Articles

Optimising the first-line treatment of patients with ROS1-rearranged non-small cell lung cancer

BJMO - 2021, issue Special, november 2021

T. Feys MSc, MBA

The discovery of druggable mutations in non-small cell lung cancer (NSCLC) has revolutionised the treatment of these patients. A prime example of this consists of targeting the constitutively activated ROS1 kinase in patients harbouring a genetic ROS1 rearrangement. In 2016, the multikinase tyrosine kinase inhibitor (TKI) crizotinib became the first targeted treatment option for patients with advanced ROS1-positive NSCLC. Unfortunately, however, crizotinib comes with some important drawbacks. First of all, the reduced central nervous system (CNS) penetration of crizotinib makes it unsuitable for patients with metastases in the CNS, a very common finding in ROS1-rearranged NSCLC. This lack of intracranial activity also leads to an increased risk for the development of new CNS lesions. In addition to this, acquired mutations in ROS1 often render patients who initially have a good response, resistant to crizotinib. To address these issue, several new highly potent and CNS penetrant ROS1 inhibitors have been developed (i.e. entrectinib, lorlatinib, repotrectinib), with several studies highlighting their potential as a frontline treatment for patients with advanced ROS1-rearranged NSCLC. Recently, entrectinib became the first of these next-generation ROS1 inhibitors to receive approval by the European Commission for the treatment of ROS1-rearranged advanced NSCLC patients who did not yet receive a ROS1 targeting agent.

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PARP inhibition as a new treatment modality in metastatic prostate cancer

BJMO - 2021, issue Special, november 2021

T. Feys MSc, MBA

Despite the fact that substantial survival improvements were achieved over the last two decades, prostate cancer remains lethal at the metastatic castration-resistant stage (mCRPC) and new therapeutic approaches are needed. The genomic landscape of metastatic prostate cancer reveals that up to 20% of patients harbour somatic mutations in genes involved in DNA damage response pathways, forming the rationale to assess PARP inhibition as a therapeutic modality in this setting. Several clinical trials have demonstrated the potential of PARP inhibition in mCRPC harbouring homologous recombination repair (HRR)-related gene mutations. Recently, these efforts culminated in the EMA approval of olaparib for the treatment of adult patients with mCRPC harbouring a BRCA1/2-mutation who progressed following prior therapy, including a novel hormonal agent (i.e. abiraterone acetate or enzalutamide).

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Targeting RET-alterations in solid tumours

BJMO - 2021, issue Special, november 2021

J. Blokken PhD, PharmD, T. Feys MSc, MBA

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.

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Treatment sequencing in patients with advanced, BRAF-mutant melanoma

BJMO - 2021, issue Special, november 2021

T. Feys MSc, MBA, J. Blokken PhD, PharmD

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.

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

BJMO - 2021, issue Special, november 2021

J. Blokken PhD, PharmD, T. Feys MSc, MBA

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.

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

BJMO - 2021, issue Special, november 2021

T. Feys MSc, MBA

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.

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Highlights in breast cancer

BJMO - volume 15, issue 5, september 2021

J. Blokken PhD, PharmD, T. Feys MSc, MBA, K. Punie MD, H. Wildiers MD, PhD

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)

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