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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the side effects of combining three drugs—necitumumab, trastuzumab, and osimertinib (Tagrisso)—for treating stage IV non-small cell lung cancer with a specific gene change (EGFR mutation) that resists osimertinib. These drugs may enhance the immune system's ability to fight cancer and inhibit tumor growth. The trial seeks participants with stage IV non-small cell lung cancer who have not responded to osimertinib. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

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.

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

Research has shown that the combination of necitumumab, trastuzumab, and osimertinib is generally well-tolerated by patients. Previous studies indicate that osimertinib is safe for treating certain types of lung cancer, with most side effects being mild and manageable with proper care.

When necitumumab and trastuzumab were added to osimertinib, patients experienced some side effects, but these were usually mild to moderate. Common issues included fatigue and mild skin reactions, which were expected and similar to those seen with other treatments using these drugs.

Overall, this combination treatment appears safe for patients with certain lung cancers. However, monitoring for any side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Necitumumab, Trastuzumab, and Osimertinib for lung cancer because it targets the disease in multiple ways. Necitumumab and Trastuzumab are monoclonal antibodies that attack cancer cells by binding to receptors on their surface, potentially blocking growth signals. In contrast, Osimertinib is a tyrosine kinase inhibitor that works inside the cells to stop cancer growth from within. This multi-pronged approach could be more effective than current standard treatments like chemotherapy and radiation, which often only target cancer cells in one way. By combining these therapies, there is a potential for a more comprehensive attack on the cancer, which is why researchers are hopeful about its effectiveness.

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

Research has shown that a combination of three drugs—necitumumab, trastuzumab, and osimertinib—might treat stage IV EGFR-mutated non-small cell lung cancer more effectively than osimertinib alone. One study demonstrated a 56% reduction in tumor size in a patient with this type of lung cancer after receiving the combination treatment. Patients who received higher doses also showed promising results. In this trial, participants will receive the combination of necitumumab, trastuzumab, and osimertinib. While osimertinib alone has been effective for this type of lung cancer, adding necitumumab and trastuzumab, proteins that help the immune system fight cancer, might enhance its effectiveness. These findings suggest that this combination could be a strong option for patients whose cancer does not respond to current treatments. ^{1 2 3 4 5}

Who Is on the Research Team?

Jonathan W. Goldman

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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, 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]

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]

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 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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.e21165

UCLA l-08: A phase ib/II study of combined HER inhibition ... A phase ib/II study of combined HER inhibition adding necitumumab and trastuzumab to osimertinib in patients with refractory EGFR-mutated lung cancer.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04285671

Study Details | NCT04285671 | Necitumumab and ... Giving trastuzumab and necitumumab together with osimertinib may work better than osimertinib alone in treating patients with stage IV EGFR-mutated non-small ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1556086422004567

MA07.05 Phase 1b/2 Study of Combined HER Inhibition in ... L861Q mutation achieved a partial response (56% tumor shrinkage, ongoing at 5.5 months), and both participants treated at the highest dose level have had a ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40466026/

ORCHARD: Osimertinib Plus Necitumumab in Patients ... Osimertinib plus necitumumab demonstrated modest clinical benefit, and the overall risk-benefit analysis indicates that further evaluation of the regimen is ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9733018/

Therapeutic strategies for EGFR-mutated non-small cell lung ... Clinical data from AURA serial studies suggested that osimertinib was an effective regimen with a manageable safety profile for EGFR-mutant, ...