MRX-2843 + Osimertinib for Lung Cancer

Overseen By Conor Steuer, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Must be taking: Osimertinib

Must not be taking: CYP450 inhibitors/inducers, Antiretrovirals

Disqualifiers: Brain metastases, Interstitial lung disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, up to 3.5 years

69 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial evaluates the best dose and side effects of MRX-2843 when given in combination with osimertinib in treating patients with EGFR gene mutant non-small cell lung cancer that has spread to other places in the body (advanced). MRX-2843 and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take medications that affect certain liver enzymes (CYP450). It's important to discuss your current medications with the study team to avoid any interactions.

What data supports the effectiveness of the drug MRX-2843 + Osimertinib for lung cancer?

Osimertinib is effective in treating advanced non-small cell lung cancer (NSCLC) with specific mutations, as it significantly prolongs the time patients live without the disease getting worse compared to older treatments. It is particularly effective for patients with a specific mutation (EGFR T790M) that often causes resistance to other treatments. ^{1 2 3 4 5}

What safety information is available for the treatment MRX-2843 + Osimertinib for lung cancer?

Osimertinib, used in treating certain types of lung cancer, has been associated with common side effects like diarrhea, rash, dry skin, and nail issues. Some patients may experience more serious heart-related side effects, such as changes in heart rhythm and heart failure. ^{6 7 8 9 10}

What makes the drug MRX-2843 + Osimertinib unique for lung cancer treatment?

The combination of MRX-2843 and Osimertinib is unique because it targets specific mutations in non-small cell lung cancer (NSCLC) that may not respond to other treatments. Osimertinib is a third-generation drug that specifically targets the EGFR T790M mutation, which is often present in patients who have developed resistance to earlier treatments. ^{1 5 11 12 13}

Research Team

Conor Steuer

Principal Investigator

Emory University

Eligibility Criteria

This trial is for adults with advanced non-small cell lung cancer that has an EGFR mutation. Participants must be able to swallow pills, have certain blood counts and liver function, and not be pregnant or breastfeeding. They should agree to use contraception if there's a risk of pregnancy. People can't join if they have heart problems, untreated brain metastases, certain infections like HIV, or are on drugs affecting liver enzymes.

Inclusion Criteria

You have enough platelets in your blood.

I agree to use birth control during and up to 4 months after the study.

I agree to use two forms of birth control during and for 90 days after the study if I can have children and am sexually active with a man.

Exclusion Criteria

I am not taking any drugs that affect liver enzymes.

I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

I do not have symptoms from untreated brain metastases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive osimertinib and MRX-2843 orally once daily on days 1-28, with cycles repeating every 28 days in the absence of disease progression or unacceptable toxicity

28 days per cycle, up to 3.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, for a minimum of 30 days or until resolution of treatment-related toxicity to ≤ grade 1

Minimum of 30 days

Treatment Details

Interventions

• MRX-2843
• Osimertinib

Trial Overview The trial is testing the combination of MRX-2843 and Osimertinib to find the safest dose and study side effects in patients whose lung cancer has spread. These drugs may block enzymes needed for tumor growth. The trial includes different groups based on prior treatments received.

Participant Groups

Group I: Treatment (osimertinib, MRX-2843) Experimental Treatment 2 Interventions

Patients receive osimertinib PO QD and MRX-2843 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

Hsp90 inhibitors, such as ganetespib and luminespib, effectively reduce cell viability and colony formation in osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines, suggesting they can enhance the effectiveness of osimertinib.

The combination of luminespib with osimertinib significantly decreases the expression of key proteins associated with resistance, indicating a potential strategy to overcome resistance in NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hsp90 inhibitors enhance the antitumoral effect of osimertinib in parental and osimertinib-resistant non-small cell lung cancer cell lines. Codony-Servat, J., Viteri, S., Codony-Servat, C., et al.[2022]

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]

The case study highlights that the acquisition of a BTN2A1-BRAF fusion may be a mechanism of acquired resistance to osimertinib in a patient with non-small cell lung cancer (NSCLC), suggesting that resistance can develop through genetic changes after initial treatment.

Despite the presence of PD-L1 expression, switching to the PD-L1 inhibitor duvalizumab did not yield significant improvements, indicating that patients with sensitive EGFR mutations may not benefit from PD-L1 inhibitors, regardless of PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTN2A1-BRAF fusion may be a novel mechanism of resistance to osimertinib in lung adenocarcinoma: a case report. Kong, WM., Guo, YJ., Ma, J., et al.[2023]

Osimertinib is effective as a first-line treatment for advanced EGFR-mutated non-small cell lung cancer (NSCLC), showing a 76% objective response rate and a median progression-free survival of 12.6 months in a study of 104 patients.

At the time of disease progression, common resistance mechanisms identified included MET amplification in 15% of patients and the EGFR C797S mutation in 11%, highlighting the need for further treatment strategies beyond osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study. Akli, A., Girard, N., Fallet, V., 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 (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, a treatment for metastatic EGFRm T790M non-small-cell lung cancer, has been analyzed using newly developed and validated LC-MC/MS methods across various biological matrices, including plasma, urine, and cerebrospinal fluid.

The assays demonstrated high selectivity, accuracy, and robustness, successfully analyzing over 20,000 clinical samples, which supports the effective clinical development of osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of osimertinib in human plasma, urine and cerebrospinal fluid. Mitchell, R., Bailey, C., Ewles, M., et al.[2022]

A 72-year-old male patient developed significant cardiac toxicities, including QTc prolongation, atrial fibrillation, and heart failure, after 15 months of osimertinib therapy for metastatic non-small cell lung cancer, highlighting the potential cardiac risks associated with this treatment.

Management strategies included discontinuing rosuvastatin, which can exacerbate QTc prolongation, and initiating medications for atrial fibrillation and heart failure, suggesting the need for careful monitoring and risk assessment in patients receiving osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple cardiotoxicities during osimertinib therapy. Kobat, H., Davidson, M., Elkonaissi, I., et al.[2023]

Osimertinib shows significant efficacy in patients with uncommon EGFR mutations, achieving an objective response rate (ORR) of 47.6% and a disease control rate (DCR) of 85.7%) in a study of 21 patients.

Patients with G719X-compound mutations responded particularly well, with a higher ORR of 62.5% and a median progression-free survival (PFS) of 13.7 months, indicating that osimertinib can be an effective treatment option for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials. Eide, IJZ., Stensgaard, S., Helland, Å., et al.[2022]

In a phase II study of 38 elderly patients with EGFR mutation-positive advanced non-small cell lung cancer, osimertinib achieved a 1-year progression-free survival (PFS) rate of 59.4%, which did not meet the primary endpoint of 50%.

Osimertinib was generally well-tolerated, with the most common severe side effects being rash and pneumonitis, affecting 17.5% of patients, indicating that while it may not have met efficacy expectations, it is a manageable treatment option for older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Trial on Osimertinib as a First-Line Treatment for EGFR Mutation-Positive Advanced NSCLC in Elderly Patients: The SPIRAL-0 Study. Chihara, Y., Takeda, T., Goto, Y., et al.[2023]

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

Osimertinib: First Global Approval. [2022]

2. China pubmed.ncbi.nlm.nih.gov

Hsp90 inhibitors enhance the antitumoral effect of osimertinib in parental and osimertinib-resistant non-small cell lung cancer cell lines. [2022]

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

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

4. China pubmed.ncbi.nlm.nih.gov

BTN2A1-BRAF fusion may be a novel mechanism of resistance to osimertinib in lung adenocarcinoma: a case report. [2023]

5. France pubmed.ncbi.nlm.nih.gov

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study. [2022]

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

New Adjuvant Drug for Lung Cancer. [2023]

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

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

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

Determination of osimertinib in human plasma, urine and cerebrospinal fluid. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Multiple cardiotoxicities during osimertinib therapy. [2023]

11. China pubmed.ncbi.nlm.nih.gov

Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials. [2022]

12. England pubmed.ncbi.nlm.nih.gov

A Phase II Trial on Osimertinib as a First-Line Treatment for EGFR Mutation-Positive Advanced NSCLC in Elderly Patients: The SPIRAL-0 Study. [2023]

13. 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]