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Adding immunotherapy to the treatment of head and neck cancers - not as simple as hoped

 

Adding immunotherapy to the treatment of head and neck cancers - not as simple as hoped - PDF Version

Immune checkpoint inhibition is a treatment modality that has revolutionised the ways in which patients, especially those who have advanced-stage cancers, are treated. Programmed cell-death protein (PD-1) and its ligand, PD-L1, are transmembrane proteins that are expressed on cancer cells and T-cells. They inhibit T-cell activation, proliferation and survival, and therefore prevent T-cell-mediated killing of cancer cells. Restoration of T-cell activation through the use of PD-1/PD-L1 inhibitors has produced significant clinical response in a number of cancer types that include head and neck squamous cell carcinoma (HNSCC), melanoma and non-small-cell lung cancer (NSCLC) (1). Radiotherapy-induced DNA damage can also stimulate the immune response. Specifically, radiotherapy can induce the release of damage-associated molecular patterns (DAMPs), which results in the activation of antigen-presenting cells that stimulate T-cell responses (2). Accumulating evidence also suggests that chemotherapy, especially through use of platinum-based agents, has immunostimulatory effects that promote their anti-cancer activity (3). Taken together, previous positive clinical trial data and a strong scientific rationale led to the hypothesis that a combination of chemoradiotherapy (CRT) and immunotherapy would be beneficial.

HNSCC is the sixth most common malignancy worldwide; approximately 600,000 new cases are reported each year. CRT plays a vital role in the curative management of locally advanced HNSCC. However, the five-year survival rate remains at about 50% despite the improvement of this figure in patients with tumours that are positive to human papillomavirus (HPV) (4). Therefore, there is an urgent need for novel therapeutic strategies and particularly for those with HPV-negative disease. Data from phase I-III clinical trials have shown an improvement in treatment outcomes for patients with recurrent and metastatic cancers, as well as locally advanced HNSCC, when anti-PD-L1 immunotherapy has been administered alone or in combination with chemotherapy (5). JAVELIN Head and Neck 100 (JAVELIN) was the first randomised phase III clinical trial that considered whether a combination of standard-of-care CRT with avelumab (an antibody-based PD-L1 inhibitor) improved outcomes in patients with locally advanced HNSCC. 

JAVELIN investigated the treatment outcome in 697 HNSCC patients, stratified by HPV status, tumour stage and nodal stage, and randomised the trial participants into an avelumab group and a placebo group. The patients received a single, intravenous avelumab lead-in dose or placebo, which was followed by radiotherapy. They also received a standard cisplatin dose in combination with avelumab or placebo. After CRT, the patients received a two-weekly maintenance dose of avelumab or placebo for 12 months or until there was evidence of disease progression.  JAVELIN did not meet its primary endpoint of improving progression-free survival through the addition of avelumab to CRT in HNSCC (6).

Given the promise and clear potential of combined immunotherapy and CRT, it is essential that we understand this lack of response, and this is something to which radiobiologists are likely to be able to contribute. A Phase III placebo-controlled trial (the PACIFIC trial) of immunotherapy with CRT in stage 3 NSCLC patients reported improvements in the primary end points of overall and progression-free survival rates. However, it is important to note that JAVELIN and the successful PACIFIC trial cannot be directly compared. Notably, NSCLC patients on the PACIFIC trial had an improved outcome with CRT, which was followed by maintenance avelumab, i.e., the treatments were not concurrent as in JAVELIN (7). Neither PACIFIC nor JAVELIN trials stratified patients for PD-L1 status, which has been demonstrated to be a predictive biomarker for response to immunotherapy (8). Retrospective analysis of data for JAVELIN patients suggested that those with higher PD-L1 levels could have a higher response rate to avelumab combined with CRT than those with lower PD-L1 levels. Notably, HPV status, which has a significant role in radiation response, did not impact patient response on the JAVELIN trial in the patients who received avelumab compared with those who received placebo (6).

CRT causes a complex interplay of immunostimulatory and immunosuppressive responses, all of which are further impacted by the tumour microenvironment. For example, the occurrence of hypoxia in HNSCC has been well-documented and leads to both radiation resistance and an immunosuppressive environment (9). Characterisation of the balance between these responses is critical to schedule the delivery of immunotherapy with CRT. It has been shown that, after radiotherapy, the proportion of immunosuppressive regulatory T-cells increases in the tumour microenvironment of HNSCC patients, whereas the proportion of cytotoxic T-cells decreases (10). Conversely, immune-stimulating effects of radiotherapy include an increase in the numbers of natural killer cells, helper T-cells, as well as the levels of PD-1 in effector T-cells (11). In addition, the presence of cisplatin can stimulate antitumour immune responses by upregulating major histocompatability complex class I expression and by recruiting and activating cytotoxic T-cells, thereby antagonising the immunosuppressive microenvironment (3). Thus, the failure to extend progression-free survival in the JAVELIN trial could be due to this complex biology and potential antagonism between CRT and avelumab. The promise of immune checkpoint inhibitors in improving patient prognosis, either as monotherapy or combined with CRT, is clear. However, the results of the JAVELIN trial have clearly demonstrated that we do not fully understand the underlying biology that dictates patient response. Increasing our understanding of the cross talk between radiobiology and the immune response and how to select patients who will benefit from these combinations is therefore essential.

Oxford Institute for Radiation Oncology
Department of Oncology
University of Oxford, Oxford

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Çağla Tosun

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Athanasios Patsalias

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Ester Hammond

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  3.  de Biasi, A.R., J. Villena-Vargas, and P.S. Adusumilli, Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence. Clin Cancer Res, 2014. 20(21): p. 5384-91.
  4.  Johnson, D.E., et al., Head and neck squamous cell carcinoma. Nat Rev Dis Primers, 2020. 6(1): p. 92.
  5. Burtness, B., et al., Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet, 2019. 394(10212): p. 1915-1928.
  6.  Lee, N.Y., et al., Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol, 2021. 22(4): p. 450-462.
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