Aumolertinib With or Without Chemotherapy as 1st Line Treatment in Locally Advanced or Metastatic Non-Small Cell Lung Cancer With Sensitizing EGFR Mutations

Efficacy and Safety of Aumolertinib With or Without Chemotherapy as First-line Treatment in Locally Advanced or Metastatic Non-Small Cell Lung Cancer With Sensitizing Epidermal Growth Factor Receptor Mutations: A Randomized, Controlled, Open-label, Phase 3 and Multicenter Clinical Study

To assess the efficacy and safety of Aumolertinib plus chemotherapy versus Aumolertinib alone as first-line treatment in locally advanced or metastatic non-small cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor mutations (EGFRm+).

Study Overview

• Status: Recruiting
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Aumolertinib; Drug: Placebo Aumolertinib

Detailed Description

HS-10296-306 is a randomized, open-label, multicenter, phase III study to assess the efficacy and safety of Aumolertinib plus chemotherapy versus Aumolertinib alone as first-line treatment in locally advanced or metastatic non-small cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor mutations (EGFRm+). Eligible patients are randomized to receive either Aumolertinib (110 mg orally, once daily) in combination with platinum-based chemotherapy (every 3 weeks for 4~6 cycles) or Aumolertinib (110 mg orally, once daily) in a 1:1 ratio.

• Study Type: Interventional
• Enrollment (Estimated): 624
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Shun Lu, MD; Phone Number: 5455 86-21-22200000; Email: shun_lu@hotmail.com
• Study Contact Backup: Name: Zhonglin Chen, MD; Phone Number: 5455 86-21-22200000; Email: chestgcp@126.com

Study Locations

• China
  • Shanghai Chest Hospital
    • Shanghai, Shanghai Chest Hospital, China
      • Recruiting
      • Shanghai Chest Hospital
      • Contact: Shun Lu; Phone Number: 13601813062; Email: shun_lu@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Provision of informed consent before any study-specific procedures, sampling and analyses.

  2. Male or female, age at least 18 years. 3. Histologically confirmed locally advanced or metastatic NSCLC (included patients with stage IIIB, IIIC or IV disease who had relapsed after prior surgery or were newly diagnosed). Patients must be treatment-naïve for locally advanced or metastatic NSCLC. Prior adjuvant and neo-adjuvant therapies are permitted as long as treatment was completed at least 12 months prior to the development of recurrent disease.

  4. The tumor harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations assessed by central testing using tumor tissue sample or blood sample.

  5. At least 1 lesion that has not previously been irradiated, and that can be accurately measured at Baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15mm).

  6. An Eastern Cooperative Oncology Group (ECOG) performance status equal to 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.

  7. Female patients should be using adequate contraceptive measures and should not be breastfeeding at the screening period, during the study, and six months after the last dosing of study. Patient must have a negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of non-childbearing potential by fulfilling 1 of the following criteria at screening:

  1. Postmenopausal defined as age more than 50 years and amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments.
  2. Women under 50 years old would be considered postmenopausal if they have been amenorrhea for 12 months or more, following cessation of exogenous hormonal treatments, and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory.

  3. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not by tubal ligation.

     8. Male patients should be willing to use barrier contraception (i.e., condoms).

     Exclusion Criteria:

• 1. Treatment with any of the following:

  1. Prior treatment with an EGFR TKI.
  2. Major surgery (excluding placement of vascular access) within 4 weeks of randomization.
  3. Radiotherapy to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of randomization.
  4. Spinal cord compression or brain metastases unless asymptomatic, stable for at least 4 weeks, and not requiring steroids for at least 2 weeks prior to start of study treatment.

  5. Medications that are predominantly CYP3A4 strong inhibitors or inducers or sensitive substrates of CYP3A4 with a narrow therapeutic range within 7 days of the first dose of study drug.

     2. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 at the time of starting study treatment.

     3. History of other malignancies, excluding full treated non-melanoma skin cancer, in-situ cancer, or other solid tumors that hadn't recurrent for > 5 years following the end of treatment.

     4. Inadequate bone marrow reserve or organ function. 5. Any of the following cardiac criteria:

  1. Mean resting corrected QT interval (QTc) > 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF).
  2. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval > 250 ms).
  3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, 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.

  4. Left ventricular ejection fraction (LVEF) < 50%. 6. Any evidence of severe or uncontrolled systemic diseases (including uncontrolled hypertension and active bleeding diatheses) or active infection. Screening for chronic conditions is not required.

     7. Refractory nausea, vomiting, or chronic gastrointestinal diseases, inability to swallow the study drug, or previous significant bowel resection that would preclude adequate absorption of Aumolertinib.

     8. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease.

     9. Women who are breastfeeding or have a positive urine or serum pregnancy test at the Screening Visit.

     10. History of hypersensitivity to any active or inactive ingredient of study drugs (pemetrexed, cisplatin, carboplatin, Aumolertinib) or to drugs with a similar chemical structure or class to Aumolertinib.

     11. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.

     12. Any severe and uncontrolled ocular disease that may, in the ophthalmologist's opinion, present a specific risk to the patient's safety.

     13. Any disease or condition that, in the opinion of the investigator, would compromise the safety of the patient or interfere with study assessments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aumolertinib and platinum-based chemotherapy	Drug: Aumolertinib; Aumolertinib 110 mg QD in combination with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC5) on Day 1 of every 21-day cycles up to 4~6 cycles, followed by Aumolertinib daily with pemetrexed maintenance (500 mg/m2) on Day 1 of every 21-day cycles. Dose may be reduced to allow for the management of investigational drug related toxicity.; Other Names: HS-10296
Active Comparator: Aumolertinib	Drug: Placebo Aumolertinib; Placebo Aumolertinib 110 mg QD Dose may be reduced to allow for the management of investigational drug related toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS (Progression Free Survival) assessed by IRC (Independent Review Committee)	IRC-PFS is defined as the time from randomization until the date of objective disease progression based on IRC assessment or death (by any cause in the absence of progression). The patients will receive long-term follow-up including chest and abdominal CT every 6 weeks until Week 18, then every 12 weeks and onwards.	From the time of randomization to disease progression or death, approximately 3 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR (Objective Response Rate) assessed by IRC (Independent Review Committee)	ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression.	From the time of randomization to the date of first occurrence of complete response (CR) or partial response (PR), approximately 3 years.
DoR (Duration of response)	DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.	From the time of randomization to disease progression or death, approximately 3 years.
DCR (Disease Control Rate)	The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD.	From the time of randomization to disease progression or death, approximately 3 years.
DepOR (Depth of Response)	DepOR is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 target lesions.	From the time of randomization to disease progression or death, approximately 3 years.
PFS (Progression Free Survival) Rate at 12, 18, 24, and 36 months	PFS Rate at 12, 18, 24, and 36 months is defined as proportion of progression free survival at 12, 18, 24, and 36 months from the date of randomization.	The PFS Rate at 12, 18, 24, and 36 months is assessed up to 36 months.
OS (Overall survival)	Overall survival (OS) is defined as the time from randomization to death due to any cause. The survival will be followed up with telephone every 12 weeks after discontinuation of the randomized treatment.	From the time of randomization to death due to any cause, approximately 6 years.
OS (Overall survival) rate at 3, 5 years	OS rate at 3, 5 years is defined as the proportion of patients alive at 3, 5 years from the date of randomization.	The OS rate at 3, 5 years is assessed up to 5 years.
Incidence and severity of AEs (Adverse Events)	AEs are graded according to CTCAE v5.0 and recorded in the case report form.	From the screening period to 28 days after treatment completion, approximately 4 years.

Collaborators and Investigators

• Sponsor: Jiangsu Hansoh Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Shun Lu, MD, Shanghai Chest Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2021
• Primary Completion (Estimated): January 31, 2024
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: June 10, 2021
• First Submitted That Met QC Criteria: June 10, 2021
• First Posted (Actual): June 11, 2021

Study Record Updates

• Last Update Posted (Actual): June 9, 2023
• Last Update Submitted That Met QC Criteria: June 8, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Concurrent Chemotherapy, Aumolertinib, EGFR-TKI, EGFRm+, Ex19Del, L858R, HS-10296, Stage IIIB-IV, Non-Small Cell Lung Cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: HS-10296-306

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No