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Not Recruiting

Phase 3 Study of Sunvozertinib vs. Platinum-Based Chemotherapy in EGFR Exon 20 Insertion Mutant Advanced NSCLC

Trial ID: 2022-502959-54-00
Protocol: DZD2022E0005
Sponsor: Dizal Pharmaceutical Co. Ltd.

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of this study is to assess the **anti-tumor efficacy** of DZD9008 compared to platinum-based doublet chemotherapy in participants with newly diagnosed or treatment-naïve non-small cell lung cancer (NSCLC) carrying the **EGFR Exon20ins** mutation. This objective is clinically relevant as it aims to determine the potential of DZD9008 as a first-line treatment option, which could offer an alternative to the current standard of care for this specific genetic mutation in NSCLC.

Secondary objectives include:

To further assess the anti-tumor efficacy of DZD9008 versus platinum-based doublet chemotherapy using other parameters.
To characterize the safety and tolerability of DZD9008 compared to platinum-based doublet chemotherapy.
To assess the pharmacokinetics (PK) of DZD9008 and its metabolites in participants receiving DZD9008.
To confirm the EGFR Exon20ins mutation status in tumor tissue by a central laboratory and support the development of tumor tissue-based companion diagnostics for DZD9008.
To retrospectively assess the EGFR Exon20ins mutation status in plasma ctDNA by a central laboratory and support the development of liquid biopsy companion diagnostics for DZD9008.

Participants

The clinical trial involves a total of **279 participants** diagnosed with **Locally Advanced or Metastatic Non-Small Cell Lung Cancer** harboring the **Epidermal Growth Factor Receptor Exon 20 Insertion Mutation**. The study population includes both male and female subjects, aged 18 years and older, with a confirmed diagnosis of non-squamous NSCLC that is either locally advanced or metastatic. Participants were selected based on their newly diagnosed status or lack of prior systemic treatment for their condition. The trial includes individuals with adequate hematopoietic and organ system functions, as well as those with stable brain metastasis. Participants are required to have a measurable disease according to RECIST 1.1 criteria. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraceptive guidelines if applicable. The trial population includes vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics.

Plans and Procedures

The clinical trial is a **Phase 3**, open-label, randomized, multi-center study designed to evaluate the efficacy of **Sunvozertinib** compared to platinum-based doublet chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring **Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutation**. The trial employs a randomized, controlled design to ensure the reliability of the results. Participants will be randomly assigned to receive either Sunvozertinib or a combination of platinum-based chemotherapy agents, including **Pemetrexed** and **Carboplatin**, administered via infusion. The trial is expected to last until February 2026, with participant involvement spanning up to 260 days for those receiving Sunvozertinib and up to 360 days for those on chemotherapy, depending on the treatment regimen.

Study visits are structured to include an initial screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis, and mutation status. Following randomization, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, including assessments of progression-free survival (PFS) and overall survival (OS). The primary endpoint is PFS as assessed by blinded independent central review per RECIST 1.1 criteria. Secondary endpoints include overall response rate (ORR), duration of response (DoR), and disease control rate (DCR), among others. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. Additionally, participants with brain metastasis must have stable disease post-treatment to continue in the study. The trial aims to provide comprehensive data on the efficacy and safety of Sunvozertinib as a first-line treatment option for this specific NSCLC population.

Treatment

The clinical trial involves the administration of **Sunvozertinib**, an experimental medication, as a selective **EGFR** inhibitor for patients with non-small cell lung cancer (NSCLC) harboring **EGFR** exon 20 insertion mutations. Sunvozertinib is provided in tablet form and is administered orally. The maximum daily dose is 300 mg, with a total maximum dose of 547,500 mg over a treatment period of up to 260 days. The medication is produced by DIZAL (JIANGSU) PHARMACEUTICAL CO., LTD and is identified by the sponsor product code DZD9008. Participant compliance with the dosing schedule is monitored throughout the trial.

In addition to the experimental treatment, the study includes a comparator treatment using **ALIMTA** (pemetrexed), which is a standard-of-care therapy for NSCLC. ALIMTA is provided as a 500 mg powder for concentrate for solution for infusion and is administered via intravenous infusion. The maximum daily dose is 500 mg, with a total maximum dose of 1,910 mg over a treatment period of up to 24 days. This medication is manufactured by ELI LILLY NEDERLAND B.V.

The trial also involves the use of **Carboplatin**, a chemotherapy agent, as part of the platinum-based doublet chemotherapy regimen. Carboplatin is available in several formulations, including Carboplat onkovis, Carboplatin Kabi, and Carboplatin Hikma, all of which are concentrates for solution for infusion. The administration route is via infusion, with a maximum daily dose of 400 mg/m² and a total maximum dose of 1,200 mg/m² over a treatment period of up to 360 days. These formulations are produced by ONKOVIS GMBH, FRESENIUS KABI DEUTSCHLAND GMBH, and HIKMA FARMACÊUTICA (PORTUGAL), S.A., respectively.

Efficacy

The efficacy of the investigational product, **Sunvozertinib**, will be assessed in a Phase 3, open-label, randomized, multi-center clinical trial. The primary endpoint for evaluating efficacy is **Progression-Free Survival (PFS)**, which will be assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 criteria. Secondary endpoints include overall survival (OS), PFS assessed by investigator, confirmed objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and percentage of tumor size change, all evaluated by both BICR and investigator per RECIST 1.1. Additional secondary endpoints involve safety assessments such as adverse events (AE) and serious adverse events (SAE) per CTCAE 5.0, laboratory tests, vital signs, ECG, ECHO/MUGA scan, and pulmonary function tests (PFT). The plasma concentration of DZD9008 and its metabolites will also be measured, and data may contribute to a pooled analysis with other studies. Furthermore, the status of the EGFR Exon20ins mutation in tumor tissues and plasma ctDNA will be analyzed to explore correlations with clinical efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Be able to understand the nature of the trial and provide a signed and dated, written informed consent form (ICF) prior to any study specific procedures, sampling and analyses. If a participant declines to participate in any optional exploratory research, there will be no penalty or loss of benefit to the participant, and he/she will not be excluded from other aspects of the study.
Aged at least 18 years old (or per local regulatory/IRB requirement).
Histologically or cytologically confirmed diagnosis of non-squamous NSCLC, locally advanced (Stage IIIB and IIIC according to the 8th edition of the AJCC TNM staging criteria) or metastatic (Stage IV), not suitable for curative therapy.
Have written documentation of EGFR Exon20ins mutation in tumor tissue from a local CLIA-certified laboratory (or equivalent) or Sponsor designated central laboratory.
An adequate amount* of archived tumor tissue or fresh biopsy (if archived tissue is not available) must be available prior to the study entry for EGFR Exon20ins mutation confirmation in Sponsor designated central laboratory and for supporting the development of tumor tissue-based companion diagnostics for DZD9008.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at ICF signature with no deterioration over the previous 2 weeks and a predicted life expectancy ≥ 12 weeks.
Participants with brain metastasis (BM) can be enrolled under the condition that BM is previously treated and stable, e.g., no evidence of progression for at least 2 weeks after CNS-directed treatment as ascertained by clinical examination and brain imaging (magnetic resonance image [MRI] or computed tomography [CT] scan) during the screening period, neurologically asymptomatic and not require corticosteroid treatment. If the participants have received surgery or radiotherapy for their BM, a time window of 2 weeks is required prior to the randomization to ensure that the surgery- and radiotherapy-related toxicities are ≤ CTCAE grade 1.
Participants should be newly diagnosed or have not received prior systemic treatment for locally advanced or metastatic NSCLC. Note: Patients who have received (neo)adjuvant therapy are allowed to participate in the study, if the (neo)adjuvant therapy is administrated at least 6 months prior to the diagnosis of locally advanced or metastatic NSCLC.
Participants must have measurable disease according to RECIST 1.1: At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for repeated measurement. When a participant only has post-radiotherapy lesions which have progressed with radiological evidence and are measurable, a post-radiotherapy lesion can be selected as a target lesion, Intracranial lesions should not be selected as target lesions.
Adequate hematopoietic and other organ system functions, as outlined in the protocol
Male participants with female partners of child-bearing potential should use barrier contraceptives (i.e., by use of condoms), during their participation in this study and for 6 months following the last dose of the study drug. Male participants must refrain from donating sperm during their participation in the study and for 6 months following the last dose of the study drug. If male participants wish to father children, they should be advised to arrange for freezing of sperm samples prior to the start of study treatment.
Females of child-bearing potential should use reliable contraceptives from the time of screening until 6 weeks after discontinuation of study treatment. Female participants should not be breast feeding and must have a negative pregnancy test prior to start dosing or must fulfil one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrhea for at least 12 months following cessation of all exogenous hormonal treatment; Women under 50 years old would be considered postmenopausal if they have been amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels in the post-menopausal range; Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

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Exclusion Criteria

Prior treatment with any of the following: Prior treatment with any systemic anti-cancer therapy for locally advanced or metastatic NSCLC; Prior treatment with any EGFR Exon20ins inhibitors, including poziotinib, mobocertinib, CLN-081, furmonertinib, etc. or prior treatment with third generation of EGFR TKI, including but not limit to Osimertinib, Almonertinib, etc.; Participants are currently receiving or unable to stop drug or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP)3A4. A washout period of at least 1 week for strong inhibitors and 2 weeks for strong inducers, is required prior to receiving the first study drug administration; Major surgery within 4 weeks of the first study drug administration.
Spinal cord compression or leptomeningeal metastasis.
Concurrent EGFR mutations: exon 19 deletion, L858R, T790M, G719X, S768I, or L861Q.
Any malignancy within 2 years of first administration of study drugs (excluding adequately treated Basal cell carcinoma or in situ cervical cancer with a tumor-free period of more than 2 years and a life expectancy of more than 2 years. Inclusion of such patients should be discussed with the study physician from Dizal Pharma).
Any unresolved toxicities from prior anti-cancer therapy (e.g., adjuvant chemotherapy, radiation therapy) greater than CTCAE grade 1 at the time of starting study drug with the exception of CTCAE grade 2 alopecia.
History of stroke or intracranial hemorrhage within 6 months before randomization.
As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses (i.e., hemophilia and Von Willebrand disease).
Participants with active infection including but not limited to hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) (refer to below table) and active infection of COVID-19 (clinical significance as judged by investigator, with signs or symptoms, etc). The testing on COVID-19 will follow local practice.
Any of the following cardiac criteria: Mean resting corrected QT interval (QTcF) > 470 msec obtained; Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, third degree heart block, and second-degree heart block, PR interval > 250 msec; Any factors that increase the risk of QTc prolongation, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval; Prior history of atrial fibrillation, except medication well-controlled; History of severe and uncontrolled cardiovascular disease (e.g., myocardial infarction, unstable angina, congestive heart failure, and inadequately controlled cardiac arrhythmias with medication) within 6 months before signing the ICF.
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease, immunotherapy induced immune-related pneumonitis.
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of DZD9008.
Received a live vaccine within 2 weeks before randomization.
Women who are pregnant or breast feeding.
Hypersensitivity to active or inactive excipient of DZD9008, pemetrexed, or carboplatin.
Involvement in the planning and conduct of the study (applies to Dizal staff or staff at the study site).
Judgement by the investigator that the participant is unlikely to comply with study procedures, restrictions or requirements.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	14 Jun 2023	3
Belgium	Not Recruiting	14 Jun 2023	4
Czechia	Not Recruiting	14 Jun 2023	5
France	Not Recruiting	14 Jun 2023	10
Germany	Not Recruiting	14 Jun 2023	10
Italy	Not Recruiting	14 Jun 2023	10
The Netherlands	Not Recruiting	14 Jun 2023	—
Poland	Not Recruiting	14 Jun 2023	8
Spain	Not Recruiting	14 Jun 2023	13
Netherlands	—	—	2

Sites & Investigators

Research sites

Azienda Ospedaliero-Universitaria Policlinico G. Rodolico-San Marco Di Catania Hospital Vall d’Hebron Clinica Universidad De Navarra Med Polonia Sp. z o.o.

Investigators

Hector Jose S. P.Enriqueta F. F.Frank G.Jacques C.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
ALIMTA 500 mg powder for concentrate for solution for infusion	Comparator	POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENIOUS INFUSION	500	24	PRD2433080
Carboplatin Kabi 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung	Comparator	KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG	INFUSION	400	360	PRD669106
Carboplatin Hikma 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung	Comparator	KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG	INFUSION	400	360	PRD10240129
Carboplat onkovis 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung	Comparator	KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG	INFUSION	400	360	PRD1808013
Sunvozertinib	Test	TABLET	ORAL USE	300	260	PRD9470251