While great strides have been made in the treatment of advanced renal cell carcinoma (RCC) with the emergence of immune checkpoint inhibitors (ICIs) and VEGFR-targeting drugs, sizable proportions of patients still do not respond to upfront therapy and long-term responses only occur in a minority of patients. There is therefore a great need for the development of better predictors of response and an increased understanding of mechanisms of resistance to these therapies. Alternative immune checkpoints outside the PD-1/PD-L1 axis, such as LAG3, have been implicated as one mechanism of resistance to ICIs. These checkpoints thus represent attractive therapeutic targets, and indeed the LAG3 inhibitor relatlimab was recently approved for the treatment of metastatic melanoma in combination with anti-PD-1 therapy. LAG3 inhibitors are being evaluated for RCC as well. In this context, a better understanding of LAG3 expression patterns in RCC and how they relate to clinicopathologic features of disease and response to immunotherapy may give insight into mechanisms of resistance to PD-1 inhibitors and aid in the identification of subgroups of patients more likely to benefit from certain drug regimens. In this study, we assessed LAG3 protein levels in leukocytes in normal kidney adjacent to RCC, primary RCC tumors, and matched metastatic tumors, including large numbers of brain metastases. We found that LAG3 protein levels are on average lower at metastatic sites compared to matched primary tumors, and that the difference was more pronounced in patients with high-risk clinical characteristics, including those with larger primary tumor size, grade 4 tumors, IMDC poor-risk disease, and initial presentation with brain metastases. We further saw that the prognostic value of LAG3 levels varies depending on the tissue site queried (i.e., primary tumor versus metastases), and that relatively higher LAG3 levels at metastatic sites may predict a better response to immunotherapy and longer overall survival after the development of metastatic disease. These findings may have important implications for the design of future studies involving LAG3 or other immunotherapies in RCC.
Lung cancer is the second most common cancer and the most common cause of cancer-related death in the United States. Brain metastases (BM) are detected in 21% of patients with lung cancer at the time of diagnosis and are the sole metastatic site in 35% of patients with stage IV disease. The best upfront therapy for non-small-cell lung cancer depends on both tumor programmed death 1 ligand-1 (PD-L1) expression and the presence or absence of a targetable genetic alteration in genes such as epidermal growth factor receptor and anaplastic lymphoma kinase. In the absence of a targetable genetic alteration, options include chemotherapy, immune checkpoint inhibitors (ICIs), and ICI combined with chemotherapy. Upfront local therapy followed by systemic therapy is the current standard of care for the management of BM, and may include whole brain radiotherapy, stereotactic radiosurgery (SRS), or craniotomy for surgical resection followed by consolidative SRS. This paradigm is effective in achieving local control, but it remains unclear if this approach is necessary for every patient. Prospective and retrospective data suggest that ICIs with or without chemotherapy can have activity against BM; however, appropriately selecting patients who are able to safely forgo local therapy and start an ICI-based treatment remains a challenge. To be considered for upfront ICI-based therapy, a patient should be free of neurologic symptoms, lesions should be small and not located in a critical region of the central nervous system, if corticosteroids are indicated the requirement should be low (prednisone 10 mg/d or less), and PD-L1 expression should be high. The decision to proceed with upfront ICI without local therapy to BM should be made in a multidisciplinary fashion and patients should undergo frequent surveillance imaging so that salvage local therapy can be administered when necessary. Prospective clinical trials are needed to validate this approach before it can be widely adopted.
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