Non-adipocytic Soft Tissue Sarcoma Research Articles

A phase I study of nanoparticle albumin-bound sirolimus (NAB-S) combined with pazopanib (PAZO) in patients with advanced soft tissue sarcoma (STS).

11521 Background: NAB-S (ABI-009, nab-rapamycin) is approved for treatment of adults with unresectable or metastatic perivascular epithelioid cell tumors. Albumin binding improves sirolimus solubility and may target it to tumoral cells. mTOR inhibition may enhance PAZO activity directly and by overcoming resistance. We assess feasibility and safety of the combination. Methods: Eligible patients (≥18y) had: advanced, unresectable, non-adipocytic STS progressing after 1-5 prior therapies; adequate end-organ function; ECOG performance status 0-1; measurable target lesions (RECIST v1.1); and no prior mTOR or angiogenesis inhibitor treatment. The study was conducted according to a 3+3 design. Initial cohorts received 800 or 400 mg PAZO daily and 60, 45 or 30 mg/m2 of NAB-S on days 1 and 8 on a 21-day cycle. Subsequently, NAB-S was administered only on day 1 based on preliminary analysis of adverse events (AEs) and pharmacokinetics (PK). Primary endpoint was determination of maximally tolerated dose (MTD). Dose-limiting toxicities (DLT) were grade 3-5 adverse events (AE) during the first cycle not due to PAZO. Secondary endpoints included AE characterization (CTCAE v5.0), descriptive evaluation of responses and their duration, and correlative/PK studies. Results: 19 patients were treated; initially, 13 received NAB-S on days 1 and 8. DLT included thrombocytopenia (TCP, n = 7), decreased WBC/neutrophils (n = 2), increased lipase (n = 1), and proteinuria (n = 1). Due to overlapping AEs or possible NAB-S/PAZO interaction, further cohorts received 400 mg PAZO daily and either 30 or 45 mg/m2 NAB-S (n = 6). There were no DLTs in the 30 mg/m2 cohort (n = 3). In the 45 mg/m2 cohort, 2 out of 3 patients had TCP meeting DLT definition. Grade 3-4 AEs in more than 10% included: TCP (58%), neutropenia (11%), leukopenia (11%), lymphopenia (11%), and diarrhea (11%). Any grade AEs in > 50% included: TCP (74%), mucositis (63%), fatigue (58%), and acneiform rash (53%). There was no grade 5 AEs. Of 19 treated, 11 (58%) discontinued due to disease progression, 3 (16%) due to AE (TCP-2, transaminitis-1), and 1 (5%) due to death from disease. Four (21%) remain on study as of 2/2023. 18 were evaluable for best response: 3 partial responses (PR; leiomyosarcoma, solitary fibrous tumor, spindle cell sarcoma), 13 stable disease (SD), 2 progressive disease. Clinical Benefit Rates (CBR = PR+SD) at 3 and 6 months were 72% (13/18) and 59% (10/17). Among the leiomyosarcoma subset, CBR at 3 and 6 months were 90% (9/10) and 80% (8/10). Correlative and pharmacokinetic results will be presented. Conclusions: Thrombocytopenia was the most prominent DLT when studying the NAB-S/PAZO combination. 3 patients out of 19 discontinued therapy due to AEs; the remainder continued therapy after adjustment. MTD and RP2D is NAB-S 30 mg/m2 day 1 and PAZO 400 mg days 1-21. Preliminary evidence of activity of the combination was observed. Clinical trial information: NCT03660930 .

Regorafenib for the Treatment of Sarcoma.

Sarcomas are a rare group of tumors with many subtypes, conventionally classified into soft-tissue sarcomas and bone sarcomas. Chemotherapeutic regimens form the mainstay of systemic therapy but are not well defined beyond the first-line setting and clinical outcomes are variable. Tyrosine kinase inhibitors (TKIs), with a broad inhibition profile which have been shown to target tumor angiogenesis, have an established role in the treatment of sarcomas without characteristic driver alterations. One such TKI, regorafenib, has been evaluated in sarcomas and clinical data are discussed in this review. An overview of regorafenib data from five phase 2 and one phase 1b clinical trials in over 10 sarcoma subtypes (both soft-tissue and bone) in adult and pediatric patients is reviewed. Regorafenib demonstrated clinical benefit in patients with non-adipocytic soft-tissue sarcomas, osteosarcoma and Ewing sarcoma who had progressed on prior therapy. Patients with otherwise limited treatment options may therefore benefit from regorafenib therapy.

Activity of regorafenib in patients with non-adipocytic soft tissue sarcoma (NASTS): Evaluation of heterogeneity of treatment effect on the updated analysis of pooled cohorts.

11555 Background: Results of the double-blind randomized phase 2 trial (NCT01900743), showed that regorafenib (REG) is an active treatment in patients (pts) previously treated with chemotherapy for an NASTS (cohorts B-leiomyosarcoma, C-synovial sarcoma, D-other sarcoma, Mir 2016), and in pts previously treated with pazopanib (PAZ) (cohort E, Penel 2019). We now present an updated analysis of progression-free survival (PFS) in all NASTS pts to assess the heterogeneity of treatment effect according to histological subtype and prior exposure to PAZ. Methods: Pts received REG 160 mg/d, 21/28 d, or placebo (PB). Pts receiving PB were offered optional cross over in case of centrally confirmed disease progression. The primary endpoint was PFS, according to RECIST-1.1, based on full blinded central review of imaging (including a re-review for cohorts B, C and D, because first analysis was based on a partial central review in these cohorts). Overall survival (OS) was a secondary endpoint. We performed a pooled analysis of cohorts B, C, D and E, on the intent-to-treat dataset, including a multivariate analysis with interaction terms to assess the heterogeneity of treatment effect according to covariates. Results: From 06/2013 to 10/2017, 175 pts were randomized (87 REG vs 88 PB; 56, 27, 55, 37 pts in cohorts B, C, D and E, respectively). The median age was 59 yrs (range, 20-81). There were 101 women (58%). Histological subtype was leiomyosarcoma in 80 pts (LMS; 41 REG vs 39 PB; 56 in cohort B and 24 in cohort E), synovial sarcoma in 28 (SS; 13 REG vs 15 PB; 27 in cohort C and 1 in cohort E), and other sarcoma in 67 (33 REG vs 34 PB; 55 in cohort D and 12 in cohort E). The median number of prior lines of systemic treatment was 2 (range, 1-6). Overall, 43 pts had received prior PAZ (21 REG vs 22 PB). Out of 88 pts assigned to PB, 69 switched to REG after progression (79%). We confirmed a significant PFS-benefit associated with REG in multivariate analysis of the pooled study population, with a HR = 0.48 (95%CI, 0.35–0.66, p < 0.001); median PFS = 2.1 vs 1.0 months, respectively. This benefit appears significant in each histological subtype. However, we observed a borderline interaction between histological subtype and treatment effect (p = 0.09): PFS benefit appears larger in pts with SS (HR = 0.21, 0.10-0.48, p < 0.001) and other sarcoma (HR = 0.49, 0.30-0.81, p = 0.006) than in LMS (HR = 0.59, 0.37-0.93, p = 0.022). PFS benefit appears rather homogeneous across strata of pts with vs without prior exposure to PAZ (interaction test, p = 0.26). Overall, in this study, regorafenib does not show any statistically significant OS-benefit (HR = 0.77, 0.57–1.05, p = 0.10), likely due to the fact that 79% of PB pts crossed over to REG at progression. Conclusions: The present study confirms the clinical PFS benefit associated with regorafenib in all NASTS pts, regardless of prior treatment with pazopanib. Clinical trial information: NCT01900743.

Real-World Outcomes of Advanced Soft Tissue Sarcoma Patients Treated with Pazopanib

Background: Pazopanib is an oral multitarget tyrosine kinase inhibitor that is currently approved for the treatment of select subtypes of advanced Soft Tissue Sarcoma (STS) in patients who have progressed on prior anthracyclinebased chemotherapy regimens. In this study, we examine data from multiple centers to assess the efficacy of pazopanib in practice outside of a clinical trial setting. Methods: A retrospective chart analysis was conducted for pre-treated, advanced soft tissue sarcoma patients who began treatment with pazopanib in Alberta, Canada and Cairo, Egypt (2012-2018). Results: In total, 39 predominantly male (56.4%) patients received pazopanib. The median age was 51, 67% of whom had an ECOG of one or less. The predominant sarcoma subtype was leiomyosarcoma (30.8%), and all patients had received at least one prior line of systemic therapy. Thirtytwo of the 39 patients (82%) were initially given the full dose of 800mg with a median time on treatment of 116 days. Seven of the 39 (18%) patients required a dose reduction while on treatment. A majority (94.9%) of patients ultimately discontinued pazopanib treatment for reasons including death (21.6%), disease progression (62.2%), and toxicity (16.4%). The median progression-free and overall survival for these patients was 4.1 months (95%CI, 3.6-4.5) and 8.4 months (95% CI, 4.3-12.5), respectively. Conclusion: Pazopanib is an efficient and generally well-tolerated oral systemic therapy for the treatment of advanced, pre-treated, non-adipocytic soft tissue sarcoma. These results show the efficacy of pazoponib outside of a clinical trial setting.

Efficacy and safety of anlotinib in patients with unresectable or metastatic well-differentiated/dedifferentiated liposarcoma: a single-center retrospective study.

Treatment options for unresectable local recurrence or metastatic well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS) remain limited. Different liposarcoma subtypes have varying clinical features and sensitivities to treatment regimens. The multitarget tyrosine kinase inhibitors (TKIs), such as pazopanib and regorafenib, have been approved for use in nonadipocytic soft tissue sarcomas (STS). Anlotinib, another TKI, has been approved in China for treating metastatic STS that has progressed after the use of anthracycline-based regimens. In this study, we aimed to evaluate the role of anlotinib in the treatment of local recurrence or metastatic WDLS/DDLS. From August 2018 to June 2020, 17 patients with unresectable local recurrence or metastatic WDLS/DDLS treated with anlotinib in our center were included. The follow-up cutoff time was set as 20 October 2020. Baseline and observation indicators were collected and analyzed. Estimated median progression-free survival (PFS) was 27.9 weeks, the PFS rate at 24 weeks was 58.8%, overall survival (OS) was 56.6 weeks, the disease control rate was 64.7% and no complete response or partial response was detected. Grade 3/4 adverse events occurred in four cases and could be managed. Anlotinib is a potential treatment option for unresectable local recurrence or metastatic WDLS/DDLS.

Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials.

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

Relationship between PDGFR expression and the response to pazopanib in intimal sarcoma of the pulmonary artery: A case report.

Intimal sarcoma of the pulmonary artery (PAIS) is a rare disease with a poor prognosis. Pazopanib, which has been indicated in metastatic non-adipocytic soft-tissue sarcomas and is expected to be active in PAIS, is a multi-kinase inhibitor that targets the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor. The present study reports findings related to two cases of PAIS with PDGF and VEGF expression following treatment with pazopanib. A case with a moderate to strong expression of PDGFR-α and -β presented a long-term stable disease when treated with pazopanib (progression-free survival, 5.8 months). In a second case with a weak expression of PDGFR-α and -β, the disease progressed rapidly on pazopanib (progression-free survival, 1.1 months). VEGFR-2 was not expressed in the tumors of both cases. The level of PDGFR expression in the tumor tissue may therefore be predictive of pazopanib efficacy.

A randomized phase II study of MLN0128 (M) versus pazopanib (P) in patients (pt) with advanced sarcoma (Alliance A091304).

11562 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of connective tissue. Although mTOR is implicated in STS pathogenesis, clinical activity from mTORC1 inhibitors is modest. M, a potent selective mTORC1/mTORC2 inhibitor, was more effective in STS preclinical models than inhibitors of mTORC1, IGF1R and mTORC1+IGF1R, owing to more complete suppression of PI3K/AKT/mTOR and abrogation of feedback AKT activation. P, an oral multikinase inhibitor, is approved for non-adipocytic STS and often used after progression (PD) on chemotherapy. In phase 1, the RP2D of M was 30 mg weekly. A091304 was to evaluate M as a novel targeted therapy for STS. Methods: In A091304, pts were randomized 1:1 to M 30 mg weekly or P 800 mg daily. Eligibility required Eastern Cooperative Oncology Group PS ≤ 1, progression on ≥ 1 prior chemotherapy and specific STS subtypes (cohort 1: UPS; 2: LMS; 3: MPNST, SS). Crossover to M was allowed after PD on P. 1° endpoint was progression-free survival (PFS). Assuming median PFS of P was 4.6 months (mo), 98 pts yielded 80% power to detect a hazard ratio of 0.66 favoring M [1-sided test, alpha = 0.15] and including 1 planned futility analysis. 2° endpoints were response rate, clinical benefit rate (CBR) at 4 mo and safety. After 4 of the first 12 pts randomized to P experienced ≥ grade (gr) 3 toxicity, the study was amended to begin at P 400 mg, allowing titration to 800 per investigator discretion. Results: After protocol amendment, 114 pt underwent randomization (M: 56, P: 58), and 111 initiated treatment. Median PFS was 2 mo for M and 2.1 mo for P (HR = 1.47; 1-sided 85% upper confidence boundary = 1.85), with 2 partial responses in each arm. CBR was 5.4% for M and 13.8% for P. Median OS was 10.7 mo for M and 13.9 mo for P (HR = 1.41; 95% CI 0.80-2.49). 26/43 pt with PD on P crossed over to M. Median PFS after crossover was 1.8 mo (95% CI 1.5-3.5). Gr 3 drug-related adverse events (AEs) occurred in 36% on M and 41% on P; gr 4 toxicity was rare. AEs were consistent with known effects of M and P. Conclusions: P at 400 mg daily (allowing escalation to 800 mg per investigator discretion) demonstrated a shorter PFS as compared prior randomized studies with P. Despite this, M failed to demonstrate superior clinical activity as compared to P at the interim analysis. Further work will examine activity within histology-specific cohorts and evaluate available tissue samples for evidence of pharmacodynamic activity. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA233324 (SWOG); https://acknowledgments.alliancefound.org . Clinical trial information: NCT02601209 .

Pazopanib for metastatic soft-tissue sarcoma: A multicenter retrospective study

Soft tissue sarcomas are associated with a poor prognosis and low chemotherapeutic efficiency. Pazopanib is an orally available multi-tyrosine kinase inhibitor that was explored in patients with non-adipocytic advanced soft tissue sarcomas. The aim of this retrospective study was to evaluate the real life data of single-agent pazopanib efficacy and safety for soft tissue sarcomas in the Turkish population. We evaluated a total of 103 patients (41 males, 62 females) who received pazopanib for advanced non-adipocytic soft tissue sarcomas diagnosis in eight centers of Turkey, retrospectively. The pazopanib dose was 800 mg once daily. Progression-free survival, overall survival, and adverse events were analyzed. The median age was 50 years (range, 38-58). Majority of the patients had leimyosarcoma (41%). Median progression-free survival was 4.3 months, and the median overall survival was 10.1 months. The main common toxicities were fatigue, anorexia, weight loss, nausea, hypertension, and grade ≥3 toxicities were fatigue, anorexia, weight loss, and liver disorder. Pazopanib is an efficient and tolerable agent and is well tolerated in good performance status patients with relapsed, advanced non-adipocytic soft tissue sarcomas.

A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib in non-adipocytic sarcoma patients previously treated with both chemotherapy and pazopanib

BackgroundMetastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. Patients and methodsThis double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours–based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). ResultsFrom December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4–not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15–0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23–1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). ConclusionThe present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

1695P - Prior exposure to pazopanib (PAZ) did not minor efficacy of regorafenib (REG) in non-adipocytic soft tissue sarcoma patients (pts)

BackgroundREG is an active drug in non-adipocytic soft tissue sarcoma previously treated with doxorubicin (Mir et al. Lancet Oncol 2016). Efficacy of REG in PAZ pretreated pts is unknown. REGOSARC is a multi-cohort double-blind placebo (PLAC)-controlled phase II trial assessing the activity of REG in soft-tissue sarcoma previously treated with doxorubicin. Cross-over after centrally confirmed disease progression was allowed. MethodsIn the present subgroup analyses of the pooled study (cohorts B,C,D and E), we analyzed the magnitude of REG activity in pts with prior exposure to PAZ. ResultsThe total study population consisted of 176 pts (101 women, 57%), with a median age of 59 (20-81). with the following histologies (n/%): leiomyosarcoma (80/45), synovial sarcoma (28/16) or other sarcoma (68/39). Most pts had PS=0 (N=83, 47%) or PS=1 (N=92, 52%). Median time from initial diagnosis to study enrollment was 30 months (range, 5.6-498). Median follow-up was 59.6 months. 88 pts each were allocated to the REG and placebo (PLAC) arms, including 21 (24%) and 22 (25%) pts with previous PAZ exposure. Overall, the significant benefit of REG compared to PLAC in terms of PFS with a median PFS of 3.8 (REG) vs 1.0 months (PLAC); HR(REG/PLAC)=0.43 [95%CI: 0.32-0.59], p<.00001, was confirmed. The magnitude of the benefit did not significantly differ when assessed by prior PAZ exposure: HR(REG/PLAC)=0.33 [0.18-0.61] for those previously exposed to PAZ and 0.45 [0.32-0.65] for those not exposed to PAZ; interaction test in Cox model, p=0.35. In the total study population non significant numerically higher median OS was observed in the REG arm:13.4 (REG) vs 9.0 months (PLAC), HR=0.76 [0.56-1.03], p=0.08. The magnitude of this difference was larger in pts previously exposed to PAZ: HR(REG/PLAC)=0.43 [0.22-0.85] (p=0.015), vs HR=0.88 [0.62-1.25] (p=0.49) for those not exposed to PAZ; interaction test, p=0.065. Safety has been previously reported (Mir et al. Lancet Oncol 2016; Penel ASCO 2019). ConclusionsWe conclude that prior exposure to PAZ did not significantly modify PFS advantage of REG. Benefit of REG in terms of OS could be larger in patients previously exposed to PAZ. Clinical trial identificationNCT01900743. Legal entity responsible for the studyCentre Oscar Lambret, Lille, France. FundingBayer. DisclosureAll authors have declared no conflicts of interest.

1731TiP - EREMISS: Efficacy of regorafenib (REG) as maintenance therapy in non-adipocytic soft tissue sarcomas (STS) having received 1st-line doxorubicin-based chemotherapy (Doxo-CT)

BackgroundIn advanced STS, median progression-free survival (PFS) remains at 4 months (mo) and median overall survival (OS) is about 12-18mo after Doxo-CT. There is currently no maintenance therapy available. A phase III trial has shown a modest benefit of a maintenance with ridafolimus compared to placebo (PBO) (PFS, 17.7 vs 14.6 weeks, HR=0.72). REG is an orally bioavailable multikinase inhibitor with meaningful activity in doxorubicin-refractory non-adipocytic STS. In a prior randomized phase II trial (REGOSARC; NCT01900743), median PFS was 4.0mo with REG compared to 1.0 with PBO (HR=0.36, p<0.0001) and median OS was 13.4 vs 9.0mo (HR=0.67; p=0.059). Trial designEREMISS (NCT03793361) is a multicenter (17 centers from the French Sarcoma Group) double-blind controlled randomized phase II trial assessing efficacy and safety of REG compared to PBO as maintenance therapy in metastatic / locally advanced STS experiencing stable disease (SD) or partial response (PR) after 6 cycles of Doxo-CT as 1st-line. The primary endpoint is PFS (RECIST 1.1, centrally reviewed). Secondary endpoints are efficacy (OS, Objective response, time to start subsequent therapy), safety and benefit/risk ratio (Q-TWIST). The randomization is balanced 1:1 and controlled for histology (leiomyosarcoma/synovial sarcoma/other sarcoma), response to CT (SD/PR) and centers. Pts receive either REG (120mg/d 21/28 days) or PBO until unacceptable toxicity, progression or consent withdrawal. There is no cross-over in this trial. Main eligibility criteria are: age ≥18; histologically-proven non-adipocytic STS, metastatic / locally advanced STS not amenable to curative intent surgery, PS<2, measurable disease, SD or PR after 6 cycles of Doxo-CT. Based on the following assumptions: PFS, 7 (REG) vs 4mo (PBO), HR=0.57, 1-sided α=5% and β=10%, the required number of events is 110 and the sample size is 126 pts. The planned study duration is 30 months. Enrolment is open since 12/2018. Clinical trial identificationNCT03793361. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA. Le Cesne: Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.

A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib (REG) in patients (pts) with nonadipocytic soft tissue sarcoma (STS) previously treated with pazopanib (PAZ).

11021 Background: After we demonstrated the activity of REG in pts with advanced non-adipocytic STS (MirTLO 2016), we conducted a dedicated study in pts previously treated with PAZ+chemo. Methods: We report here the 5th cohort of a double-blind randomized phase 2 trial (NCT01900743). Pts were treated with regorafenib (160mg/d, 21/28d) or placebo (PB). Pts receiving placebo were offered optional cross-over in case of centrally confirmed disease progression. The primary endpoint was centrally-reviewed RECIST-based progression-free survival (PFS), evaluated on the intent-to-treat dataset. A total of 24 events was required to ensure a 90%-power for HR = 0.33 (median PFS, 3·6 vs 1·2 months), with a 1-sided α = 0·1. Overall survival (OS) was a secondary endpoint. Results: From 12/2015 to 10/2017, 37 pts were randomized (18 REG vs 19 PB) and included in the final analysis. The median age was 60 (36-76). There were 28 women (76%). All pts had a performance status 0 or 1. Histological subtypes included 24 leiomyosarcoma (11 vs 13, in REG and PB, respectively), 1 synovial sarcoma (REG), 12 other sarcoma (7 vs 5). All pts had previously been treated with PAZ +chemo (including doxorubicin: 19 vs 17; ifosfamide: 11 vs 3; trabectedin: 11 vs 9; and dacarbazine: 7 vs 6), with 2-6 prior lines. The median relative dose intensity of REG was 0·86, range 0·41-1. Out of 19 pts assigned to placebo, 13 switched to REG after progression. There was no reported objective response. We observed a significant benefit of REG compared to PB in terms of PFS (HR = 0·38; 95%CI, 0·19-0·76; p = 0·007; median PFS = 2·1 vs 1·1 months, respectively), and OS despite the cross-over (HR = 0·41; 95%CI, 0·17-0·98; p = 0·04; median OS = 18·6 vs 8·2 months). Before cross-over, the most common clinically significant grade 3 or higher adverse events were diarrhea (4 vs 0), dyspnea (3 vs 1), arterial hypertension (2 vs 0), hand-foot skin reaction (2 vs 0). Conclusions: The present study demonstrates that regorafenib has a clinically meaningful anti-tumor activity in pts with non-adipocytic soft tissue sarcoma pretreated by both chemotherapy and pazopanib, improving PFS and OS. Clinical trial information: NCT01900743.

Phase II trial of gemcitabine (G) with pazopanib (P) or gemcitabine with docetaxel (T) in advanced soft tissue sarcoma (STS).

11008 Background: P is a multi-tyrosine kinase inhibitor with efficacy in many sarcoma subtypes. We designed a trial to assess the benefit of adding P to G as an alternative regimen to the commonly used combination of G+T in pts with STS (NCT01593748). Methods: We performed an open-label, randomized phase 2 trial enrolling pts with advanced non-adipocytic STS who had received prior anthracycline based therapy. Pts were assigned (1:1 stratified randomization based on leiomyosarcoma and prior pelvic radiation) to receive G 1000 mg/m2 on days 1 and 8 with P 800 mg daily or G 900 mg/m2 on days 1 and 8 and T 100 mg/m2 on day 8, repeated q 3 wks. The primary objectives were estimating median PFS and rate of grade ≥3 adverse events (AEs). Secondary objectives included estimating the hazard ratio (HR) and response rates. Cross-over was allowed for RECIST progression. Sample size of 90 was derived based on the precision of 95% confidence intervals (CI) for reporting toxicity and PFS in each arm. Results: A total of 90 pts enrolled; 45 on each arm. Pt characteristics and results are detailed in Table. Median PFS was 4.1 months for each arm (p= 0.3, based on stratified log-rank test). The clinical benefit rate (PR+SD) was 29% for each arm (p&gt;0.99, based on Fisher’s exact test). The rate of related grade ≥3 AEs were 20.6% with G+T and 19.9% with G+P. Related grade ≥3 AEs (%) occurring in ≥10% of pts (G+T; G+P): anemia (36, 20), fatigue (29; 13), low platelets (56; 51), low neutrophils (20; 49), AST increase (2; 13) and hypertension (2; 20). Conclusions: This study demonstrates comparable efficacy between G+P and G+T, suggesting that G+P can be considered for second-line therapy in advanced non-adipocytic STS. Pt Characteristics and Results. Clinical trial information: NCT01593748. [Table: see text]

Chronic active hepatitis induced by Pazopanib mimicking hypervascular liver metastases in a patient with recurrent soft tissue sarcoma: A case report.

Pazopanib is the first multitargeted tyrosine-kinase inhibitor approved for the treatment of patients with advanced non-adipocytic soft tissue sarcoma (STS). It has been demonstrated to improve progression-free survival without impairing health-associated quality of life. However, Pazopanib is associated with several adverse side effects associated with inhibition of the vascular endothelial growth factor receptor. These include hepatotoxicity, as manifested by abnormal liver function tests. To the best of our knowledge, the current study presents the first case of a patient with recurrent STS who developed biopsy proven Pazopanib-induced chronic active hepatitis and whose previous computed tomography examination demonstrated multiple hypervascular liver lesions. These lesions were indistinguishable from metastases and to the best of our knowledge, have not been described previously. These lesions therefore appear to be a novel finding of Pazopanib-induced chronic active hepatitis. It is crucial to be aware of this unusual finding within a clinical setting, to avoid overstaging and early discontinuation of effective treatment.

Efficacy and safety of regorafenib compared to placebo and to post-cross-over regorafenib in advanced non-adipocytic soft tissue sarcoma

IntroductionThe placebo-controlled phase-2 REGOSARC trial demonstrated the efficacy of regorafenib in patients with leiomyosarcoma, synovial sarcoma and other non-adipocytic sarcoma but not in liposarcoma. Patients initially allocated to placebo were allowed to receive regorafenib after progression. We report here an updated analysis of the trial including evaluation of regorafenib activity after cross-over. MethodsFrom June 2013 to December 2014, 139 patients were enrolled in the non-adipocytic sarcoma cohorts. Median follow-up is now 32.4 months. Benefit of regorafenib versus placebo in terms of progression-free survival (PFS) and overall survival (OS) from randomisation was estimated by hazard ratio (HR) in Cox models. In the placebo arm, intra-patient benefit of regorafenib after cross-over was evaluated by the growth modulation index (GMI) (GMI was here, for each patient, PFS after cross-over regorafenib divided by PFS with placebo). Furthermore, the activity of delayed (after cross-over) versus early (at study entry) regorafenib was evaluated by comparing PFS after cross-over to regorafenib to PFS after randomisation in the regorafenib arm. ResultsPFS benefit of regorafenib as compared to placebo was confirmed with longer follow-up (HR = 0.50; 95% CI: 0.35–0.71; p < .0001). OS was not statistically significant different (HR = 0.78; 0.54–1.12; p = .18). This finding may partially be explained by the fact that 55/68 patients who progressed on placebo (81%) received cross-over Regorafenib after progression: 59% of them had a GMI ≥ 1.3 (95% CI, 45–71%). Delayed start of regorafenib was associated with a statistically non-significant shorter PFS as compared to early treatment (HR = 1.21; 0.84–1.73; p = .30) without impact on OS. ConclusionsObserved PFS confirms that regorafenib warrants further clinical investigation in refractory non-adipocytic sarcomas.

Results of randomized, placebo (PL)-controlled phase II study evaluating efficacy and safety of regorafenib (REG) in patients (pts) with metastatic osteosarcoma (metOS), on behalf of the French Sarcoma Group (FSG) and Unicancer.

11504Background: Oral multikinase inhibitor REG has shown activity in GIST and non-adipocytic soft tissue sarcomas. We designed REGOBONE as a non-comparative phase II, double-blind, PL-controlled t...

The Impact of Pazopanib on the Cardiovascular System.

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Managing pazopanib toxicity in the treatment of advanced soft tissue sarcoma

Background Pazopanib is a multikinase inhibitor registered for the treatment of advanced renal clear cell carcinoma (RCC) and as second or further-line therapy in advanced non-adipocytic soft tissue sarcoma (STS). It is a relatively well-tolerated compound, but, as with many other tyrosine kinase inhibitors (TKI), chronic toxicity may become a challenge that both patient and physician need to take into account when starting treatment. This retrospective study investigated toxicities and their management in STS patients treated with pazopanib in routine clinical practice in Italy. Materials and Methods Data were collected between January 2013 and May 2016 at Candiolo Cancer Institute and Prato Medical Oncology Unit. The primary objective was to describe observed toxicities in a real-life setting, and use this information to inform strategies for adverse event management. Results A total of 43 patients with advanced STS who received treatment with pazopanib were included. Median progression-free survival was 4 months and median overall survival was 18 months. The most common toxicities were fatigue (74.4%), hypertension (72%), hair hypopigmentation (74.4%) and diarrhea (60.5%). Liver toxicities occurred in less than one-third of patients. Severe adverse events, requiring drug interruption, were relatively rare. Conclusions This study confirms the safety and efficacy of pazopanib in pretreated unresectable or metastatic soft tissue sarcoma, and highlights the importance of close follow-up and patient support to improve compliance and treatment duration.

Regorafenib in Metastatic Colorectal Cancer and Advanced Soft Tissue Sarcomas

Oncologists face multiple challenges when treating patients with cancer, especially if patients are elderly or if they experience adverse events (AEs). Several presentations at the American Society of Clinical Oncology (ASCO) 2016 meeting focussed on overcoming these challenges with regorafenib, an oral multikinase inhibitor approved for treating refractory metastatic colorectal cancer (mCRC), and gastrointestinal stromal tumours (GIST). A retrospective analysis of the Phase IIIb CONSIGN study in patients with mCRC reported while most AEs were similar between age groups, when compared to the younger subgroup, the patients in the older subgroups had a higher incidence of Grade ≥3 fatigue and a lower incidence Grade ≥3 hand-foot syndrome (HFS), while other AEs were similar between age groups. Thus, patient age should not be considered a barrier to regorafenib use. This age analysis also highlighted the key role of dose modification in the management of regorafenib-related AEs. Another tactic for AE management is to utilise specific treatments targeted to the AE of interest. Interim analysis of a Phase II study demonstrated that prophylactic dexamethasone had promising effects in reducing regorafenib-related fatigue and HFS in patients with mCRC. In an ongoing Phase II study, ReDOS, both regorafenib dose-escalation and use of clobetasol propionate to actively manage regorafenib-induced HFS are under investigation. Finally, the success of regorafenib in treating GIST, the most common soft tissue sarcoma (STS), has been extended to patients with other STS. In REGOSARC, a Phase II study, regorafenib significantly prolonged progression-free survival (PFS) in patients with non-adipocytic STS, with an AE profile similar to that seen in mCRC and GIST. These presentations offer insights into the practical management of patients treated with regorafenib.