This non-interventional, prospective phase IV trial (NCT02367924) evaluated trabectedin (Yondelis®) in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. Eligible were adults (≥18 years old) with advanced STS with either failure of anthracycline-based therapy, or who were unfit to receive these agents. The primary endpoint was progression-free survival (PFS) rates at 3 and 6 months as per investigator assessment. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Trabectedin was mostly used as second-line treatment (n=66; 51.6%) and patients received a median of 4 cycles per patient (range: 1-44). A total of 40.6% of patients received ≥6 cycles. Median PFS was 5.2 months, with 60.7% (95% CI: 51.5-68.8) and 44.5% (95% CI: 35.5-53.1) of patients free from progression at 3 and 6 months, respectively. Median overall survival (OS) was 15.2 months. One patient had a complete response and 14 patients achieved a partial response for an objective response rate of 11.7%. Additionally, 43 patients had disease stabilization for a disease-control rate of 45.3%. Decreases of white blood cells (27.0% of patients), platelets (16.2%) or neutrophils (13.1%), and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to lung infection or sepsis were considered trabectedin-related. Our study supports the use of trabectedin as a standard of care for treatment of patients with divers STS histotypes given as second or further-line treatment, comparable to activity previously reported in clinical trials and other non-interventional studies.

The widespread use of immune checkpoint inhibitors for treatment of non-small cell lung cancer patients (pts) particularly as 1st- or 2nd-line treatment inevitably begs the question about effective subsequent treatment options. The combination of docetaxel/nintedanib might be an especially effective option. Here, we provide clinical data from pts subsequently treated with docetaxel/nintedanib after checkpoint inhibition as 2nd, 3rd, and 4th line therapies. Data from seven German hospital sites and oncologists were retrospectively collected and analyzed. Treatments and response evaluations were performed according to the centers’ routine standards. 93 pts were treated with docetaxel/nintedanib after pre-treatment with checkpoint inhibitors. The majority received docetaxel/nintedanib as 3rd-line after 1st-line chemotherapy and 2nd-line checkpoint inhibition (n=57). Other regimens included 2nd-line docetaxel/nintedanib after combination of chemotherapy with checkpoint inhibitors (n=9), 3rd-line docetaxel/nintedanib after 1st-line pembrolizumab and 2nd-line chemotherapy (n=7) and docetaxel/nintedanib in >= 4th-line (n=20). Response rates (RRs) were assessed for 76 pts. While RR were not available for 11 pts, 6 pts (6.4%) had to interrupt therapy due to diarrhea of >= grade 3 before RR assessment, but no new additional toxicity was noted. Overall RR was 49% (n=37), while 28% (n=21) had stable disease and 23% (n=18) had disease progression. The highest RR was observed when pts received docetaxel/nintedanib as 3rd-line treatment (n=57, ORR=57%). Notably, of the 6 evaluable pts with docetaxel/nintedanib after 1st-line combination therapy, 3 pts had partial response and 3 pts had disease progression. Median time on therapy was 4 months for pts receiving nintedanib as a 3rd line treatment directly after checkpoint inhibition (n=57) and overall survival was 8.6 months in these pts. Nintedanib maintenance therapy occurred in 23 of 93 pts (25%) for a median time of 4.3 months. We provide the so far largest data set of pts treated with docetaxel/nintedanib after failure of checkpoint inhibition. Our data support the use of an anti-angiogenic strategy in this setting.

Background Long-term complete remissions remain a rare exception in patients with metastatic gastrointestinal stromal tumors (GIST) treated with IM (imatinib). To date the therapeutic relevance of surgical resection of metastatic disease remains unknown except for the use in palliative intent. Patients and methods We analyzed overall survival (OS) and progression-free survival (PFS) in consecutive patients with metastatic GIST who underwent metastasectomy and received IM therapy (n = 239). Results Complete resection (R0+R1) was achieved in 177 patients. Median OS was 8.7 y for R0/R1 and 5.3 y in pts with R2 resection (p = 0.0001). In the group who were in remission at time of resection median OS was not reached in the R0/R1 surgery and 5.1 y in the R2-surgery (p = 0.0001). Median time to relapse/progression after resection of residual disease was not reached in the R0/R1 and 1.9 years in the R2 group of patients, who were resected in response. No difference in mPFS was seen in patients progressing at time of surgery. Conclusions: Our analysis implicates possible long-term survival in patients in whom surgical complete remission can be achieved. Incomplete resection, including debulking surgery does not seem to prolong survival. Despite the retrospective character and likely selection bias, this analysis may help in decision making for surgical approaches in metastatic GIST.

BACKGROUND:Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.METHODS:Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.RESULTS:Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).CONCLUSION:Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

ABSTRACT Background The reversible EGFR tyrosine kinase inhibitors E and G are effective treatments for advanced NSCLC, but most pts acquire resistance. Currently, the benefit from sustained EGFR blockade during subsequent salvage therapy is unclear. LUX-Lung 5 is an international, multicenter phase III trial studying the efficacy of BIBW2992 (Afatinib®, A), an irreversible erbB family blocker, in NSCLC pts progressing after treatment with ctx and E or G irrespective of their EGFR mutation status. Here we report the outcome of NSCLC pts treated within LUX-Lung 5 at a single center in relation to EGFR and KRAS mutation status. Methods Pts with stage IV (UICC 7) NSCLC progressing after ctx and E or G were enrolled into LUX-Lung 5. In part A of the study pts received A (starting dose 50 mg/d) until progression. In part B pts with clinical benefit ≥12 wks were randomized between A plus weekly paclitaxel vs investigator's choice mono ctx. Following microdissection, tumor DNA was extracted and analyzed by PCR and Sanger sequencing. Results Between May 2010 and February 2011 39 pts (20 f, 19 m; median age 61 y, 38-83 y) were enrolled at the West German Cancer Center. Median number of pretreatments was 3 (1-8) including E or G. So far, tumor biopsies were retrieved from 25 pts (64%). Somatic EGFR mutations were detected in 11 pts (44% of analyzed tumors, 28% of entire cohort), whereas 14 pts (56%/36%) exhibited EGFR wild type (wt) sequences. EGFR mutation status remains unknown in 14 pts (36%). KRAS mutation analysis was performed in 20 pts (51% of entire cohort) and 4 mutations were observed (20%/10%), 3 in EGFR wt and one in an EGFR mutant tumor. Median survival time from initiation of A was 432 d in EGFR mutant pts, 189 d in EGFR wt pts, and 255 d in KRAS mutant pts. Median survival time of pts with unknown EGFR mutation status was 191 d. Safety of A was manageable. Conclusions A can achieve disease control in heavily pretreated NSCLC pts. Pts with EGFR mutant tumors experience prolonged survival as compared to EGFR wt tumors (HR 0.29; 95% CI 0.07–0.64; p = 0.0058). This argues for sustained tumor dependency on EGFR signaling despite progression after E or G. Disclosure J. Kohler: J. Kohler received financial support from Boehringer Ingelheim for writing a review article. T.C. Gauler: T.C. Gauler is principle investigator of the BI1200.43 trial testing Afatinib in HNSCC. D. Theegarten: D. Theegarten is member of the Lilly Advisory Board. W. Eberhardt: W. Eberhardt received honoraries for advisory board functions from Boehringer Ingelheim, Astra Zeneca, Roche, OSi Pharmaceuticals, Pfizer and honoraries for lectures from Boehringer Ingelheim, Astra Zeneca, Roche and Pfizer. M. Schuler: M. Schuler received research funding from Boehringer Ingelheim and travel support from Lilly. All other authors have declared no conflicts of interest.

Background: Neoadjuvant treatment is thought to improve resection with margin-negative surgery in locally advanced soft-tissue sarcomas (STS). Treatment-induced alterations of the tumor peripheryhave not yet been microscopically evaluated.Objective: This histopathological study compared limb STS with primary resection and those that had undergone neoadjuvant treatment, emphasizing microscopic changes of the fibrous capsule (FC) and reactive zone (RZ) after neoadjuvant treatment.Patients and methods: Patients with primary high-grade limb sarcomas (N = 76) which have not previously been treated were included. Of those, 37 were primarily resected and 39 were treated with one of the following neoadjuvant treatment modalities: 7x chemotherapy (CTX), 3x radiotherapy (RT), 15x isolated limb perfusion (ILP), 8x CTX + RT, and 6x CTX + ILP. Sizes of the FC and RZ were microscopically measured, and FC-integrity was documented. Histopathologic regression was expressed as a percent.Results: Only 35.1% of untreated sarcomas showed an intact FC. We observed significantly higher capsular integrity after treatment (76.9%). Additionally, the average width of the FC (0.21 mm vs. 0.61 mm) and RZ (0.67 mm vs. 1.48 mm) increased significantly. The extent of histopathologic regression showed a correlation with capsular integrity and width. The combination of two treatment modalities (CTX + RT or ILP) showed strongest effects at the tumor periphery.Conclusions: Neoadjuvant treatment stabilizes the tumor periphery in STS (e.g., the capsule). Concerning local treatment strategies, these novel histopathologic insights might significantly influence the decision as to whether primary resection is advisable in advanced local soft-tissue sarcoma. (c) 2012 Elsevier Ltd. All rights reserved.

10047 Background: Long-term complete remissions remain a rare exception in patients with metastatic GIST. The value of surgical resection of metastatic disease to improve survival remains unknown, and data from a prospective trial will still take years to mature. Hence, identification of patients who might benefit from metastasectomy remains a challenge in clinical practice. Methods: We analyzed our GIST data base (n=209) for overall survival (OS) in patients with metastatic disease (n=117) who underwent metastasectomy at any time of their treatment (n=65). Covariates included perioperative treatment with IM, status of resection, location of metastases and PDGFR/KIT mutational status. Results: Median follow-up (FU) from time to diagnosis and time from first IM doses was 3.4 years and 3.2 years, respectively. 65 patients underwent metastasectomy, with 46 pts (71%) receiving perioperative IM with a median FU of 4 years. Median OS for all patients undergoing metastastectomy was 8 years, as compared to 4 years in pts with metastatic disease not undergoing metastasectomy (p=0.01). Median OS was not reached in 24 pts with macroscopically complete resection (R0=20, and R1 n=4), and 69% of pts are alive after 8 years. In comparison, OS of pts with incomplete resections (R2) was 4 years (p=0.02). Median OS for patients with KIT exon 11 mutation undergoing metastasectomy (n=20) was 6.3 years. Patients with hepatic (± peritoneal) metastases showed a better survival than those with peritoneal metastases only (p=0.02). Conclusions: These findings implicate a possible long-term benefit from R0/R1 metastasectomy in patients with metastatic GIST. In contrast, incomplete resection, including debulking surgery, appears not to be beneficial. However, confounding by selection bias cannot be excluded in this hypothesis-generating, retrospective analysis. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GIST

Epidemiologie ▼ ▼ Gastrointestinale Stromatumoren (GIST) sind seltene bösartige Tumoren, stellen jedoch den häufigsten mesenchymalen Tumor des Abdomens dar. GIST sind eine homogene biologische Entität, die durch spezifische, aktivierende Mutationen der Tyrosinkinase c-KIT und PDGFRα gekennzeichnet sind. Aufgrund der großen Fortschritte in der Diagnose und Therapie gastrointestinaler Stromatumoren der letzten Jahre liegen nur wenige aktuelle epidemiologische Daten vor. In einer 2005 publizierten großen populationsbasierten Studie aus West-Schweden wurden Tumorblöcke von 1500 Patienten mit einer potentiellen GIST-Diagnose aus der Zeit von 1983 bis 2000 mit modernen immunhistochemischen Methoden nachuntersucht. Gastrointestinale Stromatumoren wiesen dabei eine Inzidenz von 14,5 pro einer Million Einwohner auf [1]. Klinische Daten einschließlich Nachsorgeund Behandlungsdaten ergaben eine Prävalenz von 129 Erkrankten auf eine Million Einwohner.

Introduction. The group of patients (pts) with multiple myeloma (MM) who benefit from two cycles of high-dose (HD) melphalan (MP) has not yet been clearly defined. In this single-institution, nonrandomized study, we evaluate the long-term results of tandem HDMP and peripheral blood stem cell transplantation (PBSCT) in previously untreated pts and investigate the pretherapeutic and therapeutic factors predictive for survival. Patients and treatment. From 2/94 to 10/05, 90 pts were included. Pt characteristics: Age median 53 (range 31–70, 29% >60 yrs), m/f 59/41%, MM stage I/II/III 5/23/72%, A/B 88/12% (Durie/Salmon), Bence Jones protein 42%, albumin <3.5 g/dL 13%, beta2-microglobulin (b2MG)>2.5 mg/mL 70%, CRP >5 mg/L 61%, IL2-receptor elevated 49%, and thymidine kinase>10 U/L 48%. 28% of pts received HD dexamethasone and 72% conventional-dose chemotherapy, mainly VAD-based, prior to intended 2 (administered 1–3) cycles of HD cyclophosphamide (CY) (2–3 g/m2, days 1+2) and 2 (administered 0–3) cycles of HDMP (100 mg/m2, days 1+2). HDCY cycles were supported by G-CSF or GM-CSF and HDMP cycles by autologous PBSC and G-CSF. PBSC were collected after the first or second cycle of HDCY. Results. 14% (n=13) of pts received only CY, 30% (n=27) 1 cycle of HDMP, and 56% 2–3 cycles (n=47/3), depending on treatment complications, number of PBSC available, and patient compliance. 54% of pts achieved CR (defined as disappearance of myeloma protein in serum and urine and <5% myeloma cells in the bone marrow), 36% PR (defined as reduction of MM protein in serum >50% and in urine >90% from baseline), and 3% no change after completion of treatment. 7% of pts died during treatment. With a median follow-up of 5.8 yrs, the probability of overall survival (OS) for the entire group of pts was 48% and 41% at 5 and 7 yrs, respectively, and the probability of progression-free survival (PFS) 35% and 21%. In multivariate analysis, CRP ≤5 mg/L and b2MG ≤2.5 mg/mL were independent positive pretherapeutic parameters for OS and b2MG ≤2.5 mg/mL for PFS. Among the therapeutic factors, achievement of CR after completion of treatment and the use of tandem HDMP independently predicted prolonged OS and PFS. Pts who achieved CR had a median OS and PFS of 110 and 64 months, respectively, compared with 45 and 27 months in pts with PR or NC (p<.008, p<.001). The median OS and PFS in pts who received 2 cycles of HDMP were 110 and 44 months, respectively, compared with 49 and 20 months in pts with only 1 cycle (p<.023 and p<.028). Among the first group of pts, however, exclusively those with PR (n=22), and not those with CR (n=28), benefited from the second cycle of HDMP, with a median OS and PFS significantly increasing from 49 to 110 and 14 to 44 months (p<.028 and p<.013), respectively. The median OS in pts with CR after the first cycle of HDMP with (n=28) or without (n=10) a second cycle has not been reached at 10 yrs (p=.736), and the probability of PFS at 5 and 7 yrs in those with a second cycle was 60% and 48% and in those without a second cycle 50% and 17% (p=.207), respectively. Conclusion. The results of this study clearly show a long-term benefit from tandem HDMP in pts with MM, including those age > 60 yrs. This benefit is particularly evident in pts achieving PR after the first cycle of HD treatment.