Genomic Testing-Based Targeted Therapy for Cancer

Overseen By RACHEL MILLER, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Rachel Miller

Must not be taking: Chemotherapy, Radiotherapy

Disqualifiers: Pregnancy, Uncontrolled illness, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

93 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a substudy (Part 2) of a larger two-part clinical trial including both observational and therapeutic (interventional) cohorts to assess the progression free survival ratio of patients treated with a targeted therapy based on genomic analysis results and recommendation by the Markey Cancer Center Molecular Tumor Board (MCC MTB).

Do I have to stop taking my current medications to join the trial?

The protocol does not specify if you must stop taking your current medications. However, you cannot have had chemotherapy or radiotherapy within 3 weeks before joining the study, and HIV patients must be on a stable dose of antiretroviral therapy for at least 1 month prior to registration.

What data supports the idea that Genomic Testing-Based Targeted Therapy for Cancer (also known as: Therapeutic Intervention, Keytruda, MK-3475, lambrolizumab) is an effective treatment?

The available research shows that Keytruda, a drug used in Genomic Testing-Based Targeted Therapy for Cancer, is effective in treating certain types of cancer. For example, in patients with metastatic non-small cell lung cancer, those treated with Keytruda lived longer and had a longer period without the disease getting worse compared to those who received chemotherapy. Specifically, in one study, patients who had not been treated before and received Keytruda had a 40% lower risk of death compared to those on chemotherapy. Another study showed that patients who had already tried other treatments and then received Keytruda had a 29% lower risk of death compared to those on chemotherapy. This data supports the effectiveness of Keytruda in treating certain cancers. ^{1 2 3 4 5}

What safety data is available for pembrolizumab (Keytruda)?

Pembrolizumab, also known as Keytruda, MK-3475, or lambrolizumab, has been evaluated in various clinical trials for different types of cancer, including melanoma and non-small cell lung cancer (NSCLC). Safety data from these trials indicate that common adverse reactions include fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders have also been reported. Despite these risks, the benefits of pembrolizumab, such as improved overall survival and progression-free survival, have been deemed to outweigh the potential adverse effects in life-threatening conditions. ^{1 2 6 7 8}

Is the drug Keytruda a promising treatment for cancer?

Yes, Keytruda is a promising drug for cancer treatment because genomic testing helps match it to specific cancer types, improving treatment success. ^{9 10 11 12 13}

Research Team

Rachel Miller, M.D.

Principal Investigator

University of Kentucky

Eligibility Criteria

Adults (18+) with solid or blood cancers, who've had genetic testing on their tumors and failed first-line therapy, can join this trial. They must be able to sign consent and have measurable disease. Excluded are pregnant women, HIV patients not stable on antiretroviral therapy, those with uncontrolled illnesses or recent chemo/radiotherapy.

Inclusion Criteria

My first treatment didn’t work or there are no treatments that can cure my disease.

My cancer can be measured by tests or seen on scans.

I have completed treatment for brain metastasis and am not on increasing doses of steroids.

Exclusion Criteria

I haven't had chemotherapy or radiotherapy in the last 3 weeks, or 6 weeks for specific drugs, and have recovered from any side effects.

I do not have any severe illnesses that my doctor thinks could interfere with the treatment.

I am HIV positive with a CD4 count above 500 and on stable antiretroviral therapy for over a month.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive targeted therapies based on genomic analysis results as recommended by the MCC MTB

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Therapeutic Intervention

Trial Overview The study tests targeted therapies chosen based on tumor genetic analysis by the Markey Cancer Center Molecular Tumor Board. It aims to see if these treatments improve the time patients live without cancer progression compared to previous therapies they've tried.

Participant Groups

Group I: Therapeutic Intervention Experimental Treatment 1 Intervention

Therapeutic Intervention

Therapeutic Intervention is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Keytruda for:

• Melanoma
• Lung cancer
• Head and neck cancer
• Hodgkin lymphoma
• Stomach cancer
• Cervical cancer
• Breast cancer

Approved in United States as Keytruda for:

• Melanoma
• Lung cancer
• Head and neck cancer
• Hodgkin lymphoma
• Stomach cancer
• Cervical cancer
• Breast cancer
• Small cell lung cancer
• Gastric or gastroesophageal junction adenocarcinoma

Approved in Japan as Keytruda for:

• Melanoma
• Lung cancer
• Head and neck cancer
• Hodgkin lymphoma
• Stomach cancer
• Cervical cancer
• Breast cancer

Who Is Running the Clinical Trial?

Rachel Miller

Lead Sponsor

Trials

5

Recruited

770+

Findings from Research

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]

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]

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

Biomarker-driven enrichment clinical trials have led to the development of over 30 targeted anti-cancer drugs with approved companion diagnostics, marking a significant advancement in personalized medicine.

Recent approvals of larotrectinib and pembrolizumab demonstrate a shift towards targeting specific molecular aberrations rather than traditional tumor types, showing efficacy across multiple cancer indications and paving the way for more individualized cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A paradigm shift in biomarker guided oncology drug development. Jørgensen, JT.[2020]

In a study of 73 patients with advanced solid tumors receiving pembrolizumab, ctDNA monitoring was shown to correlate with treatment outcomes, indicating that changes in ctDNA levels can help predict patient survival and clinical benefit from immune checkpoint blockade.

High mutation burden and specific immune signatures were linked to better responses to pembrolizumab, while certain genetic alterations, like B2M loss-of-heterozygosity, were associated with treatment resistance, highlighting the complex relationship between tumor genetics and immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity. Cindy Yang, SY., Lien, SC., Wang, BX., 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) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

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]

Cancer genomic testing offers significant opportunities for improving cancer treatment, but it also presents challenges in identifying key drivers and classifying targets for therapy due to the complexity of cancer genetics.

A proposed target classification approach that prioritizes tumor drivers based on evidence can enhance the effectiveness of genomic testing in clinical practice, improve patient consent processes, and facilitate better comparisons across clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prioritizing targets for precision cancer medicine. Andre, F., Mardis, E., Salm, M., et al.[2022]

Genotype-guided cancer therapy is crucial for personalizing treatment, as it helps to optimize drug exposure and predict potential toxicities, which is especially important given the variability among patients and the narrow therapeutic range of anticancer drugs.

Over a dozen FDA-approved anticancer drugs now include pharmacogenetic biomarkers, and this review emphasizes the need for more prospective clinical trials to enhance the effectiveness of personalized cancer treatments and address existing barriers to their implementation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of genotype-guided cancer therapy in solid tumors. Patel, JN.[2021]

First-generation precision medicine trials like NCI-MATCH have successfully demonstrated the feasibility of large-scale studies on targeted therapies in oncology, but single-agent therapies have had limited success in controlling metastatic cancer.

To improve outcomes, newer second-generation trials such as ComboMATCH, iMATCH, and myeloMATCH are being developed to explore combinations of targeted therapies and standard treatments, addressing the limitations of previous approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The New NCI Precision Medicine Trials. Harris, LN., Blanke, CD., Erba, HP., et al.[2023]

Next-generation sequencing (NGS) is crucial for identifying important biomarkers in cancer patients, but the vast data it generates complicates finding effective drug targets.

Molecular tumor boards (MTB) can effectively identify targetable mutations and facilitate patient access to targeted therapies, as demonstrated by their successful procurement of KRAS G12C inhibitors for two patients before FDA approval.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Tumor Board Case Series: Targeting KRAS G12C in Lung Cancer. Gustafson, B., Douglass, L., Pluard, T., et al.[2023]

Genomically guided targeted therapy has been shown to enhance progression-free survival in patients with metastatic breast cancer who have tumors with specific mutations that respond well to these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor Profiling Improves Breast Cancer PFS. [2022]

References

1. 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]

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

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

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

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. [2019]

4. China pubmed.ncbi.nlm.nih.gov

A paradigm shift in biomarker guided oncology drug development. [2020]

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

Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity. [2022]

6. 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]

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

New Approved Use for Keytruda. [2022]

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

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

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

Prioritizing targets for precision cancer medicine. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Application of genotype-guided cancer therapy in solid tumors. [2021]

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

The New NCI Precision Medicine Trials. [2023]

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

Molecular Tumor Board Case Series: Targeting KRAS G12C in Lung Cancer. [2023]

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

Tumor Profiling Improves Breast Cancer PFS. [2022]