XPO1 Inhibitor Approved for Multiple Myeloma

Published OnlineFirst July 22, 2019; DOI: 10.1158/2159-8290.CD-NB2019-085

NEWS IN BRIEF

acts rapidly, can be readily discontin- preventing the shuttling of molecular ued, and is already available.” cargo through XPO1, tumor sup- To investigate the drug’s potential in pressor proteins accumulate in the alleviating CRS, Hudecek collaborated nucleus, blunting the expression of with Sadelain using a mouse model genes that can fuel cancer growth. Structural formula for the small-molecule developed by the latter’s team (Nat Med “Selinexor has a novel mechanism inhibitor dasatinib. 2018;24:731–8). These mice, designed of action, and it appears to be active to develop acute, often fatal CRS upon when all of our other major drug CAR T-cell therapy “can’t be con- receiving CAR T cells, fared much better classes have failed,” says Paul Richard- trolled once it’s in [a patient],” notes if given dasatinib shortly after therapy son, MD, of Dana-Farber Cancer senior author Michael Hudecek, MD, infusion: At 48 hours, 70% were still alive Institute in Boston, MA, a lead inves- of Universitätsklinikum Würzburg compared with 25% in a control group. tigator in the phase II, single-arm in Germany. The main adverse event, Overall, “this is very timely work, and STORM trial of the drug. “It is a chal- cytokine release syndrome (CRS), can the science is sound,” says Mar co Ruella, lenging drug to administer, but in one be life-threatening and is primarily MD, of the University of Pennsylvania of the sickest populations of patients managed with tocilizumab (Actemra; in Philadelphia, who was not involved with relapsed and refractory disease Genentech) or high-dose corticoster- in the research. The data do suggest that’s been studied to date, we saw a oids. Whether to add a suicide gene to that dasatinib is less effective at inhibit- meaningful response rate—and in a the CAR construct has elicited inter- ing actively proliferating CAR T cells, subset of our patients, these responses est, but no approved CAR therapies “as occurs in the clinic during CRS,” proved durable.” include such “kill switches.” he points out. The timing of admin- In the trial, 32 of 122 patients “I thought it would be cool if, istration, then, “could be critical, and responded to selinexor plus low-dose instead, we had a pharmacologic on/ probably a preemptive approach would dexamethasone (Blood 2018;132:598). off switch to steer the function of be more successful,” he adds. Sadelain Two participants achieved stringent CAR T cells,” Hudecek says, “which agrees that “it may be important to give complete responses, six exhibited would mean interfering at the level of dasatinib early enough in the course of very good partial responses, and the signal transmission.” To that end, the treatment to prevent CRS.” rest experienced partial responses. Würzburg team, led by fi rst author Hudecek, too, points to research Responses lasted 4.4 months on Katrin Mestermann, PhD, screened that has uncovered biomarkers to average, with the longest duration of a panel of tyrosine kinase inhibitors predict the risk of severe CRS fol- response exceeding 18 months. and landed on dasatinib. Approved for lowing CAR T-cell therapy (Blood Exploratory analyses also suggest a certain blood cancers and developed 2017;130:2295–306). “We could have survival benefi t. At the 2019 American to target the BCR–ABL fusion protein, a window of opportunity to intervene Society of Clinical Oncology Annual dasatinib also blocks another kinase, with these patients,” he says. Meeting in Chicago, IL, Richardson LCK. This prevents phosphorylation Directly comparing dasatinib with reported that STORM participants of CD3ζ and ZAP70, as well as the tocilizumab and corticosteroids in who received selinexor and dexametha- induction of NFAT, a key transcrip- a future study would also be useful, sone right after their myeloma had tion factor in activated CAR T cells. Ruella thinks. “We’ll better under- become triple-class refractory lived a Given that all current CAR con- stand the actual potency of this median of 10.4 months (J Clin Oncol structs contain a CD3ζ domain, approach and its relative effects— 37, 2019 [suppl; abstr 8014]). In com- Hudecek fi gured dasatinib “could be of versus standard CRS medications—on parison, patient records in the Flatiron universal relevance” in modulating this CAR T-cell function and survival,” he Health Analytic Database indicated live therapy. In vitro, his group showed says. –Alissa Poh n a median survival of 5.2 months for that CD19-targeting CAR T cells were patients who received other types effectively inhibited—in terms of cyto- XPO1 Inhibitor Approved of therapy. Richardson describes lytic activity, cytokine secretion, and the survival data as “supportive” of proliferation—with the drug. for Multiple Myeloma the favorable responses observed in Importantly, dasatinib’s impact Patients with multiple myeloma STORM and other trials. was reversible: CAR T cells regained who have exhausted treatment options Selinexor’s safety profi le proved function soon after drug removal, and can now try selinexor (Xpovio; Karyo- less auspicious. In the STORM study, their viability was unaffected. Simi- pharm Therapeutics), but the fi rst- 89% of patients experienced a seri- lar results were obtained in a mouse in-class selective inhibitor of nuclear ous (grade 3 or worse) drug-related model of lymphoma, and again, effi - export that inhibits XPO1 can cause adverse event, with most decreasing cacy was not compromised. debilitating side effects. the drug or discontinuing treatment. As far as “remote control” options The FDA granted conditional At least two participants died because for CAR T-cell therapy go, dasatinib approval to selinexor in combination of selinexor-associated toxicities—one could be a good one to consider, says with dexamethasone for patients with from sepsis, the other from pneumo- study coauthor Michel Sadelain, MD, triple-class refractory myeloma, mean- nia. (Eight other adverse event–related PhD, of Memorial Sloan Kettering ing the disease no longer responds to deaths could not be directly attributed Cancer Center in New York, NY. “It three standard types of therapy. By to the drug.) Additionally, patients

1150 | CANCER DISCOVERY SEPTEMBER 2019 www.aacrjournals.org

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he says, “I can’t cancer, and 17 had HER2-low HR- fathom that cost.” negative breast cancer. The remaining Cytoplasm –Elie Dolgin n 47 patients had gastric, urothelial, or endometrial tumors. Eye-related side effects were again New ADC prevalent: 71% of patients were Shrinks affected by problems such as conjunctivitis, keratitis, and dry eye. These Nuclear pore HER2- adverse effects have been seen with complex Positive other ADCs—although they haven’t Tumors been described with T-DM1—but the mechanism remains unclear, says A novel co-author Philippe Aftimos, MD, of Nucleus antibody–drug the Jules Bordet Institute and the Free conjugate (ADC) University of Brussels in Belgium. Tumor suppressor protein Selective inhibitor of triggers responses nuclear export inhibitor The ADC produced partial + eiF4E-bound mRNA in patients with Regulatory factor XPO1 responses in 33% of the patients with HER2-expressing HER2-positive metastatic breast breast cancer Selinexor is a selective inhibitor of nuclear export. By blocking XPO1, it cancer; 28% with HER2-low, HR- prevents molecular cargo from moving through the nuclear pore complex, and other solid positive metastatic breast cancer; and causing cell-cycle arrest, apoptosis, and other antitumor activity. (Courtesy tumors, a phase I 40% with HER2-low, HR-negative of Karyopharm Therapeutics; modified with permission.) clinical trial metastatic breast cancer. The median indicates (Lancet progression-free survival for these Oncol 2019;20:1124–35). The drug commonly experienced side effects three groups was 7.6 months, such as thrombocytopenia, hypona- could become a new treatment for 4.1 months, and 4.9 months, respec- tremia, anemia, and nausea. patients with breast cancer who are tively. The researchers also saw signs Those safety issues prompted an resistant to the ADC trastuzumab of drug activity in the patients with FDA advisory committee of outside emtansine (Kadcyla, T-DM1; Genen- other cancer types: Partial responses experts to vote 8–5 against recommend- tech) or who have low HER2 expression. occurred in 25% of patients with ing approval until additional data are T-DM1, a second-line treatment for urothelial cancer and 39% of those available. Onlookers like David Iberri, patients with HER2-positive breast with endometrial cancer. MD, of Stanford Cancer Center in Cali- cancer, kills cells by inhibiting micro- The results suggest that patients fornia, and Al-Ola Abdallah, MD, of the tubule polymerization. However, with HER2-positive breast cancer University of Kansas Medical Center in patients usually develop resistance, resistant to T-DM1 “can still respond Westwood, support that decision. prompting researchers to develop new STORM provides “really insufficient ADCs. The ADC tested in the current to other ADCs with different payloads,” data upon which to base a recom- trial, trastuzumab duocarmazine, also says co-author Udai Banerji, MD, PhD, mendation for this drug,” Iberri says. targets HER2-expressing cells, but its of the Institute of Cancer Research and “I know a lot about its toxicity now, payload triggers DNA damage. The Royal Marsden NHS Foundation but I really don’t know if it’s going to The dose-escalation portion of Trust in London, UK. Because trastu- improve outcomes in anyone because the trial included 39 patients with zumab duocarmazine works through we don’t have randomized data.” advanced or metastatic solid tumors, a different mechanism, it may kill cells Abdallah adds, “We need more each of whom received 0.3 to 2.4 mg/kg that are resistant to T-DM1, he says. mature studies.” of trastuzumab duocarmazine. One Patients with breast cancer and low But citing the need for new medi- third of the patients reported grade 3 HER2 expression, for whom there are cines, the agency granted accelerated or 4 side effects, including fatigue and no approved anti-HER2 therapies, approval contingent on verification of neutropenia. Many also experienced could also benefit from trastuzumab clinical benefit. The phase III BOSTON eye problems, with 31% developing duocarmazine, says Aftimos. “We study is evaluating progression-free conjunctivitis, for example. Four cases have proof that targeting HER2 in survival among patients taking selinexor of pneumonitis—one fatal—occurred, HER2-low breast cancer is an effective with bortezomib (Velcade; Millennium all in patients who received doses of strategy.” Although trastuzumab alone Pharmaceuticals) and dexamethasone or 1.5 mg/kg or higher, so researchers set does not benefit these patients, the bortezomib and dexamethasone alone. the dose at 1.2 mg/kg in the dose- ADC may work through a bystander Results are expected later this year or in expansion stage of the trial. effect, allowing it to kill adjacent early 2020. For that portion of the study, the tumor cells even if they don’t overex- Until then, Iberri will not prescribe researchers enrolled 146 patients with press HER2, he says. selinexor. In addition to wanting more metastatic HER2-expressing tumors. The trial was too small to confirm data, he cites the drug’s price—$22,000 Fifty patients had HER2-positive that “this drug works at a substantial per month—as another major strike breast cancer, 32 had HER2-low hor- level in patients who have progressed against it. “Without randomized data,” mone receptor (HR)–positive breast on T-DM1,” cautions Ian Krop, MD, PhD,

SEPTEMBER 2019 CANCER DISCOVERY | 1151

XPO1 Inhibitor Approved for Multiple Myeloma

Cancer Discov 2019;9:1150-1151. Published OnlineFirst July 22, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2019-085

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