KEYNOTE-048: What the Head and Neck Cancer Trial Found

In brief

KEYNOTE-048 asked whether the immunotherapy drug pembrolizumab, given alone or added to chemotherapy, would help people live longer with head and neck squamous cell carcinoma that had come back or spread and could no longer be cured. It compared both approaches against the standard of the time: cetuximab plus platinum chemotherapy and fluorouracil. The answer turned on a laboratory measurement of the PD-L1 protein.

Trial at a glance

Field	Detail
Trial	KEYNOTE-048
Identifier	NCT02358031
Phase	Phase 3
Design	Randomized, open-label, 200 sites in 37 countries
Cancer type	Recurrent or metastatic head and neck squamous cell carcinoma
Comparator	Cetuximab plus platinum and fluorouracil
Primary endpoints	Overall survival and progression-free survival
Enrollment	882 participants

Who took part

882 people with untreated, locally incurable recurrent or metastatic head and neck squamous cell carcinoma were enrolled between April 2015 and January 2017 and assigned in equal proportions to pembrolizumab alone (301), pembrolizumab with chemotherapy (281), or cetuximab with chemotherapy (300). PD-L1 positivity was not required to join. Tumors were scored by combined positive score (CPS), a measure of how much PD-L1 the tumor and nearby immune cells express: 754 participants (85%) had a CPS of 1 or more, and 381 (43%) had a CPS of 20 or more.

What the trial found

Pembrolizumab alone improved overall survival compared with cetuximab and chemotherapy in the tumors expressing the most PD-L1. In the CPS-20-or-more group, median survival was 14.9 months versus 10.7 months (hazard ratio 0.61; 95% CI, 0.45 to 0.83; P=0.0007). In the CPS-1-or-more group it was 12.3 versus 10.3 months (hazard ratio 0.78; 95% CI, 0.64 to 0.96; P=0.0086). Across everyone in the trial, regardless of PD-L1, pembrolizumab alone was not better — it was non-inferior (11.6 versus 10.7 months; hazard ratio 0.85; 95% CI, 0.71 to 1.03).

Pembrolizumab with chemotherapy improved survival across the whole trial population: 13.0 months versus 10.7 months (hazard ratio 0.77; 95% CI, 0.63 to 0.93; P=0.0034), with larger differences at CPS 20 or more (14.7 versus 11.0 months) and CPS 1 or more (13.6 versus 10.4 months).

One result is easy to miss. Neither pembrolizumab arm improved progression-free survival, the other primary endpoint. People lived longer without the cancer being held back for longer on scans.

Side effects differed sharply by approach. Grade 3 or worse adverse events of any cause occurred in 55% of those treated with pembrolizumab alone, 85% with pembrolizumab and chemotherapy, and 83% with cetuximab and chemotherapy. Adverse events led to death in 8%, 12% and 10% respectively.

What changed in practice

Pembrolizumab moved into first-line treatment. The National Cancer Institute lists it as approved with platinum-based chemotherapy and fluorouracil as the first treatment for recurrent or metastatic disease that cannot be removed by surgery, and alone as the first treatment when the tumor has the PD-L1 protein.

What this story cannot tell you

• It does not apply to head and neck cancer that can still be treated for cure. Everyone in this trial had incurable recurrent or metastatic disease and had not yet been treated for it.
• It cannot tell you what to expect without a PD-L1 test. The benefit of pembrolizumab alone was concentrated in tumors expressing PD-L1, and in the total population it only matched the comparator.
• The comparison was against cetuximab plus chemotherapy, the standard in 2015. It does not rank pembrolizumab against later options, and the trial was open-label, so participants and investigators knew which treatment they were getting.
• Longer overall survival came without longer progression-free survival, and median figures describe groups, not individuals. Some people in these trials lived far longer than the median, and some far less.

Questions worth asking

• What is my tumor's PD-L1 combined positive score, and how does it change the options?
• Would you recommend immunotherapy alone or with chemotherapy in my situation, and why?
• What side effects should I watch for, and which need an urgent call?

Sources

This article was written from the sources below, which were checked on the source-check date shown above.

• Lancet 2019: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic HNSCC (KEYNOTE-048) (primary)
• ClinicalTrials.gov: NCT02358031 (registry)
• NCI: Pembrolizumab (reference)

Related reading: head and neck cancer and treatment by stage.

How this article was prepared

Prepared by Cancer Explained's AI-assisted editorial system and checked against the sources listed above. This article has not been reviewed by a healthcare professional unless a named reviewer is specifically shown.

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