Mutations in FLT3 have long been recognized in a portion of patients with acute myeloid leukemia (AML). Yet it took more than 15 years until an agent targeting FLT3 mutations came to fruition with the FDA approval of midostaurin (Rydapt) in April 2017, marking about 40 years since the last new agent was approved to treat patients with AML.

Midostaurin is approved for the treatment of adult patients with newly diagnosed FLT3-positive AML in combination with standard cytarabine, daunorubicin induction, and cytarabine consolidation. The drug has been approved for patients with advanced systemic mastocytosis (SM), including aggressive systemic mastocytosis (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia.

AML is a genetically complex malignancy that researchers are still seeking to elucidate. Researchers believe that AML is driven by somatic alterations in a &ldquo;2-hit&rdquo; process: a proliferative mutation in a class I gene such as FLT3, and an aberration in a class II gene that prevents cells from maturing.

FLT3 mutations are among the epigenetic drivers of AML in normal karyotypes.

Investigators have found somatic mutations in FLT3 genes in several spots, notably in 27% to 34% of samples in the internal tandem duplication (ITD) domain in various studies.

The presence of a FLT3-ITD mutation confers a poor risk for patients with AML, with worse outcomes in disease-free and overall survival (OS).

In recently updated joint guidelines, the College of American Pathologists and the American Society of Hematology strongly recommend testing all pediatric and adult patients with suspected or confirmed AML for FLT3-ITD mutations.

Midostaurin was approved along with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, to test for FLT3 mutations in DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates.

Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases; in vitro biochemical and cellular assays have also suggested that it can inhibit wild-type FLT3 activity.

The drug inhibits FLT3 receptor signaling and cell proliferation, and induces apoptosis in leukemic cells expressing ITD and tyrosine kinase domain mutant FLT3 receptors.

The midostaurin approval has generated excitement in the field. Several FLT3 inhibitors have entered the later stages of clinical development and the prospects for more targeted agents are building.

&ldquo;The good news is that AML might be dealt with in a better way than we&rsquo;ve done in the past by using targeted therapies,&rdquo; said Richard M. Stone, MD, of Dana-Farber Cancer Institute, and lead investigator of the RATIFY trial, in an interview with

The midostaurin approval is based on the phase III RATIFY trial in AML and 2 single-arm, open-label studies of patients with SM. In RATIFY, the addition of midostaurin to standard chemothera- py reduced the risk of death by 23% compared with chemother- apy alone in patients with FLT3-mutant AML.

After ltering for patients who received stem cell transplants, the OS benefit with midostaurin remained steady at 25%.

In the phase II trial considered for the SM approvals, among patients receiving 6 cycles of midostaurin, the rates of con rmed complete remission (CR) plus incomplete remission by modified Valent criteria were 38% for ASM and 16% for SM-AHN. One patient with mast cell leukemia had a CR.

In the phase III RATIFY trial, also known as CALGB 10603, 717 patients with newly diagnosed FLT3-mutant AML were random- ized to standard induction and consolidation chemotherapy plus midostaurin (n = 360) or placebo (n = 357). Hydroxyurea was allowed for up to 5 days prior to beginning therapy.

During induction therapy, daunorubicin was given at 60 mg/m2 on days 1 to 3 with cytarabine at 200 mg/m2 on days 1 to 7. Oral midostaurin was administered at 50 mg twice daily on days 8 to 22. If patients achieved a CR, consolidation therapy was given with cytarabine at 3 g/m2 for 3 hours every 12 hours on days 1, 3, and 5 plus either placebo or midostaurin. After 4 cycles of consolidation, maintenance therapy was administered for up to 1 year.

The 2 treatment arms were balanced for age, race, FLT3 subtype, and baseline complete blood counts. The primary endpoint of the study was OS, with secondary outcome measures such as event-free survival (EFS) and safety.

In uncensored data, median OS was 74.7 months with midostaurin versus 25.6 months with chemotherapy alone (HR, 0.77; 95% CI, 0.63-0.95; P = .016). The 5-year OS rate for patients in the midostaurin arm was 50.9% versus 43.9% with placebo. Median EFS with midostaurin was 8.2 versus 3.0 months with placebo (HR, 0.78; 95% CI, 0.66-0.93; P = .004). The 5-year EFS with midostaurin was 27.5% versus 19.3%, respectively.

Median OS seen in the midostaurin arm was well beyond investigator expectations of 20.9 months. A possible explanation for this could be the rates of stem cell transplantation or incomplete data. The confidence intervals for OS were not fully attained for the midostaurin arm (95% CI, 31.7 to not attained).

Overall, 57% of patients received an allogeneic stem cell transplant at some time during the trial, more commonly in the midostaurin arm versus placebo (58% vs 54%). Median time to transplant was 5.0 months with midostaurin and 4.5 months with placebo. Twenty- ve percent of transplants occurred during the rst CR. Overall, 59% of patients in the midostaurin arm and 54% in the placebo group experienced a CR (P = .18).

Median OS data were not obtained in the censored population. The 4-year censored OS rate with midostaurin was 63.8% versus 55.7% for placebo (HR, 0.75; P = .04). In those censored for transplant, median EFS with midostaurin was 8.2 versus 3.0 months with placebo (HR, 0.84; P = .025).

Grade &ge;3 AEs were similar between the midostaurin and pla- cebo arms. Overall, 37 grade 5 AEs occurred in the study, which were similar between the 2 arms, at 5.3% with midostaurin versus 5.0% with placebo. A statistically significant difference was not observed for treatment-related grade 5 AEs (P = .82).

Seegmiller A, Jagasia M, Wheeler S, Vnencak-Jones C. Molecular profiling of acute myeloid leukemia. My Cancer Genome website. www.mycancergenome.org/content/disease/acute-myeloid-leukemia. Updated January 26, 2016. Accessed May 31, 2017.

Mehdipour P, Santoro F, Minucci S. Epigenetic alterations in acute myeloid leukemias. FEBS

Journal. 2015;282(9):1786-1800. doi: 10.1111/febs.13142.

Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology [published online February 22, 2017]. Arch Pathol Lab Med. doi: 10.5858/arpa.2016-0504-CP.

Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017. doi: 10.1056/NEJMoa1614359.

Articles

Clinical Articles

Mutations in FLT3 have long been recognized in a portion of patients with acute myeloid leukemia. Yet it took more than 15 years until an agent targeting FLT3 mutations came to fruition with the FDA approval of midostaurin in April 2017, marking about 40 years since the last new agent was approved to treat patients with AML.

The First Targeted Therapy Directed at FLT3 Mutations in Patients With AML

Duvelisib (IPI-145), a PI3K-delta/gamma inhibitor, in combination with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) showed high rates of responses and bone marrow minimal residual disease (BM MRD) negativity in younger patients with previously untreated chronic lymphocytic leukemia (CLL), according to findings from a phase Ib/II study. The rate of best response achieved and bone marrow MRD negativity was 68% overall.

&ldquo;Duvelisib/FCR is for the frontline treatment of younger, fit patients, and we&rsquo;re seeing high rates of BM MRD negativity with reasonable tolerability,&rdquo; Matthew S. Davids, MD, MMSc, associate director, Center for CLL, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, stated in an interview with

during the 2017 International Workshop on CLL (iwCLL).

Patients with untreated CLL or small lymphocytic leukemia between the ages of 18 and 65 with an ECOG performance status of 0 or 1 were eligible for enrollment. The primary endpoints were safety and rate of complete remission (CR) with BM MRD negativity at 2 months after treatment with FCR. The phase Ib component used a standard 3 + 3 design with patients receiving 25 mg of duvelisib daily (n = 6) or twice daily (n = 6). In both cohorts, patients received 1 week of duvelisib followed by up to 6 cycles of FCR and then 2 years of continued duvelisib. In the phase II expansion, all patients were treated with duvelisib twice a day. The median age was 55 years (range, 45-65). Eight patients harbored del(11q) and 3 had del(17p), 2 of which also had a TP53 mutation. More than half (56%) of the patients had unmutated IGHV and 59% were ZAP-70positive. The objective response rate in 31 evaluable patients was 94%, which included 12 patients (39%) with a CR or CR with incomplete bone marrow recovery and 17 (55%) with a partial response (PR). Eleven of the 12 patients who achieved CR and 10 of the PRs also had BM MRD negativity.

After 3 cycles, 18 patients (58%) had achieved BM MRD negativity, and 19 (61%) had achieved it by 2 months after FCR treatment. The rate of CR and BM MRD negativity was 35% and the rate of PR and BM MRD negativity was 32%.

Only 1 dose-limiting toxicity was noted: a grade 3 febrile neutropenia with the once-daily dose of duvelisib. The recommended phase II dose of duvelisib when given in combination with FCR was 25 mg twice daily.

Grade &ge;3 hematologic adverse events (AEs) in all enrolled patients included grade 3 neutropenia in 6% and grade 4 in 41%, grade 3 thrombocytopenia in 3% and grade 4 in 28%, and grade 3 anemia in 16%. Nonhematologic AEs (all-grade) included nausea (69%), fever (38%), fatigue (31%; grade 3, 3%), anorexia (28%), diarrhea (28%; grade 3, 3%), transaminitis (31%; grade 3/4, 28%), vomiting (16%; grade 3, 3%), pruritus (9%; grade 3, 3%), arthritis (9%), and cytomegalovirus (CMV) reactivation (6%).

Serious AEs included pneumonia in 6 patients, including 3 cases of pneumocystis jiroveci pneumonia despite prophylaxis, the authors noted. Other serious toxicities included transaminitis (grade 3, n = 5; grade 4, n = 4), colitis (grade 2, n = 1; grade 3, n = 1), febrile neutropenia (grade 3, n = 6), pruritus (grade 3, n = 1), CMV infection (n = 1), and metastatic melanoma (n = 1).

Fifteen patients discontinued treatment due to toxicities: 5 from grade 4 transaminitis; 4 from prolonged cytopenia; 3 due to autoimmune cytopenias including autoimmune hemolytic anemia, neutropenia, and red cell aplasia; and 1 each due to grade 3 rash and grade 3 amylase increase. One patient withdrew due to unspecified toxicities.

Davids MS, Kim HT, Hanna J, et al. A phase Ib/II study of duvelisib in combination with FCR (dFCR) in previously untreated, younger patients with CLL. Poster presented at: 2017 International Workshop of Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 104.

Duvelisib, a PI3K-delta/gamma inhibitor, in combination with fludarabine, cyclophosphamide, and rituximab showed high rates of responses and bone marrow minimal residual disease negativity in younger patients with previously untreated chronic lymphocytic leukemia.

Duvelisib/FCR Achieves Higher Rate of MRD Negativity, Responses in Young CLL Patients

NF1 is a common autosomal dominant disorder caused by a mutation in the NF1 tumor suppressor gene, which results in acti- vation of the RAS pathway. These patients are highly predisposed to develop peripheral nerve tumors.

An MPNST is a rare and aggressive type of soft tissue sarcoma that is associated with a poor prognosis and is a major source of mortality in adult patients with NF1, according to Nancy Ratner, PhD. Currently, the only treatment approach for these tumors is surgery.

Ratner, program leader of the Cancer Biology and Neural Tumors Program, and the Beatrice C. Lampkin Chair of Cancer Biology, Cincinnati Children&rsquo;s Hospital Medical Center, and colleagues investigated genes that are more commonly upregulated in neurofibroma and MPNSTs, compared with normal cells, to identify potential targets for therapy.

AURKA and AURKB were both expressed at higher levels in MPNST cells than in normal cells. These oncogenes have also been noted at high levels in many other cancer types, Ratner said.

In studies of MPNST xenografts, tumor growth was prevented with Aurora kinase inhibition. &ldquo;As long as one kept applying the drug, one actually maintained a block in tumor growth,&rdquo; Ratner said. Yet once the drug was stopped, the tumor regrew.

In a phase II study of alisertib (MLN8237), an oral adenosine triphosphate-competitive AURKA inhibitor, in patients with various types of advanced or metastatic sarcoma, the drug showed a promising benefit in progression-free survival (PFS).

While the primary endpoint of response rate was not met, with only 2 confirmed responses, the PFS was notable at 11.7 weeks (95% CI, 7.0-13.0). Ten patients (14%) in the trial had MPNSTs.

In this cohort, the median PFS was 13 weeks (95% CI, 3.6- 45); at 12 weeks, the PFS rate was 60% and the median overall survival rate was 69 weeks (95% CI, 16 to not reached).

The AURKA inhibitor was well tolerated, but grade 3/4 adverse events in all patients included oral mucositis (12%), anemia (14%), platelet count decrease (14%), leukopenia (22%), and neutropenia (42%).

&ldquo;PFS at 12 weeks of >40% has been considered a sign of an active drug in sarcoma. By this metric, the results of alisertib are promising, especially in liposarcoma (PFS of 73% at 12 weeks), leiomyosarcoma (44%), and MPNSTs (60%), although the number of patients in each cohort remains small,&rdquo; Dickson et al wrote in their paper.

Ratner and colleagues sought to find treatments that could be combined with AURKA inhibition: &ldquo;this has been extremely frus- trating because many agentsfor example MEK inhibitors&mdash;failed to be better than Aurora kinase inhibition alone,&rdquo; she commented.

MEK inhibition was tested in xenograft models of MPNSTs due to the negative regulation of the MAPK pathway noted in human and mouse MPNST cells compared with normal cells. While it did translate to a modest benefit in survival, she noted that MEK inhibition was not enough.

Ratner and colleagues found a synergy between an oncolytic herpes virus and Aurora kinase inhibition.

Previously, in preclinical studies, MPNST-derived cell lines were found to be sensitive to treatment with the oncolytic herpes simplex virus as a single agent.

The virus was injected into the tumor and blood stream and resulted in a direct lysing of tumor cells and nearby cells, she explained. This effect was increased in the combination with alisertib.

In xenograft models of MPNSTs, alisertib was combined with HSV1716, a virus derived from HSV-1. Alisertib was administered at 20 mg/kg twice a day Monday to Friday, with 2 days off, and 1 dose of the virus.

At this dose, responses were noted in all tumors. However, the 20 mg/kg dose was considered too high for humans to tolerate, so it reduced to 10 mg/kg on the same schedule. The combination reduced tumor growth and increased survival.

&ldquo;The virus itself causes an increase in the percent of myeloid-derived suppressor cells and natural killer cells that is not present in the combination,&rdquo; Ratner said, adding that she believed that the combination created a more pronounced effect.

She also noted that her colleague, Timothy P. Cripe, MD, PhD, is working to bring this combination of an oncolytic herpes virus and Aurora kinase inhibition into human trials of patients with MPNSTs.

Dickson MA, Mahoney MR, Tap WD, et al. Phase II study of MLN8237 (Alisertib) in advanced/ metastatic sarcoma. Ann Oncol. 2016;27(10):1855-1860. doi: 10.1093/annonc/mdw281.

Mahller YY, Rangwala F, Ratner N, Cripe TP. Malignant peripheral nerve sheath tumors with high and low Ras-GTP are permissive for oncolytic herpes simplex virus mutants. Pediatr Blood Cancer. 2006;46(7):745-754.

Currier MA, Sprague L, Rizvi TA, et al. Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation. Oncotarget. 2017;8(11):17412-17427. doi: 10.18632/oncotarget.14885.

Aurora kinase inhibition in combination with an oncolytic herpes simplex virus could represent a novel treatment approach for patients with neurofibromatosis type 1 who develop malignant peripheral nerve&nbsp;sheath tumors.

Oncolytic Herpes Virus Shows Potential in Sarcoma Subtype

The investigators have hypothesized that PA using minimally invasive therapies can achieve organ preservation, reduce adverse events (AEs), maintain good voiding and sexual function, and avoid compromise to oncological outcomes.

They said the phase III PART trial would be the first to compare PA and RP in the context of intermediate-risk, unilateral, clinically significant, localized prostate cancer, and that it has the potential to improve understanding of how to treat this disease. Previous studies have generally assessed these treatments in low-risk prostate cancer.

&ldquo;When we were designing this study, the diagnostic pathway was a rapidly evolving process, so we tried to make a pragmatic design to allow us to move with the times by incorporating prostate MRI, targeted biopsies, and fusion biopsies within the study,&rdquo; lead study author Tom Leslie, MB ChB, DPhil, a consultant urological surgeon of Oxford University Hospitals, said.

The feasibility study was set in 5 large urology clinics in the United Kingdom. Men were targeted who were amenable to PA or RP. &ldquo;We were specifically looking [for those with] unilateral clinically significant intermediate-risk prostate cancerGleason grade 4 or higher,&rdquo; Leslie added. Study participants also could have contralateral insignificant disease within the inclusion criteria.

The patients were diagnosed by multiparametric MRI, along with either a targeted biopsy or template prostate biopsy. The patients then were randomized to receive either partial PA or RP.

The investigators sought to achieve a randomization rate of 50% and collected data on quality-of-life (QoL) factors, primary treatment failure (defined as the need for whole gland ablation or secondary therapy), long-term AEs, disease progression, and disease-caused mortality. According to Leslie, they also paid attention to primary treatment failure with multiple focal therapy and later conversions to prostatectomy or radiotherapy.

The feasibility trial recruited the targeted 80 patients. Half of the patients initially considered for the feasibility study specifically wanted RP and therefore could not be randomized or included in the study. Others preferred brachytherapy, cryoablation, or chemotherapy, and also could not be included. &ldquo;These were men who couldn&rsquo;t be randomized because they knew what they wanted, and that&rsquo;s perfectly fair,&rdquo; Leslie commented.

In terms of QoL data, initial responses suggested that there are some potential health gains for patients who received PA compared with RP. However, in terms of essential function and QoL as time went on, there was no significant difference in patient perception.

Leslie T, Davies L, Elliott D, et al. The PART triala phase III study comparing Partial prostate Ablation versus Radical prosTatectomy (PART) in intermediate risk prostate can- cer&mdash;early data from the feasibility study. Presented at: 2017 American Urological Asso- ciation Annual Meeting; May 12-16, 2017; Boston, MA. Abstract PD56-08. eventscribe. com/2017/AUA2017/.

Based on results of a feasibility study, researchers in the United Kingdom have decided to move forward with a full randomized controlled trial comparing partial prostate ablation (PA) with radical prostatectomy (RP) in patients with intermediate-risk prostate cancer, according to a presentation at the 2017 American Urological Association Annual Meeting.

Results from PART Feasibility Study Endorse Development of Full Trial

The study authors further concluded that inhibiting this gene with antiandrogen therapy, such as enzalutamide (Xtandi) and bicalutamide (Casodex), could increase the effectivity of taxane-based therapies in patients with CRPC.

Docetaxel has long been the standard first-line treatment for patients with CRPC. However, patients can either present with or develop a resistance to taxanes, leaving a large unmet need for treating patients with this resistance. Cabazitaxel is a next-generation taxane that was approved recently to treat patients previously treated with docetaxel. Despite having a benefit in overall survival over other agents in the postdocetaxel setting, patients treated with cabazitaxel also experience resistance, and ultimately disease progression. Therefore, a deeper understanding of what drives this resistance will help urologists treat these patients.

The ABCB1 gene is a cell membrane efflux pump, and a member of the MDR/TAP subfamily of ATP-binding cassette (ABC) transporters. ABCB1 is responsible for lower drug accumulation in multidrug-resistant cells and can mediate resistance to anticancer drugs.

&ldquo;Our previous work showed that increased expression of ABCB1 was largely responsible for mediating resistance to docetaxel. Thus, we sought to test whether this would alter cellular response to cabazitaxel,&rdquo; Alan P. Lombard, PhD, of the University of California Davis Medical Center, and colleagues wrote in the abstract for the poster.

The investigators performed numerous cell growth and colony formation assays to attain cell numbers to assess cellular responses to cabazitaxel. They demonstrated that TaxR and DU145-DTXR docetaxel-resistant prostate cancer cells are cross-resistant to cabazitaxel.

Further assays showed that cells resistant to docetaxel are also completely resistant to high-dose docetaxel, but do have some response to high-dose cabazitaxel. Additionally, the investigators noted, using either an shRNA or elacridar (a small molecule inhibitor of ABCB1) to decrease the expression of ABCB1 re-sensitizes cells resistant to docetaxel to treatment with cabazitaxel and restores the cell death response.

When the investigators administered bicalutamide to the resistant cells, ABCB1 activity was blocked and the cell growth assays showed that these cells were re-sensitized to treatment with cabazitaxel. Further, the investigators discovered that bicalutamide could also re-sensitize TaxR and DU145-DTXR cells to cabazitaxel. Enzalutamide behaved similarly in re-sensitizing docetaxel-resistant cells to treatment with cabazitaxel. Notably, the cell growth assays also demonstrated that enzalutamide and bicalutamide could restore cabazitaxel-induced apoptosis in TaxR and DU145-DTXR cells.

This research provides a better understanding of the mechanism of resistance for a large and underserved population of patients with CRPC. It could even indicate not only that there is potential for combination therapies with antiandrogen agents to enhance the effectiveness of cabazitaxel in the docetaxel-resistant setting, but also that cabazitaxel may be a better drug in the pre-docetaxel setting for these patients. &ldquo;Our work indicates that it may be more beneficial to move cabazitaxel into the docetaxel treatment space,&rdquo; Lombard et al concluded.

Lombard AP, Liu C, Armstrong C, et al. Elucidating cross-resistance between docetaxel and cabazitaxel in castration resistant prostate cancer. Presented at: 2017 American Urological Association Annual Meeting; May 12-16, 2017; Boston, MA. Abstract MP83-09. eventscribe.com/2017/AUA2017/.

Genetics Home Reference. ABCB1 gene. NIH US National Library of Medicine website. ghr.nlm.nih.gov/gene/ABCB1. Updated May 16, 2017. Accessed May 16, 2017.

Results of an investigation presented at the 2017 American Urological Association Annual Meeting indicate that resistance to docetaxel and cabazitaxel (Jevtana) in patients with castration-resistant prostate cancer (CRPC) is mediated by a common mechanism, overexpression of the ABCB1 gene.

Cross-Resistance to Docetaxel and Cabazitaxel in CRPC Mediated by ABCB1 Gene

Yet, physicians continue to try to treat all sarcomas the same, making drug development for these types of tumors quite slow and frustrating.

The heterogeneity of STSs poses a constant challenge for the treatment of these tumors.

As Angela Pang, MBBS, MRCP, et al state in their paper on the current treatment paradigm for STS, &ldquo;With a revolution in the understanding of the genomics and relevant pathways involved in the pathogenesis of each sarcoma subtype, accurate identification of the sarcoma subtype is critical in directing treatment for patients with metastatic STS.&rdquo;

Gastrointestinal stromal tumors (GIST) are one of the few sarcomas that have been separated from the pack.

Targeted therapies have been approved for the treatment of GIST alone, including the tyrosine kinase inhibitor (TKI) imatinib (Gleevec), which has made a big difference for patients with GIST. Only by separating this patient population could advances be made.

Another group of sarcomas that would benefit from differentiation from the STS umbrella is leiomyosarcoma, which is one of the most common subtypes, accounting for approximately 11% to 15% of STS, although the exact amount is hard to determine.

According to a characterization of the taxonomy of STS subtypes published in Nature Reviews Cancer, leiomyosarcomas have close ties to GIST and rhabdomyosarcomas.

Leiomyosarcomas are tumors that occur in smooth muscle tissues.

They frequently are found in the retroperitoneum, uterus, dermis, and vessels, though they can also occur in the bone.

They are pleomorphic myogenic sarcomas that are commonly aggressive and associated with a shorter relapse-free survival.

Prognostic factors for leiomyosarcomas are strongly tied to the location of the tumor and its size. Retroperitonael and vascular tumors have a poorer prognosis, whereas cutaneous leiomyosarcomas have a better prognosis than some of the other subtypes.

Patients with hereditary retinoblastomas caused by a germline RB1 mutation have an increased risk of developing STS, especially leiomyosarcomas.

This subgroup of sarcomas covers a wide range of variants that would benefit from more treatment options and a more individualized approach.

When patients are diagnosed with STS, they are generally treated with surgery, radiation, chemotherapy, or a combination of these modalities.

However, responses to these modalities often differ by STS subtype.

In a study of adjuvant radiotherapy in uterine sarcomas, investigators randomized 224 patients, including 99 with uterine leiomyosarcoma and 1 with myxoid leiomyosarcoma, to either pelvic radiation or observation. The study showed that there was no overall survival (OS) or progression-free survival (PFS) benefit in the patients with leiomyosarcoma who received radiation.

Responses to chemotherapy also vary with leiomyosarcomas. First-line anthracycline-based chemotherapy is standard for patients with advanced STS.

Ifosfamide is one of the standard chemotherapies given to patients with STS in the frontline, yet patients with leiomyosarcoma may not benefit as significantly from ifosfamide as from other chemotherapy monotherapies or combinations. When examining the outcomes of patients with STS treated with ifosfamide-containing chemotherapy, patients with leiomyosarcoma showed a higher risk of progression than those with synovial sarcoma.

Also, they showed a lower benefit in terms of OS with ifosfamide-based treatment than with doxorubicin monotherapy. Regorafenib (Stivarga) is a multikinase inhibitor that has shown antitumor activity in STS and has been approved for the treatment of GIST. Outside of GIST, regorafenib has shown activity in non-adipocytic sarcomas.

In the REGOSARC trial of patients with STS, which excluded patients with GIST, those in the leiomyosarcoma cohort showed a PFS of 3.7 months (95% CI, 2.5-5.0) and a median OS of 21 months (95% CI, 7.2 to not reached). Twenty-four patients (86%) in this cohort had stable disease with regorafenib. Patients in the other sarcoma cohort showed a similar PFS and no significant difference in OS, but those with liposarcoma showed a worse PFS and OS compared with placebo. Other TKIs have also shown limited benefit for patients with leiomyosarcoma.

PD-1 checkpoint inhibitors are increasingly being explored as a treatment for STS. In the phase II SARC-028 study of pembrolizumab (Keytruda) in subtypes of patients with STS and bone sarcomas, the objective response rate (ORR) was 19% for patients with STS and 40% had stable disease.

No responses were seen in patients with leiomyosarcoma in this trial, however. Yet researchers found 1 patient with uterine leiomyosarcoma who showed a complete pathologic response to pembrolizumab in all but 1 metastatic site in a phase Ib study.

The patient showed PTEN loss, reduced infiltration of PD-1positive lymphocytes, and diminished expression of neoantigens. Leiomyosarcoma is 1 of the STS subtypes that has shown a high proportion of PD-L1 expression. In a study of PD-1 and PD-L1 expression in STS, 58% of samples showed PD-L1 expression.

Among patients with leiomyosarcoma, 45% had PD-1positive expression and 70% had PD-L1 expression. Interestingly, with STS, expression was associated with a poor prognosis by multivariate analysis. Among patients with leiomyosarcoma, PD-1/PD-L1 positivity also tended to be found in those with a higher tumor stage, also accounting for a poor prognosis. The true impact of checkpoint inhibitors on patients with leiomyosarcoma is still unknown.

Treatments are starting to be investigated aimed at treating patients with leiomyosarcoma rather than all STSs. Gemcitabine and docetaxel (Taxotere) have shown responses in patients with leiomyosarcoma, particularly in patients with uterine leiomyosarcoma. A phase II trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma, 85% of which had uterine leiomyosarcoma, showed an ORR of 53% (95% CI, 35%-70%) with 3 of 34 patients achieving a complete response.

Responses were also seen in 50% of patients who had progressed following treatment with doxorubicin. The median time to progression was 5.6 months.

In a phase III trial of frontline gemcitabine and docetaxel in patients with uterine leiomyosarcoma, gemcitabine and docetaxel showed responses in 31.5% of 54 patients.

The median PFS was 6.2 months and the median OS was 26.9 months with the doublet. The addition of bevacizumab (Avastin) to gemcitabine and docetaxel did not show a significant improvement in PFS or OS, but the ORR was increased with the triplet (35.8%). Docetaxel and gemcitabine is now a standard of care in patients with uterine leiomyosarcoma, although the benefit has been called into question.

Trabectedin (Yondelis), a marine-derived drug, has received a category 1 recommendation in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of patients with liposarcomas and leiomyosarcomas, known collectively as L-sarcomas.

For all other types of STS, the combination has a category 2A recommendation.

This recommendation for L-sarcomas was based on a phase III trial of trabectedin versus dacarbazine in the second line for patients with advanced L-sarcomas. Trabectedin showed a median PFS of 4.2 months compared with 1.5 months with dacarbazine (HR, 0.55; P <.001).16 The median OS with trabectedin was 12.4 months versus 12.9 months with dacarbazine (HR, 0.87; P = .37).

Eribulin (Halaven) has also shown benefit in the L-sarcomas and received a category 1 recommendation from the NCCN for the treatment of L-sarcomas based on a phase III trial in which previously treated patients demonstrated an OS of 13.5 months with eribulin compared with 11.5 months with dacarbazine (HR, 0.77; 95% CI, 0.62-0.95; P = .0169).

Other types of STS were not included in these studies of eribulin and trabectedin.

According to a recent presentation at the 2017 ASCO Annual Meeting, 50% of all STS have complex genomic profiles, whereas 15% to 30% commonly have reciprocal translocations, and the remainder commonly have amplifications.

Leimyosarcoma was marked as one of the main subtypes with a complex profile.

In their genomic analysis of 587 patients with sarcoma from the American Association of Cancer Research&rsquo;s GENIE Consortium, 56% had a complex genomic profile. Of these patients, 34% had leiomyosarcoma, the most frequent histology. Patients with leiomyosarcoma frequently showed mutations in TP53, RB1, ATM, and APC. Amplifications of MYOCD are also common in a subset of leiomyosarcomas, as well as chromosome 10 deletions in PTEN.

Clinical trials are ongoing to further study the genomic landscape of leiomyosarcomas and derive better treatment options for patients with this sarcoma subtype. These include the MULTISARC study, a phase III precision medicine trial for patients with STS tested with next-generation sequencing to guide subsequent therapies for each patient in the experimental arm.

The Cancer Genome Atlas project is also working on a comprehensive genomic analysis of specific STS, including leiomyosarcoma.

Hopefully these studies will help determine better treatments for patients specifically with leiomyosarcoma, rather than as a subset of STS.

International Agency for Research on Cancer. World Health Organization Classi cation of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: International Agency for Re- search on Cancer; 2013.

Burningham Z, Hashibe M, Spector L, Schi man JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2(1):14. doi: 10.1186/2045-3329-2-14.

Pang A, Carbini M, Maki RG. Contemporary therapy for advanced soft-tissue sarcomas in adults: a review. JAMA Oncol. 2016;2(7):941-947. doi: 10.1001/jamaoncol.2016.0241.

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: soft tissue sarcoma. Version 2.2017. nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed June 30, 2017.

Ducimetiere F, Lurkin A, Ranchere-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6:e20294.doi: 10.1371/journal.pone.0020294.

Taylor BS, Barretina J, Maki RG, et al. Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer. 2011;11(8):541-557. doi: 10.1038/nrc3087.

Bathan AJ, Constantinidou A, Pollack SM, Jones RL. Diagnosis, prognosis, and management of leio- myosarcoma: recognition of anatomic variants. Curr Opin Oncol. 2013;25(4):384-389. doi: 10.1097/ CCO.0b013e3283622c77.

Reed NS, Mangioni C, Malmström H, et al; European Organisation for Research and Treatment Gynaecological Cancer Group. Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecologi- cal Cancer Group Study (protocol 55874). Eur J Cancer. 2008;44(6):808-818. doi: 10.016/j.ejca.2008.01.019.

Sleijfer S, Ouali M, van Glabbeke M, et al. Prognostic and predictive factors for outcome to rst-line ifosfa- mide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospec- tive analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Can. 2010;46(1):72-83. doi: 10.1016/j.ejca.2009.09.022.

Mir O, Brodowicz T, Italiano A, et al. Safety and e cacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(12):1732-1742. doi: 10.1016/S1470-2045(16)30507-1.

Tawbi HA, Burgess MA, Crowley J, et al. Safety and e cacy of PD-1 blockade using pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): Results of SARC028A multicenter phase II study. J Clin Oncol. 2016;34(suppl; abstr 11006). doi: 10.1200/JCO.2016.34.15_suppl.11006.

Miao D, Adeegbe D, Rodig SJ, et al. Response and oligoclonal resistance to pembrolizumab in uterine leiomyosarcoma: Genomic, neoantigen, and immunohistochemical evaluation. J Clin Oncol. 2016;34(suppl; abstr 11043). doi: 10.1200/JCO.2016.34.15_suppl.11043.

Kim JR, Moon YJ, Kwon KS, et al. Tumor in ltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS One. 2013;8(12):e82870. doi: 10.1371/ journal.pone.0082870.

Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leio- myosarcoma: results of a phase II trial. J Clin Oncol. 2002;20(12):2824-2831. doi: 10.1200/JCO.2002.11.050.

Hensley ML, Miller A, O&rsquo;Malley DM, et al. Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as rst-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/ Gynecologic Oncology Group study. J Clin Oncol. 2015;33(10):11801185. doi: 10.1200/JCO.2014.58.3781.

Demetri GD, von Mehren M, Jones RL, et al. E cacy and safety of trabectedin or dacarbazine for met- astatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793. doi: 10.1200/JCO.2015.62.4734.

Schö ski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629-1637. doi: 10.1016/S0140-6736(15)01283-0.

Italiano A, Khalifa E, Laizet Y, et al. Genetic landscape of soft-tissue sarcomas: moving toward per- sonalized medicine [ASCO abstract 11002]. J Clin Oncol. 2017;35(suppl). abstracts.asco.org/199/ AbstView_199_193380.html.

There are more than 70 subtypes that fall under the soft tissue sarcoma (STS) umbrella, according to the World Health Organization, and only account for approximately 1% of all cancers in adult patients.&nbsp;Yet, physicians continue to try to treat all sarcomas the same, making drug development for these types of tumors quite slow and frustrating.

Separating Treatment of Leiomyosarcomas From STS Umbrella

on June 4 in Chicago, panel members sought to explain the basic principles of biosimilar products.

Hope S. Rugo, MD, explained that a biosimilar is a new biologic product that is highly similar to an approved product in terms of structure, function, and biological activity. According to the FDA&rsquo;s definition, biosimilarity means that the product is &ldquo;highly similar to the reference product, notwithstanding minor differences in clinically inactive components,&rdquo; and importantly, that &ldquo;there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.&rdquo;

The European Medicines Agency has approved more biosimilars than the FDA due to obstacles to US approvals, including regulatory pathways, postapproval surveillance, coverage and reimbursement decisions, clinician and patient perception, and extrapolation, said Rugo, clinical professor, Department of Medicine (Hematology/ Oncology), and director, Breast Oncology Clinical Trials Program, University of California, San Francisco.

Robert Rifkin, MD, added that there are challenges to the uptake of biosimilars even once they are approved, including physician behavior, lack of patient incentive, boots on the ground, professional societies, costs, and conflicts of interest. Overcoming these challenges will require education, said Rifkin, the medical director of biosimilars, McKesson Specialty Health, US Oncology Network.

Presenter Andrew D. Zelentz, MD, PhD, described differences in biologics from a regulatory perspective. Biosimilars and interchangeables, or biosimilars that can be substituted for the reference product, go through the 351(k) pathway with the FDA. Original biologics, &ldquo;me-too&rdquo; biologics, and &ldquo;bio-betters,&rdquo; or biologics that have been altered to achieve improved outcomes, go through the 351(a) regulatory pathway.

Biosimilar developers do not need to present the FDA with complete data proving full clinical efficacy and safety. This has already been demonstrated by the innovator of the reference product, said Zelentz, medical director of quality informatics, Memorial Sloan Kettering Cancer Center. Instead, the manufacturers must prove that the biosimilars are structurally and functionally similar to the reference product in preclinical assessments, followed by animal toxicity studies.

Clinical trials of biosimilars are then conducted to prove the similarity of the pharmacokinetics and pharmacodynamics to the reference product. &ldquo;Product class-specific pharmacokinetics equivalence margins are very important for extrapolation decisions that occur later in the development program,&rdquo; Zelentz said. The agent must also show similar safety, efficacy, and immunogenicity in a phase III trial in comparison with either the US or EU reference product. Phase II trials are not necessary for biosimilars.

&ldquo;Our biggest problem is getting people onto these trials in the United States,&rdquo; said Rifkin.

Once an agent&rsquo;s similarity has been proven in a sensitive patient population, the drug can be extrapolated for use in other indications already approved for the originator drug without necessitating additional clinical trials. It is here, Rifkin said, that the cost savings come in.

BIOSIMILAR LANDSCAPE IN HEMATOLOGY/ONCOLOGY

Rifkin highlighted that there are several biosimilars and non-originator biologicals approved and in development for the supportive care agents lgrastim, peg lgrastim, and erythropoietin and for the therapeutic agent rituximab (Rituxan) in hematology.

Filgrastim rbe (Zarzio), a biosimilar to lgrastim, was approved by the FDA on March 6, 2015. Yet Rifkin noted that it took more than 180 days for the biosimilar to reach the clinic with only a 15% discount from the reference product.

With pegfilgrastim, 351(k) applications have been accepted by the FDA for 2 biosimilars, MYL-1401H and CHS-1701. A biosimilar to epoetin alfa, epoetin hospira (Retacrit) was considered for approval by the FDA but the application was recently denied due to manufacturing concerns.

The US patent for rituximab expired in 2016, and no biosimilars have yet been approved in the United States. However, several phase III trials of rituximab biosimilars are ongoing, geared toward approval in various hematologic malignancies.

Adam M. Brufsky, MD, PhD, explained that there is a huge market for both trastuzumab and bevacizumab in the United States. This is driving a great deal of biosimilar development, said Brufsky, associate chief of hematology/oncology, co-director of the Comprehensive Breast Cancer Center, and associate director of clinical investigation, University of Pittsburgh.

A number of biosimilars to trastuzumab are currently undergoing phase III trials in the setting of HER2-positive metastatic breast cancer alone; including MYL-1401O, which had a larger phase III trial than for the trial for the reference product, Brufsky noted. In the active study, the drug met the FDA&rsquo;s required definition of equivalence and similar efficacy. Brufsky commented that with biosimilars, the 90% confidence interval is what is more important in the approval process than attaining the same response rates. He anticipated that an approval for a trastuzumab biosimilar will occur in the next few years in the United States.

Bevacizumab biosimilars are also going through several phase III trials with chemotherapy for nonsmall cell lung cancer. In 1 trial with the biosimilar ABP 215, the objective response rate met the 90% confidence interval margin and so clinical equivalence was demonstrated between the biosimilar and the reference.

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. fda.gov/downloads/drugsguidancecomplianceregulatoryinformation/guidances/ ucm291128.pdf. Posted April 2015. Accessed June 27, 2017.

Pfizer provides update on proposed epoetin alfa biosimilar [news release]. New York, NY: P zer, Inc.; June 22, 2017. investors.p zer.com/investor-news/press-release-details/2017/P zer-Pro- vides-Update-on-Proposed-Epoetin-Alfa-Biosimilar/default.aspx. Accessed June 28, 2017.

The uptake of biosimilar agents is still slow in oncology and hematology in the United States. But this area is expected to grow with more understanding of biosimilars and, especially, because the US patents for trastuzumab (Herceptin) and bevacizumab (Avastin) expire in 2019.