Barbara Burtness, MD
As investigators attempt to move immunotherapy earlier in the management of head and neck squamous cell carcinoma (HNSCC), questions are arising regarding who should receive single-agent therapy, a chemoimmunotherapy approach, or the current standard of care.
Interim findings from the phase III KEYNOTE-048 trial showed that frontline pembrolizumab (Keytruda) improved overall survival (OS) and duration of response compared with standard therapy for patients with recurrent or metastatic HNSCC as a single agent. However, the benefit was not observed in progression-free survival (PFS) or overall response rate.
In an interview with OncLive,
lead study author Barbara A. Burtness, MD, professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; co-director, Developmental Therapeutics Research Program; of Yale Cancer Center, explained these data, and the impact they could have on the treatment of patients with HNSCC.
OncLive: Could you provide some background on this study?
We know that immunotherapy has activity in head and neck cancer, and both pembrolizumab and nivolumab have been approved because of survival advantages in the second-line setting. The question then became, “Could you use immunotherapy in the first-line setting?” This is partly because that is where it would have the biggest impact on survival, and partly because many patients with HNSCC are quite sick and are not often fit for second-line therapy.
This trial addressed 2 questions. The first was the superiority of pembrolizumab alone in patients with the biomarker profile that is associated with response. Secondly, given that chemotherapy is beneficial in head and neck cancer, would there be an advantage to incorporating pembrolizumab with chemotherapy?
This was a phase III study that had 3 arms. It compared pembrolizumab alone to a new regimen, which added either cisplatin or carboplatin together with 5-fluorouracil (5-FU) and combined it with pembrolizumab. The chemotherapy was given for 6 cycles, and if patients were still progression free, they could continue on pembrolizumab alone. The third arm was the EXTREME regimen—6 cycles of a platinum agent with 5-FU and cetuximab (Erbitux) followed by cetuximab alone.
Patients who were eligible were those with squamous cell cancer with recurrent metastatic disease, could not have had a curative intent local therapy, and they had to have tissue available to do biomarker testing. If [a patient] had oropharynx cancer, we had to know their p16 status so we could stratify by that. Patients were also stratified by their performance status and PD-L1 stain level, dichotomized at 50% of the tumor cell staining. They were randomized 1:1:1 to pembrolizumab, pembrolizumab plus chemotherapy, or EXTREME.
The primary endpoints of the study were OS and PFS, and those analyses were conducted for 3 separate populations. The first was the overall population, and then there were the 2 biomarker-enriched populations. The way that the biomarker-enriched populations were determined were based not only on tumor cell staining, but on a different way of scoring PD-L1 expression called the combined positive score (CPS). We looked at the patients who expressed this richly, which was a CPS score ≥20, and those who expressed any PD-L1 expression, which was a CPS ≥1 (CPS 1). CPS was defined as the number of cells that were PD-L1–positive—looking at tumor cells, lymphocytes, and macrophages—divided by the tumor number of cells counted and multiplied by 100.
The first analysis was OS for the CPS ≥20 enriched population. In that population, pembrolizumab was superior to combination chemotherapy with cetuximab. It raised the median OS from 10.7 months to 14.9 months, which is the longest survival that has ever been described for this subpopulation. The hazard ratio was 0.61, the P
value was .0007, and the effects were durable.
There were significantly more people alive at the 2-year mark on the pembrolizumab arm than on the chemotherapy arm. The interesting thing is that the response rate and PFS were not superior for pembrolizumab. There were patients who remained progression free at 2 years, but there were a substantial number of patients who had crossed over to second-line therapy. It appeared that the early use of pembrolizumab conveyed a survival advantage that was quite durable.
We then looked at the CPS ≥1 population. The initial use of pembrolizumab led to a superior OS compared with the EXTREME regimen. OS went from 10.3 to 12.3 months. The hazard ratio was 0.78, which was statistically significant, and was associated with response rate and PFS being a little lower. But, it was a durable benefit.