KEY POINTS
- This open-label multicenter phase I/II trial enrolled 33 evaluable patients with metastatic HNSCC and 2–10 lesions across three Canadian academic centers; accrual stopped short of the planned 35 patients because of COVID-19. Median age was 63 years, 61% were p16-positive, and the median metastatic burden was 4 lesions.
- Patients received durvalumab 1500 mg every 4 weeks for 12 cycles plus tremelimumab 75 mg every 4 weeks for the first 4 cycles. SBRT was delivered during cycle 2 to 2–5 lesions, with treatment completed before cycle 3; the median SBRT dose was 45 Gy in 3–5 fractions.
- This was not a treatment-naïve population. 48% had received one prior systemic line, 21% two lines and 9% three lines, while 21% had previously received immunotherapy. SBRT targeted all known sites of disease in 19 patients (58%); lung metastases accounted for 61% of irradiated lesions.
- The phase II primary efficacy endpoint was met decisively. Six-month progression-free survival was 72.7% (95% CI 59.0–89.6%), compared with the protocol-defined 27% threshold considered sufficient to justify further study. Median progression-free survival was 12.8 months (95% CI 7.17–27.2), with 54.5% remaining progression-free at 12 months.
- Survival was also encouraging for this selected metastatic population: median overall survival reached 28.4 months (95% CI 22.9–38.9), with overall survival of 93.9% at 6 months and 72.7% at 12 months. Higher PD-L1 CPS was associated with longer progression-free survival (p=0.0495), while p16 status, prior immunotherapy, number of previous systemic lines and baseline metastatic burden were not significantly associated with PFS.
- Local control after SBRT was high among the 30 evaluable treated patients, reaching 96.7% at 6 months and 89.3% at 12 months. Among 14 patients with measurable disease outside the SBRT field, 23% achieved complete response and 54% partial response, giving an out-of-field response rate of 77%.
- Safety was generally consistent with dual checkpoint blockade, but one important late event occurred. Seven patients (21%) experienced grade 3–4 adverse events attributed to durvalumab/tremelimumab, and six permanently discontinued immunotherapy for toxicity. There were no grade 3–5 events attributed to the triple combination itself, but one grade 5 soft-tissue radionecrosis occurred nine months after SBRT to previously irradiated head-and-neck mucosa.
CLINICAL TAKEAWAY
The combination produced an unusually strong progression-free survival and local-control signal in carefully selected patients with oligometastatic HNSCC, including many who had already received systemic therapy. However, this is a 33-patient single-arm study: it cannot determine how much benefit came from metastasis-directed SBRT, dual checkpoint inhibition, patient selection, or true radio-immunotherapy synergy.
SOURCE
International Journal of Radiation Oncology, Biology, Physics