Trametinib + Pembrolizumab for Lung Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, trametinib (Mekinist) and pembrolizumab (KEYTRUDA or MK-3475), to evaluate their effectiveness against recurrent and metastatic non-small cell lung cancer. Trametinib blocks certain enzymes to stop tumor growth, while pembrolizumab enhances the immune system to attack the cancer. The trial aims to determine the optimal dose and identify any side effects. Individuals with metastatic non-small cell lung cancer, who have not responded to previous treatments, may be suitable candidates. As a Phase 1 and Phase 2 trial, it seeks to understand how the treatment works in participants and measure its effectiveness in an initial, smaller group.

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

Research has shown that combining trametinib and pembrolizumab can lead to more side effects than using pembrolizumab alone. Patients might experience side effects ranging from mild to serious.

Pembrolizumab helps the immune system fight cancer, while trametinib inhibits enzymes that promote cancer growth. Although this combination can be effective, it also raises the likelihood of side effects.

Patients considering a clinical trial with these treatments should discuss the potential risks with their doctors. This conversation can help them decide if participation is right for them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using trametinib and pembrolizumab together for lung cancer because they combine two different mechanisms to tackle the disease. Trametinib targets a specific pathway that helps cancer cells grow, called the MAPK/ERK pathway, while pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells. This combination approach could offer a more powerful treatment than traditional chemotherapy, which attacks all rapidly dividing cells and can cause significant side effects. By precisely targeting cancer growth and boosting the immune response, this therapy has the potential to improve outcomes for patients with lung cancer.

What evidence suggests that trametinib and pembrolizumab might be effective for non-small cell lung cancer?

This trial will evaluate the combination of trametinib and pembrolizumab for treating non-small cell lung cancer (NSCLC). Studies have shown that this combination has some effect in treating NSCLC. Trametinib stops certain proteins that help cancer cells grow, while pembrolizumab boosts the immune system to fight cancer cells. Some research suggests that this combination might work better in cancers with many mutations, like NSCLC. However, using both drugs together may cause more side effects than using pembrolizumab alone. Overall, while this treatment shows promise, its effectiveness can vary and it may have some risks. ^{1 2 3 5 6}

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

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]

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]

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]

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]

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]

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 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]

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S2666364325000220

A Phase 1/1B Trial of Pembrolizumab and Trametinib in ... The activity of trametinib and pembrolizumab is modest in NSCLC with increased toxicity compared with programmed death ligand 1 blockade alone.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03299088

Study Details | NCT03299088 | Pembrolizumab and ... This phase Ib trial studies the side effects of pembrolizumab and trametinib in treating patients with non-small cell lung cancer and KRAS gene mutations ...

3. merck.com merck.com/news/new-data-for-keytruda-pembrolizumab-in-combination-with-talimogene-laherparepvec-dabrafenib-plus-trametinib-or-low-dose-ipilimumab-in-advanced-melanoma-presented-at-2016-asco-annual-meeting/

New Data for KEYTRUDA® (pembrolizumab) in ... The six-month progression-free survival (PFS) rate was 70 percent and the six-month overall survival (OS) rate was 93 percent. At the time of analysis, median ...

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/88/NCT03299088/Prot_SAP_000.pdf

A PHASE IB TRIAL OF PEMBROLIZUMAB (MK-3475) AND ... Higher response rates with PD-1 blockade in tumors known to be highly mutated such as melanoma and NSCLC have been noted and we have observed higher responses ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40486486/

A Phase 1/1B Trial of Pembrolizumab and Trametinib in ... Conclusions: The activity of trametinib and pembrolizumab is modest in NSCLC with increased toxicity compared with programmed death ligand 1 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12534342/

The Utility of Tissue-Agnostic Drugs in Lung Cancer ... Lung cancer-specific safety data were not reported. Real-world evidence supports the clinical effectiveness of dabrafenib plus trametinib in ...