Osimertinib + Chemotherapy for Lung Cancer

(NeoADAURA Trial)

Recruiting at 145 trial locations

Overseen By AstraZeneca Cancer Study Locator

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: CYP3A4 inducers

Disqualifiers: ILD, Prior malignancy, Pre-op radiotherapy, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

358 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing osimertinib, a drug that targets cancer cells, either by itself or with chemotherapy. It focuses on patients with a specific type of lung cancer that has a mutation in the EGFR gene. The drug works by stopping the growth of cancer cells.

Will I have to stop taking my current medications?

The trial requires that you stop using medications or herbal supplements that are strong inducers of cytochrome P450 (CYP) 3A4 at least 3 weeks before starting the study treatment.

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

Research shows that carboplatin, a component of the treatment, is effective in treating non-small-cell lung cancer (NSCLC) and can be combined with other drugs like paclitaxel for improved survival rates. Additionally, pemetrexed, another component, is effective in NSCLC and has a favorable safety profile when combined with platinum-based drugs like cisplatin or carboplatin. ^{1 2 3 4 5}

What safety data exists for the combination of Osimertinib and chemotherapy drugs like Carboplatin and Pemetrexed?

Pemetrexed combined with cisplatin or carboplatin has been studied for safety in treating lung cancer and mesothelioma, showing common side effects like low blood cell counts, fatigue, and nausea. Patients are advised to take vitamins and steroids to reduce severe side effects. Carboplatin and cisplatin have different side effect profiles, with carboplatin generally having fewer severe side effects compared to cisplatin. ^{3 6 7 8 9}

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

The combination of Osimertinib with chemotherapy, including carboplatin, cisplatin, and pemetrexed, is unique because it targets lung cancer with a multi-faceted approach, using Osimertinib's ability to inhibit specific cancer cell growth along with the broad cancer-fighting effects of chemotherapy. This combination may offer enhanced effectiveness compared to traditional chemotherapy alone, which has shown only modest improvements in survival and quality of life. ^{2 5 10 11 12}

Research Team

Jamie E Chaft, MD

Principal Investigator

Memorial Sloan Kettering, USA

Walter Weder, MD

Principal Investigator

Thoraxchirurgie Bethanien, Switzerland

Masahiro Tsuboi

Principal Investigator

National Cancer Center Hospital East, Japan

Eligibility Criteria

This trial is for adults with a specific type of lung cancer (non-squamous NSCLC) that can be surgically removed. Patients must have certain EGFR mutations, good performance status, and no history of severe lung conditions or other cancers within the last 2 years. Prior cancer treatments for NSCLC are not allowed.

Inclusion Criteria

My non-squamous NSCLC is at stage II - IIIB N2 and can be completely removed with surgery.

I can care for myself and perform light activities without help.

I am 18 years old or older.

Exclusion Criteria

I have had lung inflammation or damage that needed steroids.

My lung cancer is a mix of small cell and non-small cell types.

I am not using, nor can I stop using, certain medications or supplements that affect my liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant osimertinib as monotherapy or in combination with chemotherapy, or standard of care chemotherapy alone

12 weeks

Surgery

Participants undergo surgery to remove the tumor after neoadjuvant treatment

Follow-up

Participants are monitored for safety, effectiveness, and survival outcomes after surgery

5 years

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Osimertinib
• Pemetrexed

Trial Overview The study tests Osimertinib alone or combined with chemotherapy against standard-of-care chemotherapy in patients who can undergo surgery to remove their lung cancer. It's a Phase III trial where participants are randomly assigned to one of three groups.

Participant Groups

Group I: Arm 3: Osimertinib monotherapy Experimental Treatment 1 Intervention

Osimertinib 80 mg QD (Dose may be reduced to 40 mg QD at the discretion of the investigator)

Group II: Arm 2: Osimertinib with platinum-based chemotherapy Experimental Treatment 4 Interventions

Osimertinib 80 mg QD (Dose may be reduced to 40 mg QD at the discretion of the investigator) plus investigator's choice of platinum-based standard of care chemotherapy (pemetrexed/carboplatin or pemetrexed/cisplatin)

Group III: Arm 1: Placebo with platinum-based chemotherapy Placebo Group 4 Interventions

Placebo plus investigator's choice of platinum-based standard of care chemotherapy (pemetrexed/carboplatin or pemetrexed/cisplatin)

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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 53 patients with advanced non-small cell lung cancer (NSCLC) who had previously undergone platinum-based chemotherapy, treatment with pemetrexed plus cisplatin or carboplatin resulted in a median overall survival of 10 months and a median progression-free survival of 6 months.

The treatment was generally well-tolerated, with only a small percentage of patients experiencing severe side effects, such as grade 3 or 4 leukopenia and thrombocytopenia, indicating that pemetrexed combined with platinum-based drugs can be a safe option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients. Zhang, GZ., Jiao, SC., Meng, ZT.[2021]

The combination of paclitaxel and carboplatin has shown promising results in treating advanced non-small-cell lung cancer (NSCLC), with reported 1-year survival rates as high as 54%, making it a widely used regimen in clinical practice.

This combination therapy has been effective without additional toxicity, allowing for full doses of both drugs to be administered, and is currently being evaluated in ongoing studies for earlier stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel/carboplatin in the treatment of non-small-cell lung cancer. Belani, CP.[2015]

In a study involving 812 patients with malignant pleural mesothelioma (MPM), single-agent pemetrexed showed promising efficacy, with a median time to progressive disease of 6.0 months for chemonaïve patients and an overall response rate of 10.5%.

The treatment was well-tolerated, exhibiting mild hematologic toxicity, primarily neutropenia, in less than 18% of patients, indicating a favorable safety profile for pemetrexed in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. Taylor, P., Castagneto, B., Dark, G., et al.[2015]

Carboplatin has shown comparable efficacy to cisplatin in treating non-small cell lung cancer (NSCLC) and can be effectively used in combination chemotherapy, providing similar survival benefits.

Ongoing clinical trials are exploring various strategies to optimize carboplatin use, including dose adjustments, combinations with other treatments like stem-cell support and radiation therapy, and interactions with new agents like TAXOL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin in the treatment of non-small cell lung cancer: a review. Comis, RL.[2018]

Pemetrexed (Alimta) is an effective treatment for mesothelioma and shows comparable survival rates to docetaxel in advanced non-small-cell lung cancer (NSCLC) while causing significantly fewer and less severe side effects.

In combination with platinum agents, pemetrexed has demonstrated significant activity and a favorable toxicity profile, making it a promising option for treating thoracic malignancies and warranting further research with other novel drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in advanced NSCLC: a review of the clinical data. Zinner, RG., Fossella, FV., Herbst, RS.[2015]

In a meta-analysis of 486 patients with advanced non-squamous non-small cell lung cancer, the pemetrexed plus carboplatin regimen at 5 mg/min•mL (PCb5) showed a significantly lower incidence of treatment-emergent adverse events (TEAEs) compared to the 6 mg/min•mL (PCb6) regimen, including less thrombocytopenia, anemia, and fatigue.

Despite the differences in safety profiles, both PCb5 and PCb6 regimens demonstrated similar efficacy outcomes in terms of overall survival and progression-free survival, indicating that PCb5 may be a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. Okamoto, I., Schuette, WH., Stinchcombe, TE., et al.[2018]

Pemetrexed, when combined with cisplatin, significantly improves median survival in patients with malignant pleural mesothelioma, with a median survival of 12.1 months compared to 9.3 months for cisplatin alone, based on a phase III trial involving 448 patients.

The drug works by inhibiting key enzymes involved in DNA synthesis, but it can cause side effects like myelosuppression, neutropenia, and fatigue, necessitating supportive care with folic acid, vitamin B12, and corticosteroids during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summaries: pemetrexed (Alimta). Hazarika, M., White, RM., Johnson, JR., et al.[2022]

In a study of 903 patients with malignant pleural mesothelioma (MPM), pemetrexed combined with cisplatin was found to be generally well tolerated, with a low treatment-associated death rate of 0.8% and an interstitial lung disease (ILD) incidence of 0.9%.

The overall response rate to treatment was 25%, and the six-month survival rate was estimated at 75.9%, indicating that pemetrexed is effective in managing MPM, consistent with previous clinical trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of pemetrexed in patients with malignant pleural mesothelioma based on all-case drug-registry study. Kuribayashi, K., Voss, S., Nishiuma, S., et al.[2015]

Cisplatin, carboplatin, and oxaliplatin, while structurally similar, have different therapeutic uses and efficacy profiles; for example, carboplatin is less effective than cisplatin for certain cancers but comparable in others like ovarian cancer.

Oxaliplatin is particularly effective for colorectal cancer when combined with 5-fluorouracil and folinic acid, marking it as a significant advancement in treatment options for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Platinum compounds: metabolism, toxicity and supportive strategies]. Lipp, HP., Hartmann, JT.[2013]

Pemetrexed, commonly used for treating mesothelioma and lung adenocarcinoma, has been associated with a rare case of communicating hydrocephalus in a patient undergoing maintenance therapy, highlighting a potential unexpected toxicity.

As the use of pemetrexed increases, especially in maintenance settings, healthcare providers should be vigilant for unusual side effects, including neurological complications, during long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed and communicating hydrocephalus. Son, CO., Mott, FE.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients. [2021]

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

Paclitaxel/carboplatin in the treatment of non-small-cell lung cancer. [2015]

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

Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. [2015]

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

Carboplatin in the treatment of non-small cell lung cancer: a review. [2018]

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

Pemetrexed in advanced NSCLC: a review of the clinical data. [2015]

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

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. [2018]

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

FDA drug approval summaries: pemetrexed (Alimta). [2022]

8. Ireland pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of pemetrexed in patients with malignant pleural mesothelioma based on all-case drug-registry study. [2015]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Platinum compounds: metabolism, toxicity and supportive strategies]. [2013]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Systematic review of efficacy and safety of pemetrexed in non-small-cell-lung cancer. [2021]

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

Pemetrexed and communicating hydrocephalus. [2021]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients. [2022]