Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB ...efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.
This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.
ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5–41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5–94.9, P = 0.004).
This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.
Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) ...and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.
Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.
OS data were available for 912 patients. The median PFS was 3.3months (95% CI 2.9–3.6) and 6-month PFS rate was 27% (95% CI 24–30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3cm versus <3cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2months (95% CI 9.5–11.0) and 1year OS was 43% (95% CI 40–47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.
Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
Retroperitoneal sarcomas (RPS) are heterogeneous. No previous study has investigated the impact of specialized surgery, evaluated locoregional relapse (LRR), abdominal sarcomatosis and distant ...metastatic relapse as separate events, or considered histological subtypes separately. This study addresses these specific points in a homogeneous cohort of patients with completely resected primary RPS.
We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 and eventually referred to one of 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist.
Five hundred eighty-six patients were included. Median follow-up was 6.5 years 95% confidence interval (CI) 5.9–7.1. Five hundred thirty-seven patients had localized disease and 389 patients (76%) had macroscopically complete resection of the tumor. In this latter group, the 5-year LRR-free survival rate was 46% 41–52 and the 5-year overall survival (OS) rate was 66% 61–71. In multivariate analysis, gender, adjacent organ involvement, specialization of the surgeon, piecemeal resection and perioperative radiotherapy were independently associated with LRR. Specialization of the surgeon and piecemeal resection were independently associated with abdominal sarcomatosis whereas histology and adjacent organ involvement were independently associated with distant metastasis. Age, gender, grade, adjacent organ involvement and piecemeal resection were significantly associated with OS. Prognostic factors for LRR and OS were analyzed in well-differentiated and dedifferentiated liposarcomas and leiomyosarcomas. Grade 3 was an independent prognostic factor for OS of dedifferentiated liposarcomas.
This study underlines the crucial role of pretherapeutic assessment and meticulous histological examination of RPS as well as the need to consider histological subtypes separately. Surgery in a specialized center and avoidance of piecemeal resection stand out as the two most important prognostic factors for RPS and highlight the importance of treating these patients in specialized centers.
There are limited data about the role of chemotherapy in patients with
advanced chondrosarcomas.
The medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 ...participating institutions between 1988 and 2011 were reviewed.
Median age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months 95% confidence interval (CI) 3–6.5. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5–21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS.
Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.
Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year.
This phase I study evaluated the safety, tolerability, ...pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100-1000 mg once daily (QD; n = 38) and 200-400 mg twice daily (BID; n = 30).
First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81-15.28) for QD and 4.6 months (range: 0.33-58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99-41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD.
These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.
There are no data regarding the management of advanced soft-tissue sarcoma (STS) in elderly patients.
We retrospectively reviewed the charts of patients ≥75 years old diagnosed with metastatic or ...unresectable STS between 1991 and 2011 in 11 French and American centers.
The study included 361 patients. Of these, 223 patients (62%) received systemic therapy, whereas 123 patients (34%) were managed with best supportive care (BSC) only. Patients who received BSC were more likely to be ≥80 years, with performance status (PS) ≥ 2, Charlson comorbidity score ≥ 10, and metastatic disease. The median progression-free survival of patients treated with systemic therapy was 4 months (95% CI: 2.9–5.1). Thirty-six patients (16%) stopped chemotherapy because of toxicity. Median overall survival (OS) of patients managed with specific therapy was 10.9 months (95% CI: 8.3–13.5) versus 5.3 months (95% CI: 3.6–7.1) for patients managed with BSC (P = 0.001). On multivariate analysis, age ≥ 80 years, PS ≥ 2, and number of metastatic sites were the only independent factors associated with OS.
A high proportion of elderly patients with advanced STS were denied chemotherapy. Further efforts are needed to define better the optimal care for fit and unfit elderly patients with STS.
Tebentafusp demonstrated a superior overall survival (OS) benefit hazard ratio (HR) 0.51 compared to investigator’s choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) ...in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods.
Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan–Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted.
The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 95% confidence interval (CI) 0.35-0.78; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06).
Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.
•No randomized comparison of tebentafusp with combination N+I in mUM has been reported.•This propensity score analysis demonstrated an OS benefit for tebentafusp over N+I in first-line mUM.•The HR of 0.52 (95% CI 0.35-0.78) favored tebentafusp.•No significant difference in OS was observed between single-agent pembrolizumab and combination N+I.•This further supports the use of tebentafusp as first-line treatment of choice for HLA-A∗02:01+ adult patients with mUM.
The French Sarcoma Group assessed the efficacy, safety, and quality of life (QoL) of trabectedin versus best supportive care (BSC) in patients with advanced soft tissue sarcoma (STS).
This ...randomized, multicenter, open-label, phase III study included adults with STS who progressed after 1-3 prior treatment lines. Patients were randomized (1 : 1) to receive trabectedin 1.5 mg/m2 every 3 weeks or BSC, stratified into L-STS (liposarcoma/leiomyosarcoma) and non-L-STS groups (other histotypes). Patients from the BSC arm were allowed to cross over to trabectedin at progression. The primary efficacy endpoint was progression-free survival (PFS) confirmed by blinded central review and analyzed in the intention-to-treat population.
Between 26 January 2015 and 5 November 2015, 103 heavily pre-treated patients (60.2% with L-STS) from 16 French centers were allocated to receive trabectedin (n = 52) or BSC (n = 51). Median PFS was 3.1 months 95% confidence interval (CI) 1.8-5.9 months in the trabectedin arm versus 1.5 months (0.9-2.6 months) in the BSC arm (hazard ratio = 0.39, 95% CI 0.24-0.64, P < 0.001) with benefits observed across almost all analyzed subgroups, but particularly in patients with L-STS (5.1 versus 1.4 months, P = 0.0001). Seven patients (13.7%) in the trabectedin arm (all with L-STS) achieved a partial response, while no objective responses were observed in the BSC arm (P = 0.004). The most common grade 3/4 adverse events were neutropenia (44.2% of patients), leukopenia (34.6%), and transaminase increase (32.7%). Health-related 30-item core European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire evidenced no statistical differences between the arms for any domain and at any time point. After progression, 91.8% of patients crossed over from BSC to trabectedin.
Trabectedin demonstrates superior disease control to BSC without impairing QoL in patients with recurrent STS of multiple histologies, with greater impact in patients with L-STS.
•In adults with STS, trabectedin significantly prolonged PFS as compared to BSC.•Overall, 13.7% achieved a partial response in the trabectedin arm, while no objective response was observed in the BSC arm.•Benefits were observed across most of analyzed subgroups, but particularly in patients with liposarcoma/leiomyosarcoma.•QoL questionnaire evidenced no statistical difference between the arms for any domain or time point.•Trabectedin has superior disease control to BSC in patients with recurrent STS of multiple histologies.
Angiosarcomas are rare, heterogeneous and a retrospective study was conducted to describe their natural history.
We reviewed 161 files of angiosarcoma treated in three institutions of the French ...Sarcoma Group from 1980 to 2004. Survival and prognostic factors for survival were analyzed.
Median age was 52 years. Primary sites were the breast (35%), skin (20%) and soft tissues (13%). At initial diagnosis, 31 (19%) had metastases. Surgery was the first treatment in 121 (75%) patients combined with chemotherapy or radiotherapy in 34 and 32, respectively. Ninety (74%) of these 121 patients relapsed, mostly locally (50). With an average time since initial diagnosis of 8.1 years, 123 (76%) patients progressed and 76 (47%) died. Median survival was 3.4 years 95% confidence interval (CI) 2.4–5.8, and the 5-year overall survival (OS) rate was 43% (95% CI 33–53). In multivariate analysis, liver primary site relative risk (RR) = 12.62, performance status (PS) of two or more (RR = 3.83), presence of metastases at diagnosis (RR = 2.50), soft tissue tumor (RR = 0.31) were correlated to OS. PS, liver and soft tissue tumors were identified as independent prognostic factors for progression-free survival.
Angiosarcomas have an overall poor outcome, but with a clearly distinct prognosis depending on the primary site.
Abstract Background Uveal melanoma is characterised by a high prevalence of liver metastases and a poor prognosis. Aim To review the evolving surgical management of this challenging condition at a ...single institution over a 16-year period. Patients and Methods Between January 1991 and June 2007, among 3873 patients with uveal melanoma, 798 patients had liver metastases. We undertook a detailed retrospective review of their clinical records and surgical procedures. The data was evaluated with both uni- and multivariate statistical analysis for predictive survival indicators. Results 255 patients underwent surgical resection. The median interval between ocular tumour diagnosis and liver surgery was 68 months (range 19–81). Liver surgery was either microscopically complete (R0; n = 76), microscopically incomplete (R1; n = 22) or macroscopically incomplete (R2; n = 157). The median overall postoperative survival was 14 months, but increased to 27 months when R0 resection was possible. With multivariate analysis, four variables were found to independently correlate with prolonged survival: an interval from primary tumour diagnosis to liver metastases >24 months, comprehensiveness of surgical resection (R0), number of metastases resected (≤4) and absence of miliary disease. Conclusions Surgical resection, when possible, is able to almost double the survival and appears at present the optimal way of improving the prognosis in metastatic uveal melanoma. Advances in medical treatments will be required to further improve survival.
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