Necitumumab + Trastuzumab + Osimertinib for Lung Cancer

Overseen By Karla Russell

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jonsson Comprehensive Cancer Center

Must be taking: Osimertinib

Must not be taking: Investigational anticancer, Combined HER-inhibition

Disqualifiers: Small cell lung cancer, Coronary artery disease, Active infection, others

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

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib/II trial studies the side effects and best dose of trastuzumab and necitumumab together with osimertinib, and to see how well they work for the treatment of stage IV non-small cell lung cancer that is EGFR-mutated, resistant to osimertinib, and has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as trastuzumab and necitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and necitumumab together with osimertinib may work better than osimertinib alone in treating patients with stage IV EGFR-mutated non-small cell lung cancer.

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

The trial does not specify if you need to stop taking your current medications. However, you cannot have had any chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment in the 3 weeks before starting the trial, except for osimertinib. You can continue using hormones for non-cancer-related conditions like insulin for diabetes.

What data supports the effectiveness of the drug combination Necitumumab, Trastuzumab, and Osimertinib for lung cancer?

Osimertinib has been shown to be effective in treating non-small cell lung cancer (NSCLC) with specific genetic mutations, particularly the EGFR T790M mutation, and has received FDA approval for this use. It is known for its strong activity and lower toxicity compared to other treatments. ^{1 2 3 4 5}

Is the combination of Necitumumab, Trastuzumab, and Osimertinib safe for humans?

Osimertinib has been studied for safety in patients with lung cancer, showing common side effects like diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in about 28% of patients, and 5.6% stopped treatment due to these effects. However, specific safety data for the combination with Necitumumab and Trastuzumab is not available. ^{1 6 7 8 9}

What makes the drug combination of Necitumumab, Trastuzumab, and Osimertinib unique for lung cancer?

This drug combination is unique because it combines Necitumumab, a monoclonal antibody targeting the EGFR pathway, with Trastuzumab, another monoclonal antibody, and Osimertinib, a small molecule inhibitor, to potentially enhance treatment effectiveness for lung cancer by targeting multiple pathways involved in cancer growth. ^{10 11 12 13 14}

Research Team

Jonathan W. Goldman

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with stage IV non-small cell lung cancer that has an EGFR mutation and hasn't improved after osimertinib treatment. Participants must be in good physical condition, not planning to conceive, able to take oral medication, and meet specific blood and organ function criteria.

Inclusion Criteria

I am not pregnant and agree to use two effective birth control methods.

My blood counts, kidney, liver functions, and heart are within normal ranges.

I am fully active or can carry out light work.

Exclusion Criteria

I do not have brain metastases, serious health issues, or recent other cancers.

I haven't recently used specific cancer treatments or experimental drugs targeting EGFR/HER.

I do not have allergies to the treatment, heart disease, uncontrolled heart failure, or recent heart attacks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive necitumumab IV over 60 minutes and trastuzumab IV over 30-90 minutes on days 1 and 15, and osimertinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

2 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days, every 8 weeks through week 24, then every 12 weeks up to 1 year.

Up to 1 year

Multiple visits (in-person)

Treatment Details

Interventions

• Necitumumab
• Osimertinib
• Trastuzumab

Trial Overview The study tests the combination of trastuzumab and necitumumab with osimertinib against advanced lung cancer resistant to previous treatments. It aims to find the best dose while assessing how well this combo works compared to osimertinib alone.

Participant Groups

Group I: Treatment (necitumumab, trastuzumab, osimertinib) Experimental Treatment 5 Interventions

Patients receive necitumumab IV over 60 minutes and trastuzumab IV over 30-90 minutes on days 1 and 15. Patients also receive osimertinib 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?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

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 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, an irreversible tyrosine kinase inhibitor, showed excellent activity in treating a 69-year-old man with metastatic EGFR-mutated non-small cell lung cancer, leading to a rapid treatment response despite initial severe pancytopenia.

After experiencing pancytopenia, the patient's dose of osimertinib was reduced from 80 mg to 40 mg daily, which allowed for continued effective treatment without further adverse events, demonstrating the potential for safe dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. Di Marino, P., Chiapperino, C., Primavera, FC., et al.[2022]

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 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 (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]

In a study involving six patients with EGFR-mutated lung adenocarcinoma, the combination of osimertinib and ramucirumab was found to be generally safe, with only one case of dose-limiting toxicity (grade 3 appetite loss) and no other severe adverse events reported.

Five out of six patients showed a partial response to the treatment, with a median progression-free survival of 9.2 months for those with the EGFR T790M mutation, suggesting promising efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. Akamatsu, H., Ozawa, Y., Oyanagi, J., et al.[2023]

In a study of 52 treatment-naïve NSCLC patients with brain metastasis and EGFR mutations, the combination of osimertinib and bevacizumab resulted in a high objective response rate of 75% and a median progression-free survival of 17 months.

The treatment was well-tolerated, with manageable side effects such as mild-to-moderate hand-foot syndrome and hypertension, indicating that this combination therapy could be a promising option for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib combined with bevacizumab as the first-line treatment in non-small cell lung cancer patients with brain metastasis harboring epidermal growth factor receptor mutations. Zhang, L., You, Y., Liu, X., et al.[2023]

In a phase II study involving 167 patients with stage IV squamous non-small-cell lung cancer, the combination of necitumumab with paclitaxel-carboplatin chemotherapy resulted in a higher objective response rate (48.9%) compared to chemotherapy alone (40.0%).

The safety profile of necitumumab was consistent with other EGFR monoclonal antibodies, with increased rates of hypomagnesemia and rash, but overall adverse events were low, indicating that necitumumab can be safely combined with chemotherapy for improved treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Open-Label, Randomized, Controlled Phase II Study of Paclitaxel-Carboplatin Chemotherapy With Necitumumab Versus Paclitaxel-Carboplatin Alone in First-Line Treatment of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer. Spigel, DR., Luft, A., Depenbrock, H., et al.[2022]

In a phase Ib study involving 64 patients with Stage IV non-small cell lung cancer (NSCLC), the combination of necitumumab and pembrolizumab showed a confirmed overall response rate of 23.4%, indicating modest efficacy in this patient population.

The treatment was well-tolerated, with no dose-limiting toxicities reported, and the safety profile was consistent with typical effects of epidermal growth factor receptor inhibitors and immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer. Besse, B., Garrido, P., Cortot, AB., et al.[2021]

References

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

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

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

Osimertinib: First Global Approval. [2022]

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

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. [2022]

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

Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations. [2022]

5. 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]

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

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

8. Greece pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. [2023]

9. Singapore pubmed.ncbi.nlm.nih.gov

Osimertinib combined with bevacizumab as the first-line treatment in non-small cell lung cancer patients with brain metastasis harboring epidermal growth factor receptor mutations. [2023]

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

An Open-Label, Randomized, Controlled Phase II Study of Paclitaxel-Carboplatin Chemotherapy With Necitumumab Versus Paclitaxel-Carboplatin Alone in First-Line Treatment of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer. [2022]

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

Receptor kinase inhibitors target NSCLC: two antibodies and a small-molecule MET inhibitor. [2023]

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

Necitumumab in the treatment of non-small-cell lung cancer: clinical controversies. [2022]

13. Ireland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. [2022]