Expert Projects 2016 FDA Approvals of Nivolumab and Pembrolizumab in Head and Neck Cancer

Tanguy Y. Seiwert, MD

Immunotherapy has arrived for the treatment of patients with head and neck cancer, says Tanguy Seiwert, MD.

"I think it is very clear that these drugs have a major impact on survival and, likely, both nivolumab (Opdivo) and pembrolizumab (Keytruda) will be approved in head and neck cancer in 2016,” says Seiwert, an assistant professor of Medicine at University of Chicago Medicine. “It is an exciting time with this new treatment modality that is very active. These are game changers.”

Both nivolumab and pembrolizumab have demonstrated activity in patients with head and neck cancer. The phase III CheckMate-141 trial, which examined the anti—PD-1 agent nivolumab versus investigator’s choice of cetuximab (Erbitux), methotrexate, or docetaxel in patients with platinum-refractory squamous cell carcinoma of the head and neck, was stopped early after it was determined nivolumab had met its primary endpoint of overall survival (OS).

Eligible patients were allowed to to continue treatment or cross over to receive nivolumab. The OS data will be presented for the first time at the 2016 AACR Annual Meeting in April, according to Bristol-Myers Squibb, the manufacturer of nivolumab.

Pembrolizumab showed its promise in head and neck cancer in the phase I KEYNOTE-012 study.¹ In the trial, 117 evaluable patients who received pembrolizumab experienced an objective response rate of 24.8% (n = 29), and another 25% of patients had stable disease.

The response rate seen with pembrolizumab was similar, regardless of HPV infection status. In those with HPV-positive disease, the ORR was 20.6%, compared with 27.2% in the HPV-negative group.

OncLive: How big of an impact do you see immunotherapies making in head and neck cancer?

How significant is the Checkmate-141 study going to be?

To learn more about the expanding role of immunotherapies in head and neck cancer, OncLive spoke with Seiwert. In the interview, he discusses the impact of the CheckMate-141 trial, the importance of establishing an effective biomarker, and the significance a manageable toxicity profile may have on patients with poor performance status.Seiwert: It is currently an exciting time for head and neck cancer, because it looks like immunotherapy is quite active in this disease. We see a response rate of 20% to 24%, 1 in 4 patients benefit, and activity is seen in both HPV-positive and HPV-negative tumors. We have a new treatment modality in immunotherapy with PD-1 checkpoint blockade that looks like it has an impact. However, what is really important is survival. While response rates are nice, they likely underestimate the rate of benefit. When we primarily look at survival outcomes, we have a median survival—in a heavily pretreated population of head and neck cancer—of about 10 months. In a less favorable population, we see really good survival data.The phase III Checkmate-141 study of nivolumab in the second-line setting versus investigator’s choice was stopped at the first examination, meaning the data must be very positive. In my mind, that is not surprising.

It probably looks very similar to what we saw from Checkmate-017 in lung cancer, which was very strongly positive with a hazard ratio of 0.59. I expect Chekmate-141 to be equally positive.

What are the next steps to understanding immunotherapies in head and neck cancer?

Also, it is very much in line with the data we have seen for pembrolizumab as a single agent. That looks very active and strongly beneficial across the board, including in heavily pretreated patients and regardless of HPV status. The OS in heavily pretreated patients with pembrolizumab was 10 months, which is outstanding. It all fits together.We have to figure out who the patients are that benefit the most. It is my impression that, regardless of PD-L1 status, there is going to be a benefit. Even in patients who are PD-L1—negative, we have a response rate of close to 10% in some patients for extended periods of time.

It is really important to figure out when it is appropriate to use a biomarker. On the other hand, we can enrich for patients who have more benefit. For example, in the pembrolizumab Keynote-012 study, patients with PD-L1 selection had a response rate of about 45%.

Are there other immunotherapy biomarkers that you see potential for in head and neck cancer?

What toxicities have been seen with immunotherapies in head and neck cancer? What is the potential impact of them?

PD-L1 is a biomarker that allows us to enrich, but it probably isn’t a biomarker for us to select patients. I don’t think we should use it to exclude anybody. However, it has important implications if we want to move forward. For example, in the first-line treatment setting, we actually may need to enrich patients.PD-L1 by itself clearly is not good enough; we need something better. There is a suggestion now—which has been published in 2 different essays—of using an interferon gamma signature with PD-L1 testing. Together, they may actually afford a very negative predictive value. This means that we can potentially exclude patients who will not really benefit. A negative predictive value of 95% might be clinically good enough to say that this is a patient who probably shouldn’t be treated with a PD-L1 blocker.One of the most certain things about immunotherapy is that the side effects are very mild. Generally, these agents are very well tolerated; most side effects are grade 1/2 skin itching, or hypothyroidism.

Overall, these agents are exceptionally well tolerated. There are implications from that. We usually do not give chemotherapy or radiation treatments to patients with a poor performance status. We need to reevaluate that with immunotherapy. Perhaps this is a treatment that can be tolerated by very poor performance patients. This is something that we don’t have any data for yet.

The severe side effects, such as pneumonitis and colitis, are manageable, but it is very important that we screen for them. They are rare, but screening is necessary.

1. Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity of the anti-PD-1 antibody pembrolizumab in biomarker-unselected patients with R/M head and neck cancer: preliminary results from the KEYNOTE-012 expansion cohort. J Clin Oncol. 2015;(suppl; abstr LBA6008).