SBRT + Pembrolizumab for Head and Neck Cancer

(KEYSTROKE Trial)

Recruiting at 19 trial locations

Overseen By Stuart J. Wong, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: RTOG Foundation, Inc.

Must not be taking: Immunosuppressants, Steroids, Checkpoint inhibitors

Disqualifiers: Distant metastases, Active autoimmune, Hepatitis, 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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 2 years

102 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of treatments to determine if they can better control head and neck cancer. It combines Stereotactic Body Radiation Therapy, a precise form of radiation, with pembrolizumab, a drug that helps the immune system fight cancer. The goal is to help patients live longer without their cancer worsening. Individuals with recurrent or new head and neck cancer who cannot undergo surgery might be suitable for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on systemic steroids or immunosuppressive therapy, or if you have had prior therapy with a checkpoint inhibitor. It's best to discuss your specific medications with the study team.

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

Studies have shown that Stereotactic Body Radiation Therapy (SBRT) is generally easy for patients to handle. Most studies report serious side effects in less than 10% of patients, indicating that the treatment doesn’t cause major issues for most people. However, some patients might still experience side effects, so discussing these with a doctor is important.

Research on pembrolizumab, a type of immunotherapy, also shows it is well-tolerated. In studies involving head and neck cancer, no new safety concerns emerged, suggesting that pembrolizumab is relatively safe. However, like any treatment, it can still cause side effects, so regular check-ups with a healthcare provider are important.

Both SBRT and pembrolizumab aim to treat cancer with minimal side effects. For those considering joining a trial, these treatments have a good safety record based on past research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for head and neck cancer because they combine precision and immunotherapy in a novel way. Stereotactic Body Radiation Therapy (SBRT) delivers targeted, high-dose radiation over a short period, potentially minimizing damage to surrounding healthy tissues compared to traditional radiation therapy. The addition of pembrolizumab, an immunotherapy drug, aims to enhance the body's immune response to cancer by blocking the PD-1 pathway, which can help the immune system recognize and attack cancer cells more effectively. This combination could offer a more effective and less invasive option compared to standard treatments like conventional chemotherapy and radiation.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

Research has shown that Stereotactic Body Radiation Therapy (SBRT) can effectively treat head and neck cancer. Studies indicate that about 70% of patients receiving SBRT survive for at least two years. Additionally, patients receiving higher doses of SBRT tend to have better survival rates. In this trial, some participants will receive SBRT alone, while others will receive SBRT followed by pembrolizumab.

Pembrolizumab, a type of immune therapy, has also shown promise. It can improve survival rates in patients with head and neck cancer, especially when combined with other treatments. For example, one study found that pembrolizumab significantly extended survival when combined with chemotherapy. Together, these treatments have the potential to improve outcomes for people with head and neck cancer. ^{1 5 6 7 8}

Who Is on the Research Team?

Stuart J. Wong, MD

Principal Investigator

RTOG Foundation

Are You a Good Fit for This Trial?

This trial is for adults with a confirmed diagnosis of head and neck squamous cell carcinoma that has come back or is a new second primary. It's not for those who can be cured by surgery without high risk, have distant metastases, recent other cancer treatments, immune deficiencies, certain heart conditions within the last 6 months, active infections needing IV antibiotics, pregnant or breastfeeding women, or those unwilling to use contraception.

Inclusion Criteria

Contrast enhanced CT or MRI of the tumor and neck within 56 days prior to entry

Chest CT scan or full body PET/CT within 56 days prior to entry

I have been mostly active and able to carry on all pre-disease activities without restriction recently.

Exclusion Criteria

I have had or currently have lung inflammation treated with steroids.

I had a major heart attack in the last 6 months.

I haven't been hospitalized for lung problems in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In

Evaluate the safety of pembrolizumab with SBRT for recurrent or new second primary HNSCC

2 weeks

1 visit (in-person)

Treatment

Patients receive SBRT over 2 weeks and pembrolizumab every 3 weeks for up to 2 years

2 years

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Every 6 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Stereotactic Body Radiation Therapy (SBRT)

Trial Overview The study tests if adding Pembrolizumab (an immunotherapy drug) to Stereotactic Body Radiation Therapy improves progression-free survival in patients with recurrent or new head and neck cancer. The phase II trial includes an initial safety review before fully proceeding.

How Is the Trial Designed?

Group I: Arm II Experimental Treatment 1 Intervention

Patients receive Stereotactic Body Radiation Therapy (SBRT) over 2 weeks. Arm II patients who experience progressive disease within 2 years after the start of SBRT will be allowed to cross over to receive pembrolizumab for up to 2 years.

Group II: Arm I Experimental Treatment 2 Interventions

Patients receive Stereotactic Body Radiation Therapy (SBRT) over 2 weeks and then receive pembrolizumab every 3 weeks for up to 2 years.

Stereotactic Body Radiation Therapy (SBRT) is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Stereotactic Body Radiation Therapy for:

• Prostate cancer
• Lung cancer
• Liver cancer
• Pancreatic cancer
• Spinal tumors

Approved in European Union as Stereotactic Body Radiation Therapy for:

• Prostate cancer
• Lung cancer
• Liver cancer
• Pancreatic cancer
• Spinal tumors

Approved in Canada as Stereotactic Body Radiation Therapy for:

• Prostate cancer
• Lung cancer
• Liver cancer
• Pancreatic cancer
• Spinal tumors

Approved in Japan as Stereotactic Body Radiation Therapy for:

• Prostate cancer
• Lung cancer
• Liver cancer
• Pancreatic cancer
• Spinal tumors

Who Is Running the Clinical Trial?

RTOG Foundation, Inc.

Lead Sponsor

Trials

7

Recruited

1,500+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a phase I study involving 79 patients with metastatic solid tumors, multisite stereotactic body radiotherapy (SBRT) combined with pembrolizumab was found to be well tolerated, with acceptable levels of toxicity and no need for radiation dose reductions despite some patients experiencing dose-limiting toxicities.

The study showed a 13.2% overall objective response rate and a median overall survival of 9.6 months, suggesting that while the combination treatment is safe, further research is needed to explore its clinical benefits and identify predictive biomarkers for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. Luke, JJ., Lemons, JM., Karrison, TG., et al.[2022]

In a study of 139 patients with recurrent and metastatic head and neck squamous cell carcinoma, pembrolizumab monotherapy showed similar long-term survival rates compared to combination therapy with chemotherapy, with 2-year progression-free survival at 28.6% and overall survival at 41.8%.

Patients receiving pembrolizumab monotherapy who experienced adverse events had a better prognosis than those without adverse events, suggesting that monotherapy may be a safer and more effective long-term treatment option compared to combination therapy, which did not improve prognosis and could lead to more side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Monotherapy Versus Pembrolizumab Plus Chemotherapy in Patients With Head and Neck Squamous Cell Carcinoma. Matsuo, M., Masuda, M., Yamauchi, M., et al.[2023]

Stereotactic body radiation therapy (SBRT) is a promising treatment for patients with recurrent head and neck cancer, offering a favorable response and lower toxicity compared to other salvage options, making it suitable for those with significant comorbidities.

While SBRT carries a risk of severe toxicity, such as carotid blowout syndrome, this risk can be reduced with specific treatment schedules, and ongoing studies are exploring its combination with novel therapies like cetuximab and immune checkpoint inhibitors for enhanced effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic Body Radiation Therapy for Recurrent Head and Neck Cancer. Ling, DC., Vargo, JA., Heron, DE.[2018]

In a study of 646 adults with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), real-world outcomes showed that pembrolizumab, whether used alone or with chemotherapy, provided similar overall survival rates to those seen in clinical trials, with median overall survival of 12.1 months for monotherapy and 11.9 months for combination therapy.

Factors such as HPV-positive tumor status and lower Eastern Cooperative Oncology Group performance status were associated with longer overall survival, highlighting the importance of tumor characteristics in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world treatment patterns and outcomes among individuals receiving first-line pembrolizumab therapy for recurrent/metastatic head and neck squamous cell carcinoma. Black, CM., Hanna, GJ., Wang, L., et al.[2023]

Stereotactic body radiotherapy (SBRT) at doses up to 44 Gy was found to be safe for previously irradiated patients with squamous cell carcinoma of the head and neck, with no severe toxicities reported and only mild acute side effects in four patients.

The treatment showed a 17% objective response rate, with some patients experiencing stable disease for up to 4 months, suggesting that SBRT could be a viable option for reirradiation in this patient population, warranting further studies alongside other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: results of a phase I dose-escalation trial. Heron, DE., Ferris, RL., Karamouzis, M., et al.[2022]

In a study of 66 patients with recurrent and metastatic head and neck squamous cell carcinoma treated with pembrolizumab, the one-year overall survival rate was 69.4%, indicating the regimen's effectiveness as a first-line therapy.

The depth of response (DpR) was found to be a significant predictor of survival outcomes, with a greater tumor reduction (≥-45%) correlating with improved overall survival and progression-free survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depth of response may predict clinical outcome in patients with recurrent/metastatic head and neck cancer treated with pembrolizumab-containing regimens. Saijo, K., Imai, H., Ouchi, K., et al.[2023]

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

The combination of stereotactic body radiation therapy (SBRT) with the anti-PD-1 drug nivolumab was found to be safe and did not delay surgery in 21 patients with advanced head and neck cancer, meeting the primary safety endpoint of the study.

This treatment approach resulted in a high major pathological response (mPR) rate of 86% and a pathological complete response (pCR) rate of 67%, indicating that adding SBRT may enhance the effectiveness of immunotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma. Leidner, R., Crittenden, M., Young, K., et al.[2022]

The Phase III trial KEYNOTE-412 is designed to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, when used alongside chemoradiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Previous Phase Ib studies have indicated that combining pembrolizumab with CRT is safe and feasible, supporting its potential use in this larger trial to improve treatment outcomes for patients with locally advanced HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Machiels, JP., Tao, Y., Burtness, B., et al.[2021]

A 69-year-old patient with relapsed squamous cell carcinoma showed significant improvement after 14 cycles of pembrolizumab, indicating its efficacy as a second-line treatment for metastatic head and neck cancer.

The patient developed severe immune-related adverse effects, specifically grade 4 mucositis and esophagitis, highlighting the importance of monitoring for such complications in patients receiving PD-1 inhibitors like pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab. Acero Brand, FZ., Suter, N., Adam, JP., et al.[2019]

In a study of 68 patients with advanced solid tumors, the combination of stereotactic body radiotherapy (SBRT) followed by pembrolizumab showed a high one-year treated metastasis control rate of 89.5%, indicating effective tumor response regardless of whether the tumors received complete or partial radiation coverage.

The study found that treated metastasis control (TMC) was significantly associated with improved overall survival, and SBRT altered tumor gene expression by increasing immune-related genes while decreasing those related to cell cycle and DNA repair, suggesting a mechanism for enhanced immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. Luke, JJ., Onderdonk, BE., Bhave, SR., et al.[2021]

In a phase III trial, pembrolizumab, a single-agent treatment, showed significant effectiveness in patients with head and neck tumors that had high PD-L1 expression, leading to deep and lasting responses.

This study highlights the potential of pembrolizumab as a first-line therapy for this specific group of cancer patients, suggesting a targeted approach based on PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembro Ups Survival in PD-L1-positive HNSCC. [2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11694497/

Real-World Evidence on the Effectiveness of Pembrolizumab ... The study showed some beneficial effects of pembrolizumab monotherapy in recurrent/metastatic/unresectable HNSCC patients in real-world scenarios.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2415434

Neoadjuvant and Adjuvant Pembrolizumab in Locally ... The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02508

Updated Results of the Phase III KEYNOTE-048 Study Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02252042

Study Details | NCT02252042 | Pembrolizumab (MK-3475) ... The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.

5. merck.com merck.com/news/mercks-keytruda-pembrolizumab-significantly-improved-overall-survival-compared-to-standard-of-care-as-monotherapy-and-in-combination-with-chemotherapy-as-first-line-treatment-for-patients/

Merck's KEYTRUDA (pembrolizumab) Significantly ... “In this study, KEYTRUDA showed the potential to significantly prolong survival when used as first-line therapy for patients whose head and neck cancer had ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02252042?tab=results

Study Results | Pembrolizumab (MK-3475) Versus ... Serious AEs and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, ...

7. merck.com merck.com/news/keytruda-pembrolizumab-as-perioperative-treatment-with-standard-of-care-soc-adjuvant-therapy-significantly-improved-event-free-survival-compared-to-soc-alone-in-patients-with-resectable-loca/

KEYTRUDA® (pembrolizumab) as Perioperative Treatment ... Results at the first interim analysis of the trial showed KEYTRUDA significantly improved event-free survival (EFS) as part of a perioperative treatment regimen ...

8. clinicaltrialsarena.com clinicaltrialsarena.com/news/msd-keytruda-combo/

MSD reports outcomes from trial of Keytruda combination ... After a median follow-up at 38.3 months, the therapy had decreased the EFS event risk by 34% in subjects whose combined positive score (CPS) was ...