Osimertinib + BLU-945 for Non-Small Cell Lung Cancer

Recruiting at 38 trial locations

Overseen By Blueprint Medicines

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Blueprint Medicines Corporation

Must be taking: EGFR-targeted TKI

Must not be taking: Immunotherapy, Antibodies

Disqualifiers: Driver alterations, Mixed cell histology, CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

177 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing BLU-945, a new drug that targets cancer proteins, alone or with osimertinib. It focuses on patients with specific EGFR gene mutations. The drug aims to block a protein that helps cancer cells grow.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study drug. Specifically, you must stop taking any EGFR-targeted TKI at least 7 days before, any immunotherapy 28 days before, and any other systemic anticancer therapy 14 days before the first dose of the study drug. Some medications may be allowed with prior approval from the study sponsor.

What data supports the effectiveness of the drug combination of Osimertinib and BLU-945 for non-small cell lung cancer?

Osimertinib has shown effectiveness in treating non-small cell lung cancer, especially in patients with specific genetic mutations (EGFR mutations). It is a standard treatment for advanced cases and has been effective in clinical trials when combined with other drugs like savolitinib. ^{1 2 3 4 5}

Is the combination of Osimertinib and BLU-945 safe for humans?

Osimertinib has been shown to be generally safe in humans, with common side effects including diarrhea, rash, dry skin, nail issues, and fatigue. However, specific safety data for the combination of Osimertinib and BLU-945 is not available in the provided research. ^{1 6 7 8 9}

What makes the drug combination of Osimertinib and BLU-945 unique for non-small cell lung cancer?

The combination of Osimertinib and BLU-945 is unique because it targets specific mutations in non-small cell lung cancer, potentially overcoming resistance mechanisms that limit the effectiveness of Osimertinib alone. Osimertinib is already known for its effectiveness against certain mutations, and adding BLU-945 may enhance its ability to control the disease. ^{2 4 10 11 12}

Eligibility Criteria

Adults with metastatic non-small cell lung cancer (NSCLC) that has specific mutations in the EGFR gene. They must have previously been treated with an EGFR-targeted therapy like osimertinib and shown disease progression on it. Participants need to be generally healthy, with a good performance status, and able to use contraception.

Inclusion Criteria

I am 18 years old or older.

My lung cancer is advanced and has a specific EGFR gene change.

My NSCLC has specific EGFR mutations (T790M and C797S).

Exclusion Criteria

I have a serious heart condition that is not under control.

I received growth factor support for neutrophils or platelets within 2 weeks before starting the study drug.

I don't have lasting side effects from previous treatments above mild level.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BLU-945 as monotherapy and in combination with osimertinib

Up to 12 months

Phase 2 Expansion

Evaluate the safety, tolerability, and anticancer activity of BLU-945 as monotherapy and in combination with osimertinib in specific mutation profiles

Up to 30 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 42 months

Treatment Details

Interventions

• BLU-945
• osimertinib

Trial Overview The trial is testing BLU-945 alone or combined with osimertinib for safety, tolerability, how the body processes it, its effects on the body, and its ability to fight cancer in patients whose NSCLC has certain EGFR mutations resistant to previous treatments.

Participant Groups

Group I: Phase 2, Group 4: BLU-945 with osimertinib Experimental Treatment 2 Interventions

Phase 2 expansion group for BLU-945 with osimertinib at a dose determined during Part 1B in patients

Group II: Phase 2, Group 3: BLU-945 as monotherapy Experimental Treatment 1 Intervention

Phase 2 expansion group for BLU-945 as monotherapy at a dose determined during Part 1A in patients with EGFR C797S mutations

Group III: Phase 2, Group 2: BLU-945 as monotherapy Experimental Treatment 1 Intervention

Phase 2 expansion group for BLU-945 as monotherapy at a dose determined during Part 1A in patients with EGFR T790M mutations

Group IV: Phase 2, Group 1: BLU-945 as monotherapy Experimental Treatment 1 Intervention

Phase 2 expansion group for BLU-945 as monotherapy at a dose determined during Part 1A in patients with EGFR T790M and C797S mutations

Group V: Part 1B: BLU-945 with osimertinib Experimental Treatment 2 Interventions

Phase 1 dose escalation of BLU-945 in combination with osimertinib 80 mg tablets for oral administration

Group VI: Part 1A: BLU-945 as monotherapy Experimental Treatment 1 Intervention

Phase 1 dose escalation of BLU-945 as monotherapy at various dose levels

Who Is Running the Clinical Trial?

Blueprint Medicines Corporation

Lead Sponsor

Trials

31

Recruited

6,000+

Findings from Research

In a phase Ib trial, the combination of osimertinib and savolitinib demonstrated effectiveness in treating non-small cell lung cancer, suggesting a potential new treatment strategy.

This trial indicates that combining these two targeted therapies may enhance treatment outcomes for patients with this type of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Small Cell Lung Cancer Responds to Osimertinib plus Savolitinib. [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]

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]

In vitro studies identified the BRAF G469A mutation as a key mechanism of acquired resistance to osimertinib in non-small cell lung cancer cells, indicating that this mutation allows cancer cells to continue growing despite treatment.

Treatment with selumetinib and trametinib was effective in restoring sensitivity to osimertinib and increasing cell death in resistant clones, suggesting potential strategies to overcome resistance in patients with this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired BRAF G469A Mutation as a Resistance Mechanism to First-Line Osimertinib Treatment in NSCLC Cell Lines Harboring an EGFR Exon 19 Deletion. La Monica, S., Minari, R., Cretella, D., 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 is effective for patients with advanced non-small cell lung cancer (NSCLC) who are resistant to first-generation EGFR-TKIs, showing a 40.5% objective response rate and a median overall survival of 25.3 months based on a study of 84 patients.

The treatment has a low incidence of serious adverse reactions (9.5% grade III and above), with most side effects being manageable and primarily mild to moderate, indicating it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of osimertinib in treating patients with first-generation EGFR-TKI-resistant advanced non-small cell lung cancer and prognostic analysis. Yang, Y., Guo, Y., Wang, R., et al.[2022]

In a study of 94 patients with advanced non-small-cell lung cancer (NSCLC) who had previously been treated, osimertinib showed a 47.3% overall objective response rate and a 90.1% disease control rate, indicating its effectiveness in this population.

Patients with the T790M mutation experienced significantly longer progression-free survival (PFS) compared to those without the mutation, highlighting osimertinib's targeted efficacy, especially in those with specific genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. Mu, Y., Xing, P., Hao, X., et al.[2022]

The combination of osimertinib and platinum-based chemotherapy (OPP) demonstrated a high objective response rate of 90.9% in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer, indicating strong efficacy.

The treatment was well-tolerated, with no treatment-related deaths and an acceptable safety profile, as only 14.9% of patients discontinued due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. Saito, R., Sugawara, S., Ko, R., et al.[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]

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]

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]

References

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

Non-Small Cell Lung Cancer Responds to Osimertinib plus Savolitinib. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Osimertinib as first-line treatment for advanced epidermal growth factor receptor mutation-positive non-small-cell lung cancer in a real-world setting (OSI-FACT). [2022]

3. 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]

4. 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]

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

Acquired BRAF G469A Mutation as a Resistance Mechanism to First-Line Osimertinib Treatment in NSCLC Cell Lines Harboring an EGFR Exon 19 Deletion. [2022]

6. 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]

7. Cyprus pubmed.ncbi.nlm.nih.gov

Effect of osimertinib in treating patients with first-generation EGFR-TKI-resistant advanced non-small cell lung cancer and prognostic analysis. [2022]

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

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. [2022]

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

Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. [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. 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]

12. 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]