Osimertinib + Bevacizumab for Lung Cancer

Recruiting at 460 trial locations

Overseen By Vamsi K. Vasireddy

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anti-VEGF agents, CYP3A4 inducers

Disqualifiers: Pregnancy, Cardiovascular disease, Hypertension, Interstitial lung disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 21-day cycles, ongoing until progression or toxicity

300 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial compares the effect of bevacizumab and osimertinib combination vs. osimertinib alone for the treatment of non-small cell lung cancer that has spread outside of the lungs (stage IIIB-IV) and has a change (mutation) in a gene called EGFR. The EGFR protein is involved in cell signaling pathways that control cell division and survival. Sometimes, mutations in the EGFR gene cause EGFR proteins to be made in higher than normal amounts on some types of cancer cells. This causes cancer cells to divide more rapidly. Osimertinib may stop the growth of tumor cells by blocking EGFR that is needed for cell growth in this type of cancer. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving osimertinib with bevacizumab may control cancer for longer and help patients live longer as compared to osimertinib alone.

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

The trial protocol does not specify if you need to stop taking your current medications, but you must not be taking medications or supplements that strongly induce CYP3A4. If you are on such medications, you need to stop them before starting the trial treatment.

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

Osimertinib has shown effectiveness in treating non-small cell lung cancer (NSCLC) with specific genetic mutations, improving disease-free survival in early-stage cases and being well-tolerated. A study is evaluating the combination of Osimertinib and Bevacizumab for advanced NSCLC, suggesting potential benefits of this drug combination. ^{1 2 3 4 5}

Is the combination of Osimertinib and Bevacizumab safe for humans?

Osimertinib has been generally well tolerated in clinical trials for lung cancer, with common side effects including diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in about 28% of patients, and a small percentage stopped treatment due to these effects. No new safety concerns were identified in recent studies. ^{3 4 5 6 7}

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

The combination of Osimertinib and Bevacizumab is unique because Osimertinib is a third-generation drug that targets specific mutations in lung cancer cells, while Bevacizumab works by inhibiting the growth of blood vessels that supply tumors. This dual approach targets both the cancer cells and their blood supply, potentially improving treatment effectiveness. ^{3 5 8 9 10}

Research Team

Helena A Yu

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults with advanced non-small cell lung cancer (NSCLC) that has spread and have specific EGFR gene mutations. They should not have had previous treatments with EGFR TKI or anti-VEGF agents, no major heart issues, and must not be on strong CYP3A4 inducers. Patients can join if they've finished certain radiation therapies before starting the study drugs and if they don't have severe diseases or conditions that could affect their participation.

Inclusion Criteria

I had hepatitis C but am cured, or I'm being treated with no detectable virus.

I don't have severe side effects from previous treatments, except for hair loss or mild nerve pain.

I have not received any systemic treatment for my metastatic disease.

Exclusion Criteria

N/A

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive osimertinib alone or in combination with bevacizumab. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21-day cycles, ongoing until progression or toxicity

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for 10 years.

10 years

Follow-up visits every 3 months

Treatment Details

Interventions

• Bevacizumab
• Osimertinib

Trial Overview The trial is testing whether adding Bevacizumab to Osimertinib improves outcomes in patients compared to using Osimertinib alone. Both are cancer medications: Osimertinib targets a protein involved in tumor growth, while Bevacizumab may prevent tumors from creating new blood vessels needed for them to grow.

Participant Groups

Group I: Arm B (osimertinib, bevacizumab) Experimental Treatment 7 Interventions

Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, MUGA, CT and may undergo MRI and blood and urine sample collection on study.

Group II: Arm A (osimertinib) Active Control 6 Interventions

Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, MUGA, CT and may undergo MRI and blood and urine sample collection on study.

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

Approved in United States as Tagrisso for:

• Locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutations
• Metastatic EGFR T790M mutation-positive NSCLC

Approved in European Union as Tagrisso for:

• Locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutations
• Metastatic EGFR T790M mutation-positive NSCLC

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 2 study involving 122 patients with advanced nonsquamous NSCLC and EGFR-sensitizing mutations, the combination of osimertinib and bevacizumab did not significantly improve progression-free survival (PFS) compared to osimertinib alone, with median PFS of 22.1 months versus 20.2 months, respectively.

The study reported a higher incidence of grade 3 or worse adverse events in the combination therapy group (56%) compared to the monotherapy group (48%), indicating that while the combination did not enhance efficacy, it may increase the risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study. Kenmotsu, H., Wakuda, K., Mori, K., et al.[2023]

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 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 (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 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 (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 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]

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]

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]

The combination of osimertinib with selumetinib or savolitinib showed a promising objective response rate of around 42-44% in patients with advanced EGFR-mutant non-small-cell lung cancer, indicating potential efficacy of these combinations.

However, combining osimertinib with durvalumab was not feasible due to a higher incidence of interstitial lung disease, highlighting safety concerns with this particular combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Oxnard, GR., Yang, JC., Yu, H., et al.[2022]

References

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

Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study. [2023]

2. 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]

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

Osimertinib: First Global Approval. [2022]

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

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

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

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

New Adjuvant Drug for Lung Cancer. [2023]

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. 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]

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

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. [2022]