Study Seeks New AML Therapies Olaratumab

Published OnlineFirst November 8, 2016; DOI: 10.1158/2159-8290.CD-NB2016-141

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

Olaratumab Approved for Soft-Tissue Sarcoma

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

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2016-141

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