Summary Background Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this ...agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. Methods In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov , NCT01900743. Findings From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9–2·3) with regorafenib versus 1·7 months (0·9–1·8) with placebo (HR 0·89 95% CI 0·48–1·64 p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5–5·0) with regorafenib versus 1·8 (1·0–2·8) months with placebo (HR 0·46 95% CI 0·46–0·80 p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4–11·6) with regorafenib versus 1·0 (0·8–1·4) with placebo (HR 0·10 95% CI 0·03–0·35 p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0–7·8) with regorafenib versus 1·0 (0·9–1·9) with placebo (HR 0·46 95% CI 0·25–0·81 p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 19% events in the 89 patients in the regorafenib group vs two 2% events in the 92 patients in the placebo group), hand and foot skin reaction (14 15% vs no events) and asthenia (12 13% vs six 6%). One treatment-related death occurred in the regorafenib group due to liver failure. Interpretation Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. Funding Bayer HealthCare.
Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid ...structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7-59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7-49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6-16.5) and 2.4% (95% CI, 0.1-12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients' selection for pembrolizumab treatment.
The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma.
Thirty patients were entered onto the ...study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m(2) on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles.
The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities.
Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.
Regorafenib has proven activity in patients with pretreated gastrointestinal stromal tumours and colorectal and hepatocellular carcinoma. We designed REGOBONE to assess the efficacy and safety of ...regorafenib for patients with progressive metastatic osteosarcoma and other bone sarcomas. This trial comprised four parallel independent cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. In this Article, we report the results of the osteosarcoma cohort.
In this non-comparative, double-blind, placebo-controlled, phase 2 trial, patients aged 10 years or older with histologically confirmed osteosarcoma whose disease had progressed after treatment with one to two previous lines of chemotherapy for metastatic disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive either oral regorafenib (160 mg/day, for 21 of 28 days) or matching placebo. Patients in both groups also received best supportive care. Randomisation was done using a web-based system and was stratified (permuted block) by age at inclusion (<18 vs ≥18 years old). Investigators and patients were masked to treatment allocation. Patients in the placebo group, after centrally confirmed progressive disease, could cross over to receive regorafenib. The primary endpoint was the proportion of patients without disease progression at 8 weeks. Analyses were done by modified intention to treat (ie, patients without any major entry criteria violation who initiated masked study drug treatment were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02389244, and the results presented here are the final analysis of the osteosarcoma cohort (others cohorts are ongoing).
Between Oct 10, 2014, and April 4, 2017, 43 adult patients were enrolled from 13 French comprehensive cancer centres. All patients received at least one dose of assigned treatment and were evaluable for safety; five patients were excluded for major protocol violations (two in the placebo group and three in the regorafenib group), leaving 38 patients who were evaluable for efficacy (12 in the placebo group and 26 in the regorafenib group). 17 of 26 patients (65%; one-sided 95% CI 47%) in the regorafenib group were non-progressive at 8 weeks compared with no patients in the placebo group. Ten patients in the placebo group crossed over to receive open-label regorafenib after centrally confirmed disease progression. 13 treatment-related serious adverse events occurred in seven (24%) of 29 patients in the regorafenib group versus none of 14 patients in the placebo group. The most common grade 3 or worse treatment-related adverse events during the double-blind period of treatment included hypertension (in seven 24% of 29 patients in the regorafenib group vs none in the placebo group), hand–foot skin reaction (three 10% vs none), fatigue (three 10% vs one 3%), hypophosphataemia (three 10% vs none), and chest pain (three 10% vs none). No treatment-related deaths occurred.
Regorafenib demonstrated clinically meaningful antitumour activity in adult patients with recurrent, progressive, metastatic osteosarcoma after failure of conventional chemotherapy, with a positive effect on delaying disease progression. Regorafenib should be further evaluated in the setting of advanced disease as well as potentially earlier in the disease course for patients at high risk of relapse. Regorafenib might have an important therapeutic role as an agent complementary to standard cytotoxic chemotherapy in the therapeutic armamentarium against osteosarcoma.
Bayer HealthCare.
The aim of this randomized, phase II trial was to explore the activity and safety of adding bevacizumab to paclitaxel once per week in treatment of angiosarcomas (AS).
Patients were treated with ...paclitaxel alone (90 mg/m(2) per week for six cycles of 28 days each; arm A) or with paclitaxel combined with bevacizumab (10 mg/kg once every 2 weeks; arm B). In the combination treatment arm, bevacizumab was administered after the six cycles of chemotherapy as maintenance therapy (15 mg/kg once every 3 weeks) until intolerance or progression occurred. Stratification factors were superficial versus visceral AS and de novo versus radiation-induced AS. The primary end point was the 6-month progression-free survival (PFS) rate, which was based on RECIST, version 1.1. Statistical assumptions were P0 = 20%, P1 = 40%, a = 10%, and b = 20%. P0 was the PFS rate at 6 months defining inactive drug, and P1 was the PFS rate at 6 months defining promising drug.
A total of 52 patients were enrolled, and 50 were randomly assigned in 14 centers. The most common primary sites were the breast (49%) and skin (12%). There were 17 (34%) visceral and 24 (49%) radiation-induced AS. The performance status was 0 in 24 patients (49%) and 1 in the remaining 25 patients (51%). The median follow-up time was 14.5 months. Both treatment regimens were considered active, with 6-month PFS rates of 54% (14 of 26) in arm A and 57% (14 of 24) in arm B. The median overall survival rates were 19.5 months in arm A and 15.9 months in arm B. Toxicity was higher with the combination arm and included one fatal drug-related toxicity (intestinal occlusion).
The primary objective was met in both treatment arms. However, the present data do not support additional clinical investigation of combined paclitaxel/bevacizumab for the treatment of advanced AS.
The benefit of chemotherapy (CT) in rare bone sarcomas is not documented in prospective studies. Our retrospective study from the French sarcoma network for bone tumors ResOs was performed in adult ...patients (pts) from 1976 to 2014, with histologically verified diagnosis of leiomyosarcomas (LMS), undifferentiated pleomorphic sarcoma (UPS) or radiation‐associated sarcomas of bone. The median follow‐up was 4.7 years (95% CI: 3.7‐6.5). Clinical features, treatment modalities and outcomes were recorded and analyzed from 145 pts (median age 53 years range 20‐87). Site of disease was extremities (66%) or axial skeleton (34%), 111 (77%) presented with localized and potentially resectable disease. The most common histological subtypes were UPS (58%) and LMS (33%); 58% were high‐grade tumors. Surgery was performed in 127 pts. In the 111 localized pts, 28 pts (25%) underwent upfront surgery or exclusive radiotherapy (RT; >50 Gy) without CT, whereas 83 pts (75%) received either neoadjuvant (n = 26) or adjuvant CT (n = 13) or both (n = 44). Neoadjuvant and adjuvant CT was mostly doxorubicin‐based (95%/86%) and cisplatin‐based (67%/63%). R0 resection was achieved in 59 pts, and a good histological response in 15 patients (25%). Adjuvant RT was performed in 24 (22%) pts. For the whole cohort (n = 145), the 5‐year overall survival (OS) rate was 53% 42; 62. In univariate analysis, age ≤ 60 was associated with a longer disease‐free survival (DFS) (P = .0436). Neoadjuvant and adjuvant CT tended to be associated with better DFS (P = .056) with no significant impact on OS in this retrospective series.
What's new?
Rarer types of primary bone sarcoma (non‐osteosarcoma, non‐chondrosarcoma, and non‐Ewing sarcoma) present a major diagnostic challenge, and are often excluded from clinical trials. In this study, the authors found that patients who had localized disease and were treated with both neo‐adjuvant and adjuvant chemotherapy tended to have better disease‐free survival (DFS). However, there was no significant impact on overall survival (OS). The role of adjuvant chemotherapy and radiation therapy remains unclear, which highlights the need for prospective randomised trials in these uncommon bone malignancies.
In the OS2006 study, patients younger than 18 years were treated with a methotrexate‐based regimen (MTX), patients older than 25 years with a doxorubicin–cisplatin–ifosfamide‐based regimen (API–AI), ...whereas patients aged 18–25 years received either API–AI or MTX. We herein report the prespecified subgroup analysis of the outcome of 106 patients treated with API–AI. Preoperative chemotherapy combined three doxorubicin–ifosfamide–cisplatin (API) and two doxorubicin–ifosfamide (AI) courses. Postoperative chemotherapy was assigned by risk group: localised patients with a good histological response (<10% viable cells) received two AI and two cisplatin–ifosfamide (PI) courses; patients with synchronous metastases, poor histological response or unresectable primary received five cycles of etoposide–ifosfamide (EI). Of the 106 patients, 61 were randomised to receive or not zoledronate. Median age was 30 years (range 18–67), 66 (62%) patients were >25 years. The primary tumours were axial in 28 patients (26%), and 28 (26%) presented with metastases. Ninety‐six patients (91%) had surgery, conservative in 82 (85%); 36 patients (38%, 95% CI 28–48%) were good responders. Toxicity was manageable, with no significant difference in severe acute toxicity between patients aged >25 years and those younger. With a median follow‐up of 4.8 years, the 5‐year event‐free survival and overall survival rates were 46% (95% CI 36–56) and 57% (95% CI 47–67), respectively. The primary tumour size and initial metastases correlated with a higher risk of event. In these 106 osteosarcoma adult patients, API–AI proved feasible with no excess of toxicity, and favourable activity despite poor‐prognosis factors.
What's new?
Osteosarcoma paediatric patients are commonly treated with high‐dose methotrexate combined to other active agents. Methotrexate pharmacokinetics varies considerably with age, however, with few prospective studies dedicated to adult patients and currently no consensus concerning the optimal chemotherapy regimen in these patients. This paper describes the population of 106 adult osteosarcoma patients enrolled in the OS 2006 phase III study, their treatment and their outcomes using a chemotherapy backbone without methotrexate that combines doxorubicin, cisplatin, and ifosfamide. This study confirms prior findings that the API‐AI regimen has acceptable toxicity and yields favourable activity in adult osteosarcoma patients with poor prognosis factors.
Abstract Introduction Primary cardiac sarcomas (PCS) are rare tumours of dismal prognosis. Methods Data of 124 patients with PCS referred to institutions of the French Sarcoma Group (FSG) from 1977 ...and 2010 were reviewed. Results Median age was 48.8 years. PCS were poorly-differentiated sarcomas ( N = 45, 36.3%), angiosarcomas ( N = 40, 32.3%), leiomyosarcomas ( N = 16, 12.9%) and others ( N = 23, 18.6%). At diagnosis, 100 patients (80.6%) were localised and 24 (19.4%) metastatic. Tumours were located in the right ( N = 47, 38.8%), left atrial cavities ( N = 45, 37.2%) or encompassed several locations in nine cases (7.4%). Surgery was performed in 81 cases (65.3%). Heart transplant was performed in five patients. Radiotherapy adjuvant ( N = 18, 14.5%) or alone ( N = 6, 4.8%) was performed in non-metastatic patients only ( N = 24, 19.4%). With a median follow-up of 51.2 months, median overall survival (OS) was 17.2 months for the entire cohort, 38.8 months after complete resection versus 18.2 after incomplete resection and 11.2 months in non-resected patients. Radiotherapy was associated with improved progression-free survival (PFS) on multivariate analysis. Chemotherapy was significantly associated with better OS only in non-operated patients but not in operated patients. In non-metastatic patients, surgery (hazard ratio HR = 0.42, p < 0.001), male gender (HR = 0.56, p = .032) was associated with better OS and surgery (HR = 0.61; p = .076), radiotherapy (HR = 0.43; p = .004) and chemotherapy (HR = 0.30, p = .003) improved PFS. Conclusion Only surgical resection is associated with a perspective of prolonged survival. Chemotherapy is associated with a better outcome in non-resected patients.
There is a strong rationale for treating sarcomas with immunotherapy.
To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy ...in sarcomas.
This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks.
Pembrolizumab in combination with metronomic cyclophosphamide.
There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples.
Between June 2015 and July 2016, 57 patients were included (median range age, 59.5 18.5-84.0 years; 24 women 42%); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1-positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment.
We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation.
clinicaltrials.gov Identifier: NCT02406781.
Summary Background Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a ...single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. Methods Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m2 intravenous doxorubicin followed by 1·1 mg/m2 trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov , number NCT02131480. Findings Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3–73·6) achieved a partial response and 13 (27·7%, 15·6–42·6) stable disease; 41 (87·2%, 74·3–95·2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4–11·7) achieved a complete response, 22 (36·1%, 25·0–50·8) had a partial response, and 32 (52·5%, 40·8–67·3) had stable disease; 56 (91·8%, 81·9–97·3) of patients achieved disease control. The most common grade 3–4 treatment-associated adverse events were neutropenia (84 78% of 108 patients), increased alanine aminotransferase concentration (42 39%), thrombocytopenia (40 37%), anaemia (29 27%), febrile neutropenia (26 24%), and fatigue (21 19%). Interpretation Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care. Funding Pharmamar and Amgen.
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