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Page 2 of 9 Gauduchon et al. J Cancer Metastasis Treat 2019;5:72 I http://dx.doi.org/10.20517/2394-4722.2019.023

the therapeutic arsenal. Head and neck cancers are cancers inducing immunosuppression and therefore
particularly likely to respond well to immunotherapy. The purpose of this article is to review studies
validating the use of first-line and second-line checkpoint inhibitors (CPIs) in HNSCC, as well as studies
evaluating new indications. The aim is also to evaluate the new immunotherapy modalities under
evaluation and to discuss the difficulties of using these new treatment.

VALIDATED TREATMENT IN SECOND LINE
Nivolumab was the first molecule to be approved by the Food and Drug Administration with the
Checkmate 141. This showed an overall survival improvement of 7.7 months vs. 5.1 months (HR = 0.68,
95%CI: 0.54-0.86) compared with monotherapy with docetaxel, methotrexate or cetuximab in HNSCC
progressing after a first platinum-based line. This difference was greater in PD-L1 patients > 1% with an
OS of 8.2 months vs. 4.7 months, but the curves were also separated for PD-L1 negative patients (< 1%).
[3]
Nivolumab was therefore approved regardless of PD-L1 expression .
Pembrolizumab was studied in the same situation with the Keynote 0-40 Phase III study, but this time
2
docetaxel was given every 3 weeks at a dose of 75 mg/m . While the first analysis was not significant, the
discount reached statistical significance with a median overall median survival of 8.4 months (95%CI: 6.4-9.4)
vs. 6.9 months (95%CI: 5.9-8.0), HR = 0.80 (95%CI: 0.65-0.98, P = 0.0161). The reduction in HR relative to
nivolumab can be explained by several factors. First, a cross-over effect in the chemotherapy group with
many patients receiving immunotherapy secondarily, secondly because a majority of patients received
docetaxel, which is the most effective chemotherapy and also by the use of docetaxel every three weeks
used in this study which is probably more effective than the weekly rhythm used with nivolumab. In the
subgroup analyzes, survival was significantly increased from 7.9 to 11.6 months in favor of pembrolizumab
in patients with PD-L1 > 50%. There was no difference in the PD-L1 population < 50%. These results led to
[4]
the approval in Europe of pembrolizumab in PD-L1 patients > 50% .

A third phase 3 trial, the EAGLE study, compared an anti-PD-L1 (durvalumab) alone or with an anti-
CTLA4 (Tremelimumab) to a standard chemotherapy. This study was negative for the overall survival,
but the durvalumab arm as monotherapy was consistent with nivolumab and pembrolizumab with a
median overall survival at 7.6 months and a response rate of 17.9%. In addition, the control arm was
superior to what was expected because weekly paclitaxel was predominantly used (which is probably the
best treatment option for these patients) and there was an important crossover with control arm patients
[5]
receiving immunotherapy .

FIRST LINE TREATMENT
The Keynote 048 trial is an open-label, randomized, phase 3 trial comparing 887 patients in first line with
[6]
pembrolizumab to the extreme protocol [cisplatin or carboplatin, 5-fluorouracile (5FU) and cetuximab] .
Pembrolizumab was administered at a fixed dose of 200 mg every 3 weeks alone or in combination
with cisplatin and 5FU chemotherapy. The stratification factors were the expression of PD-L1 by tumor
proportion score (TPS: expression of PD-L1 by tumor cells ≥ 50% vs. < 50%), p16 status for oropharyngeal
tumors (positive vs. negative) and Eastern Cooperative Oncology Group status (0 vs. 1). Pembrolizumab
showed a benefit in overall survival over chemotherapy and cetuximab in the combined positive score
(CPS) population ≥ 20 (a score that studies expression on both tumor cells and immune cells in the
microenvironment) with a median of 14, 8 months vs. 11 months; HR 0.58 (95%CI: 0.44-0.78). This
advantage was found in the group of CPS ≥ 1 with a median of 12.3 months vs. 10.4 months; HR 0.74 (95%CI:
0.61-0.90). But it is important to note that if survival is better with pembrolizumab, at the beginning
immunotherapy is deleterious for some patients with more deaths in the first six months. In terms of
tolerance, treatment-related adverse event levels of Gr 3-5 were 17% with pembrolizumab against 69% with