Immunotherapy Improves Prognosis for Head and Neck Cancer

In celebration of World Head and Neck Cancer Day, which is celebrated this Saturday, the Spanish Society of Medical Oncology (SEOM) highlights the most important advances recorded in this type of tumor, the seventh most frequently diagnosed in our environment. According to the report Cancer rates in Spain in 2024 According to the latest data from the National Statistics Institute (INE), this year our country will register around 10,700 new cases of the disease and 3,660 deaths due to this cause.

Tobacco and alcohol are the main causative agents of head and neck cancer, accounting for about 75–85% of cases, although there is a progressive increase in tumors associated with human papillomavirus (HPV), which may be responsible for 30–35% of cancers, although there is great geographic variability. These tumors represent a different clinical and molecular entity.

As SEOM specialists explain within the campaign In oncology, each ADVANCE is written in capital letters.Head and neck cancer occurs in an anatomically complex area. Local treatment with curative intent is associated with serious physical consequences that are highly stigmatizing and have a major impact on quality of life and the functionality of the triple sphere of phonation, swallowing and breathing. In addition, these patients often have problems with malnutrition due to the tumor, treatment and comorbidities that must be addressed and treated from the time of diagnosis.

Local disease

In maxillofacial and otolaryngological surgery, there has been an evolution from Hasted techniques to reconstructions and transplants. Of particular note is the advent of robotic surgery, especially transoral, which allows for resections that were previously technically unachievable. Similarly, conservative procedures such as supraglottic laryngectomy have been improved, allowing for the preservation of phonation and avoidance of tracheostomy.

In radiotherapy, advances have been made in the development of techniques that allow dose concentration with less toxicity, such as intensity-modulated radiotherapy (IMRT) and radiosurgery, and methods for very precise dose delivery are being developed using technologies that allow very high-resolution planning. Similarly, deintensification techniques are being tested in HPV-associated tumours.

As SEOM explains, in most cases of stage I or II cancer, surgery or radiotherapy is the treatment of choice. For locally advanced stage III or IV (M0) tumors, treatment is currently multimodal and includes surgery, radiotherapy, and chemotherapy depending on the stage, location, and clinical factors. In some cases, induction chemotherapy and subsequent radiotherapy can preserve the larynx.

Locally advanced head and neck cancer

Treatment of patients with locally advanced head and neck cancer has evolved, and concurrent radiotherapy and cisplatin remains the standard of care today. In 2006, Bonner demonstrated that the efficacy of radiotherapy was increased when combined with cetuximab without increasing toxicity, making it now a good alternative to concomitant cisplatin except in patients with HPV-related tumors. In 2022, the Treatment of Tumors in the Head and Neck (TTCC) published a phase III trial that attempted to demonstrate non-inferiority of cetuximab radiotherapy to cisplatin radiotherapy, but failed to achieve its non-inferiority goal.

Studies of immunotherapy combined with radiotherapy have been negative in the general population. We are currently waiting to learn the role of immunotherapy in the induction phase, whether or not associated with chemotherapy, and in the adjuvant phase after surgery or radiotherapy.

Recurrent/metastatic disease

In the area of ​​relapses, the experts of the scientific society explain, the possibility of emergency surgery or radiation treatment in combination with chemotherapy or cetuximab should always be considered. In cases already irradiated, the possibility of re-irradiation will be considered, but rescue at this stage of evolution is not always possible. Patient selection is the key to achieving long-term survival; Salvage treatment is indicated depending on the volume of the relapse, the time elapsed since the previous radiation therapy, and the initial condition of the patient.

In terms of systemic treatment, the addition of cetuximab to standard chemotherapy represented a significant advance for these patients. In recent years, the EXTREME (cisplatin, 5-fluorouracil, and cetuximab) and TPEX (cisplatin, docetaxel, and cetuximab) regimens have been promoted as treatment options for patients with advanced head and neck cancer.

The TPEX regimen has proven to be a less toxic alternative to the EXTREME regimen and eliminates the need for a fluorouracil pump. ERBITAX (paclitaxel and cetuximab) is an effective therapeutic option for frail patients who are not candidates for cisplatin.

Immunotherapy for Head and Neck Cancer

However, a major advance in the treatment of head and neck tumors has been the inclusion of immunotherapy in the therapeutic algorithm. Before this, there was a therapeutic gap in cases refractory to cisplatin, especially in patients refractory to EXTREME treatment.

That was until 2016, when the FDA approved immunotherapies for these cases—two anti-PD-1 drugs whose main benefit is long-term survival for responders. The FDA accelerated approval of nivolumab in April 2016 after data from the first pivotal phase III CHECKMATE 141 trial were presented, in which nivolumab demonstrated an overall survival (OS) benefit over investigator-chosen chemotherapy in patients who crossed over to platinum-based treatment for localized disease. There was an improvement in OS (7.7 vs. 3.3 months), but most striking was that more than 10% of patients in the nivolumab group were alive at three years.

On September 1, 2016, the FDA granted accelerated approval to pembrolizumab based on data from the non-randomized Phase Ib KEYNOTE-012 trial. Most patients in the study had previously received at least two different cycles of treatment. A median overall survival of 8 months was achieved, with 38% of patients still alive one year after starting treatment. A Phase II trial (KEYNOTE-055) subsequently confirmed these data in a 2017 publication in Journal of Clinical Oncology.

Lower mortality rate

In 2018, the results of the KEYNOTE-048 study were published, demonstrating the superiority of pembrolizumab as monotherapy and pembrolizumab in combination with cisplatin-based chemotherapy in first-line patients with recurrent and/or metastatic disease with platinum-sensitive disease and a positive PDL1 result. Since 2021, it has been included in the standard treatment of this group of patients with positive PDL1, and this is reflected in the SEOM guidelines for the treatment of these tumors.

But perhaps the most impressive aspect is the reduction in mortality risk seen with the introduction of these drugs. In an updated study published in 2023, with four years of follow-up, treatment with pembrolizumab showed a reduction in the risk of death compared with standard chemotherapy of 26-39%, depending on PD-L1 expression, and a combination of chemotherapy and pembrolizumab of 38%.