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.