Study of EGFR TKI in Patients With Advanced NSCLC Harbouring EGFR Mutations

An Open-label Phase II Study of EGFR TKI in Patients With Advanced NSCLC Harbouring EGFR Mutations Categorized According to Structural Based Classification

The goal of this clinical trial is to explore the efficacy of afatinib in NSCLC harbouring EGFR PACC mutation subtype. The main question it aims to answer is:

Afatinib is active in patients with advanced NSCLC harbouring EGFR PACC mutation subtype.

Participants will undergo screening, follow by treatment if eligible for study participation and then enter follow up phase after study medication has stopped. Patients will take afatinib 40mg daily continuously, until the development of progressive disease or meeting discontinuation criteria. A treatment cycle is defined as 28 days.

Study Overview

• Status: Recruiting
• Conditions: NSCLC
• Intervention / Treatment: Drug: Afatinib 40 MG

Detailed Description

This is a multi-center, open-label, phase II study of patients with stage IIIb-IV NSCLC harbouring EGFR PACC mutations.

Before taking the study drug, patients will need to undergo baseline assessments to ensure that they are eligible for the study. Then they will enter treatment period, where afatinib 40mg will be administered daily continuously, until the development of progressive disease or meeting discontinuation criteria. A discontinuation visit will be performed if patients stopped study drug for any reason. Thereafter, patients will be placed on Follow Up visit.

Clinical assessment, routine blood tests and routine imaging:

Physical examinations, imaging, and blood tests will be performed during baseline assessment, on the first day of each treatment cycle, after patients have completed the study and when clinically required by the treating physician. Patients will need to visit the doctor's office approximately 1-2 times every 4 weeks when they are receiving active treatment during the course of the study. More frequent visits may be needed as clinically indicated by the treating physician.

Treatment procedure:

Afatinib will be taken once a day at approximately the same time each day initially starting at a dose of 40mg. Afatinib must be taken on an empty stomach (at least one hour before or at least two hours after a meal).

Research Blood samples:

Blood samples for research will be taken at baseline, before starting cycle 3 and at the time of cancer progression. The estimated total volume of research blood that will be drawn is 10mL (2-3 teaspoons) each time for a total of 30mL.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kenneth Sooi; Phone Number: +65 6908 2222; Email: kenneth_sooi@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore
    • Recruiting
    • National University Hospital
    • Contact: Kenneth Sooi; Phone Number: +65 6908 2222; Email: kenneth_sooi@nuhs.edu.sg
    • Principal Investigator: Kenneth Sooi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histological or cytologically confirmed NSCLC.
2. No prior systemic therapy for advanced stage disease.
3. Presence of a PACC mutation (detected either in blood or tumour) as defined by Robichaux et al (24). Compound mutations classified as PACC mutations are permitted (24).
4. The presence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (28).
5. Estimated life expectancy of at least 3 months.
6. ECOG performance status 0-1.
7. Age ≥21 years old.

8. Have adequate organ and hematologic function, as defined by:

   • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤3.0 x upper limit of normal (ULN) or ≤5 times ULN if related to liver metastases.
   • Total serum bilirubin ≤1.5 × ULN (<3.0 × ULN for patients with Gilbert syndrome)
   • Creatinine clearance >=45mL/min (Cockcroft Gault)
   • Absolute neutrophil count ≥1.5 × 10^9/L
   • Platelet count ≥100 × 10^9/L
   • Hemoglobin ≥ 9.0 g/dL
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
10. For female patients of childbearing potential, have a negative pregnancy test documented ≤ 14 days prior to start of study medication.

11. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to use a highly effective form of contraception with their sexual partners during the dosing period and for a period of at least 4 months after the end of treatment. Evidence of non-child-bearing potential is fulfilled by one of the following criteria at screening:

    • The post-menopausal period defined as age ≥50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
    • Women <50 years old they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range.
    • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not a tubal ligation
12. Signed written informed consent.

Exclusion Criteria:

1. Prior EGFR TKI therapy.
2. Prior chemotherapy for Stage IIIB/IV adenocarcinoma of the lung. Neo-/adjuvant chemotherapy, CT-RT or RT is permitted if it has been elapsed for ≥12 months prior to disease progression.
3. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated non melanoma skin cancer or cervical cancer in situ; definitively treated non metastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
4. Known leptomeningeal carcinomatosis.
5. Unstable spinal cord compression/brain metastases unless asymptomatic and not requiring steroids for at least 2 weeks prior to the start of study treatment. For patients with brain metastases, gamma knife or stereotactic brain surgery is allowed prior to study treatment.
6. Symptomatic and untreated spinal cord compression.
7. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: myocardial infarction within 6 months prior to study enrolment; unstable angina within 6 months prior to study enrolment; congestive heart failure within 6 months prior to study enrolment; history of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician; any history of clinically significant ventricular arrhythmia; prolonged QTc.
8. Had a cerebrovascular accident or transient ischemic attack within 6 months prior to enrolment.
9. Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. Minor surgery is allowed.
10. Radiotherapy to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks before the study entry.
11. Inability to swallow oral medication.
12. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection that would preclude adequate absorption of afatinib.
13. Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis.
14. Have an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics.
15. Have a known history of human immunodeficiency virus infection or active hepatitis B or C infection, active tuberculosis.
16. Have a known or suspected hypersensitivity to afatinib or its excipients.
17. Are pregnant, planning a pregnancy, or breastfeeding.
18. Males and females of reproductive potential who are not using an effective method of contraception and females who are pregnant or breastfeeding or have a positive serum pregnancy test prior to study entry.
19. Previous allogeneic bone marrow transplant.
20. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Afatinib; Afatinib given as monotherapy daily in a 28-days cycle.	Drug: Afatinib 40 MG; Afatinib 40mg administered orally daily.; Other Names: Gilotrif

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Defined as best overall response (Complete Response or Partial Response) across all assessment time-points according to RECIST criteria v1.1	At baseline and every 8 weeks for the first 6 cycles, every 12 weeks from cycle 7 to 12 and every 16 weeks from cycle 13 onwards (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	Defined as the time from the date of study enrolment to the first date of documented disease progression	within 4 weeks from starting treatment and every 8 weeks for the first 6 cycles, every 12 weeks from cycle 7 to 12 and every 16 weeks from cycle 13 onwards (each cycle is 28 days)
Overall survival	Defined as the time from the date of randomisation until documented progression (according to RECIST v1.1) or death	48 months
Duration of response	Defined as the time from first documented Complete Response or Partial Response to the time of radiological progression or death, whichever occurs earlier.	every 8 weeks for the first 6 cycles, every 12 weeks from cycle 7 to 12 and every 16 weeks from cycle 13 onwards (each cycle is 28 days)
Time to treatment failure	Defined as the time from afatinib treatment to the time of treatment discontinuation for any reason including disease progression, treatment toxicity, and death	48 months
Number of participant with treatment related toxicities	Toxicities will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading Version 5	48 months

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Investigators: Principal Investigator: Kenneth Sooi, National University Hospital, Singapore

Publications and helpful links

General Publications

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.
• Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010 Dec 15;127(12):2893-917. doi: 10.1002/ijc.25516.
• Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. doi: 10.1056/NEJMoa0810699. Epub 2009 Aug 19.
• Bonomi PD. Implications of key trials in advanced nonsmall cell lung cancer. Cancer. 2010 Mar 1;116(5):1155-64. doi: 10.1002/cncr.24815.
• Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.
• Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963-71. doi: 10.1056/NEJMoa1406766. Epub 2014 Sep 27.
• Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. doi: 10.1016/S1470-2045(15)00026-1. Epub 2015 Jun 4.
• Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland A, Giannone V, D'Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4. Epub 2017 Sep 11.
• Lynch TJ Jr, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007 May;12(5):610-21. doi: 10.1634/theoncologist.12-5-610.
• Lacouture ME, Schadendorf D, Chu CY, Uttenreuther-Fischer M, Stammberger U, O'Brien D, Hauschild A. Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther. 2013 Jun;13(6):721-8. doi: 10.1586/era.13.30. Epub 2013 Mar 18.
• Aw DC, Tan EH, Chin TM, Lim HL, Lee HY, Soo RA. Management of epidermal growth factor receptor tyrosine kinase inhibitor-related cutaneous and gastrointestinal toxicities. Asia Pac J Clin Oncol. 2018 Feb;14(1):23-31. doi: 10.1111/ajco.12687. Epub 2017 May 2.
• Robichaux JP, Le X, Vijayan RSK, Hicks JK, Heeke S, Elamin YY, Lin HY, Udagawa H, Skoulidis F, Tran H, Varghese S, He J, Zhang F, Nilsson MB, Hu L, Poteete A, Rinsurongkawong W, Zhang X, Ren C, Liu X, Hong L, Zhang J, Diao L, Madison R, Schrock AB, Saam J, Raymond V, Fang B, Wang J, Ha MJ, Cross JB, Gray JE, Heymach JV. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature. 2021 Sep;597(7878):732-737. doi: 10.1038/s41586-021-03898-1. Epub 2021 Sep 15.
• Russo A, Franchina T, Ricciardi G, Battaglia A, Picciotto M, Adamo V. Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario. Int J Mol Sci. 2019 Mar 21;20(6):1431. doi: 10.3390/ijms20061431.
• Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 2016 Sep;107(9):1179-86. doi: 10.1111/cas.12996. Epub 2016 Aug 9.
• Gu L, Huang H, Xu Z, Niu X, Li Z, Xia L, Yu Y, Lu S. Landscape and Predictive Significance of the Structural Classification of EGFR Mutations in Chinese NSCLCs: A Real-World Study. J Clin Med. 2022 Dec 28;12(1):236. doi: 10.3390/jcm12010236.
• Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167-77. doi: 10.1056/NEJMoa1408440.
• Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, Peters S; ESMO Guidelines Committee. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv192-iv237. doi: 10.1093/annonc/mdy275. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: August 28, 2023
• First Submitted That Met QC Criteria: September 25, 2023
• First Posted (Actual): October 2, 2023

Study Record Updates

• Last Update Posted (Actual): July 24, 2025
• Last Update Submitted That Met QC Criteria: July 22, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: EGFR mutations; Afatinib; PACC mutation
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: NS01/02/23

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
• product manufactured in and exported from the U.S.: No