Discussion

Growing body of preclinical studies have demonstrated additional immunomodulatory effects with ionizing radiation which has promoted interest in potential synergy between radiotherapy and immunotherapy in the clinical setting (3). However, there remains an unmet clinical need to identify which patients with recurrent or metastatic HNSCC derive benefit from the combination of radiotherapy and immunotherapy.
In this study we have demonstrated that in a homogenous population of patients with platinum resistant recurrent and metastatic HNSCC treated with nivolumab, radiotherapy is administered in addition in 21% of patients, although radiotherapy and continued nivolumab was only administered in 12%. We describe 2 of 9 (22%) patients who received radio-immunotherapy then continued with nivolumab subsequently in whom durable complete response was seen. One of these patients had oligoprogression and the second had incomplete response so this observation would suggest that there is a signal of meaningful benefit for a sub-set of patients and provides the rationale for prospective studies to define the management of this patient group more clearly.
There are emerging data from prospective studies showing proof of concept that radiation may enhance immunotherapy response in other tumour types normally considered refractory to immune checkpoint blockade such as microsatellite stable colorectal and pancreatic adenocarcinoma (4). However, there are very limited prospective data evaluating radiotherapy alongside nivolumab in recurrent or metastatic HNSCC (5), In a randomized phase 2 trial (6), 62 patients with recurrent or metastatic HNSCC were treated with nivolumab with or without radiotherapy (SBRT) to a single metastatic site. They received 9 Gy ×3 fractions between the first and second doses of nivolumab. This study did not demonstrate any difference in response rates with the addition of SBRT (34.5% for nivolumab vs  29.0% for nivolumab with radiotherapy, p =ns), however other studies are ongoing in recurrent or metastatic HNSCC as well as the locally advanced setting (7).
There are limitations in this study. As all patients were treated at a single cancer centre, there is a high degree of confidence in data presented evaluating the frequency with which concomitant radiotherapy is administered and the clinical outcomes with this treatment. However, single-centre cohort studies will be biased by any variation in practice which would impact on patient selection for the combination of radio-immunotherapy. To further confirm these findings, other multi-centre studies would be valuable. Also, in the current study, the dose of radiotherapy varied between patients and was determined as per standard of care. However defining the optimal dose of radiotherapy and the context of previous irradiation may be critical in determining the immune response (8).
Conclusion
A sub-set of patients receiving radiotherapy-immunotherapy combination in platinum resistant HNSCC derived durable complete response associated with significant clinical benefit. This study highlights the need for a personalised approach in treatment decision making for patients who develop oligoprogression on nivolumab and provides a rationale for prospective clinical studies or registry studies to further address the role for multi-modality therapy in the recurrent or metastatic setting.