First EZH2 Inhibitor Approved—For Rare Sarcoma

Published OnlineFirst February 10, 2020; DOI: 10.1158/2159-8290.CD-NB2020-006

NEWS IN BRIEF

2.9 million—according to a recent In contrast, survival rates for cancers Patients with metastatic disease may analysis (CA Cancer J Clin 2020;70:7–30). of the uterine corpus and cervix have receive doxorubicin or gemcitabine, Although it’s tempting to ascribe the not declined since the mid-1970s. but retrospective studies suggest that mortality reduction to recent treatment Human papillomavirus vaccination chemotherapy is effective only 15% to advances, such as the introduction of will likely drive down cervical cancer 20% of the time. Even then, tumors immune-checkpoint inhibitors, the incidence and mortality, but the lack of can recur years later and metastasize, reality is more complex. new treatments and effective screening notes Charles Keller, MD, of the Chil- The largest drop in age-adjusted mor- methods for other uterine cancers does dren’s Cancer Therapy Development tality was seen between 2016 and 2017, not portend mortality improvements. Institute in Beaverton, OR. making speculation about the role of the “We’re going to continue to see increases About 90% of patients with epithe- newest therapies particularly alluring, in endometrial cancer incidence and lioid sarcoma have lost INI1, a tumor but the overall pattern is perhaps more mortality,” says Ashley Felix, PhD, MPH, supressor of the SWI/SNF complex. of the Ohio State University Compre- noteworthy than the 2.2% decline. “It’s Tazemetostat inhibits EZH2, a compo- hensive Cancer Center in Columbus. very much a continuation of a long-term nent of polycomb repressive complex 2 Incidence is likely to increase due to trend,” says Kathy Cronin, PhD, MPH, (PRC2) that spurs histone methylation factors such as reduced hysterectomy deputy associate director of the NCI and gene silencing. These two com- rates, declining pregnancy rates, and Surveillance Research Program. plexes work against each other: SWI/ rising obesity rates—the last of which is SNF favors differentiation, whereas These reductions have primarily a contributor to many other cancers. been driven by a decrease in lung PRC2 prompts cells to retain their Further progress in cancer treatment stem-cell characteristics and capacity cancer deaths. “If you take lung cancer may help maintain the downward trend out [of the analysis for 2016 to 2017], for self-renewal. The loss of INI1 from in mortality, but advances may also be SWI/SNF complexes may disrupt this that 2.2% goes down to 1.4%,” says possible by other means. “There’s much lead author Rebecca Siegel, MPH, of balance and enable PRC2 to promote more opportunity to accelerate the pro- abnormal growth; tazemetostat may the American Cancer Society. Lung gress by ensuring that all people, especially counteract this effect by blocking cancer is the leading cause of U.S. those who are low income, have access to EZH2. cancer mortality, accounting for more high-quality care,” says Siegel. The data that led to tazemetostat’s deaths than breast, colorectal, and “I think the treatments are impor- approval came from a phase II study prostate cancers combined, explain- tant, but I think also that the public- that tested the drug in a range of ing its outsized influence on cancer health initiatives to reduce smoking tumors. Fifteen percent of 62 patients survival. are really playing an important role, with INI1-negative epithelioid In the 5 years leading up to 2017— too,” Cronin adds. –Nicole Haloupek n sarcomas had a complete or partial even prior to the approval of immu- response. In 67% of these patients, the notherapies—the lung cancer death response lasted 6 months or longer. rate fell by about 4% per year. Reduced First EZH2 Inhibitor The three most common side effects incidence due to decreases in smoking Approved—for Rare Sarcoma were fatigue, nausea, and pain. accounts for part of the shrinking death The FDA has approved tazemetostat Approval of the drug “provides a rate, but improved treatments, includ- well-tolerated treatment option for ing new surgical options, and other (Tazverik; Epizyme), the first EZH2 inhibitor to receive the agency’s nod, patients who have few options,” says factors may play a role. Survival follow- Robin Jones, MD, of The Royal Mars- ing lung cancer diagnosis is increas- and the first therapy specifically approved to treat epithelioid sarcoma. den NHS Foundation Trust and The ing, which hints at the importance of The accelerated approval greenlights Institute of Cancer Research in Lon- treatment advances. However, the study the drug for patients who have locally don, UK. “In patients who do respond, cannot pinpoint causality. advanced or metastatic tumors with the drug gives durable clinical benefit Major strides have also been made in INI1 deletions. as a single agent.” Jones, who partici- treating pediatric cancers, with mortal- Epithelioid sarcoma, which doctors pated in the phase II trial, says that ity slashed by 68% for pediatric cancers often describe as “relentless,” affects ongoing work on tissue samples from and 63% for adolescent cancers since about three in 10 million people, sequential biopsies will provide infor- 1970. “It’s not new therapies,” says usually teenagers and young adults. mation on mechanisms of response Siegel—instead, the drop is primarily In one form of the disease, the tumors and resistance. attributable to optimizing dosages and grow under the skin on the limbs, Newly diagnosed patients appear combining existing chemotherapies. The hands, or feet; in the other, they affect more likely to benefit from the drug, greatest success has been in childhood the trunk, head, or neck. Although Keller notes: Their response rate was acute lymphocytic leukemia, which epithelioid sarcomas typically grow 25%, versus 8% in patients who had now has a remission rate nearing 100%. slowly, they infiltrate surrounding relapsed. “The approval, in light of This steady decline comes even as the tissues and frequently metastasize to the low response rate, shows a com- incidence of childhood and adolescent lymph nodes. Surgery, often combined mitment on the part of the FDA and cancers has increased by about 0.7% per with radiation, is the standard treat- Epizyme to cultivate drug development year since 1975, for unknown reasons. ment for localized tumors. for soft-tissue sarcomas, even if the

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NEWS IN BRIEF degree of long-term benefi t is still being the data cutoff in November 2018. NOTED measured,” he says. (Studies assessing The most common severe side effects the drug in other malignancies, such as included anemia, diarrhea, abdominal The FDA approved maintenance olapa- synovial sarcoma and rhabdoid tumors, pain, and cognitive impairment. rib (Lynparza; AstraZeneca) in patients are under way.) Jason Sicklick, MD, of the University with BRCA-mutated metastatic pancre- “We should watch the post-market of California, San Diego, who was not atic cancer whose disease has not wors- use and reporting, and we’ll learn involved in the trial, expects avapritinib ened after 16 weeks of chemotherapy. about the true measure of tazemeto- to prompt more molecular profi ling of The approval was based on the phase III stat’s effi cacy,” Keller adds, noting that GIST tumors, testing that’s currently POLO trial, in which patients treated the approval could spur research into uncommon. “We need to start thinking with the PARP inhibitor had a median combination therapies. –Mitch Leslie n about these subsets of GIST in a more progression-free survival (PFS) of genomically directed fashion,” says 7.4 months, compared with 3.8 months Avapritinib Approved for Sicklick. in patients who received a placebo. GIST Subgroup Lead investigator Michael Heinrich, Incyte will pay MorphoSys $750 million MD, of the Portland VA Hospital and for tafasitamab in a deal that could be The FDA has granted marketing Oregon Health and Science University, worth another $1.1 billion in milestone authorization to avapritinib (Ayvakit; agrees. “It will clearly make a differ- payments. An anti-CD19 agent, tafa- Blueprint Medicines) for the treatment ence [in treatment] to know what the sitamab is being tested in combination of inoperable or metastatic gastrointes- mutation is,” he says. “We’re hoping with lenalidomide (Revlimid; Bristol- tinal stromal tumors (GIST) with exon that this approval is really going to Myers Squibb/Celgene) in diffuse large 18 mutations of platelet-derived growth drive testing.” B-cell lymphoma. In the phase II L-MIND factor receptor-alpha (PDGFRA). In addition to patients with PDG- trial, the combination elicited a response GIST is a rare sarcoma of the diges- FRA exon 18 mutations, the NAVIGA- rate of 60%. tive tract typically driven by mutations TOR trial also enrolled 103 others Lilly announced it will stop developing in KIT or PDGFRA. Approximately with GIST who had at least three the PEGylated IL10 pegilodecakin after 6% of patients have PDGFRA exon prior lines of treatment. In that group it failed to show a benefit in combination 18 alterations, the most common of patients, the majority of whom with immunotherapies in two phase II of which is D842V. This mutation harbored KIT mutations, the overall lung cancer trials. Previously, the agent renders tumors insensitive to all previ- response rate was 17% and the median failed to improve survival in combination ously approved GIST therapies—mul- DOR approximately 10 months. with chemotherapy in a phase III trial of tikinase inhibitors such as imatinib Blueprint is also testing the drug pancreatic cancer. The company acquired (Gleevec; Novartis) that block a against regorafenib (Stivarga; Bayer) the agent when it bought ARMO limited number of KIT- and PDGFRA- in patients with GISTs of all muta- Biosciences for $1.6 billion in 2018. mutant forms. tional causes who previously received Avapritinib was designed to have imatinib and one or two other tyrosine PD-1 inhibitors may have a greater sur- activity across a range of mutations kinase inhibitors. However, results of vival benefit than PD-L1 inhibitors (JAMA Oncol 2019 Dec 26 [Epub ahead of like D842V that occur in the activa- that phase III trial, called VOYAGER, print]). Researchers analyzed 19 random- tion-loop domain of the target kinases won’t be available for several months— ized clinical trials involving the agents and (Sci Transl Med 2017;9:eaao1690). “It’s at which point another KIT/PDGFRA found that PD-1 inhibitors led to better a super-potent drug for the PDGFRA inhibitor may have beaten avapritinib overall survival and PFS compared with D842V mutation,” says Sebastian to market for the treatment of non– PD-L1 inhibitors; side effects did not Bauer, MD, of the West German Can- mutationally defi ned GISTs resistant significantly differ between the groups. cer Center in Essen, who was involved to all other approved therapies. in testing avapritinib. “In this previ- The FDA is evaluating ripretinib Tobacco smoking increases mutations in ously completely refractory subtype of (Deciphera Pharmaceuticals) for this bronchial epithelial cells, but kicking the GIST, it’s working miraculously well.” indication. In the phase III INVICTUS habit can reverse this mutational pro- In the phase I NAVIGATOR trial— trial, which enrolled 129 patients with cess—at least somewhat (Nature 2020 the results of which formed the basis advanced GIST whose prior drug regi- Jan 29 [Epub ahead of print]). Researchers of avapritinib’s approval—43 patients men included at least imatinib, suni- performed whole-genome sequencing on with PDGFRA exon 18 mutations (38 tinib (Sutent; Pfi zer), and regorafenib, 632 cell colonies created from bronchial of whom had D842V-mutant dis- 9.4% of those who received ripretinib epithelial cells and found that tobacco ease) received the drug. Overall, 86% responded, leading to a signifi cant pro- smokers had 1,000 to 10,000 more muta- responded, with the median treatment longation in median PFS—6.3 months, tions per cell than nonsmokers. However, benefi t lasting at least 11 months. compared with 1 month among former smokers were four times more Neither median duration of response patients who received placebo. A likely than current smokers to have cells with mutational burdens similar to those (DOR) nor median progression-free regulatory decision is anticipated in seen in cells of nonsmokers. survival (PFS) had been reached at May. –Elie Dolgin n

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First EZH2 Inhibitor Approved−−for Rare Sarcoma

Cancer Discov 2020;10:333-334. Published OnlineFirst February 10, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2020-006

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