Triple Drug Therapy for Non-Small Cell Lung Cancer

Overseen By Selina Laqui, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jonathan Riess

Must not be taking: Strong CYP2C8 inhibitors

Disqualifiers: Pneumonitis, Seizures, Thromboembolism, others

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

Compensation: Varies

Number of Visits: 32

Duration: Up to 10 months

36 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on an EGFR-TKI other than osimertinib, it must be stopped at least 7 days before starting the study treatment.

What data supports the effectiveness of the drug combination for treating non-small cell lung cancer?

Research shows that adding cetuximab to chemotherapy significantly improves overall survival in patients with advanced non-small cell lung cancer compared to chemotherapy alone. Cetuximab, when combined with chemotherapy, has shown response rates ranging from 29% to 53% in untreated metastatic cases, and a 28% response rate in recurrent cases, which is higher than typical rates with chemotherapy alone. ^{1 2 3 4 5}

Is the triple drug therapy for non-small cell lung cancer safe?

Cetuximab, one of the drugs in the therapy, has been associated with side effects like skin rash, diarrhea, nausea, vomiting, and fatigue, but severe cases are rare. Safety data from studies on cetuximab in other cancers, like colorectal cancer, also show similar side effects, indicating it is generally safe for use in humans with manageable side effects. ^{1 6 7 8 9}

What makes the triple drug therapy of Cetuximab, Osimertinib, and Tucatinib unique for non-small cell lung cancer?

This triple drug therapy is unique because it combines Cetuximab, which targets the epidermal growth factor receptor (EGFR) to inhibit tumor growth, with Osimertinib and Tucatinib, which are known for their effectiveness in targeting specific cancer pathways. This combination aims to improve response rates and progression-free survival in non-small cell lung cancer, offering a novel approach compared to traditional treatments. ^{3 5 10 11 12}

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of osimertinib, cetuximab, and tucatinib in treating patients with EFGR-mutant non-small cell lung cancer that is stage IV or has come back (recurrent). Osimertinib and tucatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is a chimeric human/mouse IgG1 monoclonal antibody that targets epidermal growth factor receptor (EGFR), a receptor overexpressed in many types of cancer, and may interfere with the ability of tumor cells to grow and spread. Giving osimertinib, cetuximab, and tucatinib may work better in treating patients with non-small cell lung cancer.

Research Team

Jonathan W. Riess

Principal Investigator

University of California, Davis

Eligibility Criteria

Adults (18+) with stage IV or recurrent non-small cell lung cancer and specific EGFR mutations, who've seen their disease progress on osimertinib. They should be in good physical condition (ECOG 0-1), have a life expectancy over 3 months, stable brain metastases if any, and meet certain blood/heart health criteria. Pregnant women and those with recent thrombosis, uncontrolled heart conditions, severe infections or allergies to trial drugs are excluded.

Inclusion Criteria

Ability to adhere to the study visit schedule and protocol requirements

Your blood and other body chemistry levels must be within certain limits.

Ability to swallow pills

Exclusion Criteria

Any condition that would prohibit the understanding or rendering of informed consent

Any condition that in the opinion of the investigator would interfere with the participant's safety or compliance while on trial

My doctor suspects or has confirmed I have cancer in the lining of my brain or spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tucatinib, osimertinib, and cetuximab in 28-day cycles

Up to 10 months

IV administration every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Follow-up at 30 days and every 12 weeks

Treatment Details

Interventions

• Cetuximab
• Osimertinib
• Tucatinib

Trial Overview The safety and optimal dosages of osimertinib, cetuximab, and tucatinib are being tested for treating advanced non-small cell lung cancer with EGFR mutations. This phase I trial aims to see if combining these drugs is more effective than current treatments by blocking tumor growth enzymes.

Participant Groups

Group I: Treatment (tucatinib, osimertinib, cetuximab) Experimental Treatment 3 Interventions

Patients receive tucatinib 200mg orally BID, osimertinib 80mg orally daily, and cetuximab 250mg/m\^2 IV every 2 weeks of a 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

Jonathan Riess

Lead Sponsor

Trials

2

Recruited

50+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor, which plays a crucial role in the growth of various cancers.

It received accelerated approval from the US FDA in February 2004 for treating metastatic colorectal cancer based on positive tumor response rates observed in Phase II clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab. Goldberg, RM.[2020]

In a study involving 65 patients with advanced colorectal cancer who had previously been treated with multiple therapies, the combination of cetuximab and irinotecan showed a response rate of 20% and a median overall survival of 10.4 months, confirming the efficacy of this treatment regimen.

The treatment was associated with low rates of severe toxicity, with only 8% experiencing grade 3 skin toxicity, indicating that cetuximab and irinotecan can be a safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Pfeiffer, P., Nielsen, D., Yilmaz, M., et al.[2018]

In a phase II study involving 53 patients with advanced non-small cell lung cancer, the combination of cetuximab, paclitaxel, and carboplatin resulted in a response rate of 57%, indicating significant clinical activity.

The treatment was well tolerated with manageable toxicities, including rash and neutropenia, and no grade 5 toxicities reported, suggesting a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017. Borghaei, H., Langer, CJ., Millenson, M., et al.[2018]

In a study of 57 patients with advanced non-small cell lung cancer (NSCLC), gefitinib and erlotinib showed significantly better progression-free survival (PFS) and overall survival (OS) compared to pemetrexed, with median PFS of 3.5 and 4.4 months versus 1.7 months for pemetrexed.

Both gefitinib and erlotinib had comparable efficacy and manageable safety profiles, indicating they may be more effective treatment options for certain patient subgroups, particularly those with non-squamous histology, males, and a smoking history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer. Hong, J., Kyung, SY., Lee, SP., et al.[2021]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Chemotherapy with cetuximab or chemotherapy alone for untreated advanced non-small-cell lung cancer: a systematic review and meta-analysis. [2018]

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

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Three emerging new drugs for NSCLC: pemetrexed, bortezomib, and cetuximab. [2022]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC). [2019]

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

Cetuximab in advanced non-small cell lung cancer. [2018]

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

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. [2022]

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

Cetuximab. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. [2018]

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

First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy: a subgroup analysis of data from the FLEX phase 3 study. [2022]

10. Greece pubmed.ncbi.nlm.nih.gov

The need for third-line treatment in non-small cell lung cancer: an overview of new options. [2018]

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

Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017. [2018]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer. [2021]