Dacomitinib + Osimertinib for Lung Cancer

Recruiting at 8 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Pregnancy, Recent surgery, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

22 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety of dacomitinib and osimertinib, at increasing doses, to find out what effects, if any, this combination of drugs has on people with metastatic EGFR mutant lung cancer that has not been treated with an EGFR TKI.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you have not been treated with any EGFR inhibitors before. If you are on other medications, it's best to discuss with the trial team to see if they are compatible with the study drugs.

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

Osimertinib is effective in treating non-small cell lung cancer (NSCLC) with specific mutations, significantly prolonging the time patients live without the disease getting worse. It is particularly effective for patients with certain genetic changes in their cancer, and it is generally well-tolerated. ^{1 2 3 4 5}

What safety data exists for Dacomitinib + Osimertinib in humans?

Osimertinib, used for certain types of lung cancer, has been generally well tolerated in studies, 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. ^{4 6 7 8 9}

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

The combination of Dacomitinib and Osimertinib is unique because it targets specific mutations in lung cancer cells, particularly the EGFR T790M mutation, which is often resistant to other treatments. Osimertinib is a third-generation drug that has shown improved disease control in patients with these mutations, making it a promising option for those who have progressed after previous therapies. ^{3 4 8 10 11}

Research Team

Helena Yu, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults over 18 with advanced non-small cell lung cancer that has a specific EGFR mutation. They must not have had prior EGFR inhibitor treatments but can have other chemotherapies. Participants need to be in good physical condition, able to take oral meds, and willing to use birth control. People with recent surgeries or radiotherapy, significant heart issues, interstitial lung disease, uncontrolled side effects from past treatments, or certain ECG abnormalities cannot join.

Inclusion Criteria

Agree to use effective methods of contraception from the time of screening until 3 months after treatment discontinuation (for males and females of child-bearing potential)

Written informed consent

I can swallow pills.

Exclusion Criteria

I do not have any active lung diseases that affect the tissue and space around the air sacs.

Pregnant or lactating women

I have not had any radiation therapy in the week before starting the treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination dacomitinib and osimertinib with dose escalation over 28-day cycles

1 year

Telemedicine visits may be utilized for cycles without imaging; physical exams, vital signs, and labs concurrent with imaging visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dacomitinib
• Osimertinib

Trial Overview The study tests the safety of combining two drugs—Dacomitinib and Osimertinib—at increasing doses on patients with metastatic EGFR mutant lung cancer who haven't been treated with an EGFR TKI before. The goal is to find out the effects of this drug combination.

Participant Groups

Group I: Dacomitinib and Osimertinib Experimental Treatment 2 Interventions

Patients will begin on combination dacomitinib and osimertinib at the prescribed doses. A cycle will be 28 days in duration. The study will use a standard 3+3 dose escalation design. Per MD discretion, telemedicine visits may be utilized for cycles where imaging is not collected, and physical exam, vital sign and labs collection will only be required concurrent with imaging visits.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that effectively targets specific mutations in advanced non-small cell lung cancer (NSCLC), including the T790M mutation, leading to significantly longer progression-free survival compared to first-generation EGFR TKIs like erlotinib or gefitinib.

The benefits of osimertinib in prolonging progression-free survival were consistent across all patient groups, regardless of the type of EGFR mutation or the presence of CNS metastases, and it has a generally manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use. Scott, LJ.[2020]

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 is an oral medication specifically designed to target the EGFR T790M mutation in advanced non-small cell lung cancer (NSCLC), which helps overcome resistance to previous EGFR TKI therapies.

It received accelerated approval in the USA in November 2015 for patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed after EGFR TKI treatment, and is currently undergoing further development for broader treatment applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: First Global Approval. Greig, SL.[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]

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 (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]

In a phase 2 study involving 210 patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), osimertinib demonstrated significant efficacy, with 70% of patients achieving an objective response, including 3% with complete responses.

Osimertinib was found to have manageable side effects, although serious adverse events occurred in 25% of patients, with interstitial lung disease being the only fatal event possibly related to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Goss, G., Tsai, CM., Shepherd, FA., et al.[2022]

Osimertinib (Tagrisso) is an approved adjuvant treatment for non-small cell lung cancer patients with specific tumor mutations, highlighting its targeted therapeutic approach.

Common side effects of osimertinib include blood-related issues like leukopenia and thrombocytopenia, as well as gastrointestinal and skin reactions, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Drug for Lung Cancer. Aschenbrenner, DS.[2023]

Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, was effective for 2.5 years in a 78-year-old woman with T790M-positive lung cancer, but she eventually experienced disease progression due to the emergence of a new resistance mutation (C797G).

The case highlights the potential of liquid biopsy and next-generation sequencing to monitor clonal evolution and identify novel resistance mechanisms in patients treated with osimertinib, which could inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. DE Carlo, E., Schiappacassi, M., Pelizzari, G., et al.[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]

References

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

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use. [2020]

2. 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]

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

Osimertinib: First Global Approval. [2022]

4. France pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. [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. United States pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. [2022]

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

New Adjuvant Drug for Lung Cancer. [2023]

10. Greece pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. [2022]

11. Singapore pubmed.ncbi.nlm.nih.gov

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