sunvozertinib (DZD9008) / Dizal Pharma - LARVOL DELTA

SUCCESSFUL SUNVOZERTINIB RECHALLENGE FOR ADVANCED LUNG ADENOCARCINOMA WITH HER2 EXON20 INSERTION MUTATION: A CASE REPORT (CHEST 2024) - "He participated in a clinical trial with pemetrexed, carboplatin, and either tislelizumab or ADCs, in an undisclosed allocation group...Considering patient's preference and preliminary efficacy of sunvozertinib in NSCLC with HER2 exon20ins, he was given sunvozertinib 300mg daily with bevacizumab 500mg every 3 weeks, with self-administration of Chinese herbal medicine. By mid-November, he developed recurrent fever, headache, diarrhea, and severe liver dysfunction, prompting discontinuation of sunvozertinib and initiation of erlotinib 200mg plus anlotinib 12mg once daily, with adjunctive hepatoprotective and intracranial pressure-lowering measures (Figure 1C). In December, he exhibited pronounced cough, sputum production, and dyspnea leading to self-administration of dacomitinib 45mg once daily plus anlotinib 12mg once daily orally (Figure 1D)... For NSCLC with HER2 exon20ins, sunvozertinib demonstrates efficacy in posterior-line therapy with tolerable adverse..."

Case report • Clinical • IO biomarker • Metastases • Cardiovascular • Cough • Hematological Disorders • Hepatology • Liver Failure • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • Solid Tumor • EGFR • HER-2 • PD-L1 • TP53

Targeting EGFR Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer: Changes in Treatment Strategies are Coming. (PubMed, Cancer Control) - "Recently, amivantamab and sunvozertinib have demonstrated notable efficacy as first-line treatments, and several other promising novel targeted drugs are also challenging the status quo of traditional first-line platinum-based chemotherapy regimens. These developments are anticipated to further improve survival outcomes for NSCLC patients with EGFR ex20ins mutations. Hence, this review summarizes the epidemiology, molecular attributes, detection methodologies, and therapeutic advancements for EGFR ex20ins mutations in NSCLC, and briefly discusses the mechanisms of drug resistance."

EGFR exon 20 • IO biomarker • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Sunvozertinib Granted Breakthrough Therapy Designation by China CDE for the First-Line Treatment of Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations (PRNewswire) - "Dizal...announced that the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation (BTD) for sunvozertinib for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins) who have not received prior systemic therapies....The CDE granted the BTD based on results from the pooled analysis of the global multi-center phase I/II study (WU-KONG1) and the phase II study (WU-KONG15) focused on patients from China."

Breakthrough therapy • EGFR exon 20 • Non Small Cell Lung Cancer

NMPA Grants Marketing Approval to the First Co-Developed NGS-Based Companion Diagnostic for Lung Cancer in China (GlobeNewswire) - "Burning Rock Biotech Limited...and Dizal...jointly announced that the companion diagnostic (CDx) for EGFR exon 20 insertion mutation (exon20ins) for sunvozertinib, developed through their collaboration, has been approved by the National Medical Products Administration (NMPA) of China. This marks the first co-developed NGS-based CDx for lung cancer approved by NMPA since the release of the CDx guideline in China. The approval of this CDx test is the result of the simultaneous development of Burning Rock's independently developed LungCure CDx (a kit for the combined detection of 9 human gene mutations) and Dizal's innovative EGFR exon20ins targeted therapy - sunvozertinib, providing an innovative precision treatment solution for non-small cell lung cancer patients with EGFR exon20ins."

China approval • Diagnostic • EGFR exon 20 • Non Small Cell Lung Cancer • Oncology

The prediction of treatment outcome in NSCLC patients harboring an EGFR exon 20 mutation using molecular modeling. (PubMed, Lung Cancer) - "In conclusion, MD simulations can effectively predict patient outcomes by connecting computational results with clinical data and advancing our understanding of EGFR mutations and their therapeutic responses."

EGFR exon 20 • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

WUKONG-32: Sunvozertinib Plus Anlotinib as 1L Treatment in EGFR-Sensitive Mutations Combined With Co-Mutations Advanced NSCLC (clinicaltrials.gov) - P2 | N=52 | Recruiting | Sponsor: Hunan Province Tumor Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

WUKONG-32-RW: Sunvozertinib Plus Anlotinib as 1L Treatment in EGFR Mutant Advanced NSCLC-RW (clinicaltrials.gov) - P2 | N=100 | Recruiting | Sponsor: Hunan Province Tumor Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

EGFR Exon 20 Insertion Mutation: Research Status and New Treatment Strategies (PubMed, Zhongguo Fei Ai Za Zhi) - "Firstly Mobocertinib and Amivantamab obtained approval from U.S. Food and Drug Administration (FDA) for EGFR ex20ins mutant NSCLC patients, then other drugs, such as Sunvozertinib, made breakthroughs and combination therapies also obtained gains. As mentioned above, it's definitely important to gain deeper understanding of molecular mechanism of EGFR ex20ins and assess effect and difference between novel drugs. This review is devoted to make a summary about newest achievement so to provide valuable reference about precise therapy for patients with EGFR ex20ins.."

EGFR exon 20 • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

A multinational pivotal study of sunvozertinib in platinum pretreated non-small cell lung cancer with EGFR exon 20 insertion mutations: Primary analysis of WU-KONG1 study. (ASCO 2024) - P1/2 | "All patients received prior platinum-based chemotherapy for advanced NSCLC, and 43.4% and 13.3% had prior onco-immunotherapy or amivantamab treatment. In this primary analysis of WU-KONG1 multinational pivotal study, sunvozertinib demonstrated promising antitumor efficacy in platinum pre-treated NSCLC with EGFR exon20ins, with a tolerable safety profile. The updated data will be presented at the meeting."

EGFR exon 20 • IO biomarker • Dermatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Modeling the Relationship of Clinical Safety Profile of EGFR Inhibitors with Wild-Type EGFR Inhibition in Cellular Model (IASLC-WCLC 2024) - "The EGFR inhibitors include commercially available proxy compounds of gefitinib, afatinib, osimertinib, mobocertinib, sunvozertinib, zipalertinib, BLU-945, BDTX-1535, etc. Clinical safety data are obtained from drug labels or publications, including all grades AEs and Grades ≥3 rash and diarrhea. The potency of inhibition of WT EGFR in a uniform nonclinical assay strongly correlated with overall rates and severity of rash and diarrhea observed in the clinical setting. These results may be useful in enhancing the understanding of the potential clinical safety profile of novel EGFR targeted therapies at the nonclinical development stage."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Efficacy and safety of sunvozertinib in prior platinum treated NSCLC patients with EGFR exon 20 insertion mutations: Primary analysis from the multinational WU-KONG1B pivotal study (ESMO 2024) - P1/2 | "The primary efficacy analysis set included 107 patients post platinum-based chemotherapy: 57.9% Asian, 54.2% from Asia, 25.2% with baseline brain metastasis, 13.1% with prior amivantamab, 48.6% with prior onco-immunotherapy and 13.1% with EGFR TKI treatment. The primary results of WU-KONG1B showed promising anti-tumor efficacy of sunvozertinib in advanced NSCLC with EGFR exon20ins, regardless of different subgroups. The updated results will be presented at the conference."

Clinical • EGFR exon 20 • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with NSCLC Harboring EGFR Exon 19 Insertions: A Report from the LC-SCRUM-Asia (IASLC-WCLC 2024) - "We also studied preclinical Ba/F3 models expressing EGFR -K745_E746insIPVAIK (Ba/F3-IPVAIK) and EGFR -delE746_A750 (Ba/F3-Del19) to investigate the sensitivity to 1st-generation (gen) (gefitinib and erlotinib), 2nd-gen (afatinib, dacomitinib, and poziotinib), 3rd-gen (osimertinib), and EGFR exon 20 insertion active TKIs (mobocertinib, sunvozertinib, and zipalertinib). The preclinical therapeutic window of Ba/F3-IPVAIK and Ba/F3-Del19 for all the 2nd generation TKIs were similarly favorable, whereas Ba/F3-IPVAIK had much unfavorable therapeutic windows to other EGFR-TKIs compared to Ba/F3-Del19. Conclusions : Our clinical and preclinical findings indicate 2nd-gen EGFR-TKIs are more effective than 1st and 3rd-gen EGFR-TKIs in patients with EGFR exon 19 insertions."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDKN2B • EGFR • FGFR • PIK3CA • TP53

Subgroup Analysis from Pivotal WU-KONG1B Study Exhibits Robust Efficacy of Sunvozertinib in Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations Across Different Baseline Characteristics (PRNewswire) - P1/2 | N=315 | WU-KONG1 (NCT03974022) | Sponsor: Dizal Pharmaceuticals | "Dizal...presented subgroup analysis findings of its WU-KONG1 Part B (WU-KONG1B) study at the 2024 European Society for Medical Oncology (ESMO) Congress. The results showed promising anti-tumor efficacy of sunvozertinib in relapsed or refractory non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins) across different baseline characteristics, underpinning its significant clinical value for this patient population around the globe...As of March 22, 2024, a total of 107 patients with at least 33 EGFR exon20ins subtypes were included in the efficacy analysis set...Per independent review committee (IRC) assessment, target lesions shrinkage was observed in 92.4% (98/106) of patients; the best objective response rate (ORR) was 53.3%, including 3 complete response (CR); With median follow-up of 7 months, duration of response (DoR) was not reached..."

EGFR exon 20 • P1/2 data • Non Small Cell Lung Cancer

NUMER: Neoadjuvant Umbrella Trial for Patients With Unresectable Stage III NSCLC Harboring Rare Mutations. (clinicaltrials.gov) - P2 | N=120 | Not yet recruiting | Sponsor: Sun Yat-sen University

Biomarker • New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Dr Reckamp on Emerging EGFR TKIs in EGFR Exon 20 Insertion+ NSCLC (OncLive) - "Karen L. Reckamp, MD, MS, discusses emerging EGFR TKIs in EGFR Exon 20-Mutated NSCLC."

Video

Current clinical practice and physicians' insights on Chinese patients with advanced non-small cell lung cancer habouring epidermal growth factor receptor 20 insertion mutation. (PubMed, BMC Cancer) - "This study investigated the current diagnosis and treatment status and physicians' perspective, of patients with EGFR exon20ins-mutant NSCLC. The results highlight significant unmet clinical needs in this subgroup of patients. EGFR exon20ins-targeted TKIs were recognized as the most promising treatment regimen and may benefit more patients considering their awareness and acceptance of targeted therapy."

Journal • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Sunvozertinib overcoming resistance to afatinib and osimertinib in lung adenocarcinoma harboring an EGFR exon 18 DelE709_T710insD mutation. (PubMed, J Transl Med) - No abstract available

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

First case report of sunvozertinib for the treatment of HER2 exon 20 insertion in lung adenocarcinoma. (PubMed, Anticancer Drugs) - "In the 2023 National Comprehensive Cancer Network guidelines for NSCLC, antibody-drug conjugate trastuzumab emtansine is recommended for the treatment of HER2-mutant lung cancer. In our study of a patient with HER2 exon 20 insertion lung adenocarcinoma who had previously failed multiple epidermal growth factor receptor (EGFR)-TKI treatments, we discovered that sunvozertinib could stabilize the patient's condition, achieving a progression-free survival of 87 days. This is a novel finding that may provide new treatment options for HER2 exon 20 insertion patients who have failed TKI therapy."

HER2 exon 20 • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

Plasma ctDNA biomarker study in patients with non-small cell lung cancer with EGFR exon 20 insertion mutation treated with sunvozertinib. (ASCO 2024) - "Exploratory work on overcoming resistance to sunvozertinib suggests that combination of golidocitinib, a selective JAK1 inhibitor, with chemotherapy could be a potential approach. This study showed that positive EGFR exon20ins in plasma ctDNA is associated with advanced disease characteristics. Sunvozertinib can effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway. The resistance to sunvozertinib can be through EGFR-dependent and EGFR-independent mechanisms."

Biomarker • Circulating tumor DNA • Clinical • EGFR exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer. (PubMed, Int J Mol Sci) - "This review explores key therapeutic agents, such as Amivantamab, Mobocertinib, Poziotinib, Zipalertinib, and Sunvozertinib, which have shown promise in treating NSCLC with EGFR exon 20 insertions. Despite these advances, challenges in overcoming resistance mutations and improving central nervous system penetration remain. Future research should focus on optimizing first-line combination therapies and enhancing diagnostic strategies for comprehensive mutation profiling."

EGFR exon 20 • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET

Sunvozertinib's Global Pivotal WU-KONG1B Study Meets Primary Endpoint in Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations (PRNewswire) - P1/2 | N=315 | WU-KONG1 (NCT03974022) | Sponsor: Dizal Pharmaceuticals | "Dizal...presented the latest data from the inaugural global pivotal study WU-KONG1 Part B (WU-KONG1B) of sunvozertinib in relapsed or refractory non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins) at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. The study demonstrated statistically significant outcomes on the primary endpoint for sunvozertinib and highlighted its significant clinical value to patients around the globe....Per IRC assessment, sunvozertinib achieved a best ORR of 53.3%; The median DoR has not been reached, and the 9-month DoR rate was 57%, indicating durable efficacy of sunvozertinib; Anti-tumor efficacy was observed regardless of amivantamab treatment. The best ORRs in patients with or without prior amivantamab treatment were 50% and 53.8%, respectively."

EGFR exon 20 • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • Exon 20

Detection of EGFR exon 20 insertion mutations in non-small cell lung cancer: implications for consistent nomenclature in precision medicine. (PubMed, Pathology) - "A total of 1,418 EGFR E20ins mutations were collected from six studies (FoundationInsights, Geneseeq Technology Inc, mobocertinib phase I/II trial, poziotinib phase II trial, sunvozertinib phase I trial, and Samsung Medical Center) and reorganised according to Human Genome Variation Society (HGVS) nomenclature. To ensure comprehensive coverage in real-world settings, it is essential to standardise the annotations for each variant, for example using the HGVS nomenclature. The accurate classification and analysis of drug responsiveness in EGFR E20ins necessitate consideration of the nomenclature, particularly with respect to the locations where the actual mutations occur."

EGFR exon 20 • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Assessing an Oral EGFR Inhibitor, DZD9008 in Patients With Advanced Non-small Cell Lung Cancer(NSCLC) With EGFR Mutations (WU-KONG15) (clinicaltrials.gov) - P=N/A | N=180 | Recruiting | Sponsor: Peking Union Medical College Hospital | N=110 ➔ 180 | Trial completion date: Jun 2024 ➔ Jun 2026 | Trial primary completion date: Dec 2023 ➔ Dec 2025

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

WK-KONG1: Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer With EGFR or HER2 Mutation (WU-KONG1) (clinicaltrials.gov) - P1/2 | N=315 | Active, not recruiting | Sponsor: Dizal Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2024 ➔ Jul 2025 | Trial primary completion date: Oct 2023 ➔ Jul 2024

Enrollment closed • HER2 exon 20 • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Dizal Reveals New Findings from Biomarker Analysis, Highlighting Sunvozertinib as an Effective Treatment for Non-small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations (PRNewswire) - P1/2 | N=315 | WU-KONG1 (NCT03974022) | Sponsor: Dizal Pharmaceuticals | "Dizal...announced new findings from a biomarker study in non-small cell lung cancer (NSCLC) patients with exon 20 insertion (exon20ins) mutations, highlighting sunvozertinib as an effective treatment for this patient population....Anittumor efficacy of sunvozertinib was observed in patients regardless of baseline EGFR exon20ins status in plasma ctDNA: Patients with baseline negative EGFR exon20ins in plasma ctDNA achieved a higher objective response rate (ORR) (68.0% vs. 45.8%) and longer median progression free survival (PFS) (7.4 months vs. 5.5 months) than those with positive EGFR exon20ins....Sunvozertinib could effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway: Decrease of EGFR exon20ins mutant allele was observed in 85.7% of patients with sunvozertinib treatment."

Biomarker • EGFR exon 20 • P1/2 data • Non Small Cell Lung Cancer