Osimertinib Monotherapy or Combination With Chemotherapy for Advanced NSCLC Concurrent EGFR and TP53 Mutations (TOP)

A Phase III, Multicentre, Randomized Controlled Study Comparing Osimertinib Monotherapy to Combination Therapy With Osimertinib, Carboplatin and Pemetrexed for Untreated Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer With Concurrent EGFR and TP53 Mutations(TOP)

This is a phase III randomized trial in patients with advanced non-squamous NSCLC harboring EGFR-sensitizing mutations and concurrent TP53 mutations with a performance status of 0 to1 who are planned to receive first-line therapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-small Cell Carcinoma; EGFR Gene Mutation
• Intervention / Treatment: Drug: Carboplatin; Drug: Osimertinib; Drug: Pemetrexed

Detailed Description

This is a multicenter, randomized, open label, phase III study comparing the progression free survival, overall survival, response rate, toxicity, quality of life between Osimertinib monotherapy and combination of osimertinib, pemetrexed, carboplatin in first-line treatment of advanced non-small cell lung cancer patients with concurrent EGFR and TP53 mutation. Besides, the association between other genetic mutations and efficacy will also be analyzed as exploratory endpoint. Eligible patients will be randomized to receive either osimertinib or osimertinib combined with pemetrexed and carboplatin in a 1:1 ratio.

• Study Type: Interventional
• Enrollment (Actual): 294
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Zhanjiang, China
    • Central Hospital of Guangdong Nongken, Zhanjiang Cancer Hospital
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Department of Medical Oncology,Cancer Center of Sun Yat-Sen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures;
2. Male or female, aged at least 18 years;
3. Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1;
4. Life expectancy of at least 3 months;
5. Histologically or cytologically confirmed stage IV or recurrent non-squamous non-small cell lung carcinoma with activating EGFR mutations (exon 19 deletion or exon 21 L858R point mutation) and concurrent TP53 mutations;
6. No prior palliative chemotherapy, or palliative biological (including targeted therapies such as EGFR and vascular epidermal growth factor (VGEF) inhibitors) or immunological therapy （Previous adjuvant chemotherapy is permitted if treatment was completed more than 6 months before day 1. Palliative radiotherapy to a metastatic site is permitted, but palliative wide field radiotherapy to the lung must be completed at least 4 weeks before day 1 with no persistence of any radiotherapy-related toxicity;

7. Adequate organ function, including the following:

   • Adequate bone marrow reserve: absolute neutrophil (segmented and bands) counts (ANC) ≥ 1.5X109/L, Platelets ≥100X109/L, HGB ≥90g/L. The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted;
   • Tumour Hepatic: total bilirubin ≤ 1.5 times the upper limit of normal (x ULN) if no liver metastases or ≤ 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases; alanine aminotransferase (ALT) & aspartate aminotransferase (AST) ≤ 2.5 x ULN if no demonstrable liver metastases or AST&ALT ≤ 5 x ULN in the presence of liver metastases;
   • Serum Creatinine ≤ 1.5 times the ULN and Creatinine Clearance ≥ 50 ml/min.
8. Females must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening
9. Post-menopausal defined as aged 50 years or more and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
10. Women under 50 years old would be consider postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site);
2. Previous randomization in the present study or previous treatment with Osimertinib;
3. Known severe hypersensitivity to Osimertinib or any of the excipients of this product;
4. Known severe hypersensitivity to carboplatin, pemetrexed or any of the excipients of these products;
5. Known severe hypersensitivity to pre-medications required for treatment with carboplatin/ pemetrexed doublet chemotherapy;
6. History or presence of any other malignancy with the exception of basal cell carcinoma or cervical cancer in situ;
7. Past medical history of interstitial lung disease, drug induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease;
8. Any unresolved chronic toxicity ≥ CTCAE grade 2 from previous anticancer therapy;
9. As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease);
10. Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study;
11. Pregnancy or breast feeding;
12. Use of unapproved drugs or research drugs within 30 days before the start of the study;
13. Symptomatic brain metastases.

14. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value;
    • Any clinically important 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;
    • Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN), 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 and cause Torsades de Pointes;
    • Correction of electrolyte abnormalities to within normal ranges can be performed during screening;
15. Pre-existing idiopathic pulmonary fibrosis evidence by CT scan at baseline;
16. Unable to tolerate carboplatin/pemetrexed doublet chemotherapy, as judged by the investigator;
17. Life expectancy of ≤ 12 weeks;
18. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection (e.g. patients receiving treatment for infection) including hepatitis C and human immunodeficiency virus (HIV), or active uncontrolled HBV infection;

19. Screening for chronic conditions is not required. Should participants with HBV infection be included, patients are only eligible if they meet all the following criteria:

    • Demonstrated absence of HCV co-infection or history of HCV co-infection;
    • Demonstrated absence of HIV infection;
    • Participants with active HBV infection are eligible if they are: Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is suppressed to <100 IU/mL and transaminase levels are below ULN;
    • Participants with a resolved or chronic infection HBV are eligible if they are:
    • Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG]. In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (TBD by hepatologist) post treatment or
    • Positive for HBsAg, but for >6 months have had transaminases levels below ULN and HBV DNA levels below<100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (TBD by hepatologist) post treatment.

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
Active Comparator: osimertinib monotherapy; Osimertinib, 80mg, QD, p.o. until disease progression	Drug: Osimertinib; Osimertinib, 80mg, QD, p.o. until disease progression
Experimental: combination of osimertinib and chemotherapy; Osimertinib, 80mg, QD, p.o. Pemetrexed 500 mg/m2 and carboplatin area under curve 5 intravenously every 3 weeks for four cycles, followed by maintenance pemetrexed.	Drug: Carboplatin; carboplatin area under curve 5 intravenously every 3 weeks for four cycles; Drug: Osimertinib; Osimertinib, 80mg, QD, p.o. until disease progression; Drug: Pemetrexed; pemetrexed 500 mg/m2 intravenously every 3 weeks until disease progression

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression free survival	defined as the time from randomization to the date of first documentation of from date of randomization until the date of first documented progression or date of death from any cause, whichever came first	assessed up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage of participants with objective response (partial response [PR] plus complete response [CR])	assessed using RECIST v.1.1	up to 36 months
Incidence and severity of adverse events (AEs)	Overall incidence of AEs; the incidence of grade 3 or above AEs; the incidence of severe adverse events (SAE); the incidence of drug-related AEs; the incidence of AEs resulting in permanent withdrawal of drugs; the incidence of AEs leading to dose adjustment	through study completion, an average of 60 months
Change from baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Score.	The EORTC QLQ-C30 consists of 30 questions that comprise aspects of participant's functioning assessment (physical, emotional, role, cognitive, and social); symptom scales (fatigue; nausea, vomiting, and pain; the global health/quality of life [QoL]); and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties), within a recall period of "the past week." Most questions used a 4-point scale (1=Not at all to 4=Very much; two questions used a 7-point scale (1=Very poor to 7=Excellent). Scores were averaged and transformed to a 0-100 scale; a higher score for Global Qol/functional scales=better level of functioning; a higher score for symptom scale=greater degree of symptoms.	up to 36 weeks
overall survival	from date of randomization until the date of death from any cause	OS maturity reaches 60%, assessed up to 60 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between subtypes of EGFR mutations, TP53 mutations and other potential predictive biomarkers and response to treatment.	We do next generation sequencing in tumor tissue and blood sample to detect EGFR, TP53 and additional mutations in other oncogenic drivers and tumor-suppressor genes at baseline. NGS in blood sample is required at the first efficacy assessment (6th week). Upon PD, NGS in blood sample is required while in tumor tissue is preferred.	up to 36 months

Collaborators and Investigators

• Sponsor: Li Zhang, MD
• Collaborators: Henan Cancer Hospital; First People's Hospital of Foshan; Cancer Hospital of Guangxi Medical University

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2021
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: December 20, 2020
• First Submitted That Met QC Criteria: January 3, 2021
• First Posted (Actual): January 5, 2021

Study Record Updates

• Last Update Posted (Estimated): October 15, 2025
• Last Update Submitted That Met QC Criteria: October 12, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• 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; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Pemetrexed; Carboplatin; osimertinib
• Other Study ID Numbers: ESR-21-21647

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes