T. Feys MBA, MSc

Immune checkpoint inhibition for pancreatic cancer: is there light at the end of the tunnel?

Pancreatic adenocarcinoma (PDAC) continues to be one of the most lethal cancers. In recent years, immunotherapy using immune checkpoint inhibitors (ICIs) resulted in dramatic clinical benefits in many solid tumor types. However, PDAC patients are yet to experience the potential benefits of this treatment strategy. This article will provide a brief overview of the available data obtained with ICI-based treatments in patients with advanced PDAC. These studies illustrate that PDACs are inherently immune-cold tumors who are largely refractory to ICI-based therapy in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harness the potential durable benefits of immune-modulating therapy in this setting.

Immunotherapy for ovarian cancer: a challenging endeavor

Ovarian cancer (OC) remains to be one of the most common gynecological malignancies and is characterized by a high mortality and a poor prognosis. Cytoreductive surgery and chemotherapy remain the backbone of the OC treatment, but despite this strategy most women will experience disease recurrence. For these patients there is a large unmet need for more effective therapies. Despite the compelling evidence for the fact that OC is an immunogenic tumor, studies evaluating immune checkpoint inhibitors have yielded largely disappointing results. Several therapeutic strategies are currently being studied to boost response rates to anti-PD1/PD-L1, including the addition of chemotherapy, anti-angiogenic agents, PARP inhibitors, or other immune checkpoint inhibitors. In addition to this, other immunotherapeutic approaches such as adoptive T-cell therapy, vaccines and therapeutic targeting of myeloid immune checkpoints such as the “don’t eat me” signal CD47 are also being investigated in OC. While several of these options are promising, large controlled randomized studies are still needed to implement new immunotherapeutic options into clinical practice.

Contemporary biomarker testing for non-small-cell lung cancer

In recent years, the number of approved targeted therapies for patients with advanced non-small-cell lung cancer (NSCLC) has steadily increased, making an efficient and effective molecular profiling of paramount importance in the management of NSCLC patients. To ensure that patients receive the most appropriate treatment, broad upfront molecular testing including both established and new targetable alterations should nowadays be routine practice in the diagnostic work-up of newly diagnosed patients with advanced NSCLC. Specifically for Belgium, ComPerMed guidelines recommend to test the mutational status of EGFR, KRAS and BRAF, screen for MET exon 14 skipping mutations and look for the presence of genetic fusions/rearrangements involving ALK, ROS1, RET, and NTRK1-3. These biomarkers should be analyzed in all patients with non-squamous NSCLC and in selected NSCLC patients with a squamous histology (i.e., never smokers, very young patients). Given the multitude of biomarkers that need to be tested, multigene testing using next generation sequencing (NGS) has gradually replaced sequential single gene testing as the preferred molecular screening tool in NSCLC. In fact, combined DNA/RNA NGS is now considered to be the most reliable and efficient approach for comprehensive detection of all approved and emerging biomarkers in advanced NSCLC (excluding PD-L1 detection). Both tissue samples as cytology specimens can be used for these NGS analyses as long as they contain a sufficient percentage of neoplastic cells and are processed in a way that safeguards nucleic acid integrity. In Belgium, a program is in place offering reimbursed DNA/RNA NGS testing to NSCLC patients through a network of 10 reference centers.

Rapid PCR testing as adjunct to next-generation sequencing for the detection of alterations in patients with non-small-cell lung cancer

Next-generation sequencing (NGS) is increasingly replacing single gene assays in the screening for therapeutic biomarkers in patients with NSCLC. While NGS has the clear advantage that it can detect all targetable oncogenic driver alterations simultaneously, this technique does come with the risk for a longer turnaround time, in part as a result of the centralized way in which this testing is often organized. However, with a delayed test result, you risk that some patients with a high disease burden miss the opportunity to be treated with a specific targeted therapy, or even die before the NGS result comes in. To mitigate this risk, it may be interesting to adopt a rapid PCR-based testing strategy for selected oncogenic driver mutations in parallel to broad NGS testing.

Antibody-drug conjugates in the treatment of advanced breast cancer

Antibody-drug conjugates (ADCs) combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads. In 2013, the human epidermal growth factor receptor 2 (HER2)-targeted ADC ado-trastuzumab emtansine (T-DM1) entered the treatment arsenal for patients with metastatic breast cancer (BC), making it the first ADC to be approved for the treatment of a solid tumor. The pace of ADC development for solid tumors has since increased dramatically, with currently more than 100 ADCs being investigated in clinical trials. Specifically in breast cancer, there are now 3 EMA-approved ADCs: T-DM1, trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG). This article will briefly touch upon the key components and mode of action of ADCs after which the clinical experience with the EMA-approved ADCs in breast cancer will be discussed.

The KRAS oncogene: a long and winding road to druggability

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in about a quarter of all human cancers and is at the centre of several pathways involved in tumorigenesis. As such, novel therapeutic strategies that can target this oncoprotein are potentially extremely valuable. However, since its discovery as on oncogene, almost four decades have gone by without any major breakthrough in the therapeutic targeting of mutant KRAS. In recent years, however, we are finally witnessing a paradigm shift with the discovery of druggable pockets on KRAS and the clinical activity of covalent KRAS^G12C inhibitors such as sotorasib and adagrasib.

Highlights in thoracic oncology

SUMMARY

In the field of thoracic oncology, many refinements and longer follow-up results of previously reported trials were presented during the annual ASCO 2022 meeting. Although there were no presentations of new, truly practice-changing trials, several exciting and promising data are worthwhile to mention in this highlights in thoracic oncology overview.

(Belg J Med Oncol 2022;16(5):229–35)