Emerging Agents Poised to Advance Soft Tissue Sarcoma Care

Brian A. Van Tine, MD, PhD

With scores of subtypes and a paucity of molecular markers, soft tissue sarcoma (STS) remains a complex and challenging tumor type to treat yet significant strides being made in the field are likely to alter the therapeutic paradigm, according to experts who participated in a recent OncLive Peer Exchange^® program.

The program, entitled “Multidisciplinary Treatment of Advanced Soft Tissue Sarcomas,” delved into promising new agents and therapeutic strategies that are helping to extend survival and improve quality of life for patients with STS. Led by moderator Brian A. Van Tine, MD, PhD, the panel also discussed the complexities associated with diagnosis and treatment of STS, and the importance of individualizing care.

“This field, for the first time in a very long time…has an influx of potential new drugs that are going to very quickly start changing the landscape of how the non-surgeons approach the tumors,” stated Van Tine, director, Sarcoma Program Barnes and Jewish Hospital Washington University in St. Louis.

Importance of Multidisciplinary Care

Indeed, the armamentarium expanded in October with the FDA’s approval of trabectedin (Yondelis) for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have previously received anthracycline- based chemotherapy.With fewer than 12,000 annual diagnoses in the United States and 50 or more subtypes, STSs are both rare and heterogeneous. Multidisciplinary care, which may include a pathologist, radiologist, surgeon, oncologist, a gastroenterologist, nurse, geneticist, and social worker, is of particular importance in this complex group of diseases, the Peer Exchange panelists said.

Some of the most common STS subtypes fall under the categories of leiomyosarcoma, liposarcoma/ adipocytic sarcoma, and nondescript spindle cell sarcoma.

Robin L. Jones, MD, MRCP

randa Obtaining a clear and accurate histological diagnosis prior to starting treatment is essential, since each subtype can differ in underlying biology, clinical behavior, and response to treatment, according to Robin L. Jones, MD, MRCP.

The system in the United Kingdom, where Jones practices, differs from the system in the United States, in that all sarcoma patients in the United Kingdom are referred directly to a sarcoma center following an STS diagnosis, explained Jones, Medical Oncologist Royal Marsden Hospital Institute of Cancer Research London, England. “The complexity both in terms of heterogeneity, rarity, and the wide variety of anatomic primary sites just make it very, very challenging [to treat],” Jones said.

According to the French grading system, tumors are graded as low, intermediate, and high, based on tumor differentiation, tumor necrosis, and mitotic count. This assessment has important implications in terms of prognosis, Jones stated.

R. Lor Randall, MD

Also, prior to any intervention, it is important to conduct chest imaging, as the chest is the most common site for STS tumors to metastasize,new said R. Lor Randall, MD, FACS. Radiological images and clinical features, together with a report from a pathologist experienced with STS, are needed to make a definitive diagnosis prior to beginning treatment.

“As a surgeon I need to understand the biology, the medical oncology, the radiation therapeutics available, the leading-edge thought,” noted Randall, director, Sarcoma Services medical director, Surgical Services, Huntsman Cancer Institute. “The physicians that are involved more in the systemic management also need to understand the local control issues, because we know that surgery and radiation therapy are backbones…for curing and managing sarcomas.”

The medical and surgical teams need to be in communication with the pathologist about the location and behavior of the tumor, agreed Andrew J. Wagner, MD, PhD, senior physician, Adult Oncology, Dana-Farber Cancer Institute. The pathologist’s findings help drive the decisions regarding other testing that may need to be done.

Andrew J. Wagner, MD, PhD

Multidisciplinary care is essential from the time of diagnosis, added Jonathan C. Trent, MD, PhD, director, UM Sylvester Comprehensive Cancer Center, “because some of these sarcomas, particularly the small cell sarcomas, can grow quite rapidly.”

Neoadjuvant/Adjuvant Therapeutic Considerations

“[Multidisciplinary care] also provides the opportunity to look at new approaches and new treatments in a group setting,” noted Wagner.The standard of care for smaller, lower grade lesions is wide local excision followed by surveillance. For more aggressive lesions, adjuvant and/or neoadjuvant treatment, often with radiotherapy, may be warranted, noted Randall. Chemotherapy may be initiated prior to surgery for cytoreduction.

Jonathan C. Trent, MD, PhD

It is often possible to transition an unresectable tumor to one that is resectable using chemotherapy or targeted therapy to shrink the tumor, said Trent. However, chemotherapy is not used with certain histologies because the tumors are known to be resistant to chemotherapy.

New Look at Standard Regimens

Wagner noted that it is important to consult with the surgeon before deciding whether to use neoadjuvant therapy. One key question to ask the surgeon is whether it will help to shrink the tumor. “The radiation is really important for tumors, to help with margins and local control, but the problem sometimes with giving neoadjuvant chemotherapy is that you can introduce toxicity, and in some cases, it’s not effective and the tumor worsens, instead of reducing in size,” he said.The phase III GeDDIS trial sought to determine whether a chemotherapy doublet used in relapsed settings would be more effective than single-agent doxorubicin as first-line treatment in advanced unresectable or metastatic STS.¹ The trial randomized 257 patients to receive doxorubicin or gemcitabine/docetaxel. The primary endpoint was progression-free survival (PFS) rate (PFR) at 24 weeks.

The PFR was 46.1% for single-agent doxorubicin and 46.0% for the combination. PFS was 23 weeks versus 24 weeks for doxorubicin and docetaxel/ gemcitabine, respectively.¹

Shreyaskumar R. Patel, MD

The results showed a similar PFS at 24 weeks, at which point doxorubicin was found to be superior, said Shreyaskumar R. Patel, MD, medical director, Sarcoma Center, The University of Texas MD Anderson Cancer Center. These study results indicated that doxorubicin should remain the standard of care in this setting, added Patel.

Single-agent doxorubicin was also found to have fewer toxicities compared with the combination. The associative toxicities are an important consideration, said Patel, and care should always be individualized and involve the patient’s preferences.

Cancer is constantly evolving, and managing toxicities is part of treating the disease, stated Randall. “While the Holy Grail is cure, it’s really maintenance,” he said. “Like managing diabetes, we want to get to the goal where we can keep people’s quality of life high and their tumor burden low, but we may not truly be curing a lot of people.”

Another trial in the first-line setting, the EORTC 62012 study, assessed whether dose intensification of doxorubicin with ifosfamide would improve survival of patients with advanced STS compared with doxorubicin alone.²

Emerging Approaches

The study found no improvement in overall survival, but found an improvement in response rate and PFS with the combination.² Jones noted that the combination was associated with more toxicities and thus may be most appropriate in patients with rapidly progressing disease, inoperable locally advanced disease, or high tumor burden.Pazopanib

The phase III PALETTE study examined the effect pazopanib, an oral tyrosine kinase inhibitor of VEGF receptors, versus placebo on PFS in 369 patients with metastatic non-adipocytic STS who had failed standard chemotherapy.

The results showed a median PFS of 4.6 months with pazopanib compared with 1.6 months with placebo (HR, 0.31; P <.0001), but no significant improvement in overall survival.³ The study showed promising activity in synovial sarcoma and leiomyosarcoma, and also had activity in solitary fibrous tumors, said Trent.

Without molecular markers to guide therapy considerations, STS specialists must rely on histology-based subsetting, noted Patel. In synovial sarcoma, for example, if the patient received doxorubicin/ ifosfamide upfront, pazopanib would likely be second line, he said. In other settings, anthracycline-based therapy would be front line, gemcitabine/docetaxel second line, and pazopanib third line.

An ongoing Children’s Oncology Group clinical trial is investigating the effect of adding pazopanib to chemotherapy and radiation therapy in the neoadjuvant setting in patients with newly diagnosed non-rhabdomyosarcoma STS that can be removed through surgery, noted Randall. The four-arm trial compares (a) pazopanib plus chemoradiation, (b) chemoradiation, (c) pazopanib plus radiation, and (d) radiation alone.⁴

Pazopanib, which is approved for the treatment of patients with advanced STS who have received prior chemotherapy, carries a black box warning for liver toxicities. The drugs in this class share similar toxicities, including potential elevations in alanine transaminase, aspartate aminotransferase, and bilirubin, said Wagner. Other potential toxicities include hypertension, diarrhea, palmar/plantar erythrodysesthesias, and oral dysesthesia.

A clonazepam mouthwash can help counteract the mouth pain. Patients should be monitored carefully; if toxicities occur, the drug should be suspended or held until improvement, and the dose reduced, Wagner added.

Trabectedin

Trabectedin, a marine compound derived from the sea squirt, has been available in the European Union and many other countries for more than 5 years, explained Jones.

A drug application was approved by the FDA in October 2015, based on phase III open label data from a randomized trial of trabectedin compared with dacarbazine in patients with advanced leiomyosarcoma and liposarcoma in more than 500 patients previously treated with anthracycline and ifosfamide or chemotherapy.

Treatment with trabectedin was associated with a 45% reduction in the risk of disease progression or death compared with dacarbazine (HR, 0.55; P <.001).⁵

The RECIST response rates have consistently been in the 8% to 10% range, said Patel. “I think there is a group of patients who can tolerate this treatment for a very long time,” added Patel. “There are subsets like myxoid liposarcoma that are more sensitive to this drug than others. So, the drug clearly has had a role.”

Fatigue can be a major problem, said Jones, and liver toxicity is important to monitor. Very rarely, the drug can cause rhabdomyolysis. The dose may need to be modified, added Wagner.

Community oncologists should be aware that if the liver function tests show an obstructive pattern with alkaline phosphatase elevations, those are the patients who can have life-threatening toxicities, said Patel.

The real key is figuring out how to make optimal use of pazopanib and trabectedin, said Trent. It should be “a personalized decision based on patients’ expected toxicities, expected tolerance, and other factors that may be specific to that individual patient,” he said.

Table. Key Results in Pivotal Trabectedin Trial

Endpoint (95% CI)

Trabectedin

(N = 345)

Dacarbazine

(N = 173)

Hazard ratio

(P value)

Median PFS, months

4.2 (3.0-4.8)

1.5 (1.5-2.6)

0.55 (P <.001)

Median OS, months

13.7 (12.2-16.0)

13.1 (9.1-16.2)

0.93 (P = .49)

ORR,^a number of patients (%)

23 (7%)

10 (6%)

n/a

Response duration, months

6.9 (4.5-7.6)

4.2 (2.9-NE)

n/a

^aORR consists of complete and partial responses.

NE indicates not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Yondelis [prescribing information]. Horsham, PA: Janssen Products, LP; 2015.

Evofosfamide

Solid tumors, particularly sarcomas, tend to be hypoxic, explained Jones. Evofosfamide is activated in the hypoxic region of the tumor. The drug, an alkylating agent formerly known as TH-302, appears to be safer than the biologically equivalent dose of ifosfamide, noted Trent. Certain toxicities are associated with evofosfamide, including skin rash. It can also activate melanocytes, said Van Tine, increasing skin pigmentation in some individuals.

Patel noted that the available data suggest that this drug is “a kinder, gentler ifosfamide.”

Evofosfamide could end up replacing ifosfamide, or it could be reserved for select patients who are not candidates for ifosfamide, said Patel.

An ongoing phase III study is comparing evofosfamide in combination with doxorubicin versus doxorubicin alone in an estimated 620 patients with locally advanced or metastatic STS.⁶

The results from the trial and postmarketing data, if the drug were approved, would help determine patient selection for the regimen.

Olaratumab

Olaratumab is a monoclonal antibody that targets PDGFR-α. Phase I/II data are very promising, noted Van Tine. The study compared olaratumab plus doxorubicin with doxorubicin alone. The final PFS analysis showed that the combination was associated with a median PFS of 6.6 months compared with 4.1 months with doxorubicin (P = .0615), which investigators said met the primary endpoint.

Interim analysis showed improvement in overall survival of more than 10 months (25.0 months for the combination vs 14.7 months for doxorubicin alone; P = .0005).⁷

A phase III study is needed to confirm the results, said Trent. He also noted that it would be meaningful to compare the olaratumab regimen to another doublet, such as doxorubicin plus ifosfamide, rather than single-agent doxorubicin.

Eribulin

Eribulin is a dynamic microtubule inhibitor that has shown activity in sarcoma. Most recently, the drug was compared to dacarbazine in patients with metastatic leiomyosarcoma or adipocytic sarcoma. In the phase III study, eribulin demonstrated a 2-month improvement in overall survival (13.5 months with eribulin vs 11.5 months with dacarbazine; HR, 0.768; P = .017).⁸

Regorafenib

Perspectives on Future

Regorafenib is a multikinase inhibitor that is approved as a later-line therapy in metastatic colorectal cancer. A recent trial examined regorafenib in patients who had pretreated metastatic STS. Included in the study, were leiomyosarcoma, and synovial and adipocytic sarcomas. The study showed promising activity and an acceptable toxicity profile in STS.⁹With the availability of these new agents, the choice as to which agent to use will depend on the individual patient’s unique set of circumstances, said Trent. “It’s going to be a dealer’s choice, I think… [based on] the features of the patient,” he said. “What’s the patient’s performance status like? What’s their need for cytoreductive therapy and shrinkage of the tumor? What’s their need for their tolerance for different toxicities?”

The panelists also stressed the importance of patient participation in clinical trials. “It used to be thought that these are rare diseases, you can’t do these types of studies,” said Wagner. “I think it reflects upon the sarcoma community, which extends to community oncologists who refer patients in for clinical trials but also the national and international groups that participate quite collaboratively in conducting these studies, and relatively rapidly getting to answers about whether or not the drugs are effective. I think that that’s how we’re going to keep moving forward.”

References

1. Seddon BM, Whelan J, Strauss SJ, et al. GeDDiS: A prospective randomised controlled phase III trial of gemcitabine and docetaxel compared with doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft tissue sarcomas (EudraCT 2009-014907-29). Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, Illinois. Abstract 10500.
2. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial [published online March 5, 2014]. Lancet Oncol. 2014; 15(4):415—423.
3. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial [published online May 16, 2012]. Lancet. 2012;379(9829):1879-1886.
4. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02180867.
5. Demetri GD, von Mehren M, Jones RL, et al. A randomized phase III study of trabectedin or dacarbazine for the treatment of patients with advanced liposarcoma or leiomyosarcoma. Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, Illinois. Abstract 10503.
6. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01440088.
7. Tap WD, Jones RL, Chmielowski B, et al. A randomized phase Ib/II study evaluating the safety and efficacy of olaratumab (IMC-3G3), a human anti-platelet-derived growth factor α monoclonal antibody, with or without doxorubicin, in advanced soft tissue sarcoma. Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, Illinois. Abstract 10501.
8. Schöffski P, Maki RG, Italiano A, et al. Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients with leiomyosarcoma and adipocytic sarcoma. Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, Illinois. Abstract LBA10502.
9. Mir O, Brodowicz T, Wallet J, et al. Activity of regorafenib in leiomyosarcomas and other types of soft-tissue sarcomas: results of a double-blind, randomized placebo controlled phase II trial. Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, Illinois. Abstract 10504.