Trametinib + Pembrolizumab for Lung Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Anti-PD-1, Anti-PD-L1

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active infection, Autoimmune, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 33

Duration: Up to 2 years

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase Ib/II trial studies the side effects and best dose of trametinib when given together with pembrolizumab and to see how well they work in treating patients with non-small cell lung cancer that has come back and spread to other places in the body, cannot be removed by surgery, or spread to nearby tissues or lymph nodes. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving trametinib and pembrolizumab may work better in treating patients with non-small cell lung cancer.

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 medications that can prolong the QT interval (a measure of heart rhythm), you may need to stop or switch them before starting the trial.

Is the combination of Trametinib and Pembrolizumab safe for humans?

Pembrolizumab (also known as Keytruda) has been used in various cancer treatments and is generally considered safe, but it can cause side effects like fatigue, cough, nausea, and more serious immune-related issues like pneumonitis (lung inflammation). Trametinib, when combined with Pembrolizumab, has been studied for safety in certain cancers, and while it shows promise, it can also lead to side effects, so monitoring by healthcare professionals is important. ^{1 2 3 4 5}

How is the drug combination of Trametinib and Pembrolizumab unique for lung cancer treatment?

The combination of Trametinib and Pembrolizumab is unique because it combines a MEK inhibitor (Trametinib) with an immune checkpoint inhibitor (Pembrolizumab), potentially enhancing the immune system's ability to fight lung cancer by targeting different pathways. This approach is novel compared to standard treatments that typically focus on a single mechanism. ^{1 2 4 6 7}

What data supports the effectiveness of the drug pembrolizumab for lung cancer?

Research shows that pembrolizumab, a drug that helps the immune system fight cancer, has improved survival in patients with advanced non-small cell lung cancer. It is approved for use in certain lung cancer cases and has shown positive results in early trials. ^{1 2 7 8 9}

Who Is on the Research Team?

Ferdinandos Skoulidis, MD,PHD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with non-small cell lung cancer that has spread, can't be surgically removed, or has returned after treatment. Participants must have had disease progression within 12 weeks of prior immunotherapy, be in good physical condition (ECOG 0-1), and have adequate organ function. They should not be pregnant or breastfeeding and must agree to use contraception. People who've received certain treatments recently or have specific health conditions like active hepatitis B/C, brain metastases, or uncontrolled heart issues cannot join.

Inclusion Criteria

I have had specific immune therapy and my cancer did not respond well.

My kidney function, measured by creatinine, is within the normal range.

My NSCLC is advanced, cannot be surgically removed, and has been treated before.

Exclusion Criteria

I haven't had monoclonal antibody therapy in the last 4 weeks or have recovered from its side effects.

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the study, or in the opinion of the investigator, is not in the best interest of the subject to participate

Has known psychiatric or substance abuse disorders that could interfere with cooperation with the requirements of the protocol

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive trametinib orally once daily 14 days prior to cycle 1 and days 1-10 of each course. Beginning in cycle 2, participants also receive pembrolizumab intravenously on day 1. Cycles repeat every 3 weeks for up to 2 years.

Up to 2 years

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

30 days post-treatment, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Trametinib

Trial Overview The trial is testing the combination of two drugs: Trametinib and Pembrolizumab. Trametinib blocks enzymes needed for tumor growth while Pembrolizumab boosts the immune system's ability to fight cancer. The study aims to determine the best dose and effectiveness of this drug combo in treating advanced stages of non-small cell lung cancer.

How Is the Trial Designed?

Group I: Treatment (trametinib, pembrolizumab) Experimental Treatment 3 Interventions

Patients receive trametinib PO QD 14 days prior to cycle 1 and days 1-10 of each course (10 days on, 11 days off). Beginning in cycle 2, participants also receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a Phase 2 study involving 35 patients with non-small cell lung cancer, neoadjuvant pembrolizumab was found to be safe and well tolerated, with only one surgery delay due to thyroiditis and no mortality within 90 days post-surgery.

The study showed a high rate of R0 resection (88%) and a major pathologic response in 28% of patients, indicating that pembrolizumab may be more effective than standard neoadjuvant chemotherapy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. Tong, BC., Gu, L., Wang, X., et al.[2022]

In a study involving 1033 patients with advanced non-small-cell lung cancer (NSCLC), pembrolizumab significantly improved overall survival compared to docetaxel, with a hazard ratio of 0.66, indicating a 34% reduction in the risk of death.

The effectiveness of pembrolizumab was consistent across both archival and newly collected tumor samples, with better outcomes observed in patients with higher PD-L1 expression (TPS ≥50%), showing hazard ratios of 0.64 and 0.40 for overall survival, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial. Herbst, RS., Baas, P., Perez-Gracia, JL., et al.[2023]

In a study involving 1,453 patients with advanced melanoma and non-small cell lung cancer (NSCLC), pembrolizumab showed no dependency on dosage for overall survival, indicating that varying doses (2 to 10 mg/kg) did not significantly affect patient outcomes.

A strong association was found between the baseline clearance (CL0) of pembrolizumab and overall survival, suggesting that higher clearance rates may indicate more severe disease, rather than affecting the drug's efficacy directly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Turner, DC., Kondic, AG., Anderson, KM., et al.[2019]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

Citations

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

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. [2022]

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

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial. [2023]

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

Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. [2022]

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

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]