Immunotherapy May Mean No Chemotherapy for Some With Metastatic Head and Neck Cancer

Immunotherapy may lead to a major change in how the treatment of metastatic recurrent head and neck cancer is approached, according to Barbara Burtness, M.D., a professor of medicine at Yale School of Medicine.

In an interview with CURE, she explained the interim results of the KEYNOTE-048 clinical trial, designed to evaluate whether Keytruda (pembrolizumab) alone or in combination with chemotherapy prolongs progression-free and overall survival compared with standard treatment.

Can you provide background on the study?

We know that immunotherapy has some activity in head and neck cancer. Both Keytruda and Opdivo (nivolumab) have been approved because of survival advantage in the second-line setting. And so, the question was: Could you use immunotherapy? Could you use a PD-1 inhibitor is the first-line treatment? Partly because that’s likely to have the biggest impact on survival and partly because many patients with head and neck cancer are quite sick and they’re not always fit for second-line therapy.

What was the design and aim of it?

This trial, which looked at the first-line use of Keytruda sort of asks two questions: Would Keytruda alone be superior in those patients with the biomarker profile that was associated with being pretty responsive to it? And given that chemotherapy has been beneficial in head and neck cancer — in that it leads to rapid disease control in patients who can be symptomatic – would there be an advantage to incorporating Keytruda directly with chemotherapy?

This was a phase 3 study that had three (groups) and it compared Keytruda alone to a new regimen which took a platinating agent, either cisplatin or carboplatin, together with fluorouracil (5-FU) together with Keytruda. The chemotherapy was given for six cycles and, if the patients were still progression-free, they could continue on Keytruda alone. The third (group) was the extreme regimen — six cycles of a platinating agent, 5-FU and Erbitux (cetuximab) followed by Erbitux alone. (Eligible patients) had squamous cell cancer and recurrent metastatic disease. They had to have tissue available, so we could do the biomarker testing and if they had an oropharynx cancer we had to know their p16 status (p16-positive cancers contain HPV DNA and tend to have better outlook than p16-negative cancers, according to the American Cancer Society).

The first analysis was overall survival for the CPS (combined proportion score)-20 enriched population (CPS can help predict response to Keytruda). And in that population, Keytruda was superior to combination chemotherapy with Erbitux. It raised the median overall survival from 10.7 to 14.9 months. That’s the longest survival ever been described in head and neck cancer for this sub-population. The effects were durable. So, there were still significantly more people alive at the two-year mark in the Keytruda (group) than in the chemotherapy (group). The interesting thing is that the response rate and the progression-free survival were not superior for Keytruda, so there were patients who remained progression-free for two years. But there were also a substantial number of patients who had apparently crossed over to second-line therapy, but it appeared that the early use of Keytruda conveyed a survival advantage that was quite durable. We then looked at the CPS-1 population, and their initial use of Keytruda also led to a superior overall survival compared with the extreme regimen. There it went from 10.3 to 12.3 months. Across both of those groups, the patients who had a response had much more durable responses than if they had gotten the extreme regimen. We then looked at the overall survival benefit of using Keytruda with chemotherapy compared to the extreme regimen in the biomarker-unselected population, and here the overall survival was also improved from 10.7 to 13 months.

This demonstrates that early use of Keytruda in patients with recurrent metastatic cancer leads to an improvement in overall survival in head and neck cancer. And so, for patients who have the biomarker enrichment who are PD-L1 expressing it appears as if Keytruda alone as first-line therapy is superior to anything that we have been doing before. And for patients who are not biomarker enriched the combination of chemotherapy plus Keytruda is also superior to what we have been doing before. This is an interim analysis of this study and there are several analyses that are planned to be forthcoming.

I think that people were expecting to see a benefit with immunotherapy given how potent it had been in second-line. But to see that there’s some patients who may not ever need to see chemotherapy for metastatic recurrence disease is really a remarkable change.

You stated that these patients may not have to see chemotherapy. In the current paradigm, where is the unmet need that this could fill?

The extreme regimen has been the best that we have, but I don’t think anyone has enjoyed using it. It’s quite toxic. There is a risk of neutropenia and patients develop a rash. There are days when they really don’t feel well. And then it has a response rate of 36 percent and a median overall survival of 10.7 months. And for anybody who has metastatic head and neck cancer you don’t want to hear that that’s your average life expectancy. I think the unmet need is the fact that we are using a toxic regimen and although it does lead to responses and helps people live longer, it’s been a modest effect. Keytruda clearly looks better.

I think we are also anticipating that there will be trials forthcoming in the incorporation of these agents. For now, seeing a regimen that is no more toxic in the case of Keytruda plus chemotherapy is more effective and in the case of the CPS-20 patients who may not need to see chemotherapy, is much less toxic. I think that really meets what had been identified as unmet needs in these patients. Obviously, we are looking for novel immunotherapy combinations that will get even more patients into complete response and be even more durable.