Pembrolizumab Benefit in SCCHN Confirmed in Expansion Study

Tanguy Y. Seiwert, MD

Antitumor activity of pembrolizumab (Keytruda) was confirmed in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) in a recently reported expansion cohort of KEYNOTE-012.

Of the 99 patients available for preliminary efficacy analysis, overall response rate (ORR) was 18.2% (95% CI, 11.1-27.2) with 18 partial responses and 31.3% with stable disease. Each patient received a fixed dose of 200 mg of IV pembrolizumab every 3 weeks.

KEYNOTE-012 had previously demonstrated clinical activity of pembrolizumab at the dose of 10 mg/kg every 2 weeks in patients with recurrent/metastatic SCCHN enriched for PD-L1—positive tumors. Twenty percent of patients in the original study had a response.

In the expansion cohort, drug-related adverse events (AEs) of any grade occurred in 47% of patients and drug-related grade 3 AEs occurred in 7.6%. The most common drug-related AEs of any grade were fatigue (12.1%), decreased appetite (6.8%), pyrexia (6.1%), and rash (5.3%).

OncLive spoke with KEYNOTE-012 lead study author Tanguy Y. Seiwert, MD, assistant professor of Medicine, University of Chicago Medicine, to learn more about the significance of the expansion results.

OncLive: What were the most significant findings from this study?

Seiwert: This was an expansion cohort that included 132 patients with head and neck cancer that were treated with pembrolizumab as a single-agent. These were patients with recurrent metastatic disease who had poor prognosis. Moreover, many of these patients were heavily pretreated.

Remarkably, pembrolizumab was able to show response in 25% of patients. Putting that into perspective, our best targeted therapy currently is cetuximab with only about 10% to 13%. While this is still early data, it is a relatively large study that shows a lot of promise.

The other part that I think is important is, not only do 25% of patients benefit, about 56% of patients show shrinkage of their lesions and there is a substantial fraction of patients with stable disease and those patients may also benefit. It also seemed like once there was a response, it was common that responses were durable. Eighty-six percent of the patients who achieved a response continued to be in response.

Were there any toxicity concerns in this study?

Pembrolizumab was very well tolerated. The safety profile was very mild when compared with what we usually treat patients with. There were a few patients with severe side effects, but this was low.

What will be the impact of this study?

For head and neck cancer, this study really shows us that there may be another class of active agents. The hope is that, eventually, we can prolong survival in a disease that has a very poor prognosis. We have not had very many active therapies. Cetuximab was the last one that was approved, and since then we have not had any new therapies in several decades.

Pembrolizumab and other PD-1 agents look very promising, and I hope that this early efficacy with response will also translate into survival benefit. More broadly speaking, I think it shows that immunotherapy is widely applicable and head and neck cancer is just another example.

What could a community oncologist take away from this study?

Right now, these agents are only available in clinical trials. It is really important that clinical trials are done to establish and ultimately get these agents approved. It is fair to inform patients that there may be additional options available, and refer patients to clinical trials. I would encourage patients at the right time and, when appropriate, refer these patients to centers that have immunotherapy trials available. This will move the field forward and eventually lead to quicker approval of a potentially effective therapy.

What are the unanswered questions that remain for pembrolizumab in head and neck cancer?

There are a lot of unanswered questions. This is really just the first data we have of pembrolizumab as a single-agent in head and neck cancer. We don’t know how much it will impact survival. I believe it will have an impact, but we will have to wait for the results of the ongoing phase III studies. It is also not clear if we should have a biomarker that could potentially enrich patient selection.

Some data suggest that a new signature in head and neck cancer could provide us with some information about which patients may respond to pembrolizumab, but that is still early. If we had a biomarker, could we integrate pembrolizumab into earlier lines of treatment? Could we use it in the first-line setting or in a curative setting? Glancing at this very early data, there is a lot more to come for head and neck cancer.

What research has been done to identify a biomarker?

Right now, PD-L1 is the most common biomarker being investigated. There is some data on this from the 2014 ASCO Annual Meeting. However, it is an imperfect biomarker because even patients that don’t have PD-L1 benefit.

At the 2015 ASCO Annual Meeting, more data were presented suggesting that using a gene signature, an interferon gamma signature, is very good at predicating those patients that do not respond to pembrolizumab. It had a very high negative predictive value of 95%. In addition, the signature might actually improve upon what we already know in PD-L1 testing.

There are other biomarkers that are being investigated, including mutational burden, microsatellite instability, and immunogenic mutations. All these may prove to be important biomarkers, but they all need to be explored. Perhaps in the future, combinations of biomarkers will be the key to telling us which patients to treat with immunotherapy.