Osimertinib + Gefitinib for Lung Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dana-Farber Cancer Institute

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 24 weeks

48 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is studying a combination of two drugs as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The interventions involved in this study are: * Osimertinib (Tagrisso) * Gefitinib (Iressa)

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications or herbal supplements that are known to strongly inhibit CYP3A4, as well as warfarin. You should avoid any medications or foods that induce CYP3A4. Check with the trial team for a full list of medications to avoid.

What data supports the effectiveness of the drug combination Osimertinib and Gefitinib for lung cancer?

Osimertinib is effective in treating non-small cell lung cancer (NSCLC) with specific gene mutations, especially when resistance to other treatments develops. Gefitinib is also used for NSCLC with certain gene mutations, and combining these drugs may enhance their effectiveness in targeting cancer cells. ^{1 2 3 4 5}

Is the combination of Osimertinib and Gefitinib safe for humans?

Osimertinib has been studied for safety in patients with lung cancer, with common side effects including diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in about 28% of patients, and 5.6% stopped treatment due to these effects. Gefitinib, another drug used in lung cancer treatment, has a similar safety profile, but specific safety data for the combination of Osimertinib and Gefitinib is not provided in the available research. ^{2 6 7 8 9}

What makes the drug combination of Osimertinib and Gefitinib unique for lung cancer treatment?

The combination of Osimertinib and Gefitinib is unique because Osimertinib is a third-generation drug that targets specific mutations in lung cancer cells, potentially offering more effective treatment with fewer side effects compared to older drugs. This combination may provide a novel approach by using two different drugs to target cancer cells more effectively. ^{10 11 12 13 14}

Research Team

Pasi Janne

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults over 18 with advanced Non-Small Cell Lung Cancer and specific EGFR mutations, who haven't had prior treatments for lung cancer or recent major surgery. They must not be pregnant, agree to use contraception, have a life expectancy over 12 weeks, and good organ function. Those with unstable health conditions or taking certain drugs are excluded.

Inclusion Criteria

You must have a disease that can be measured using specific criteria.

I am 18 years old or older.

Participants must have a life expectancy of greater than 12 weeks

Exclusion Criteria

I haven't taken any chemotherapy or experimental drugs for my advanced lung cancer.

I am not taking any strong CYP3A4 inhibitors.

I have been treated with drugs targeting EGFR or similar proteins.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination therapy with gefitinib and osimertinib, either concurrently or on an alternating schedule, for 6 cycles of 28 days each

24 weeks

Visits every 2 cycles for CT scans

Follow-up

Participants are monitored for overall survival and progression-free survival with clinic visits or phone calls

3 years

Treatment Details

Interventions

• Gefitinib
• Osimertinib

Trial Overview The trial is testing Osimertinib (Tagrisso) combined with Gefitinib (Iressa) as a treatment for NSCLC patients who have never received EGFR inhibitors before. It aims to see if this drug combo can effectively treat the cancer.

Participant Groups

Group I: Gefitinib + Osimertinib Experimental Treatment 2 Interventions

* Gerfitinib will administered orally at a pre determine dose daily * Osimertinib will administered orally at a pre determine dose daily

Gefitinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Iressa for:

• Non-small cell lung cancer (NSCLC)

Approved in United States as Iressa for:

• Non-small cell lung cancer (NSCLC)

Approved in Canada as Iressa for:

• Non-small cell lung cancer (NSCLC)

Approved in Japan as Iressa for:

• Non-small cell lung cancer (NSCLC)

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a study of 240 advanced non-small-cell lung cancer (NSCLC) patients with acquired resistance to EGFR TKIs, 52.9% had the T790M mutation after rebiopsy, highlighting the mutation's prevalence in treatment resistance.

Patients with the T790M mutation who had previously used osimertinib experienced significantly longer post-progression survival (42.6 months) compared to those without osimertinib (18.0 months) or without the mutation (18.8 months), suggesting osimertinib's effectiveness as a standard treatment for T790M-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. Chiang, CL., Huang, HC., Shen, CI., et al.[2022]

Osimertinib (Tagrisso) is a targeted therapy approved by the FDA for patients with metastatic non-small cell lung cancer (NSCLC) who have the EGFR T790M mutation and have progressed after previous treatments.

The drug received special designations from the FDA, including breakthrough therapy and priority review, highlighting its significance in treating resistant forms of NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Skoulidis, F., Papadimitrakopoulou, VA.[2022]

Osimertinib (AZD9291) is effective in prolonging survival for non-small cell lung cancer patients with EGFR mutations, but resistance to the drug is a common issue, prompting the need to explore resistance mechanisms.

In this study, AZD9291-resistant NSCLC cell lines were established, revealing significant changes in circular RNA (circRNA) expression profiles, which may contribute to drug resistance and could serve as potential targets for future gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. Chen, T., Luo, J., Gu, Y., et al.[2022]

In a study of 46 treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer, alternating therapy with osimertinib and afatinib resulted in a median progression-free survival of 21.3 months, indicating promising efficacy despite not meeting the primary endpoint of 12-month progression-free survival probability.

The treatment was generally well-tolerated, with common side effects including diarrhea (73.9%) and rash (63.0%), and only a few cases of serious pneumonitis, suggesting a manageable safety profile for this alternating therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). Hayashi, H., Yonesaka, K., Nakamura, A., et al.[2022]

Osimertinib (TAGRISSO) received accelerated FDA approval for treating metastatic non-small cell lung cancer with the EGFR T790M mutation, showing significant tumor response rates of 57% and 61% in two major trials involving 411 patients.

While osimertinib demonstrated promising efficacy, common side effects included diarrhea (42%) and rash (41%), with 28% of patients experiencing severe adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Khozin, S., Weinstock, C., Blumenthal, GM., et al.[2022]

Osimertinib significantly improves progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation, showing a median PFS of 10.1 months compared to 4.4 months with chemotherapy in a trial of 419 patients.

The safety profile of osimertinib is favorable compared to other EGFR tyrosine kinase inhibitors and chemotherapy, with common side effects including diarrhea and rash, making it a viable treatment option for patients who have progressed on previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. Odogwu, L., Mathieu, L., Goldberg, KB., et al.[2022]

Osimertinib significantly improves disease-free survival (DFS) in adults with completely resected, early-stage EGFR mutation-positive non-small cell lung cancer (NSCLC), as shown in the pivotal ADAURA trial, regardless of prior adjuvant chemotherapy.

The treatment is well tolerated with a manageable safety profile, and it does not negatively impact health-related quality of life, making it a suitable option for adjuvant therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. Frampton, JE.[2022]

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor specifically designed to target the EGFR T790M mutation, which is a common cause of resistance to first-line EGFR TKIs in advanced non-small-cell lung cancer.

This review highlights the efficacy of osimertinib in clinical trials, demonstrating its ability to effectively treat patients with non-small-cell lung cancer harboring the T790M mutation while minimizing effects on normal EGFR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib making a breakthrough in lung cancer targeted therapy. Zhang, H.[2020]

In a retrospective analysis of 32 patients with EGFR T790M-mutant non-small-cell lung cancer, osimertinib showed a 50% objective response rate and a median progression-free survival of 11.3 months, indicating its efficacy in clinical practice.

The median overall survival was 18.3 months, with better outcomes observed in patients without cerebral metastases and those with better performance status, highlighting the importance of these factors in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. Knetki-Wróblewska, M., Kowalski, DM., Czyżewicz, G., et al.[2022]

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, effectively inhibited the growth of a brain metastasis in a patient with lung adenocarcinoma that was resistant to both radiotherapy and surgery.

The case highlights the importance of re-biopsy in patients with EGFR-mutated non-small cell lung cancer who develop resistance to TKI treatments, as it can provide critical information for effective treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Intracranial Response to Osimertinib in a Patient with Epidermal Growth Factor Receptor T790M-Positive Adenocarcinoma of the Lung. Reichegger, H., Jochum, W., Förbs, D., et al.[2022]

Osimertinib, an irreversible tyrosine kinase inhibitor, showed excellent activity in treating a 69-year-old man with metastatic EGFR-mutated non-small cell lung cancer, leading to a rapid treatment response despite initial severe pancytopenia.

After experiencing pancytopenia, the patient's dose of osimertinib was reduced from 80 mg to 40 mg daily, which allowed for continued effective treatment without further adverse events, demonstrating the potential for safe dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. Di Marino, P., Chiapperino, C., Primavera, FC., et al.[2022]

The study established an osimertinib-resistant cell line (HCC827/OSIR) from EGFR-sensitive HCC827 cells, demonstrating that these resistant cells have higher resistance to multiple EGFR tyrosine kinase inhibitors compared to the original cells.

Increased expression of IRE1α was identified as a potential mechanism for resistance to osimertinib, and targeting IRE1α with an inhibitor showed promise in reducing the number of viable resistant cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased Expression of IRE1α Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells. Tang, ZH., Su, MX., Guo, X., et al.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

3. Pakistan pubmed.ncbi.nlm.nih.gov

Comparison of Gefitinib in the treatment of patients with non-small cell lung cancer and clinical effects of Osimertinib and EGFR Gene mutation. [2022]

4. Singapore pubmed.ncbi.nlm.nih.gov

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. [2022]

8. France pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Osimertinib making a breakthrough in lung cancer targeted therapy. [2020]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Rapid Intracranial Response to Osimertinib in a Patient with Epidermal Growth Factor Receptor T790M-Positive Adenocarcinoma of the Lung. [2022]

12. China pubmed.ncbi.nlm.nih.gov

Real world efficacy of osimertinib in second line/beyond in patients with metastatic EGFR+ non-small cell lung cancer and role of paired tumour-plasma T790M testing at tyrosine kinase inhibitor resistance. [2023]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. [2022]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Increased Expression of IRE1α Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells. [2022]