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SARCOMAS: Edited by Jean-Yves Blay

Cabozantinib as an emerging treatment for sarcoma

Schöffski, Patricka; Blay, Jean-Yvesb; Ray-Coquard, Isabellec

Author Information
Current Opinion in Oncology: July 2020 - Volume 32 - Issue 4 - p 321-331
doi: 10.1097/CCO.0000000000000644
  • Open

Abstract

INTRODUCTION

Sarcomas are a heterogeneous group of rare solid tumors of mesenchymal origin representing approximately 1% of all adult and 15% of pediatric malignancies [1]. Because of this rarity and heterogeneity, with more than 120 subtypes in the most recent classification [2], the development of adequately powered clinical trials has been a challenge [3]. The treatment landscape has evolved little in the last decade and novel therapies are needed, particularly for patients with metastatic disease [3–5].

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma, advanced hepatocellular carcinoma, and progressive, metastatic medullary thyroid cancer [6–11]. In phase 1/2 clinical trials, cabozantinib has shown activity in acute myeloid leukemia [12], adrenocortical carcinoma [13], breast cancer [14–16], glioblastoma [17,18], lung cancer [16,19–21], melanoma [16,22], and ovarian cancer [16].

Cabozantinib is given orally, once daily, as a tablet (60 mg, renal cell and hepatocellular carcinoma) or capsule (140 mg, medullary thyroid cancer) formulation [6,7]. For most clinical studies, including the trials for sarcomas, the tablet formulation at the 60 mg dose has been preferred based on prior experience from clinical trials across tumor types [23–26]. In these earlier studies, the 60 mg dose had better long-term tolerability than higher dosages initially evaluated, while maintaining an adequate efficacy profile [23–26]. In phase 3 trials with the 60 mg dose, cabozantinib has a manageable safety profile with adverse events managed with dose interruptions, dose reductions, and supportive care [8,9]. Common (≥25%) adverse events reported for the 60 mg dosage in the phase 3 trials were decreased appetite, diarrhea, fatigue, hypertension, nausea, palmar-plantar erythrodysesthesia, and vomiting [8,9]. Common (≥5%) grade 3–4 adverse events were diarrhea, fatigue, hypertension, and palmar-plantar erythrodysesthesia [8,9].

Several molecular targets of cabozantinib are of potential relevance in sarcomas, particularly in gastrointestinal stromal tumors (GIST) and in osteosarcoma (Table 1) [27–52]. Consequently, cabozantinib represents a promising candidate for the treatment of these tumors. Here we present an overview of the current preclinical and clinical status of cabozantinib in sarcoma and discuss emerging strategies for clinical development. 

Table 1
Table 1:
Preclinical association of cabozantinib kinase targets with sarcoma
Box 1
Box 1:
no caption available

SOFT TISSUE SARCOMAS

In the United States in 2019, soft tissue sarcomas accounted for approximately 12 750 new cancer cases and 5270 deaths [5]. In Europe, the incidence rate during 2000–2007 was 4.71 per 100 000 persons per year with 25 851 new cases estimated in 2013 [53]. Surgery, with radiation therapy and/or chemotherapy prior to surgery for high-grade tumors, is the standard primary treatment for most patients [1]. With established treatments, the 5-year survival rate is 64.9% [5]. However, for patients with distant metastases at the time of diagnosis, the 5-year survival rate is only 15.9% [5]. Patients with advanced, inoperable, or metastatic disease are commonly treated with chemotherapy, which is associated with a low response rate and unsatisfactory median progression-free and overall survival [1].

Cabozantinib inhibits the activity of a variety of tyrosine kinases that are expressed in soft tissue sarcomas, including MET, vascular endothelial growth factor receptor, AXL, and TYRO3 (Table 1) [35,36,38,40,43]. Initial reports on the potential of cabozantinib to treat soft tissue sarcomas came from in vitro studies and animal models [54,55]. Cabozantinib was shown to inhibit the growth of the alveolar soft part sarcoma cell line ASPS-KY in vitro, and in vivo in nude mice inoculated with these cells [54]. After 4 weeks of treatment, cabozantinib (30 mg/kg/day) significantly (P < 0.01) inhibited tumor growth in these mice to approximately 300 mm3 compared with 900 mm3 for control, with no effect on body weight [54]. Cabozantinib also moderately inhibited the growth of rhabdomyosarcoma cell lines in vitro[55].

We identified eight ongoing or recently completed trials for cabozantinib as a single agent and in combination regimens for patients with soft tissue sarcomas, including five phase 2 trials (Table 2  ) [56–59,60▪,61–66]. Studies have enrolled patients with pelvic/gynecological sarcoma [56,57] or patients with multiple tumor types, such as alveolar soft part sarcoma, clear cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, and synovial sarcoma [58,59,60▪,61–63]. Most of these trials are in their initial phase.

Table 2
Table 2:
Trials of cabozantinib for soft tissue sarcomas
Table 2 (Continued)
Table 2 (Continued):
Trials of cabozantinib for soft tissue sarcomas
Table 2 (Continued)
Table 2 (Continued):
Trials of cabozantinib for soft tissue sarcomas

Two studies have been completed and have reported results with cabozantinib for the treatment of soft tissue sarcomas [56,60▪]. In the phase 1 ADVL1211 trial of children and adolescents with recurrent or refractory solid tumors, patients were treated with cabozantinib to achieve a weekly cumulative dose equivalent of 30 (n = 6), 40 (n = 23), or 55 (n = 12) mg/m2/day in 28-day cycles [60▪]. Six patients (15%) in the study had soft tissue sarcomas including two with alveolar soft part sarcoma, one with clear cell sarcoma, two with embryonal rhabdomyosarcoma, and one with synovial sarcoma. Partial response was achieved for one patient with clear cell sarcoma at 55 mg/m2/day with progressive disease after seven cycles. Prolonged stable disease was observed for patients with alveolar soft part sarcoma (n = 1) (40 mg/m2/day with progressive disease and discontinuation after 8–10 cycles) and synovial sarcoma (n = 1) (30 mg/m2/day, discontinued therapy owing to dose-limiting weight loss in cycle 10). Overall, 3 of 41 patients (7%) discontinued owing to dose-limiting toxicities.

In a second study, patients with heavily pretreated, relapsed uterine leiomyosarcoma received temozolomide (80 mg/body/day) and bevacizumab (2 mg/kg on days 1, 8, and 15 every 4 weeks) without (n = 9) or with cabozantinib (140 mg/body/week, n = 6) [56]. The addition of cabozantinib to temozolomide/bevacizumab increased the clinical benefit rate (complete response + partial response + stable disease >3 months) from 67 to 100%, whereas the objective response rate (ORR; complete response + partial response) was 33% for both cohorts. Complete response was achieved in three patients (two with temozolomide/bevacizumab and one with cabozantinib with temozolomide/bevacizumab). Toxicity for both cohorts was manageable with three grade 3 (all anemia) and no grade 4 adverse events reported.

Two additional trials have reported preliminary results [59,65]. In a phase 2 trial of patients with multiple types of metastatic, refractory soft tissue sarcomas (n = 45) receiving 60 mg cabozantinib daily, four patients had confirmed partial response (two alveolar soft part sarcoma, one myxoid liposarcoma, one extraskeletal myxoid chondrosarcoma) [59]. Grade 3/4 adverse events included hypertension (21%) and neutropenia (13%). In another phase 2 trial of patients with multiple tumor types, 5 of 14 patients with sarcoma had at least 10% reduction in tumor size with 60 mg cabozantinib daily [65].

GASTROINTESTINAL STROMAL TUMOR

GIST is a rare disease with an incidence of 0.78 per 100 000 persons per year in 2011 in the United States and 0.30 per 100 000 persons per year during 2000–2007 in Europe [53,67]. GIST are primarily driven by activating mutations in cKIT and platelet-derived growth factor receptor, which occur in approximately 80 and 5–8% of patients, respectively [47,68,69]. Both kinases are targeted by imatinib as first-line therapy; however, more than 50% of patients develop resistance during the first 2 years of treatment, primarily because of secondary activating mutations [1,70]. Subsequent lines of therapy (e.g. sunitinib, regorafenib) provide temporary benefit with treatment options limited following development of resistance [1,71,72].

Cabozantinib represents another candidate for resistant GIST tumors as it has demonstrated activity in a variety of GIST animal models, imatinib-sensitive and imatinib-resistant tumor cell lines, and patient-derived primary cells [30,73–75]. In addition, MET activation has been implicated as a mechanism of resistance to cKIT inhibition, providing a rationale for cabozantinib as a therapeutic strategy in this setting [30,75]. In a murine xenograft model using the human imatinib-resistant HG209 cell line, cabozantinib (50 mg/kg/day) reduced tumor growth to 104 mm3 compared with 2131 mm3 for vehicle and 2560 mm3 for imatinib (600 mg/l), after 15 days of treatment (P < 0.05) [30]. In a second murine xenograft model using the human imatinib-resistant GIST-5R cell line, a dose-dependent decrease in tumor volume was observed with cabozantinib treatment for approximately 28 days with a tumor growth inhibition rate of 89% at 20 mg/kg/day dose [73]. Imatinib treatment (100 mg/kg/day) had no effect on tumor volume [73]. A similar reduction was observed using the imatinib-sensitive cell line GIST-T1 in the same xenograft model, with the reduction persisting at least 2 weeks following treatment withdrawal [73]. In a murine xenograft model using patient-derived imatinib-resistant tumor specimens, cabozantinib treatment (30 mg/kg/day) for 15 days resulted in significant decrease in tumor growth (141% of baseline) compared with imatinib (50 mg/kg twice daily) (199% of baseline; P = 0.01) [74].

Two trials evaluating cabozantinib in patients with GIST have been reported (Table 3) [76▪,77▪▪,78]. Four patients with GIST were enrolled in a phase 1 dose-finding study of cabozantinib in 43 Japanese patients with advanced cancer; all patients with GIST had received prior imatinib and sunitinib therapy [76▪]. Following treatment with cabozantinib, all four patients achieved disease stabilization, with three having reduction in tumor volume. One patient remained on treatment for 20.6 months. Of all 43 patients in this study, 70% experienced grade 3 or higher adverse events, and 13% discontinued owing to an adverse event. Overall, the safety profile for cabozantinib was manageable.

Table 3
Table 3:
Trials of cabozantinib for gastrointestinal stromal tumors, osteosarcoma, and Ewing sarcoma

The European Organisation for Research and Treatment of Cancer 1317 study is an ongoing phase 2 multicenter, open-label, single-arm trial evaluating the activity and safety of cabozantinib in patients with GIST [77▪▪,78]. Fifty patients were enrolled in the study; 8% (n = 4) remained on treatment at the database cut-off date (September 2019), and 8% (n = 4) had discontinued because of adverse events. All patients had previously received imatinib and sunitinib, for a median (range) of 33.4 months (2.0–136.0) and 8.4 months (1.6–51.3), respectively. The primary efficacy endpoint of progression-free rate at week 12 (first 41 patients only) was met, with a rate of 58.5% [95% confidence interval (CI) 42–74%, n = 24]. Median progression-free survival (PFS) was 5.5 months (95% CI 3.6–6.9) and overall survival (OS) was 18.2 months (95% CI 14.3–22.3) (n = 50). The ORR was 14% (n = 7), with clinical benefit (complete response + partial response + stable disease) achieved by 82% (n = 41) of patients across a variety of KIT mutational subtypes. This included 13/16 patients with mutations in KIT exon 11, 4/4 patients with mutations in KIT exon 9, 2/2 patients with mutations in KIT exon 13, 2/2 patients with mutations in KIT exon 17, 1/1 patient with mutations in KIT exon 11+14, and 4/4 patients with mutations in KIT exon 11+17. Two patients with NF1-driven GIST also experienced clinical benefit. Analysis of liquid biopsies using circulating cell-free DNA to predict response is ongoing. The most common grade 3 adverse events reported were hypertension (36%), diarrhea (26%), and palmar-plantar erythrodysesthesia (8%). No grade 4 or 5 treatment-related adverse events were reported.

OSTEOSARCOMA AND EWING SARCOMA

Osteosarcoma and Ewing sarcoma are the most common primary malignancies of the bone in children and adolescents, but they can also occur in older adult patients [81]. Estimates project that 3600 new cases and 1700 deaths associated with bone cancer will occur in the United States in 2020 [82]. In Europe, during 2000–2007, the incidence rate of bone cancer was 0.85 per 100 000 persons per year, with 4382 new cases estimated in 2013 [53]. These sarcomas are both highly sensitive to conventional chemotherapy, but patients with synchronous or metachronous metastasis, inoperable disease or relapse after initial polychemotherapy have a very poor outcome with no established standard of care [81].

Cabozantinib potently inhibits the activity of kinases that are overexpressed and whose activity is negatively associated with outcomes for patients with osteosarcoma or Ewing sarcoma (Table 1) [27,33,34,37,38,42,52]. Cabozantinib has been shown to inhibit the growth and viability of Ewing sarcoma and osteosarcoma cell lines in vitro[33,83]. In addition to directly reducing osteosarcoma cell growth, cabozantinib modulates the bone microenvironment by inhibiting receptor activator of nuclear factor κB (RANK) ligand production by osteoblasts, thereby preventing the growth-stimulating interaction of osteoblasts with RANK-expressing osteosarcoma cells [83].

Two cabozantinib trials included patients with osteosarcoma and Ewing sarcoma along with patients with soft tissue sarcomas and nonsarcomas (Table 2  , NCT01709435, NCT02867592) [60▪,63], and one trial specifically evaluated patients with bone sarcomas (Table 3, NCT02243605) [80▪▪]. In the phase 1 ADVL1211 trial of children and adolescents with recurrent or refractory solid tumors described above, four patients had Ewing sarcoma, and two had osteosarcoma. Prolonged stable disease was observed for one patient with Ewing sarcoma [continued 40 mg/m2/day at data cut-off (cycle 13)] [60▪]. In the phase 2 CABONE trial enrolling heavily pretreated patients with osteosarcoma (n = 45) or Ewing sarcoma (n = 45), patients were treated with cabozantinib 60 mg once daily (adults) or 40 mg/m2 once daily (adolescents). At data cut-off, in the efficacy population, 24% (n = 10/42) of patients with osteosarcoma were alive, with 7% (3/42) still on treatment [median follow-up 31.1 months (95% CI 24.4–31.7)]; and 33% (n = 13/39) of patients with Ewing sarcoma were alive, with 8% (n = 3/39) still on treatment [median follow-up 31.3 months (95% CI 12.4–35.4)]. Forty-two patients in both the osteosarcoma and Ewing sarcoma safety populations discontinued treatment, with 7% (n = 6) in each group discontinuing because of adverse events. The primary endpoints were ORR (osteosarcoma and Ewing sarcoma) and progression-free rate (osteosarcoma) by 6 months. For the efficacy-evaluable patients with osteosarcoma (n = 42), ORR was 12% (n = 5), and the progression-free rate by 6 months was 33% (n = 14). Median PFS was 6.7 months (95% CI 5.4–7.9), and median OS was 10.6 months (95% CI 7.4–12.5). For the efficacy evaluable patients with Ewing sarcoma (n = 39), ORR was 26% (n = 10) by 6 months, median PFS was 4.4 months (95% CI 3.7–5.6), and median OS was 10.2 months (95% CI 8.5–18.5). For all patients (n = 90), the most frequent grade 3 adverse event was hypophosphatemia (9%, n = 8); grade 4 adverse events were lipase increase (2.2%, n = 2), hypomagnesemia (1.1%, n = 1), and neutropenia (1.1%, n = 1).

ONGOING SARCOMA STUDIES WITH CABOZANTINIB

There are currently five ongoing phase 2 or 1/2 clinical trials evaluating cabozantinib in sarcoma, for which efficacy and safety results are pending (Table 2  ). Three trials are expected to have results in the second half of 2020 for advanced soft tissue sarcomas (NCT01755195; 55 patients) [58], sarcomas including alveolar soft part sarcoma, clear cell sarcoma, Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma (NCT02867592; 146 patients with sarcoma and nonsarcoma malignancies) [63], and high-grade undifferentiated uterine sarcoma (NCT01979393; estimated 78 patients) [66]. Two additional cabozantinib trials are expected to present primary results for soft tissue sarcomas, including leiomyosarcoma (NCT04200443; estimated 72 patients) [61], and soft tissue sarcoma of the trunk and extremities with cabozantinib with radiation therapy (NCT04220229; estimated 44 patients) [62], in 2021 and 2023, respectively.

CONCLUSION

Cabozantinib is a tyrosine kinase inhibitor that targets kinases associated with the growth and development of sarcomas. Phase 1 and 2 clinical studies have provided promising results for the use of cabozantinib in treating these tumors, particularly in GIST, osteosarcoma, and Ewing sarcoma. Encouraging activity with cabozantinib has been demonstrated in patients with few treatment options, such as those with GIST that are resistant to imatinib and sunitinib therapy and heavily pretreated patients with osteosarcoma or Ewing sarcoma. These results support the investigation of cabozantinib in more definitive clinical studies to confirm efficacy and safety findings for patients with sarcomas. Future studies should aim to evaluate cabozantinib in subgroups defined by molecular characteristics as well as histology. Given the high unmet need for effective treatments and the rarity of individual sarcoma subtypes, collaboration across the research community will be needed in order to conduct well-powered studies that improve outcomes for patients with sarcoma.

Acknowledgements

Medical writing and editorial assistance were provided by Alan Saltzman, PhD, CMPP, and Karen O’Leary, PhD, (Fishawack Communications Inc., Conshohocken, Pennsylvania, USA), and were supported by Exelixis, Inc. (Alameda, California, USA).

Financial support and sponsorship

Financial support for the preparation of this manuscript was provided by Exelixis, Inc. (Alameda, California, USA).

Conflicts of interest

P.S. has had an institutional advisory/consultancy role with Plexxikon; Eisai; Loxo Oncology; Eli Lilly; Blueprint Medicines; Ellipses Pharma; Deciphera Pharmaceuticals, LLC; Merck; Servier; Genmab; Adaptimmune; Intellisphere, LLC; and Transgene. His affiliated institution has received research grants/funding from Blueprint Medicines, Boehringer Ingelheim, CoBioRes NV, Eisai, Eli Lilly, Exelixis, G1 Therapeutics, Novartis, Pharmamar, and Plexxikon. J.-Y.B. has acted in an advisory/consultancy role with and received honoraria and research grants/funding from Deciphera Pharmaceuticals, LLC; Novartis; Bayer; Eli Lilly; Roche; and Pharmamar. I. R.-C. has participated as a scientific advisory board member for AbbVie, AstraZeneca, Clovis, GSK, Pharmamar, and Roche.

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    Keywords:

    cabozantinib; Ewing sarcoma; gastrointestinal stromal tumor; osteosarcoma; soft tissue sarcoma

    Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.