Osimertinib + Abemaciclib for Non-Small Cell Lung Cancer after Osimertinib Resistance

Overseen By Sarah Moore

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must be taking: Osimertinib

Must not be taking: CYP3A4 inducers

Disqualifiers: Cardiovascular disease, Hepatitis, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

18 Participants Needed

Trial Summary

What is the purpose of this trial?

Lung cancer is the leading cause of cancer deaths. Advances in the systemic treatment of non-small cell lung cancer (NSCLC) have increased survival in metastatic EGFR-mutated NSCLC. However resistance to therapy can develop.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have taken chemotherapy or other investigational agents within three weeks before starting the study treatment, and you should not use medications or supplements that are major inducers of CYP3A4.

What data supports the effectiveness of the drug combination of Osimertinib and Abemaciclib for treating non-small cell lung cancer after resistance to Osimertinib?

Research shows that Abemaciclib, when used alone or with Osimertinib, can inhibit cell growth and delay resistance in non-small cell lung cancer cells that have become resistant to Osimertinib. This suggests that the combination might help manage resistance in patients with EGFR mutations. ^{1 2 3 4 5}

What safety information is available for Osimertinib in treating non-small cell lung cancer?

Osimertinib is generally considered safe for treating non-small cell lung cancer, with common side effects including diarrhea, rash, dry skin, nail issues, and fatigue. Its safety profile is favorable compared to other similar treatments. ^{2 3 5 6 7}

What makes the drug combination of Osimertinib and Abemaciclib unique for treating non-small cell lung cancer?

The combination of Osimertinib and Abemaciclib is unique because it targets resistance to Osimertinib, a common issue in treating non-small cell lung cancer with EGFR mutations. Osimertinib is a third-generation drug that targets specific mutations, while Abemaciclib, typically used for breast cancer, may help overcome resistance by inhibiting cell cycle progression. ^{2 4 5 8 9}

Research Team

Hatim Husain, MD

Principal Investigator

University of California, San Diego

Eligibility Criteria

Adults over 18 with Stage IV, recurrent or metastatic non-small cell lung cancer that has an EGFR mutation and have shown resistance to osimertinib treatment. They must be able to swallow pills, not have serious heart conditions or uncontrolled illnesses, and agree to use contraception. Those with certain prior treatments or health issues like interstitial lung disease are excluded.

Inclusion Criteria

At least one measurable lesion according to RECIST version 1.1

Age >18 years

Histologically or cytologically confirmed NSCLC-lung adenocarcinoma histology

Exclusion Criteria

You have a lung disease called interstitial lung disease, except if it was caused by radiation treatment and is not currently being treated or causing symptoms.

You have certain health conditions like unstable angina, congestive heart failure, or gastrointestinal diseases that may affect how well you can take the study medication. You also have mental health issues or other personal situations that may make it difficult for you to participate or follow the study requirements.

Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of osimertinib (e.g. Crohn's disease, ulcerative colitis, chronic diarrhea, and malabsorption)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Osimertinib 80 mg QD and Abemaciclib 150 mg BID

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Abemaciclib
• Osimertinib

Trial Overview The trial is testing the combination of Osimertinib and Abemaciclib in patients whose non-small cell lung cancer has become resistant to Osimertinib alone. It aims to see if this combo can overcome resistance and improve outcomes.

Participant Groups

Group I: Single Arm, POC Experimental Treatment 2 Interventions

Single arm, POC Safety and Efficacy Osimertinib 80 mg QD Abemaciclib 150mg BID

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

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 (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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib. [2021]

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

Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations. [2022]

5. Singapore pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of osimertinib for patients with EGFR-mutated NSCLC: a systematic review and meta-analysis of randomized controlled studies. [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. England pubmed.ncbi.nlm.nih.gov

Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience. [2022]

9. China pubmed.ncbi.nlm.nih.gov

Acquired L718V/TP53 co-mutation and discordant molecular pattern between plasmatic and cerebrospinal fluid in a bone and meningeal metastatic L858R+ non-small cell lung cancer: a case report. [2023]