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Jean-Pascal Machiels, MD, discusses the KEYNOTE-412 trial and the overall potential for pembrolizumab in the head and neck cancer landscape.
Jean-Pascal Machiels, MD
The ongoing phase III KEYNOTE-412 trial is evaluating the efficacy of pembrolizumab (Keytruda) in combination with chemoradiation (CRT) versus CRT alone as frontline therapy in patients with newly diagnosed locally advanced head and neck squamous cell carcinoma (LA-HNSCC).1
Pembrolizumab is currently FDA approved for patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. The accelerated approval in this setting was based on findings from the phase Ib KEYNOTE-012 study.2 In the trial, the overall response rate with pembrolizumab was 16% (95% CI, 11-22), which included a complete response rate of 5%. Responses lasted for ≥6 months for 82% of patients.
Data have suggested additive benefits with CRT, as CRT is associated with immunomodulatory effects, providing the rationale to combine it with pembrolizumab.
Eligibility for the KEYNOTE-412 (NCT03040999) study include adult patients with newly diagnosed, pathologically proven, locally advanced HNSCC. Investigators of the study are looking to enroll 780 patients, who will be randomized to receive either 200 mg of pembrolizumab every 3 weeks plus CRT, or standard CRT.
In an interview with OncLive during the 2017 ASCO Annual Meeting, lead author Jean-Pascal Machiels, MD, head of the Department of Medical Oncology, Cliniques Universitaires Sain-Luc, discussed the KEYNOTE-412 trial and the overall potential for pembrolizumab in the head and neck cancer landscape.Machiels: We have data in the recurrent setting that shows that anti—PD-1 agents improve survival. Nivolumab (Opdivo) and pembrolizumab are approved by the FDA in this indication, so it is interesting to put this component earlier in the disease course to try to cure more patients— for example, in combination with CRT.
In locally advanced head and neck cancer, most patients will have locoregional disease and you will probably be able to cure 40% to 50% of these patients. Clearly, if you can improve the treatment, we will maybe be able to cure more patients.The trial will give CRT, the standard of care. It will be 6 or 7 weeks of radiation with 2 or 3 cycles of high-dose cisplatin. On top of that, in the experimental arm, we will add pembrolizumab. We will start pembrolizumab 1 week before chemoradiation, give some duration chemoradiation, and continue 1 year after the end of chemoradiation.
The primary endpoint is event-free survival, which will be looked at after 2 years of treatment. If the results are positive, it will be a great step forward. We will have to see which group derives the best benefit. [If positive] it means that, indeed, immunotherapy is able to help to cure more patients. Today, we only have data in the recurrent setting—so only in incurable disease…We are probably not going to be able to cure all of the patients, but we will find other ways to stimulate the immune system.We all know that, indeed, radiation therapy can induce immunogenic cell death, and this can probably help to stimulate the immune system. We have some data that support the fact that radiation plus immunotherapy will have synergistic action. But, we also have some data that show CRT and immunotherapy could be interesting. You have seen it in lung cancer.In monotherapy, it is clearly less toxic than chemotherapy, at least from a statistical point of view. When you have some grade 3/4 autoimmune toxicities, it can be very difficult to manage with patients, and we need to recognize this side effect quite rapidly.
The main side effects we can expect are endocrine side effects, but we should also be careful about some serious adverse events like colitis, pneumonitis, and liver toxicity. All of these need to be carefully monitored.
We don't know exactly what the interactions will be between the PD-1 inhibitor and chemoradiation. We have some data, but it is very limited data that suggest that it will be okay. But, in the first step to the trial, we have to be extremely careful about toxicities.We know that it improves survival, so we hope that we can give this earlier in the disease. There are different investigations being performed in combination with chemotherapy, but also combinations with immune checkpoints. The other thing is to try to put this agent in the curative setting. There are studies starting with CRT, or we could imagine giving this in combination as adjuvant treatment.
If our study turns out positive, it will mean that we can cure patients, which is better than just prolonging the survival of a recurrent patient.We have big challenges because, at least in Europe, head and neck cancer is still mostly induced by tobacco and alcoholism, so these patients have a lot of comorbidities. We used to say that one-third of patients are going to die from the disease, but another one-third are going to die due to comorbidities—meaning the toxicity of smoking or alcoholism. Therefore, to overcome this challenge, we need to make prevention programs.There is a quite similar trial being performed with avelumab (Bavencio) combined with CRT—the JAVELIN [HEAD AND NECK 100] study. [Avelumab] is a PD-L1 monoclonal antibody, while pembrolizumab is an PD-1 monoclonal antibody. We have several trials that may answer this important question: Can we improve outcomes in patients?