T. Feys MBA, MSc

Targeting RET-alterations in solid tumours

Over the past decade, researchers have tried to tackle RET-driven cancers with various multikinase inhibitors. However, their efficacy was only modest and came at the cost of significant toxicities, leading to high rates of treatment discontinuation. Therefore, the development of RET-specific inhibitors has become paramount. Recently, the highly selective RET tyrosine kinase inhibitors selpercatinib and pralsetinib have demonstrated high response rates in patients with RET-altered non-small cell lung cancer (NSCLC) and thyroid cancer. As brain metastases eventually occur in approximately 50% of patients with RET fusion-positive NSCLC, special attention should go to the intracranial activity of these drugs.

Treatment sequencing in patients with advanced, BRAF-mutant melanoma

Over the last decade, the introduction of immune checkpoint inhibitors and targeted agents inhibiting BRAF, and MEK signal transduction pathways revolutionised the treatment paradigm for patients with metastatic melanoma. However, to date there is still no consensus on the optimal treatment sequence in BRAF-mutant metastatic melanoma. In the absence of prospective, randomised data, the treatment choice in clinical practice is mainly driven by patient characteristics. More recently, clinical trials are assessing the optimal treatment sequence of targeted therapy and immunotherapy, while other studies are looking into the potential of combining both treatment modalities in first-line.

Targeted therapy making its move in early-stage EGFR-mutant NSCLC

Approximately 25% of patients with non-small cell lung cancer (NSCLC) are being diagnosed in an early stage of the disease. Even though these patients are eligible for radical surgery, the five-year survival rates for fully resected early-stage NSCLC remains disappointing. In fact, for patients who receive adjuvant chemotherapy after surgery, recurrence rates are high, with approximately half of patients suffering from disease relapse. The design of molecularly oriented studies and the availability of novel potent and less toxic targeted agents paved the way for the evaluation of these drugs in the (neo)adjuvant setting for patients with early-stage NSCLC harbouring oncogenic driver mutations. Here we summarise the results obtained with EGFR-targeted drugs in early-stage NSCLC.

The role of HER2-targeted therapy in metastatic gastrointestinal cancer: gastric cancer (and beyond)

Molecular targeted therapy of cancer has long been the focus of clinicians, with the human epidermal growth factor receptor-2 (HER2) signalling pathway being one of the most popular targets. However, in contrast to the plethora of anti-HER2 agents that have entered the breast cancer treatment paradigm, trastuzumab remains the only anti-HER2 drug that is approved for the first-line treatment of HER2 positive advanced gastric cancer. Recently, however, promising data are emerging with new anti-HER2 agents, including antibody-drug-conjugates (ADC) and bispecific antigens. In addition, also the combination of anti-HER2 therapy with immune checkpoint inhibition holds lots of promise for the treatment of HER2-positive stomach cancer. Despite being standard of care in the treatment of HER2-positive gastric cancer, the role of HER2 as a therapeutic target is far less established in other gastrointestinal malignancies. However, promising data with the ADC trastuzumab-deruxtecan are emerging in colorectal cancer and also in biliary tract cancer phase I studies start to point towards a potential role for HER2 targeting.

Highlights in breast cancer

ASCO 2021 featured one crucial, practice-changing trial in early breast cancer: the OlympiA trial showed that one year of adjuvant olaparib improves invasive disease-free survival by 8.8% compared to placebo, when administered to high risk early breast patients (triple negative or hormone sensitive and HER2 negative) with a germline BRCA1 or 2 mutation. Furthermore, ECOG-ACRIN EA1131 failed to show improved outcome in triple negative breast cancer treated without pathological complete response after neoadjuvant chemo-therapy with platinum based chemotherapy compared to the current standard capecitabine. GeparNUEVO for the first time showed long term outcome with anti-PD(L)1 therapy administered with neoadjuvant chemotherapy in triple negative breast cancer. In the advanced setting, interesting overall survival updates of the PALOMA-3 and MONALEESA-3 studies were presented. Furthermore, the SYsucc-002 trial demonstrated that trastuzumab plus endocrine therapy was non-inferior to and had fewer toxicities compared with trastuzumab plus chemotherapy in patients with HR+/HER2- metastatic breast cancer. In addition, this article will touch upon several other studies that are notable.

(BELG J MED ONCOL 2021;15(5):208-17)

Highlights in respiratory oncology

At ASCO 2021 much of the attention in the field of lung cancer went to early-stage non-small cell lung cancer (NSCLC) discussing both (neo)adjuvant strategies and local treatment modalities. In metastatic NSCLC, we would like to highlight some recent (chemo)immunotherapeutic advances in the treatment of non-oncogene addicted tumours as well as promising strategies to overcome osimertinib resistance, targeting of KRAS G12C mutated tumours and updated results for EGFR exon 20, HER2 exon 20, MET and RET targeting. As a final abstract, the results of the randomised phase III CALGB 30610/RTOG 0538 trial evaluating high-dose thoracic radiotherapy in small cell lung cancer will be summarised. We would like to acknowledge Prof. Veerle Surmont (University Hospital Ghent) for her help in selecting the abstracts discussed in this overview.

Highlights in gastro-intestinal cancers

At ASCO 2021, the most important studies in gastro-intestinal (GI) cancer related to the use of immuno-therapy in cancers of the upper gastro-intestinal tract. For advanced oesophageal squamous cell carcinoma (ESCC), the CheckMate 648 trial demonstrated that both nivolumab plus chemotherapy and nivolumab plus ipilimumab represent a new potential first-line standard of care, especially for patients with a tumour PD-L1 expression of at least 1%. For adenocarcinoma of the oesophagus and oesophago-gastric junction, there is no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy. For tumours of the lower gastro-intestinal tract, the most important results came from the DESTINY-CRC01, CHRONOS, FIRE-4.5 and PANAMA studies.

(BELG J MED ONCOL 2021;15(5):248-53)