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

No longer recruiting at 44 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for non-small cell lung cancer (NSCLC). The focus is on a new drug, BLU-945, used alone or with osimertinib, a treatment already used for NSCLC. The trial aims to assess the safety and effectiveness of these treatments, particularly for those with specific genetic mutations. Suitable participants have NSCLC with EGFR mutations and have previously taken osimertinib, but their cancer has progressed. As a Phase 1 trial, the research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that BLU-945, whether used alone or with osimertinib, is generally well tolerated by people with non-small cell lung cancer. One study found that both treatments effectively targeted and reduced specific cancer markers in the blood. Importantly, the study reported that patients mostly handled the treatments well, with no severe side effects commonly observed.

Osimertinib is already FDA-approved for treating certain lung cancers, indicating a known safety record. Since this trial is in the early stages, it primarily focuses on assessing the safety of BLU-945 when used alone or with osimertinib. Early trials often look for any signs of harmful effects, and so far, results appear promising for both options. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about BLU-945, especially in combination with osimertinib, because it offers a fresh approach to tackling non-small cell lung cancer with specific EGFR mutations. Unlike standard treatments that often face resistance due to mutations like T790M and C797S, BLU-945 is designed to specifically target these mutations, potentially overcoming existing treatment hurdles. Additionally, the combination with osimertinib may enhance efficacy by attacking the cancer from multiple angles, potentially leading to more durable responses. This dual approach could be a game-changer for patients who have limited options after developing resistance to current therapies.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research has shown that BLU-945 may help treat non-small cell lung cancer (NSCLC) in individuals with specific EGFR gene changes. In studies, BLU-945 proved effective in patients whose cancer progressed despite other treatments. This trial includes treatment arms where participants will receive BLU-945 as monotherapy, potentially benefiting those with specific types of lung cancer. Another arm of the trial will test the combination of BLU-945 with osimertinib, another cancer drug. Osimertinib has already shown effectiveness for some patients with EGFR mutations, and combining it with BLU-945 may enhance its efficacy. This combination aims to target cancer cells more precisely and could improve patient outcomes. ^{2 5 6 7 8}

Are You a Good Fit for This Trial?

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

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

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

I am fully active or can carry out light work.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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 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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39444426/

BLU-945, a potent and selective next-generation EGFR TKI ... Our findings demonstrate the preclinical and early clinical activity of BLU-945 in EGFRm NSCLC progressing on previous EGFR-TKIs.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS9156

A phase 1/2 study of BLU-945 in patients with common ... A phase 1/2 study of BLU-945 in patients with common activating EGFR-mutant non–small cell lung cancer (NSCLC): SYMPHONY trial in progress.

3. jto.org jto.org/article/S1556-0864(22)01068-1/fulltext

EP08.02-045 Phase 1/2 Study of BLU-945 in Patients With ... EGFR-targeted therapies have improved outcomes in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations, such as EGFR ex19del and L858R; ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0928098725003355

The Fourth-Generation EGFR Tyrosine Kinase Inhibitor ... Our findings reveal that BLU-945 stimulates the ATPase activity of ABCG2, indicating direct interaction as a potential substrate or modulator.

5. pubs.acs.org pubs.acs.org/doi/10.1021/acs.jmedchem.2c00704

Discovery of BLU-945, a Reversible, Potent, and Wild-Type ... A first-in-human, phase 1 dose escalation study is currently underway with BLU-945 in patients with EGFR-mutated NSCLC who have previously ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11497503/

BLU-945, a potent and selective next-generation EGFR TKI ... BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer.

7. medchemexpress.com medchemexpress.com/blu-945.html?srsltid=AfmBOopFxwJF4qT2ld0ZC14hCmMTdDBrVQlN9tBsGZtA8HioZ9js5EBR

BLU-945 (ZL-2313) | EGFR Inhibitor BLU-945 can be used for the research of lung cancer including non-small cell lung cancer (NSCLC). For research use only. We do not sell to patients. BLU-945 ...

8. blueprintmedicines.com blueprintmedicines.com/wp-content/uploads/2023/06/Blueprint-Medicines-ASCO-2023-BLU-945-EGFRmNSCLC-Monotherapy-Combination-Osimertinib-Short-Oral.pdf

BLU-945 monotherapy and in combination with osimertinib ... aPatients with EGFR-mutant positive NSCLC were enrolled based on local mutation assessment of tumor biopsy or blood ctDNA with a follow-up central ctDNA ...