PracticeUpdate Oncology Best of 2018

TOP STORIES 2018 6

Venetoclax for Multiple Myeloma By Rafael D. Fonseca MD

F or me, the top story for multiple myeloma in 2018, is venetoclax. Venetoclax represents the culmination of efforts to develop a therapeutic agent tailored to work in certain genetic subtypes of the disease. How did we get here? How can this development be the most important one for 2018, when everyone is talking about CAR T-cell therapies and bispecific antibodies? How can this develop- ment be so important given that we have the results of phase III trials showing improvement in disease control with daratumumab-based combinations? How could this be the story of the year when we have the possible addition of new drugs such as selinexor? The answer is simple. This is the first time that a truly targeted therapeutic has been developed for multiple myeloma. Let me explain. Myeloma has been, for several years, one of the best understood tumors when it comes down to dis- ease biology and genetic changes. Description of the major subtypes of the disease and secondary genetic changes dates back now close to 15 years. Although we have had important refinements to this

knowledge framework, the basic genetic groups are the same. The addition of novel tools, such as gene-expression profiling and mutation analysis with next-generation sequencing, has increased the depth of our understanding of the genetic nature of the disease. Myeloma is divided into two broad subgroups, the hyperdiploid and the non-hyperdip- loid variants. One of the hallmarks of myeloma is that the non-hy- perdiploid variant is enriched for chromosome translocations involving the immunoglobulin heavy- chain locus. Although the translocation t(11;14) could be detected through cytogenetic analysis, it was not until molecular genetic studies performed by Berg- sagel, Kuehl, and Chesi identified the presence of the translocations t(4;14) and t(14;16). Despite having this detailed knowledge of the disease, genetics had been predominantly used to stratify patients into risk categories and to propose different treat- ment pathways. However, none of these treatments has directly targeted the consequence of genetic aberrations. Previous efforts to target the FGFR3 gene, associated with t(4;14), have failed. Genetic understanding did not provide to myeloma the opportunity that was fully realized in chronic mye- logenous leukemia. Nevertheless, genetics in myeloma did help with a better understanding of the prognostic catego- ries of disease. This has allowed for a more tailored conversation with patients regarding the likelihood of better outcomes. Furthermore, the knowledge about high-risk genetic features changed the par- adigm upon which we recommend maintenance therapy in the post–stem cell transplant setting. Knowing that patients with high-risk genetic features derive greater benefit from the use of proteasome inhibitors became important practical knowledge. Arguably, the natural history of patients with t(4;14) was changed because of the addition of bortezomib to treatment. At the same time, great strides were made in the fight against multiple myeloma by the

Renal Cell Carcinoma: Ipilimumab + Nivolumab By Eric Jonasch MD T he top story for renal cell carcinoma in 2018 is the approval of ipilimumab plus nivolumab for the upfront treatment of patients with intermediate- and poor-risk renal cell carcinoma. 1 The approval arises from a phase III trial that randomized nearly 1100 patients with untreated advanced and metastatic renal cell carcinoma between ipilimumab 1 mg/kg IV every 3 weeks times four plus nivolumab 3 mg/kg IV together with ipilimumab followed by nivolumab maintenance therapy every 2 weeks. 2 The co-primary endpoints of overall survival and objective response rate in intermediate- and poor-risk patients were met. Strikingly, in patients with intermediate-/poor-risk features who were PD-L1–positive, the complete response rate was 16%, a result never before seen in renal cell carcinoma and particularly impressive for this patient subgroup. This combination is beset with significant immune toxicities, and care needs to be taken to manage these if they arise. Nonetheless, the combination of ipilimumab plus nivolumab is a high-water mark in the treatment of metastatic RCC and should be consid- ered as standard therapy for the appropriate patients. References 1. U.S. Food and Drug Administration: FDA approves nivolu-mab plus ipilimumab combination for intermediate- or poor-risk advanced renal cell carcinoma. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm604685.htm. Accessed November 8, 2018. 2. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378(14):1277-1290. www.practiceupdate.com/c/75853

PRACTICEUPDATE ONCOLOGY