Investigators Express Confidence in a Novel TKI That Targets Rare Sarcomas

Jonathan C. Trent, MD, PhD

Anlotinib, a novel tyrosine kinase inhibitor capable of mounting a multipronged attack against oncogenic processes, is being tested in rare soft tissue sarcoma subtypes where patients have limited therapeutic options.

The phase III APROMISS trial (NCT03016819) is evaluating the safety and efficacy of anlotinib monotherapy versus dacarbazine in patients with metastatic or advanced alveolar soft part sarcoma (ASPS), leiomyosarcoma (LMS), and synovial sarcoma (SS).

These malignancies are among many sarcoma subtypes thought to depend upon signaling through VEGFR (vascular endothelial growth factor receptor), PDGFR (platelet-derived growth factor receptor) FGFR (fibroblast growth factor receptor) and possibly KIT, Jonathan C. Trent, MD, PhD, said in an interview with OncologyLive^®. “Inhibition of these pathways may be able to induce tumor cell death directly through inhibition of PDGFR as well as FGFR, but also indirectly through the antivascular effects of inhibition of VEGFR,” Trent said. Anlotinib targets multiple proteins in these cell signaling networks. Trent is a professor and associate director for clinical research at the University of Miami Sylvester Comprehensive Cancer Center in Florida.

In APROMISS, patients with ASPS will receive anlotinib at a dose of 12 mg once daily in 21-day cycles (14 days on treatment, 7 days off treatment) until disease progression. Enrolled patients with metastatic or advanced LMS or SS will be randomized 2:1 to receive anlotinib at the same dosage or intravenous dacarbazine until disease progression (Figure).¹

In general, eligible patients must show objective disease progression after the last administration of standard therapy or have discontinued therapy due to intolerability. For patients with ASPS, discontinuation of prior therapy is not a criterion for enrollment.¹

Prior Study Results

Figure. APROMISS Evaluates Anlotinib in Soft Tissue Sarcoma Subtypes¹

APROMISS was initiated based on the results of the phase II ALTER0203 study (NCT02449343) in which anlotinib showed activity in subtypes of soft tissue sarcoma. Investigators reported findings at the 2018 American Society of Clinical Oncology Annual Meeting. The study enrolled 233 patients who were randomized 2:1 to receive either anlotinib (n = 158) or placebo (n = 75).² Progression-free survival (PFS) in the anlotinib arm was 6.27 months (95% CI, 4.30-8.40) versus 1.47 months (95% CI, 1.43-1.57) in the placebo arm (HR, 0.33; P <.0001).² In the subgroup analysis, patients with ASPS (n = 56) showed the strongest response to anlotinib, with a PFS of 18.23 months (95% CI, 13.97-22.49) versus 3 months (95% CI, 1.19-4.81) in the placebo arm (HR, 0.14; P <.0001).²

Trent noted that the drug was well tolerated in patients and that investigators expect to see a similarly mild adverse event (AE) profile in the ongoing phase III trial. The most common all-grade AEs from the phase II trial included hypertension (62.7%), thyroid-stimulating hormone increase (56.3%), hypertriglyceridemia (50.0%), diarrhea (48.1%), and hand—foot syndrome (48.1%). Grade 3/4 AEs affecting more than 3% of patients receiving anlotinib included hypertension (18.9%), increased gamma-glutamyl transferase (4.43%), and hypertriglyceridemia (4.43%).²

Few Treatment Options

An FDA approval for anlotinib would mark a first in these rare sarcomas, Trent said. “There are no FDA-approved drugs specifically for ASPS or specifically for SS as a disease. We do have FDA-approved drugs that we use broadly in sarcoma.” SS affects 3 individuals in 1 million; ASPS accounts for 0.5% to 1% of all soft tissue sarcomas.^3,4

The current treatment landscape for advanced soft tissue sarcoma includes, among other treatments, pazopanib (Votrient) for patients who have received prior chemotherapy.⁵ However, “In preliminary early phase studies, anlotinib may be more active than pazopanib against several sarcoma histologies including leiomyosarcoma, alveolar soft-part sarcoma, and synovial sarcoma,” Trent said.

In addition to pazopanib, doxorubicin is approved by the FDA for all indications of soft tissue sarcoma, and trabectedin (Yondelis) is allowed for the treatment of patients with metastatic liposarcoma or leiomyosarcoma.^6,7 “After these [treatments] are exhausted, there are limited other options,” Trent added.

Future of Anlotinib

Enrollment to the APROMISS trial is going well, according to Trent. “[The study] has accrued very rapidly to LMS; in fact, that arm is on a temporary hold for interim analysis,” Trent noted. Data from the LMS arm are currently under evaluation to determine whether the endpoint has been reached or additional patients should be enrolled. The ASPS and SS arms are still actively enrolling.

“We’re very excited about this agent and would like to explore it in other tumor types and in combination, but really the focus now is to get it FDA approved for these indications,” Trent concluded.

References

1. A Phase III Trial of Anlotinib in Metastatic or Advanced Alveolar Soft Part Sarcoma Leiomyosarcoma and Synovial Sarcoma (APROMISS). clinicaltrials.gov/ct2/show/NCT03016819. Updated April 5, 2019. Accessed May 27, 2019.
2. Chi Y, Yao Y, Fang Z, et al. Anlotinib for metastasis soft tissue sarcoma: a randomized, double-blind, placebo controlled multi-centered clinical trial (ALTER0203). Presented at: 2018 American Society of Clinical Oncology Annual Meeting; Chicago, IL: June 1-5, 2018.
3. Espesset E. What is synovial sarcoma? Liddy Shriver Sarcoma Institute website. sarcomahelp.org/synovial-sarcoma.html. Updated October 2012. Accessed May 31, 2019.
4. Torres K, Pollock R. Alveolar soft part sarcoma. Liddy Shriver Sarcoma Institute website. sarcomahelp.org/asps.html. Updated December 2010. Accessed May 31, 2019.
5. Votrient [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2014. www.accessdata.fda.gov/drugsatfda_ docs/label/2014/022465s019lbl.pdf. Accessed May 27, 2019.
6. Doxorubicin hydrochloride [prescribing information]. New York, NY: Pfizer Labs; 2013. www.accessdata.fda.gov/drugsatfda_ docs/label/2013/050467s073lbl.pdf. Accessed May 27, 2019.
7. Yondelis [prescribing information]. Horsham, PA: Janssen Products, LP; 2015. www.accessdata.fda.gov/drugsatfda_docs/ label/2015/207953s000lbl.pdf. Accessed May 27, 2019.