The RTOG 3507, also known as the ‘KEYSTROKE’ trial, is a currently active RTOG Foundation protocol that will be accessing the safety of the combination of pembrolizumab and re-irradiation with stereotactic body radiotherapy (SBRT) for patients with recurrent or new secondary primary head and neck squamous cell carcinoma (Safety-run in). Following the safety run-in for this study, RTOG 3507 will compare progression free survival for patients with receiving SBRT re-irradiation with or without pembrolizumab.

Interview with Stuart Wong, MD, of the Medical College of Wisconsin and Principal Investigator of RTOG 3507

Q: Can you provide an overview of the study in your own words?

A: KEYSTROKE tests the hypothesis that re-irradiation with stereotactic body radiation therapy (SBRT) plus pembrolizumab is a safe and effective form of therapy for well-selected patients who have limited cancer recurrence or new primary in a previously irradiated field. Patients will receive five doses of radiation over a two-week period with or without the immune checkpoint inhibitor, pembrolizumab, that is administered during and after SBRT. The primary endpoint of the study is progression free survival. The study is over halfway through its targeted accrual goal (102 patients).

Q: What is the significance of this study? Does this study have the potential to change practice?

A: RTOG has an excellent track record of completing groundbreaking studies of re-irradiation in head and neck cancer with RTOG 96-10 and RTOG 99-11. The success of these studies has ushered in an era where re-irradiation has been integrated into routine clinical practice. Smaller studies have shown that SBRT may be an effective treatment for some head and neck patients who experience locoregional recurrence or new second primary tumors in a previously irradiated field. Other evidence indicates that SBRT, compared to conventional radiation, may have less damaging effects on the tumor microenvironment. The result is potentially a more permissive environment to allow an immune checkpoint inhibitor to elicit a more robust immune-mediated anti-tumor response. A positive result of RTOG Foundation 3507 may indeed have practice changing implications.

Q: What are the most common questions you expect to receive about this study and how would you address them?

A: Frequent questions center around alternative approaches to re-irradiation in this population. The first issue regards the alternative approach of systemic therapy (pembrolizumab alone or chemotherapy plus pembrolizumab). It is important to appreciate that systemic therapy benefits only a minority of patients. While the outcome of these patients is favorable, those patients who do not respond may suffer many ill consequences particularly related to failure of local disease control. This is why many clinicians favor re-irradiation over systemic therapy when it is available. Another common question regards surgery. Surgical salvage for a local recurrence is sometimes attempted as a heroic measure. However, failure to achieve clear margins, leaving gross disease behind, may be detrimental to patient outcome. Again, many experienced clinicians would favor a re-irradiation approach in this scenario. We encourage physicians to consider clinical trial options, including RTOGF 3507, for these patients.

Q: Is there anything else researchers should know about this study?

A: A best practice for difficult situations, such as a patient with local disease recurrence or new second primary in a previously irradiated field, is multidisciplinary tumor board discussion. Patient referral should be considered in situations where additional expert opinion is warranted. Treatment on a clinical trial therapy, such as RTOG Foundation 3507, should be considered to offer patients the full range of options, to advance scientific knowledge, and to improve the care of future patients.

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