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\begin{document}

\title{Durable complete response rates following radiotherapy and immunotherapy
combination in recurrent and metastatic head and neck squamous cell
carcinoma: A retrospective single centre cohort study}



\author[1]{Raj Khera}%
\author[2]{Laura Feeney}%
\author[1]{Martin Swinton}%
\author[1]{Sam Rack}%
\author[1]{Andrew Sykes}%
\author[1]{ROBERT METCALF}%
\affil[1]{The Christie NHS Foundation Trust}%
\affil[2]{Queen's University Belfast}%


\vspace{-1em}



  
  \date{June 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Key Points 1. This study reports clinical outcome data on 76 patients
with platinum-resistant recurrent or metastatic head and neck squamous
carcinoma treated with nivolumab, making it the largest published single
centre case series of its kind. 2. Radiotherapy was administered
alongside systemic therapy with nivolumab, defined as radiotherapy
within 8 weeks of prior systemic therapy, in 16 of 76 patients (21\%).
3. Nivolumab was continued following radiotherapy completion due to
ongoing clinical benefit from the drug in 9 of 16 patients (56\%). 4.
Durable complete response following radio-immunotherapy was seen in 2 of
the 9 patients (22\%) who continued nivolumab subsequent to
radiotherapy. 5. Indications for radiotherapy included symptom control
(3 of 9), oligoprogression (5 of 9) and incomplete response (1 of 9).%
\end{abstract}%



\sloppy


Durable complete response rates following radiotherapy and immunotherapy
combination in recurrent and metastatic head and neck squamous cell
carcinoma: A retrospective single centre cohort study



\section*{Key Points}

{\label{key-points}}

\begin{enumerate}
\tightlist
\item
  This study reports clinical outcome data on 76 patients with
  platinum-resistant recurrent or metastatic head and neck squamous
  carcinoma treated with nivolumab, making it the largest published
  single centre case series of its kind.
\item
  Radiotherapy was administered alongside systemic therapy with
  nivolumab, defined as radiotherapy within 8 weeks of prior systemic
  therapy, in 16 of 76 patients (21\%).
\item
  Nivolumab was continued following radiotherapy completion due to
  ongoing clinical benefit from the drug in 9 of 16 patients (56\%).
\item
  Durable complete response following radio-immunotherapy was seen in 2
  of the 9 patients (22\%) who continued nivolumab subsequent to
  radiotherapy.
\item
  Indications for radiotherapy included symptom control (3 of 9),
  oligoprogression (5 of 9) and incomplete response (1 of 9).
\end{enumerate}

\textbf{Key Words}

Head and neck cancer, nivolumab, immunotherapy, radiotherapy.

\section*{Introduction}

{\label{introduction}}

The advent of immune checkpoint inhibition has improved survival for
patients with recurrent or metastatic platinum-resistant head and neck
squamous cell carcinoma (HNSCC). In this setting, nivolumab has shown
significantly improved outcome in comparison to chemotherapy (1).
Evidence from pre-clinical studies suggests the addition of radiotherapy
to immunotherapy may improve disease control (2). However, uncertainty
remains as to whether combination treatment translates to improved
outcomes in this clinical setting of recurrent or metastatic HNSCC.
Currently, the decision to administer radiotherapy alongside systemic
therapy in the palliative setting is made for selected patients on a
case-by-case basis. However, there remains a need to define the
additional clinical benefit of administration of radiotherapy alongside
immunotherapy in this patient group.



\section*{Objectives}

{\label{objectives}}

This study sought to determine the frequency with which radiotherapy was
administered alongside nivolumab in patients with platinum-resistant
recurrent or metastatic HNSCC and define the frequency of durable
complete responses following radio-immunotherapy treatment.



\section*{Method}

{\label{method}}

Design and Setting

This was a retrospective single-centre cohort study, conducted at a
single tertiary cancer centre.

Participants and Outcome Measures

Clinical records of 76 patients with histologically confirmed HNSCC and
confirmed disease progression within six month of prior platinum therapy
were reviewed to identify patient who had received one or more doses of
nivolumab in the recurrent or metastatic setting between February 2018
and August 2020. To determine the frequency with which multi-modality
radio-immunotherapy was administered in this population, radiotherapy
planning records were then reviewed to identify all patients who had
received radiotherapy within 8 weeks of a prior dose of nivolumab. To
determine the outcomes of patients following radio-immunotherapy,
clinical data was reviewed in this subset of patients.

Ethical Considerations

The clinical record review of patients with platinum resistant HNSCC
treated with nivolumab to identify those treated with
radio-immunotherapy was conducted as part of the institutional clinical
audit with the appropriate local institutional approvals. In accordance
with the UK Policy Framework for Health and Social Care Research,
subsequent data analysis was performed on anonymized data without any
patient level identifiable information and no specific consent was
acquired from each patient included in this study. For the inclusion of
anonymized medical photography in the data presentation, individual
patient consent was obtained under the MCRC Biobank Research Tissue Bank
Ethics (NHS NW Research Ethics Committee 18/NW/0092).



\section*{Results}

{\label{results}}

As the primary aim of this study was to determine the outcomes for
patients with HNSCC who received both nivolumab immunotherapy and
radiotherapy, we first identified 76 patients at our institution who had
received nivolumab immunotherapy with a diagnosis of platinum resistant
recurrent or metastatic HNSCC between February 2018 and August 2020.

On review of their radiotherapy planning records, we identified that
among these 76 patients, 16 (21\%) had received radiotherapy within two
months of a prior dose of nivolumab. The clinical characteristics of the
patients who were treated with radiotherapy whilst in receipt of
nivolumab are summarised in Table 1. These patients were predominantly
male (13/16, 81\%), and the median age at diagnosis was 61 (range 48-76
years). Metastatic disease at first presentation was recorded in 19\%
(3/16), the remainder recurred following previous definitive treatment
to localised disease. As primary treatment, 5 (31\%) patients had
surgery, 5 (31\%) had chemoradiotherapy alone and 2 (13\%) had
radiotherapy alone. Recurrent or metastatic disease developed within
less than a year in 5/16 (31\%) patients range 2 to 41 months). 5
patients (31\%) were given nivolumab as second line systemic therapy
following progression within 6 months of prior platinum as part of
multi-modality treatment for localised disease. The remainder received
nivolumab following progression on platinum based chemotherapy
administered in the recurrent or metastatic setting.

The mean duration of nivolumab therapy prior to the initiation of
radiotherapy was 16 weeks (range 0 to 43 weeks). On review of the
systemic therapy records, of the 16 patients who received radiotherapy
within two months of a prior dose of nivolumab, 9 (63\%) received
further nivolumab subsequent to the radiotherapy and the remainder
discontinued nivolumab at that point. The study schematic is shown in
Figure 1.

The sites of disease which were irradiated included neck (7/16), abdomen
(2), spine (3), and chest (1), skull base (1), oral cavity (1) left
maxilla (1). The dose of radiation administered was 8 Gy for 7/16
patients, 20 Gy 5/16, 27.5 Gy 1/16 and 30 Gy for 3/16 patients.

In those that continued with nivolumab subsequent to radiotherapy, two
independent clinicians (A.S. and R.M) reviewed the case records of each
patient to determine the clinical rationale for radiotherapy alongside
nivolumab. For 3/9 patients (33\%) radiotherapy was pre-planned
alongside the start of nivolumab for symptom control. The indications
for symptom control were haemostasis, metastatic cord compression
management and pain control. For 5/9 patients (55\%), radiotherapy was
administered for oligoprogression. For 1/9 patients, radiotherapy was
administered to a patient with a very good partial response to the only
site of persistent disease.

Durable complete response following radio-immunotherapy was seen in 2 of
the 9 patients who continued nivolumab subsequent to radiotherapy. For
the first of these patients, previous treatment included concurrent
chemo-radiotherapy with Carboplatin for T4N0M0 SCC of the maxilla.
Nivolumab was being given for metastatic recurrence and although there
was initial response, this patient received radiotherapy to a hilar
lymph node which was the only site of progression, after 9 months of
nivolumab, when there was radiological response elsewhere. There was a
confirmed radiological response to radiotherapy (20 Gy in 5 fractions,
Figure 2) and his patient subsequently continued with nivolumab
achieving a complete response. At the time of analysis, this patient was
alive at 29 months following initiation of nivolumab. The second patient
who achieved a durable complete response was initially diagnosed with
T3N2M0 SCC of the posterior oropharynx treated with chemoradiotherapy,
with recurrence within 6 months of platinum chemoradiotherapy (Figure 3A
and 3B). There was a good partial response to nivolumab however, due to
persistent clinically evident disease, radiotherapy (30 Gy in 10
fractions) was administered to the oro-mandibular residual disease after
22 weeks of nivolumab (Figure 3C and 3D). There was subsequent complete
response clinically (Figure 3E and 3F) and radiologically (Figure 3G and
3H) and the patient is alive at 26 months following start of nivolumab
with no evidence of disease.



\section*{Discussion}

{\label{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 \selectlanguage{ngerman}×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 \emph{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.





\section*{References}

{\label{references}}

\begin{enumerate}
\tightlist
\item
  Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra
  L, et al., Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head
  and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi:
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\item
  Arina A, Gutiontov SI, Weichselbaum RR. Radiotherapy and Immunotherapy
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  Feb 11. PMID: 32047000.
\item
  Daguenet E, Louati S, Wozny AS, Vial N, Gras M, Guy JB, et al.,
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  PMC7403362.
\item
  Parikh AR, Szabolcs A, Allen JN, Clark JW, Wo JY, Raabe M, et al.,
  Radiation therapy enhances immunotherapy response in microsatellite
  stable colorectal and pancreatic adenocarcinoma in a phase II trial.
  Nat Cancer. 2021 Nov;2(11):1124-1135. doi: 10.1038/s43018-021-00269-7.
  Epub 2021 Nov 18. PMID: 35122060; PMCID: PMC8809884.
\item
  Qian JM, Schoenfeld JD. Radiotherapy and Immunotherapy for Head and
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\item
  McBride S, Sherman E, Tsai CJ, Baxi S, Aghalar J, Eng J, et al.,
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\item
  Leidner R, Crittenden M, Young K, Xiao H, Wu Y, Couey MA, et al.,
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\item
  Botticelli A, Mezi S, Pomati G, Sciattella P, Cerbelli B, Roberto M,
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  PMID: 32326034; PMCID: PMC7349768.
\end{enumerate}

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