ASH Clinical News ACN_5.4s_March_supplement_web - Page 23

and 7 are less likely to achieve PET-negative disease. Generally, however, “overall survival (OS) irrespective of approach has been excellent,” she concluded. sophisticated method for measuring tumor burden and “may represent a better way to risk-stratify patients,” she concluded. Brentuximab Vedotin In his presentation, Alex Herrera, MD, assistant professor in the Department of Hematology & Hematopoietic Cell Transplanta- tion at City of Hope in Duarte, California, also highlighted the challenges of using PET scans to guide treatment decisions in an era of novel treatment, particularly with the use of checkpoint inhibitors like nivolumab or pembrolizumab. “What we’ve come to understand over many years is that there is extensive crosstalk between Reed Sternberg cells and nearby immune cells, which results in a niche that’s favorable for these Reed Sternberg cells,” he said, explaining the development of checkpoint inhibitors for HL. “PD1 normally serves to damp- en immune response, but tumor cells can highjack this … and basically shut down the immune response against them.” This interaction makes HL a “ripe target for PD1 blockade,” he continued, and agents like nivolumab and pembrolizumab are designed to interrupt PD1 signaling and restore an effective immune response. In clinical trials, nivolumab and pembrolizumab have been associated with overall response rates ranging between 66 and 69 percent, with similar responses seen across BV- or AHCT-exposure groups. However, “after PD1 blockade, it is common to have new FDG lesions or growth of non-target le- sions [on the scan], even though the overall tumor burden has reduced,” Dr. Herrera noted. This can complicate the treatment decision-making process, he added because, although survival was associated with depth of response, the OS curves in trials of these agents overlapped whether a patient had a complete response, partial response, or stable disease. “[These findings] suggest that PD1 blockade may persist after patients stop receiving therapy, and patients may benefit from treatment beyond progression,” he explained. He cautioned careful interpretation of PET scans because patients might benefit from ongoing therapy. For the future of PD1 blockade in the treatment of HL, Dr. Herrera stated that a main goal of research should be “trying to increase the proportion of patients who have a complete response to these drugs.” Immune checkpoint inhibitors have represented a major advance in HL therapy, he added, but “when we look at PFS curves, there appears to be an ongoing risk of relapse” that also needs to be addressed. Given the low curative potential of checkpoint inhibitor monotherapy observed in clinical trials, Dr. Herrera believes that the optimal role of checkpoint inhibitors is as part of a com- bination therapy and that incorporating checkpoint blockade earlier might improve depth of responses. Of course, with so many new options available, and some data suggesting a benefit with prolonged treatment of nivolumab, members of the audience questioned whether it is advisable to replace ABVD, a therapy with known efficacy and toxicity profiles, with approaches that have unknown toxicities – including significant financial toxicity. ● The recent approval of brentuximab vedotin (BV) for the front- line treatment of stage III or IV classic HL also has changed the landscape, and its availability is one of the “building blocks for individualized therapy,” according to Dr. Moskowitz, who reviewed the potential impact of BV on the treatment of HL. BV initially was approved for the secondline treatment of HL, “which is mainly where we use it at our institution, and where I think it has the potential to improve the PET-negative rate for patients going to transplant,” Dr. Moskowitz said. How- ever, recent clinical trials data suggest that BV may have a role outside of advanced-stage disease, with the potential to reduce or eliminate the need for radiation therapy in early-stage disease and to offer a less toxic treatment regimen for older patients with HL. Although her review of recent studies led her to believe that “we are not quite ready to use [frontline BV in early-stage HL] outside of a clinical trial,” Dr. Moskowitz said that it is a reasonable option for patients with high-risk disease who cannot receive bleomycin, including older patients with HL. Sequential BV+AVD – an approach that eliminates bleomycin and its asso- ciated pulmonary toxicity, as well as minimizes the toxicity seen with combined BV+AVD – is a promising option. Single-agent BV has been evaluated in this setting as well, but with disap- pointing PFS results. Ongoing studies also are evaluating BV as a single agent or in combination with agents like bendamustine and the PD1 inhibi- tor nivolumab in patients with relapsed/refractory HL, and these approaches are starting to show durability of responses. For patients in remission following AHCT, BV maintenance is being evaluated, with data showing that it significantly reduced risk of relapse, but the effect was strongest in patients with certain high- risk characteristics. Longer follow-up is needed to determine which patients are the best candidates for this approach. Of course, “[BV-containing combinations] may not be for everyone,” Dr. Moskowitz said. In the pivotal ECHELON trial, adding BV to ABVD conferred a 5-percent improvement in modified PFS; however, the results were difficult to interpret, given the observation that ABVD appeared to have performed worse in the trial’s North American population than other sites. As expected, the BV+ABVD regimen was associated with higher toxicity, specifically neuropathy and febrile neutropenia. The trials’ experience with BV points to the need for im- proved risk-stratification techniques to optimize its use across disease settings. “Risk stratification now is based upon historical series and may not be optimal for today,” Dr. Moskowitz said. Bulky disease and interim PET scans have proven to be reli- able prognostic indicators of patient outcome, but definitions of bulky disease are changing, as are methods for interpreting PET scans. Newer techniques, like metabolic tumor burden or circulating tumor DNA (ctDNA) levels, give clinicians a more Checkpoint Inhibition March 2019 21