Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib

BackgroundControversies exist about computed tomography (CT) response evaluation criteria for patients with gastrointestinal stromal tumor (GIST).Patients and methodsFifty-one patients with advanced GIST treated second line with sunitinib were evaluated with contrast-enhanced CT every 3 months. Response was rated according to RECIST and Choi criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier analysis.ResultsAccording to RECIST, patients were categorized as complete response (CR; n = 0; 0%), partial remission (PR; n = 1; 2.0%), stable disease (SD; n = 37; 72.5%), and progressive disease (PD; n = 13; 25.5%) at 3 months. When Choi criteria were applied responses were CR (n = 0; 0%), PR (n = 16; 31.4%), SD (n = 21; 41.1%), and PD (n = 14; 27.5%). Despite these discrepancies, patients rated as SD with RECIST and PR as well as SD according to Choi criteria displayed similar PFS (41.3, 40.7, and 41.3 weeks, respectively) and OS (100.4, 91.6, and 108.0 weeks, respectively). Patients with PD had significantly shorter PFS (10.1 weeks for both criteria) and OS (29.1 weeks for RECIST; 28.9 weeks for Choi) regardless of the response classification applied.ConclusionIn contrast to absence of progression, discrimination of PR from SD with Choi criteria was of no predictive value.     

Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial

BackgroundThe oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.MethodsIn this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4–10 and 18–24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety.ResultsMedian overall treatment duration with any study drug was 9.9 months (range 0.6–19.6); median treatment duration with regorafenib was 7.7 months (range 0.1–19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5 months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications.ConclusionRegorafenib + mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.ClinicalTrials.gov identifier: NCT01289821.     

Comparison of Response Evaluation Criteria in Solid Tumours and Choi criteria for response evaluation in patients with advanced soft tissue sarcoma treated with trabectedin: A retrospective analysis

BackgroundTo assess the additional value of density measurement using contrast-enhancement sequences (Choi assessment) in a real-life cohort of adult soft tissue sarcoma patients treated with trabectedin.MethodsEligibility criteria included adults (age ⩾18) treated between 01/2007 and 12/2011, with at least two trabectedin cycles after failure or intolerance to doxorubicin/ifosfamide. Baseline and first computed tomography (CT)-scans were centrally reviewed by an experienced radiologist.ResultsThe retrospective cohort consists of 134 (73 female) patients treated with trabectedin 1.5 mg/m² given as a 24-h infusion every 3 weeks. Patients received a median of five trabectedin cycles (range: 2–33) and the main cause of discontinuation was progressive disease (PD) (n = 105, 78.4%). Response Evaluation Criteria in Solid Tumours (RECIST) assessment was feasible in 128 (95.5%) patients, with Choi assessment performed in 92 (68.7%) patients, generally due to inadequate sequences or exclusive lung metastases. Concordance between both methods was fair (Kappa = 0.290). We identified five patients with false PD (i.e. PD according to RECIST but stable disease/partial response as per Choi). Univariate analysis did not identify any predictive factors for false PD. Median overall survival (OS) of patients with PD as per RECIST but stable disease/partial response (SD/PR) according to Choi was better than for patients with PD according to both RECIST and Choi (14 months versus 8 months; p = 0.052).ConclusionsChoi assessment may identify patients with false PD who achieved improved efficacy outcomes, suggesting that trabectedin may delay tumour progression even in the case of non-dimensional response. Dual size and tumour density assessment may be more suitable to evaluate responses to trabectedin in sarcoma patients as well as to improve the decision-making strategies for the continuation of trabectedin therapy.     

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study

BackgroundPatients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented.Materials and methodsKey eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review.ResultsMedian patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%–38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred.ConclusionPembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1–positive prostate cancer, and its side effect profile was favorable.ClinicalTrials.gov IdentifierNCT02054806     

Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST)

BackgroundMasitinib is a tyrosine kinase inhibitor with greater in vitro activity and selectivity for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib, without inhibiting kinases of known toxicities. This phase II study evaluated masitinib as a first-line treatment of advanced GIST.Patients and methodsImatinib-naïve patients with advanced GIST received oral masitinib at 7.5 mg/kg/d. Efficacy end-points included response rate (RR) at 2 months, best response according to RECIST, metabolic response rate, disease control rate (DCR), progression-free survival (PFS) and overall survival rate (OS).ResultsThirty patients were enrolled with a median follow-up of 34 months. The most frequent grade 3–4 toxicities were rash (10%) and neutropaenia (7%). Two patients withdrew due to treatment-related adverse events. At 2 months, RR was 20% according to response evaluation criteria in solid tumours (RECIST) and 86% according to FDG-PET response criteria. Best responses were a complete response in 1/30 patient (3.3%), partial response in 15/30 patients (50%), stable disease in 13/30 patients (43.3%) and progressive disease in 1/30 patient (3.3%); (DCR: 96.7%). Median time-to-response was 5.6 months (0.8–23.8 months). Estimated median PFS was 41.3 months with PFS rate of 59.7% [37.9; 76.0] and 55.4 [33.9; 72.5] at 2 and 3 years, respectively. The OS at 2 and 3 years was stable at 89.9% [71.8; 96.6].ConclusionsMasitinib appears to be effective as a first-line treatment of advanced GIST with comparable results to imatinib in terms of safety and response. PFS and in particular OS data show promise that masitinib may provide sustainable benefits. There is sufficient compelling evidence to warrant a phase III clinical trial.     

Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure

AimsTo assess the antitumour activity, safety, pharmacokinetics and pharmacodynamics of continuous daily sunitinib dosing in patients with imatinib-resistant/intolerant gastrointestinal stromal tumour (GIST) and to assess morning dosing versus evening dosing.Patients and methodsIn this open-label phase II study, patients were randomised to receive morning or evening dosing of sunitinib 37.5 mg/day. The primary end-point was clinical benefit rate (CBR; percent complete responses + partial responses [PRs] + stable disease [SD] ?24 weeks). Secondary end-points included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters and plasma biomarker levels.ResultsSixty of 61 planned patients received treatment (30 per dosing group); 26 completed the study. Overall, the CBR was 53% (95% exact CI, 40–66): eight patients (13%) achieved objective PRs; 24 (40%) achieved SD ?24 weeks. Median PFS was 34 weeks (95% CI, 24–49); median OS was 107 weeks (95% CI, 72 – not yet calculable). Most adverse events (AEs) were of grade 1 or 2 in severity, and were manageable through dose modification or standard interventions. No new AEs were apparent compared with the approved intermittent dosing schedule. Antitumour activity and safety were generally similar with morning and evening dosing. Continuous daily sunitinib dosing achieved and sustained effective drug concentrations without additional accumulation across cycles. Decreases from baseline in plasma levels of soluble KIT after 20 and 24 weeks of dosing correlated with longer OS.ConclusionFor patients with imatinib-resistant/intolerant GIST, continuous daily sunitinib dosing appears to be an active alternative dosing strategy with acceptable safety.     

Postprogression survival for first-line chemotherapy in patients with advanced gastric cancer

BackgroundWith the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer.Patients and methodsA literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (ΔOS) and those in PFS (ΔPFS) between trial arms was also investigated.ResultsThe average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between ΔPFS and ΔOS (r = 0.365).ConclusionAn increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer.     

Categories of response to first line vascular endothelial growth factor receptor targeted therapy and overall survival in patients with metastatic renal cell carcinoma

IntroductionSequential use of targeted therapy (TT) has improved overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC). The value of objective response (OR) as compared to stable disease (SD) is unclear. We aimed to investigate OR of first-line TT and its impact on OS.Material and methodsRetrospective analysis of OS among 331 mRCC patients with a first-line assessment according to RECIST 1.0. Characteristics between objective responders (complete response [CR] or partial remission [PR]), patients with SD and non-responders (progressive disease [PD] and toxicity [Tox]) were compared with the Chi-square test and the Kruskal–Wallis test. Kaplan–Meier analysis of OS and progression-free survival (PFS). Cox model analysis of Predictors of OS .ResultsBest response was CR, PR, SD, PD and Tox in 9 (2.7%), 61 (18.4%), 167 (50.5%), 80 (24.2%) and 14 (4.2%) patients respectively resulting in an OR rate of 21%. Median OS in months: CR 63.2; PR 37.6; SD 35.9; PD 14.6; TOX 22.5 (p < 0.0001). Median PFS for responders was 14.8, 11.5 for patients with SD and 2.5 for non-responders (p < 0.0001). Similarly median OS was 38.7, 35.9 and 15.5 (p < 0.00001). Primary resistance and a first-line PFS <6 months were the strongest independent predictors of OS. The achievement of OR as compared to SD did not impact OS.ConclusionsIn our cohort of unselected patients OR was not associated with superior OS as compared to SD.     

Correlation of progression-free and post-progression survival with overall survival in advanced colorectal cancer

BackgroundPolychemotherapy and biological drugs have increased therapeutic options and outcomes of advanced colorectal cancer (CRC). We examined the relation between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in trials of modern (oxaliplatin- and irinotecan-based) chemotherapy alone or with targeted therapies for advanced CRC. We also evaluated surrogacy of PFS and OS.Patients and methodsA PubMed search identified 34 randomized trials. We split the OS, PFS and PPS and evaluated the correlation between OS and either PFS or PPS.ResultsThe median PPS and PFS were 10.75 and 8.4 months, respectively. For all trials, PPS was strongly associated with OS [regression coefficient (R²) = 0.8; Spearman's rank correlation coefficient (r) = 0.88], whereas PFS was moderately associated with OS (R² = 0.43; r = 0.64). In trials with targeted therapies, the correlation of PPS with OS was 0.88. However, across all trials, correlation between differences in median PFS (ΔPFS) and median OS (ΔOS) is 0.59 (P = 0.0007), confirming PFS/OS surrogacy.ConclusionOur findings indicate that in recent first-line, phase III, trials, OS becomes more associated with PPS than PFS. However, improvements in PFS are strongly associated with improvements in OS. In this setting so, PFS may be an appropriate surrogate for OS.     

Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel,docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator’s choice of paclitaxel (175 mg/m² Q3W), docetaxel (75 mg/m² Q3W), or vinflunine (320 mg/m² Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (>2 years’ follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436.     

Prognostic importance of cell-free DNA in chemotherapy resistant ovarian cancer treated with bevacizumab

AimTreatment of multiresistant epithelial ovarian cancer (EOC) is palliative and patients who have become resistant after multiple lines of chemotherapy often have an unmet need for further and less toxic treatment. Anti-angiogenic therapy has attracted considerable attention in the treatment of EOC in combination with chemotherapy. However, only a minor subgroup will benefit from the treatment and there is an obvious need for new markers to select such patients.The purpose of this study was to investigate the effect of single-agent bevacizumab in multiresistant EOC and the importance of circulating cell-free DNA (cfDNA) in predicting treatment response.MethodsOne hundred and forty-four patients with multi-resistant EOC were treated with single-agent bevacizumab 10 mg/kg every three weeks. Baseline plasma samples were analysed for levels of cfDNA by real-time polymerase chain reaction (PCR).ResultsEighteen percent responded to treatment according to CA125 and 5.6% had partial response by Response Evaluation Criteria in Solid Tumours (RECIST). Stable disease was seen in 53.5% and 48.6% of the patients by CA125 and RECIST, respectively. Median progression free survival (PFS) and overall survival (OS) were 4.2 and 6.7 months, respectively. Cell-free DNA was highly correlated to PFS (p = 0.0004) and OS (p = 0.005) in both univariate and multivariate analyses (PFS, hazard ratio (HR) = 1.98, p = 0.002; OS, HR = 1.66, p = 0.02), as patients with high cfDNA had a poor outcome.ConclusionsSingle-agent bevacizumab treatment in multiresistant EOC appears to be a valuable treatment option with acceptable side-effects. Cell-free DNA showed independent prognostic importance in patients treated with bevacizumab and could be applied as an adjunct for treatment selection.     

Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancer

BackgroundTo improve the therapeutic index of whole-brain radiation therapy (WBRT) in the treatment of brain metastases (BM) from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population.Patients and methodsThis phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal BMs from breast cancer, unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy × 10–30 Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m²/day during the irradiation period. The primary end point was objective response rate (ORR) 6 weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary end points were progression-free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability.ResultsBetween February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years (29–79). Median follow-up was 9.4 months [1.0–68.1]. ORRs at 6 weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥grade 2 acute toxicity was reversible lymphopenia.ConclusionWBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer.Clinicaltrials.govNCT00875355.     

A randomised,double-blind,placebo-controlled trial of trametinib,an oral MEK inhibitor,in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas

BackgroundTrametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.MethodsAdults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m² (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2 mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups.ResultsBaseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67–1.44; P = .453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n = 103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia.ConclusionsThe addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.     

A randomized,double-blind,placebo-controlled phase II study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy

BackgroundThis phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy.Patients and methodsPatients were randomly assigned (1:1) to receive tasquinimod (0.25–1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded.ResultsA total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7 weeks (range 0.6–102.7 weeks) for the tasquinimod arm and 19.2 weeks (range 0.4–80.0 weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3–53.7) and 22.7 (16.1–25.9) weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4–0.9), P = 0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3–5) incidence was higher in the tasquinimod group (50.7% versus 27.1%).ConclusionsRandomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%.ClinicalTrialsgov identifier NCT01732549.     

Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy

BackgroundThis investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST.Patients and methodsThe trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1–21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed.ResultsThirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2–18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8–43.5 months). The median OS was 25 months (95% CI 13.2–39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand–foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST.ConclusionsLong-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities.Clinical trial numberNCT01068769.     

Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy

BackgroundResponse Evaluation Criteria in Solid Tumors (RECIST) permits rapid evaluation of new therapeutic strategies in cancer. However, RECIST does not capture the heterogeneity of response in highly active therapies. Depth of tumor response may provide a more granular view of response. We explored the association between, depth of response (DepOR), with overall survival (OS) and progression-free survival (PFS) for patients with NSCLC being treated with an ALK inhibitor (ALKi) or an anti-PD-1 antibody (Ab).MethodsExperimental arms from two randomized controlled trials (RCTs) of an ALKi and two RCTs of an anti-PD-1 Ab were separately pooled. Patient responses were grouped into DepOR ‘quartiles’ by percentage of maximal tumor shrinkage (Q1 = 1%–25%, Q2 = 26%–50%, Q3 = 51%–75%, and Q4 = 76%–100%), Q0 had no shrinkage. We carried out a retrospective exploratory responder analysis to evaluate the association between DepOR and OS or PFS using hazard ratios (HR) generated by the Cox proportional hazards model.ResultsIn the pooled ALK analysis there were 12, 39, 70, 144, and 40 patients in quartiles 0–4, respectively. The DepOR versus PFS/OS analyses HR were: 0.19/0.94 for Q1 0.11/0.56 for Q2, 0.05/0.28 for Q3, and 0.03/0.05 for Q4. In the PD-1 trials within quartiles 0–4 there were 168, 70, 44, 45, and 28 patients, respectively. The DepOR versus PFS/OS analyses HR were 0.3/0.52 for Q1, 0.22/0.47 for Q2, 0.09/0.07 for Q3, and 0.07/0.14 for Q4.ConclusionsOur analysis suggests a greater DepOR is associated with longer PFS and OS for patients receiving ALKi or anti-PD1 Ab. Overall, this suggests that DepOR may provide an additional outcome measure for clinical trials, and may allow better comparisons of treatment activity.     

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

AimThis randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS).MethodsPatients were randomly assigned (1:1) to receive trabectedin 1.5 mg/m² 24-h intravenous (i.v.) infusion every 3 weeks (q3wk) (Arm A), or doxorubicin 75 mg/m² i.v. q3wk, or doxorubicin 60 mg/m² i.v. plus ifosfamide (range, 6–9 g/m²) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point.ResultsOne hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p = 0.9573; hazard ratio = 0.86, p = 0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm.ConclusionNeither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.     

Trabectedin in patients with advanced soft tissue sarcoma: A retrospective national analysis of the French Sarcoma Group

AimThe French Sarcoma Group performed this retrospective analysis of the ‘RetrospectYon’ database with data of patients with recurrent advanced soft tissue sarcoma (STS) treated with trabectedin 1.5 mg/m² as a 24-h infusion every three weeks.MethodsPatients who achieved non-progressive disease after six initial cycles could receive long-term trabectedin treatment until disease progression.ResultsOverall, 885 patients from 25 French centres were included. Patients received a median of four trabectedin cycles (range: 1–28). The objective response rate was 17% (six complete/127 partial responses) and 50% (n = 403) of patients had stable disease for a disease control rate of 67%. After a median follow-up of 22.0 months, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 12.2 months, respectively. After six cycles, 227/304 patients with non-progressive disease received trabectedin until disease progression and obtained a significantly superior median PFS (11.7 versus 7.6 months, P < 0.003) and OS (24.9 versus 16.9 months, P < 0.001) compared with those who stopped trabectedin treatment. Deaths and unscheduled hospitalisation attributed to drug-related events occurred in 0.5% and 9.4% of patients, respectively.ConclusionThe results of this real-life study demonstrate that treatment with trabectedin of patients with STS yielded comparable or improved efficacy outcomes versus those observed in clinical trials. A long-term treatment with trabectedin given until disease progression is associated with significantly improved PFS and OS.     

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III,international, randomized,placebo-controlled study

BackgroundAngiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.Patients and methodsEligible patients (Eastern Cooperative Oncology Group performance status 0–1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review.ResultsFrom October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1–15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86–1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49–0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%).ConclusionsThe study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated.ClinicalTrials.gov numberNCT02149108 (LUME-Colon 1).     

Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: An individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation

BackgroundResponse criteria have always been difficult to apply to malignant pleural mesothelioma (MPM), due to its unique pattern of growth. We developed some models to show that progression free survival rate (PFSR) could be a better predictor of overall survival (OS) than the response rate (RR) in MPM patients. The results were validated independently in the European Organisation for Research and Treatment of Cancer (EORTC) 08052, a phase II study in MPM.MethodsIndividual patient data from 10 EORTC-Lung Cancer Group (LCG) studies of first-line chemotherapy in MPM were pooled. Response to therapy was assessed according to World Health Organisation (WHO) criteria in all except the two most recent trials, which used Response Evaluation Criteria in Solid Tumours (RECIST). Landmark analyses (LA) at 9 weeks and 18 weeks after registration/randomisation were performed to assess the association between PFSR and OS. Independent validation of the results was conducted in EORTC 08052 study (82 patients) employing the same LA.ResultsAll 10 studies (N = 523 patients) were included in the LA of PFSR at 9 and 18 weeks (PFSR-9 and PFSR-18). PFSR-9 and PFSR-18 were confirmed as predictors of OS, with hazard ratio (HR) of 0.37 (95% confidence interval (CI), 0.30–0.47) and 0.50 (0.38–0.65) and C-index of 0.62 and 0.58, respectively.In the validation study, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-9 and PFSR-18 weeks were both strongly correlated with OS (HR of 0.35 [80% CI, 0.25–0.49] and 0.46 (0.32–0.67) and C-index of 0.66 and 0.60, respectively).ConclusionPFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier end-point, PFSR-9 was also strongly correlated to OS with better discriminating capacity. The results were independently validated.