Page 9 - Read Online

Quenelle et al. J Unexplored Med Data 2018;3:7 I http://dx.doi.org/10.20517/2572-8180.2018.02 Page 3 of 10

This led to a phase II study in HNSCC with pembrolizumab, KEYNOTE 055 . In this single arm study,
[14]
patients were enrolled who had previously failed platinum and cetuximab therapy. A total of 171 patients
were enrolled regardless of PD-L1 status and treated with the set dose of 200 mg every 3 weeks. The primary
endpoints were safety and ORR. Twenty-two percent of these patients were HPV positive, and though not
required for enrollment, 82% had > 1% PD-L1 positivity. Seventy-five percent of patients had received at least
2 prior lines of therapy. ORR was 16%, and grade 3 or 4 adverse events were 15%. The PFS was 2.1 months
and OS 8 months.

Based on this data, the FDA granted accelerated approval to pembrolizumab on 5 August 2016. This
approval is contingent upon completing a phase III study, which is the KEYNOTE 040 trial presented at
the European Society for Medical Oncology (ESMO) annual meeting in September 2017 ; the data has not
[15]
yet been formally published as of this writing. In this prospective study, 495 platinum-treated patients were
randomized 1:1 to pembrolizumab 200 mg every 3 weeks or standard therapy with docetaxel, methotrexate,
or cetuximab. The primary endpoint was median OS in the intent to treat population; secondary endpoints
included median PFS, ORR, PFS and OS in patients withPD-L1 combined positive score ≥ 1% (slightly
different to the previously used definition of PD-L1 expression). A pre-specified efficacy boundary for OS in
the intention to treat (ITT) population was set at one-sided P = 0.0175. The overall survival in pembrolizumab
treated patients was 8.4 vs. 7.1 months in the standard therapy group, hazard ratio (HR) 0.81 (CI 0.66-0.99,
P = 0.0204); this did not meet the pre-specified OS benefit, but did provide 19% reduction in the risk of
death. PFS was 2.1 and 2.3 months respectively. Incidence of grade 3 or greater adverse events was 13.4% in
the pembrolizumab group and 36.3% in the standard therapy group. Although the pre-specified statistical
benefit was not met, the data is consistent with the phase 1 and 2 results, as is the toxicity profile.

PD-L1 status was again re-examined in this study, looking at two separate cut-offs not well described in the
abstract: PD-L1 based on tumor proportion score, with the cut off being either greater than or less than 50%,
and PD-L1 combined positive score ≥ 1%. There did appear to be some predictive benefit to these varying
markers of expression, with PD-L1-TPS ≥ 50% suggesting an OS benefit of 11.6 vs. 7.9 months. It is unknown
if this data will ultimately alter the FDA labeling for pembrolizumab in HNSCC to include PD-L1 expression
testing similar to non-small cell lung cancer.

NIVOLUMAB
Nivolumab (Opdivo®) acts via a similar mechanism to pembrolizumab: it is a human immunoglobulin G4
(IgG4) monoclonal antibody that binds the PD-1 receptor and blocks its interaction with PD-L1 and PD-
L2, releasing PD-1 pathway-mediated inhibition of the immune response . It received FDA approval for
[16]
advanced HNSCC in November 2016 based on the randomized phase III CHECKMATE 141 trial . The
[17]
trial randomized 361 patients in a 2:1 fashion to nivolumab 3 mg/kg or investigator’s choice of methotrexate,
docetaxel, or cetuximab. Primary endpoint in this trial was overall survival, with secondary endpoints
including PFS, ORR, safety, and quality of life. Fifty-five percent of patients had at least two lines of prior
systemic therapy. P16 expression was not available for every patient who participated, but in the nivolumab
group 26% of 113 patients tested were positive; in the standard therapy group 24% of 65 patients were positive.
Median OS was 7.5 months in nivolumab group vs. 5.1 months in the standard group (P = 0.01, HR 0.70).
Interestingly, PFS was non-significant between the two groups, with nivolumab PFS being 2 months and
standard therapy 2.3 months (HR 0.70, P = 0.32). ORR for nivolumab was 13.3% vs. 5.8% in standard therapy.
However, looking at the median PFS and median OS curves, there is a late separation consistent with more
durable responses to nivolumab therapy. Toxicity in these patients (grade 3 or higher) was 13.1% vs. 35.1%.

PD-L1 expression was not required for the CHECKMATE 141 trial, but a pre-specified analysis looked at the
degree of expression to determine if there was any clear correlation. PD-L1 expression could be evaluated
in 260 of the 361 patients; significant expression (considered ≥ 1%) was found in 57.3% of these patients.