HJBR Mar/Apr 2023

HEALTHCARE JOURNAL OF BATON ROUGE I  MAR / APR 2023 59 Victor Lin, MD, PhD Medical Oncologist Mary Bird Perkins Cancer Center triggered a race to find new targets. As a re- sult, targeted approaches in NSCLCs have been developed for certain types of altera- tions in BRAF, RET, MET, HER2, and KRAS, and this remains a hotbed of research. Where does precision oncology go from here? The ultimate hope is that predictive bio- markers may prove to be tumor-agnostic, meaning that they can be used regardless of tumor type. The FDA caused a paradigm shift with the first tumor-agnostic approval of the immune checkpoint inhibitor pem- brolizumab in all tumors with dMMR or MSI-H and subsequently expanded that to include tumors with high tumor mu- tation burden (TMB-H). Other approvals have followed for dostarlimab in tumors with dMMR; entrectinib and larotrectinib for tumors harboring fusions in one of the NTRK genes; selpercatinib for tumors with a RET fusion mutation; and dabrafenib and trametinib in combination in tumors with a BRAF V600E mutation. Notably, this last regimen is known to be ineffective in colorectal cancers, which highlights the complexity of the biology involved. Other opportunities for tumor-agnostic approvals continue in development. The use of PARP inhibitors in tumors with inactivat- ing mutations in BRCA1, BRCA2, or PALB2, or with other evidence of homologous re- combination deficiency (HRD), such as a high degree of loss of heterozygosity (LOH), is an area of active investigation. Inhibitors of the KRAS G12C mutation have been ap- proved in NSCLC, and their efficacy in other tumor types with this mutation is being ex- plored. There is also hope that the use of newer antibody drug conjugates (ADCs) tar- geting tumors that express the HER2 protein, such as trastuzumab deruxtecan (T-DXd), can be expanded beyond their current in- dication in breast cancer. Aquirk of biology is that these alterations tend to be enriched in specific tumor types and are otherwise quite rare in other cancers, often at rates of 1-2% or even lower. Thus, generating the data required for a formal tumor-agnostic approval can be expected to take many years. In the interim, medical oncologists are using CGP to try to iden- tify potential targets for additional lines of therapy after patients have exhausted other avenues of standard care, either via existing tumor-agnostic indications, clinical trials, or off-label use of drugs approved in other settings. However, maximizing this type of approach requires expert interpretation of the test results, good understanding of the treatment landscape, and access to the appropriate clinical trials. Furthermore, al- though CMS has issued guidance supporting the use of CGP in advanced cancers, more policy work is required to ensure coverage for all patients regardless of the insurer. n Victor Lin,MD,PhD, is amedical oncologist and also provides leadership for Mary Bird Perkins Cancer Center’s clinical research, genetics, and precision medicine programs. Lin completed a Bachelor of Science in biochemistry with honors at Brown Uni- versity before training in the NIH-supportedMedical ScientistTraining Program (MSTP) at the University ofAlabama at Birmingham,receiving both anMD and a PhD in cell biology.After training,he joined the UAB Department of Medicine as an instructor in the Divi- sion of Hematology andOncology with a clinical focus on lung cancer and sarcoma and a research focus in precision oncology. He also served as the associate director of the UABMolecularTumor Board and was a member of the UAB MSTPAdvisory Committee. colorectal cancer, deficiencies in mismatch repair proteins (dMMR) and resultant high microsatellite instability (MSI-H) are used to screen patients for hereditary cancer syn- dromes, to determine if adjuvant cytotoxic chemotherapy after surgical resection is warranted, and to predict response to im- munotherapy in the metastatic setting. In acute promyelocytic leukemia (APL), the presence of the pathognomonic PML-RARA translocation is both diagnostic and effec- tively targetable with the chemotherapy- sparing combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, the precision oncology para- digm has revolutionized the treatment of metastatic non-small cell lung cancers (NSCLCs) like no other type of malignancy. Multiple subtypes of NSCLC have now been defined by a variety of biomarkers. In the not-too-distant past, the only relevant cat- egorization of NSCLC regarding treatment selection was non-squamous versus squa- mous histology, which is used to predict the efficacy of pemetrexed over taxanes. Now, clinicians assess the level of expression of PD-L1 by immunohistochemistry (IHC) to predict the likelihood of response to im- mune checkpoint inhibitors, in addition to performing comprehensive genomic pro- filing (CGP) in search of actionable driver mutations. Less than a decade ago, it was deter- mined that NSCLCs with specific types of mutations in EGFR, ALK, and ROS1 could be treated with highly effective oral targeted therapies. Not only are these more conve- nient and less toxic for patients, they have also proven to be more efficacious than con- ventional chemotherapy. This revelation has