Study Seeks New AML Therapies Olaratumab

Published OnlineFirst November 8, 2016; DOI: 10.1158/2159-8290.CD-NB2016-139

NEWS IN BRIEF

objective was to demonstrate that Olaratumab Approved is the fi rst PDGFRα-selective inhibi- using molecular profi ling to guide tor for STS, however, and “the fact that therapeutic decisions would extend for Soft-Tissue Sarcoma such a dramatic survival advantage progression-free survival by 30% in at The FDA has greenlighted the mono- was seen is very intriguing,” Tap says. least 25% of patients,” Soria explained. clonal antibody olaratumab (Lartruvo; “We need to more fully fi gure out His team uncovered potentially action- Lilly Oncology), combined with doxo- olaratumab’s mode of action—besides able targets in 411 of the patients pro- rubicin, as fi rst-line therapy for patients direct effects on the tumor, it may fi led; aberrations in the FGFR, PI3K/ with inoperable soft-tissue sarcoma affect metastatic potential or even the AKT, HER, and Notch pathways were (STS). This combination is the only immune microenvironment.” the most common. up-front treatment for STS to gain the A phase III trial to confirm the The investigators then matched 199 agency’s approval in 40 years—until now, study’s results is under way. Tap and of these patients with targeted treat- doxorubicin has been the mainstay. his colleagues are also discussing olara- ments. Most were enrolled in one of STS has multiple subtypes, making tumab as possible adjuvant therapy the 60 ongoing phase I trials at Institut it diffi cult to diagnose and treat. Aber- for patients with localized STS at high Gustave Roussy, Soria said, but a few rant platelet-derived growth factor risk of developing metastases. These cases involved off-label use of drugs receptor (PDGFR) activity, a known patients are fi rst treated with surgery indicated for other cancer types. The occurrence in this disease, is implicated and radiation, but metastatic disease remaining 212 patients were excluded in tumor cell proliferation and migra- often still follows, so “this would be a from the study, either because their tion. It also promotes the recruitment very important indication for olara- actionable mutations were well estab- of fi broblasts that maintain a protu- tumab,” Tap says. –Alissa Poh ■ lished, with approved agents avail- mor microenvironment by producing able—for instance, ALK inhibitors for angiogenic factors. Olaratumab was Study Seeks New ALK-translocated non–small cell lung therefore designed to bind to and cancer—or because there were no suit- block PDGFRα, one of two PDGFR AML Therapies able phase I trials at the time. isoforms, with high specifi city. For more than 40 years, treatment Soria reported that MOSCATO-01 The FDA’s nod was based on data for acute myeloid leukemia (AML) achieved its primary endpoint and is from the phase II JGDG study, in hasn’t changed, with patients generally the fi rst study of its kind to show that which 133 patients with STS were receiving a chemotherapeutic combi- precision medicine works: Of 193 randomly assigned to receive doxoru- nation of cytarabine and daunorubicin, evaluable patients, 33% experienced an bicin plus olaratumab, or doxorubicin followed by a stem cell transplant for extended PFS of 30% with tailored alone. The objective response rates those who can tolerate it. Yet, the prog- therapy, compared with previous were 18.2% and 7.5%, respectively; the nosis has remained poor, particularly treatments. Overall survival (OS) also median progression-free survival was for patients over age 60, whose 5-year improved, he noted, citing patients 8.2 months for patients given the com- survival rate is less than 20%. with alterations in HER3 as an example. bination and 4.4 months for those who In an effort to change that picture, The median OS was 8 months for received only the chemotherapy. Nota- a group of physician-scientists, drug patients who received non–HER-specifi c bly, the difference in median overall manufacturers, government regula- therapy, and not reached for those survival between the arms was sizeable: tors, and patients, led by the Leukemia given trastuzumab (Herceptin; Roche) 26.5 months versus 14.7 months. and Lymphoma Society (LLS), has or afatinib (Gilotrif; Boehringer “Patients with leiomyosarcoma were launched the Beat AML Master Trial. Ingelheim), both inhibitors of HER- highly represented in this study,” says This large umbrella study will simul- family signaling. lead investigator William Tap, MD, taneously test multiple investigational The team is now turning its attention chief of the sarcoma medical oncology agents—both targeted drugs and to two other prospective precision medi- service at Memorial Sloan Kettering immunotherapies—advancing ones cine–based trials for lung cancer and Cancer Center in New York, NY. that show promise and dropping those breast cancer, respectively. Both SAFIR- “Olaratumab had very impressive activ- that prove ineffective. New drugs can 02 studies will evaluate the utility of mol- ity in this subtype, but overall, many be added to the protocol over time. ecular profi ling in selecting maintenance subtypes responded.” Nausea, mus- The umbrella trial design, in which therapy for patients with advanced but culoskeletal pain, and mucositis were multiple drugs are tested on different stable disease, who will be randomly among the most common side effects genetic aberrations in a single cancer assigned to receive either a targeted agent seen with this drug combination. type, isn’t new. Lung MAP (for lung or standard chemotherapy. Tap notes that other, less specifi c cancers) and I-SPY (for breast cancers) MOSCATO-02 is also in the works, PDGFR inhibitors have been evalu- employ a similar strategy. However, Soria said. This time around, he and ated in STS, including the multiki- the Beat AML Master Trial is one of his group have added analyses of dif- nase inhibitor pazopanib (Votrient; the fi rst to be led by an independent ferent tumor-infi ltrating immune cell GlaxoSmithKline), which was approved nonprofi t organization, which will also populations “to enrich our molecular several years ago for patients with pursue FDA approval for any drugs readout and enable optimal triage of previously treated disease. Pazopanib deemed successful in the trial, said patients toward the relevant phase I blocks a variety of targets, including Louis DeGennaro, PhD, president and studies.” –Alissa Poh ■ PDGFRα and PDGFRβ. Olaratumab CEO of the LLS, at a press conference

DECEMBER 2016CANCER DISCOVERY | 1297

NEWS IN BRIEF

announcing the trial. With LLS acting • Gilead Sciences’ entospletinib, an degrade proteins and organelles.) He as a neutral party, more pharmaceuti- inhibitor of the tyrosine kinase Syk, then cultivated cells that lacked vacuolar cal companies may join the effort to which blocks B-cell receptor signaling degradation enzymes, starved them, and bring drugs to market more quickly. was able to observe the vacuoles fi ll with “The secret sauce of this trial is the Three to six more drugs may be small vesicles holding proteins to be idea that we’re going to work faster by added over the course of the trial, which degraded—known as autophagosomes. collaborating in open and transparent will run for 3 to 5 years. In another set of experiments, Ohsumi ways,” said Ross Levine, MD, of Mem- “This is about working toward a exposed engineered yeast cells to a chem- orial Sloan Kettering Cancer Center common goal,” said Levine. “We really ical that randomly introduced mutations (MSKCC) in New York, NY. In addition want to make a difference for our in many genes, then induced autophagy. to MSKCC, the Ohio State University patients.” –Karen Weintraub ■ As a result, he identifi ed many different Comprehensive Cancer Center (OSUCCC) proteins and protein complexes that in Columbus, Oregon Health & Science Nobel Prize Honors regulate distinct stages of autophago- University Knight Cancer Institute some initiation and formation. in Portland, and Dana-Farber Cancer Autophagy Discovery “Ohsumi used yeast as a model Institute and Massachusetts General Japanese cell biologist Yoshinori system to identify the mechanisms it Hospital, both in Boston, will serve as Ohsumi, PhD, has been awarded this uses to survive nitrogen starvation and the initial trial sites. year’s Nobel Prize in Physiology or the genes essential for the autophagy Researchers plan to enroll 500 Medicine for his discovery of autophagy. pathway,” says Eileen White, PhD, patients over age 60 newly diagnosed His groundbreaking studies in yeast professor of molecular biology and with AML in the trial. Participants will illuminated how cells collect and biochemistry at Rutgers University have their cancer’s genome sequenced break down intracellular proteins and and deputy director and associate and be put into a trial arm based on organelles, a process that is critical to director for Basic Science at Rutgers nine different genomic signatures, said the survival of both normal cells and Cancer Institute of New Jersey, in New John Byrd, MD, of OSUCCC. some cancerous ones. Brunswick. “By doing this, he opened Unlike other trials, none of the “His discoveries opened the path up a whole new fi eld of investigation.” participants will receive standard to understanding the fundamental Recent research has revealed that some chemotherapy alone. If there is not importance of autophagy in many cancer cells in hypoxic regions also use a suitable drug match for a patient’s physiological processes, such as in the autophagy to survive metabolic stress, genetic markers, they will be offered adaptation to starvation or response to suggesting that the process may be a via- chemotherapy in combination with infection,” noted the Nobel Committee ble drug target, says White. Companies an existing targeted therapy, Byrd in announcing the award in October. are now working on autophagy inhibi- explained. Patients who do not res- The concept of autophagy was fi rst tors, possibly to augment the activity of pond to their investigational drug can observed in the 1960s, but little was targeted drugs. Multiple clinical trials also receive conventional therapy with known about its underlying mecha- are testing hydroxychloroquine (HCQ), the targeted therapy, he added. nisms until Ohsumi conducted a series an antimalarial drug that interferes Most of the patients who will be of experiments with baker’s yeast in the with lysosome function, in combination eligible for the trial are unable to tol- early 1990s. Those studies eventually cancer therapy. For example, a phase II erate intensive chemotherapy, so their led him to identify the genes—and the trial is assessing HCQ combined with outcomes are even worse than average, proteins they encode—that control the BRAF inhibitor dabrafenib (Tafi nlar; said Brian Druker, MD, director of the autophagy, and to show that a corre- Novartis) and trametinib, a MEK inhibi- Knight Cancer Institute. The targeted sponding mechanism exists in humans. tor (Mekinist; Novartis), in patients with therapies are expected to be better Autophagy is a self-defense mecha- advanced BRAF-mutant melanoma. tolerated than toxic chemotherapy, and nism that prevents the accumulation “The discovery of autophagy genes will be given after diagnosis, when they of garbage or potentially toxic material and how they enable lysosomal deg- will likely be more effective, instead of in cells, such as damaged proteins and radation and recycling of organelles waiting for disease relapse, he added. organelles. In normal cells, it serves and proteins has provided a critical DeGennaro said that the trial will as a buffer during metabolic stress by platform for understanding how begin by testing these four drugs: recycling intracellular components. It autophagy plays a role in resistance to also helps to eliminate invading bac- cancer therapy,” says Ravi Amaravadi, • Alexion’s samalizumab (ALXN6000), teria and viruses following infection, MD, a medical oncologist at the Uni- a humanized monoclonal antibody promote embryo development and versity of Pennsylvania in Philadelphia, that targets CD200 cell differentiation, and counteract the who led a series of early-phase clinical • Boehringer Ingelheim’s BI 836858, negative consequences of aging. trials testing HCQ in combination which induces antibody-dependent Ohsumi verifi ed that the process with targeted therapies. “Ohsumi’s cellular cytotoxicity against CD33- exists in yeast cells by studying how work provided the framework to pro- expressing tumor cells autophagy delivers cargo for degra- pose biomarkers and targets for drug • Celgene and Agios’s enasidenib (AG- dation in the vacuole. (In human cells, discovery that could improve the effi cacy 221/ CC-90007), a selective IDH2 similarly, autophagosomes fuse with of cancer therapies in a number of inhibitor lysosomes, which contain enzymes that cancers.” –Janet Colwell ■

1298 | CANCER DISCOVERYDECEMBER 2016 www.aacrjournals.org

Study Seeks New AML Therapies

Cancer Discov 2016;6:1297-1298. Published OnlineFirst November 8, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2016-139

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