J.B. Vermorken MD, PhD

Novel, rationally designed combination strategies, based on (phospho)-proteomic analyses, to enhance the response to cetuximab therapy in head and neck cancer

SUMMARY

Head and neck squamous cell carcinoma (HNSCC) is often characterised by overexpression of the epidermal growth factor receptor (EGFR), which is associated with aggressive disease and poor prognosis. While the EGFR-targeting antibody cetuximab initially showed promise for the treatment of HNSCC, the development of therapeutic resistance has hindered its efficacy. Therefore, this PhD thesis focused on unravelling mechanisms underlying cetuximab resistance and developing strategic combination therapies to overcome this resistance in HNSCC. Literature review illustrated the importance of the PI3K/Akt pathway as a potential target, with studies indicating its role in resistance to anti-EGFR targeting agents. Protein phosphorylation profiling indicated that increased Akt1/2/3 phosphorylation seems to be characteristic for acquired cetuximab resistance in HNSCC cell lines. Interestingly, we observed synergy between cetuximab and Akt inhibitor MK2206 or PI3K inhibitor buparlisib in multiple cell lines with different sensitivity to cetuximab. Furthermore, the combination treatment of cetuximab plus buparlisib altered the tumour microenvironment, increasing tumour immunogenicity by triggering immunogenic cell death markers and reducing immunosuppression. This research underscores the potential for novel, rationally designed combination therapies to combat cetuximab resistance in HNSCC and suggests avenues for further exploration, including triple combination therapies involving immune checkpoint inhibitors, offering hope for improved outcomes in cancer therapy.

(BELG J MED ONCOL 2024;18(6):244-247)

Highlights in gynaecological cancer

“The United States is a long way from achieving clinical equity among its people” said Joe Elia, editor of NEJM Group in the introduction of the eBook on Racial Disparities in Clinical Medicine which was distributed among all ASCO members in June 2021. It is not without reason that this eBook is coming out now. In the President’s Address, Lori J Pierce mentioned how segregation impacts on health care. “Today”, she said, “ensuring equity of care – that is our good fight, this is the foundation of ASCO”. It was interesting to notice that this topic also got attention in the Gynaecological Cancer track of the meeting. Overall, ASCO 2021 featured 14 presentations on cervical cancer, 32 on uterine cancer and 60 on ovarian cancer. The most important messages of these different presentations will be discussed in this article.

(BELG J MED ONCOL 2021;15(5):197-205)

Immune-modulating antibodies in head and neck cancer: past, present, and future

Squamous cell carcinoma of the head and neck (SCCHN) has recently expanded the growing range of oncologic diseases successfully treated with immune-modulating agents. With the origins dating back to the nineteenth century, the concept of immunotherapy was repeatedly revisited and refined but also rejected and criticized. Currently, its armamentarium comprises tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating antibodies. Among these approaches it has been the latter one drawing major attention from healthcare professionals. Nivolumab and pembrolizumab are monoclonal immunoglobulins directed against programmed cell death protein-1 (PD-1), an immune-checkpoint negatively regulating T-cells. In second-line recurrent and/or metastatic SCCHN, two phase III studies demonstrated meaningful clinical benefit achieved by these drugs, dubbed checkpoint inhibitors, compared with standard monotherapy (methotrexate, docetaxel, or cetuximab). In the CheckMate-141 trial, nivolumab significantly improved median overall survival (OS) from 5.1 to 7.5 months. A similar benefit achieved by pembrolizumab in KEYNOTE-040 fell short of statistical significance (8.4 vs. 6.9 months), probably due to post-study immune-checkpoint therapy leading to a better-than-expected survival in the control arm. However, the classical outcome measures do not fully capture the exceptional activity of these agents. Apart from low frequency of severe adverse events (13% vs. 35% with standard therapy), these antibodies can induce durable tumour responses and retain activity even after several previous chemotherapy lines. With their advent in first-line palliative regimens and protocols for locally advanced disease, further progress is expected. Reliable predictive biomarkers are urgently needed, and several candidates are being evaluated. Among them, tumour mutational burden and gut microbiota offer an innovative approach to biomarker-enrichment strategies.

The role of chemoradiotherapy in elderly patients with locoregionally advanced head and neck cancer

Paralleled by rising cancer burden, recent global demographic changes have been marked by a constantly growing number of people aged 65 or more. In the United States, presently 54% of malignant head and neck cancer cases occur in the geriatric population, and by 2030, this proportion is expected to attain 66%. Despite the obvious importance of addressing specific needs of elderly patients, these individuals have often been undertreated and refrained from geriatric assessment in clinical practices and underrepresented in prospective trials. Unfortunately, many health care professionals still believe that older patients cannot tolerate intensified treatment regimens. In this paper, we focused on concurrent chemoradiation as definitive or post-operative treatment in locoregionally advanced squamous cell carcinoma of the head and neck. Although confirmatory data from large randomised phase III trials conducted in the elderly are lacking, available evidence from meta-analyses of prospective trials and retrospective reviews of population-based cross-sectional registries indirectly support this approach, primarily in the definitive treatment setting. However, irrespective of calendar age, distinction between fit and frail senior patients is of paramount priority. In this respect, several geriatric screening tools have been developed for use by practicing physicians to help select which patients need a comprehensive geriatric assessment, who requires a specific examination only (e.g. focused on certain comorbid conditions, cognition, nutritional status, social support, or psychological state), and where no further testing is warranted.

(BELG J MED ONCOL 2018;12(3):110–117)

Locally advanced cancer of the uterine cervix: Diagnosis and multidisciplinary treatment

Patients treated for locally advanced cancer of the uterine cervix, FIGO stages IB2 to IVA, may expect a 5-year survival varying from 75% to 16%, respectively. Even though screening programs in Latin America and the Caribbean were established since the 1960´s, advanced stages continue to impact mortality in these countries. Morbidity and quality-of-life are compromised because most of the patients present with symptoms in these later stages. It is crucial to accurately determine tumour size and extension to surrounding organs, not only to establish prognosis, but also for therapy planning. Positron emission tomography combined with computed tomography is the preferred imaging modality but magnetic resonance imaging has high accuracy characterising the primary lesion. Concurrent cisplatin-based chemoradiotherapy is the standard nonsurgical approach, with a relative risk of death of 0.81 compared to the same radiation therapy alone, showing an absolute survival benefit at five years of 6%. Before or after chemoradiation, additional systemic therapy could be used to improve outcomes in patients with locally advanced cancer of the uterine cervix.

(BELG J MED ONCOL 2018:12(3):118–124)

Immune-modulating antibodies in head and neck cancer: past, present, and future

Squamous cell carcinoma of the head and neck (SCCHN) has recently expanded the growing range of oncologic diseases successfully treated with immune-modulating agents. With the origins dating back to the nineteenth century, the concept of immunotherapy was repeatedly revisited and refined but also rejected and criticized. Currently, its armamentarium comprises tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating antibodies. Among these approaches it has been the latter one drawing major attention from healthcare professionals. Nivolumab and pembrolizumab are monoclonal immunoglobulins directed against programmed cell death protein-1 (PD-1), an immune-checkpoint negatively regulating T-cells. In second-line recurrent and/or metastatic SCCHN, two phase III studies demonstrated meaningful clinical benefit achieved by these drugs, dubbed checkpoint inhibitors, compared with standard monotherapy (methotrexate, docetaxel, or cetuximab). In the CheckMate-141 trial, nivolumab significantly improved median overall survival (OS) from 5.1 to 7.5 months. A similar benefit achieved by pembrolizumab in KEYNOTE-040 fell short of statistical significance (8.4 vs. 6.9 months), probably due to post-study immune-checkpoint therapy leading to a better-than-expected survival in the control arm. However, the classical outcome measures do not fully capture the exceptional activity of these agents. Apart from low frequency of severe adverse events (13% vs. 35% with standard therapy), these antibodies can induce durable tumour responses and retain activity even after several previous chemotherapy lines. With their advent in first-line palliative regimens and protocols for locally advanced disease, further progress is expected. Reliable predictive biomarkers are urgently needed, and several candidates are being evaluated. Among them, tumour mutational burden and gut microbiota offer an innovative approach to biomarker-enrichment strategies.

TPFE (docetaxel, cisplatin, 5-FU and cetuximab) for recurrent mucoepidermoid carcinoma of the parotid gland: an aggressive strategy for an aggressive disease

SUMMARY

The prognosis of patients with advanced malignant salivary gland cancer is usually poor. Systemic therapy combined with best supportive care is recommended for patients with metastatic or recurrent advanced salivary gland cancer ineligible for surgery or radiotherapy. Sensitivity to chemotherapy is thought to be histotype specific. However, to date, none of the systemic therapies, whether cytotoxic or non cytotoxic, can be considered standard for these tumours.

We report the case of a 43 year-old male patient with a third (loco)regional recurrence and metastases in lymph nodes below the clavicles of a mucoepidermoid carcinoma of the right parotid gland. He participated in a feasibility study and was treated with 3-weekly cycles of docetaxel, cisplatin, 5-fluorouracil plus weekly cetuximab (TPFE). After four TPFE cycles, additional radiation was given to the left neck. A complete response was reached which is ongoing for ten years. TPFE induced acute toxicities: skin rash grade 3, hypotension grade 3, neutropenia grade 3, anaemia grade 2 and alopecia grade 2. This observation underlines the importance of offering patients the possibility to participate in clinical trials. International collaboration for rare head and neck cancers, such as mucoepidermoid carcinoma, is urgently needed.

(BELG J MED ONCOL 2017;11(8):386-392)