There were two important differences in the selection of patients between these two trials. Although both trials included patients with platinum refractory R/M HNSCC, KEYNOTE 040 excluded patients who recurred or progressed within 3 months of previous multimodal therapy containing platinum for locally advanced disease. Thus, KEYNOTE 040 was excluding the rapidly progressing patient population from the trial. In addition, in KEYNOTE 040, only 1.2% (N = 6 of 495) of the HNSCC patients had received ≥ 3 prior lines of therapy as compared to 19.9% (N = 72 of 361) in CheckMate141. Thus, in KEYNOTE 040, the population was less heavily pre-treated and aggressive tumor growth characteristics were excluded from the trial and these exclusion criteria most likely contributed to the improved OS observed in the control arm. This inadvertently set a higher threshold in the bio-statistical analysis of KEYNOTE 040 so that the clinical outcome of every patient was influential in the analysis.

In addition, even though the mono chemotherapy treatment options in the SOC arms were the same in both clinical trials, there were differences in the dosing and the overall distribution of the patients in the SOC treatment regimen received. Specifically, there were differences in the dosing of docetaxel. In the KEYNOTE 040 trial, docetaxel was given at 75 mg/m² q3weeks whereas in CheckMate 141 the docetaxel dose was 30 mg/m² qweek. Whether this difference in dosing of docetaxel makes a difference is unclear but we may speculate that the q3week dosing may be reserved for more robust patients in KEYNOTE040. In addition, docetaxel q3 weeks has been reported as slightly more efficient in terms of response rate or survival than the weekly schedule in other sensitive tumor types, such as breast and prostate cancer [5, 6]. There was also a higher percentage of patients who were treated with docetaxel (42% versus 21%) and cetuximab (30% versus 11%) in KEYNOTE 040 as compared to CheckMate 141, respectively. In contrast, in CheckMate 141, there was a higher number of patients who received methotrexate (38% versus 27% in KEYNOTE 040). While the CheckMate 141 trial was not designed to compare the three regimens used in the SOC arm, docetaxel appeared to result in a slightly improved OS as compared to patients receiving methotrexate and cetuximab, although the overall numbers were small to be able to make definitive conclusions. Thus, the difference in the number of R/M HNSCC patients receiving docetaxel in KEYNOTE 040 as compared to methotrexate in CheckMate 141 may have also contributed to the improved OS in the control arms (6.9 months versus 5.1 months).

Both phase III trials had a subset of patients who were allocated to the SOC arm but did not receive SOC therapy. In KEYNOTE 040, 5.6% (N = 14 of 248) of patients as compared to 8.2% (N = 10 of 121) of patients in CheckMate 141 did not receive SOC therapy. Most importantly, the treatment option provided at the time of progression was very different between the two clinical trials based on the timing of the studies and most likely had a large influence in the OS observed in the control arms. At the time of the KEYNOTE 040 study, both pembrolizumab and nivolumab were Food and Drug Administration (FDA) approved for the treatment of R/M HNSCC patients in contrast to when the CheckMate 141 study had completed, in which an immune checkpoint inhibitor (ICI) was only accessible through clinical trials. In CheckMate 141, the data cutoff point for the analyses of OS, progression free survival (PFS), and safety was December 18, 2015 with a median duration of follow-up for OS of 5.1 months (range, 0 to 16.8) and data on rate of response was based on a cutoff of May 5, 2016. Pembrolizumab had received FDA approval in August of 2016 and nivolumab in November of 2016. KEYNOTE 040 had a data cutoff point of May 15, 2017. Correspondingly, in KEYNOTE 040, 12.5% (31 of 248) of patients in the SOC arm received an ICI at the time of clinical progression. The impact of receiving subsequent ICI in the SOC arm had a significant impact on median OS, with patients in the SOC arm receiving subsequent ICI having a prolonged median OS of 20.1 months (N = 15, 95% CI: 14.0-NE months) as compared to a median OS of 9.7 months (N = 58, 95% CI: 9.0–11.3 months) in patients who went on to receive a non-ICI therapy or a median OS of 4.5 months (N = 134, 95% CI: 3.7–5.0 months) in patients who received no subsequent therapy.

These trials also highlight the importance of patient selection in clinical trial design and raises the question whether patient selection based on expression of a prognostic biomarker, such as PD-L1, should be considered as an eligibility criteria for future PD-1/PD-L1 targeted clinical trials. Both of the phase III clinical studies provide insight into this question through a sub-analysis performed on OS based on PD-L1 expression > 1% within the tumor microenvironment. In KEYNOTE 040, using a PD-L1 combined positive score (CPS) of ≥ 1, which is defined by PD-L1 expression on both immune and tumor cells, the HR was 0.74 (95% CI: 0.58–0.93, p = 0.0049) with a median OS of 8.7 months with anti-PD1 treatment. Similarly, in CheckMate 141, a PD-L1 tumor cell expression score of ≥ 1% resulted in a HR of 0.55 (95% CI: 0.36–0.83) with a median OS of 8.7 months. If PD-L1 expression serves as a true prognostic biomarker of response for PD-1 therapy, an increasing percentage of PD-L1 expression within the tumor microenvironment should correlate with improved OS and this is indeed what is observed. In KEYNOTE 040, a PD-L1 tumor proportion score (TPS) of ≥ 50% improved the HR to 0.53 (95% CI: 0.35–0.81, p = 0.0014) with a median OS of 11.6. Correspondingly, the complete response (CR) rates also increase with PD-L1 expression. In KEYNOTE 040, the overall CR rate in the pembrolizumab treated group was 1.6% (N = 4 of 247). However, in patients with a CPS ≥ 1 the CR was 2.0% (N = 4 of 196), and in patients with a TPS ≥ 50%, CR was 4.7% (N = 3 of 64). Furthermore, PFS and RR also increased with increasing PD-L1 expression (Table 1).Tab1

Comparison of key subgroups in Checkmate 141 and KEYNOTE 040 trials