene fusion driving it can be especially stressful and isolating," said Susan Spinosa, president and patient co-founder of NTRKers, a patient advocacy group. "It’s exciting to know that there’s a new targeted therapy option for patients with NTRK-positive gene fusions, as this may offer hope to patients and their loved ones navigating this difficult journey."

Based on clinical and pharmacokinetic data, the recommended dose for Augtyro for pediatric patients aged 12 years and older is the same as for adults, 160 mg orally once daily for 14 days followed by 160 mg twice daily until disease progression or unacceptable toxicity.1 The safety and effectiveness of Augtyro have not been established in pediatric patients younger than 12 years of age with solid tumors who have an NTRK gene fusion.1 This is the second indication for Augtyro in the U.S., following its full approval for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC in November 2023.1

Disclosure: Dr. Drilon has provided advisory and speaking services to Bristol Myers Squibb.

About TRIDENT-1

TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of Augtyro in patients with locally advanced or metastatic neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive (NTRK1/2/3) solid tumors.1,5 The trial excludes patients with symptomatic brain metastases, among other exclusion criteria.1 Phase 1 of the trial included the dose escalation that determined the recommended Phase 2 dose.5

Phase 2 of the trial in NTRK-positive locally advanced/metastatic solid tumor cohorts has a primary endpoint of objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR).5 Among others, key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by BICR, and intracranial response in patients with measurable brain metastases.5

Select Safety Profile from TRIDENT-1

The safety profile for Augtyro was evaluated in 426 patients who received Augtyro in the TRIDENT-1 pivotal trial.1 Permanent discontinuation of Augtyro due to an adverse reaction occurred in 7% of patients.1 There were no specific adverse reactions that accounted for ≥1% of permanent discontinuations. Augtyro dosage was interrupted due to an adverse reaction in 50% of patients, and dose reductions due to an adverse reaction occurred in 38% of patients.1 Serious adverse reactions occurred in 35% of patients who received Augtyro. 1 Serious adverse reactions in ≥2% of patients included pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%) and hypoxia (2.6%).1 Fatal adverse reactions occurred in 3.5% of patients who received Augtyro, including pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.1 The most common (≥20%) adverse reactions were dizziness (65%), dysgeusia (54%), peripheral neuropathy (49%), constipation (38%), dyspnea (30%), fatigue (30%), ataxia (28%), cognitive impairment (25%), muscular weakness (20%) and nausea (20%).1 Grade 3 dizziness occurred in 2.8% of patients.1

About NTRK-Positive Solid Tumors

Neurotrophic tropomyosin receptor kinase (NTRK) are a family of receptors involved in neural development.6 An NTRK gene fusion is an alteration that occurs when a piece of the chromosome containing the NTRK gene breaks off and joins with a gene on another chromosome.7 These fusions lead to abnormal proteins, which may cause cancer cells to grow.7 While NTRK gene fusions are rare in patients with solid tumors, testing for NTRK gene fusions allows for the identification of patients who may benefit from TRK inhibitor therapy.8,9,10,11

INDICATIONS

AUGTYRO is indicated for the treatment of:

adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC)
adult and pediatric patients 12 years of age and older with solid tumors that:
have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion,
are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and
have progressed following treatment or have no satisfactory alternative therapy.
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Warnings & Precautions

Central Nervous System Adverse Reactions

Among the 426 patients who received AUGTYRO in the Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients with Grade 3 or 4 events occurring in 4.5%.
Dizziness, including vertigo, occurred in 65%; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 7 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 11% required dose reduction of AUGTYRO due to dizziness.
Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 5% of patients, 8% required dose reduction and one patient (0.2%) permanently discontinued AUGTYRO due to ataxia.
Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 2.1% required dose reduction and 0.5% permanently discontinued AUGTYRO due to cognitive adverse reactions.
Mood disorders occurred in 6% of patients. Mood disorders occurring in >1% of patients included anxiety (2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients. Dose interruption was required in 0.2% of patients and 0.2% required a dose reduction due to mood disorders.
Sleep disorders including insomnia and hypersomnia occurred in 18% of patients. Sleep disorders observed in >1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%). Dose interruption was required in 0.7% of patients, and 0.2% required a dose reduction due to sleep disorders.
The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases.
Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Interstitial Lung Disease (ILD)/Pneumonitis

Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.5% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed.
Hepatotoxicity

Among the 426 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.2% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.5%.
Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and then as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity.
Myalgia with Creatine Phosphokinase (CPK) Elevation

AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation. Among the 426 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation.
Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement.
Hyperuricemia

Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.7% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.
Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Skeletal Fractures

Among 426 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients.
Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12-year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO was interrupted in both patients. AUGTYRO is not approved for use in pediatric patients less than 12 years of age.
Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures.
Embryo-Fetal Toxicity

Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose.
Adverse Reactions

The safety of AUGTYRO was evaluated in 426 patients in TRIDENT-1. The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
Drug Interactions

Effects of Other Drugs on AUGTYRO

Strong and Moderate CYP3A Inhibitors

Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.
P-gp Inhibitors

Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO.
Strong and Moderate CYP3A Inducers

Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.
Effects of AUGTYRO on other Drugs

Certain CYP3A4 Substrates

Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.
Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates.
Contraceptives

Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.
Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females of childbearing potential to use an effective nonhormonal contraceptive.
Please see U.S. Full Prescribing Information for AUGTYRO .