PracticeUpdate Oncology Best of 2018

TOP STORIES 2018 7

PD-1 BlockadeWith Cemiplimab for Advanced SCC of the Skin By Roxana S. Dronca MD

I n the past, the treatment of locally advanced or metastatic squamous cell carcinoma (SCC) of the skin has relied mostly on platinum-based systemic chemo- therapy, agents targeting the epidermal growth factor receptor (EGFR) pathway, and/

or radiation therapy. However, none of these approaches has definitively been proven to be effective, nor has any been spe- cifically approved to treat this condition. On September 28, 2018, the FDA approved a new anti–PD-1 agent, cemiplimab-rwlc, for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or radiation. Cemiplimab-rwlc has received breakthrough therapy designa- tion for this indication. The approval was based on data from an international phase I expansion cohort study and a phase II cohort that included 85 patients with metastatic or unresecta- ble locally advanced disease. 1 Overall, cemiplimab induced a response in approximately half the patients treated (50% in the expansion cohorts of the phase I study and 47% in the metastatic disease cohort of the phase II study) and provided disease con- trol in another 10% to 15%. Although there are only limited data on the role of systemic chemotherapy or biological agents tar- geting EGFR in the treatment of advanced CSCC, the response rate for cemiplimab-rwlc seems significantly higher than that previously reported with these older agents. Moreover, as was the experience with other cancer types, the responses to immu- notherapy are seen fairly early after treatment initiation, usually within the first 2 to 3 months, and they seem to be more dura- ble, with most patients continuing to have a response beyond 6 months. In subgroup analyses, similar efficacy was observed in patients with regional advanced disease and in those with distant metastatic disease. Novel cancer immunotherapies targeting the immune suppres- sive PD-1/PD-L1 pathway have become a true paradigm shift in the treatment of patients with many advanced tumors. These results represent a significant practice change for the treat- ment of patients with advanced SCCs of the skin, and will likely change substantially the way this malignancy is being treated. At present, other immunotherapies are also being tested, such as the anti–PD-1 agent pembrolizumab and combinations of anti–PD-1 and talimogene laherparepvec (TVEC). An unresolved issue, however, is the treatment of patients with advanced CSCC who cannot receive immunotherapies, such as organ transplant recipients or severely immunocompromised patients. Reference 1. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379(4):341-351. www.practiceupdate.com/c/75967

incorporation of medications that target “normal plasma cell differ- entiation” and protein metabolism. The introduction of proteasome inhibitors and IMIDs, followed by the introduction of monoclonal antibodies, greatly improved the survival for myeloma patients. Nevertheless, genetics have not augmented our treatment arma- mentarium. However, that will change with venetoclax! Although there is still significant room for a better understanding of the mechanism of action of venetoclax in multiple myeloma, it is now very clear that this drug seems particularly effective for patients with the translocation t(11;14). Even if better biomarkers are developed for the selection of the right patients, venetoclax pro- vides options for patients with this translocation and for whom no treatments have been available. We are all hoping that venetoclax will be approved by the FDA soon. Patients have been treated with venetoclax, often in combination with steroids or with proteasome inhibitors, off-label when no further treatment options were availa- ble to them. Several clinical trials have now demonstrated a very high rate of response to combination strategies that use veneto- clax, particularly in patients with t(11;14). We have seen patients who have been heavily pretreated and who have achieved a complete response with venetoclax and dexamethasone alone. The obvious corollary questions are as follows. Should venetoclax be used as maintenance therapy in patients who have the translo- cation t(11;14)? What is the role of venetoclax in patients who have light-chain amyloidosis (50% have this translocation) and in patients with primary plasma cell leukemia (50% also have this translocation)? Should venetoclax be used earlier in the course of the disease in patients with this genetic abnormality as a part of combination strat- egies? If venetoclax can treat effectively the 15% of patients with this genetic abnormality, what about MCL-1 inhibitors? Recent data from the Mayo Clinic has shown that, although sur- vival for most myeloma patients has improved over the past 15 years, these improvements have lagged among patients with the translocation t(11;14). Perhaps this has been because t(11;14) plasma tends to be more lymphoid and their cytoplasm contains fewer proteins. Accordingly, the protein stress associated with the use of proteasome inhibitors and IMIDs is lessened in patients with t(11;14). Fortunately, we now envision the addition of venetoclax to our toolbox! www.practiceupdate.com/c/75855

VOL. 2 • NO. 4 • 2018