Molecular response patterns in relapsed/refractory AML patients treated with selinexor and chemotherapy.

Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.

Radiochemotherapy with or without cetuximab for unresectable esophageal cancer: final results of a randomized phase 2 trial (LEOPARD-2).

PURPOSE: To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer. METHODS: This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2­year overall survival (OS). Arm A was considered insufficiently active if 2­year OS was ≤40% (null hypothesis = H0), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable. RESULTS: Two-year OS was 71% in arm A (95% CI: 55-87%) vs. 53% in arm B (95% CI: 36-71%); H0 was rejected. Median OS was 49.1 vs. 24.1 months (p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30-1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25-1.04) for progression, 0.43 (0.13-1.40) for locoregional failure, and 0.43 (0.17-1.05) for distant metastasis. Overall response was 81% vs. 69% (p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 (p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044). CONCLUSION: Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.

Selinexor (KPT-330), an Oral Selective Inhibitor of Nuclear Export (SINE) Compound, in Combination with FOLFOX in Patients with Metastatic Colorectal Cancer (mCRC) - Final Results of the Phase I Trial SENTINEL.

BACKGROUND: Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1. OBJECTIVE: To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients. METHODS: In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival. RESULTS: Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed. CONCLUSION: In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.

Inclusion of targeted therapies in the standard of care for metastatic colorectal cancer patients in a German cancer center: the more the better?!

PURPOSE: Significant prolongation of overall survival (OS) has been reached in metastatic colorectal cancer (mCRC) treatment within the last 5-10 years. Our study was conducted in order to evaluate and compare OS of different standard of care treatment options in a university-based outpatient clinic. METHODS: One hundred and three mCRC patients were identified by retrospective analysis and treated according to available guidelines. OS was analyzed according to the different combinations of first- and second-line treatments. RESULTS: mCRC patients revealed an mOS of 34.4 months. Patients receiving anti-vascular endothelial growth factor (VEGF) blockade in at least one treatment line showed a significantly longer survival time (p = 0.0056) versus patients without any bevacizumab. No OS differences were detected comparing the different first- and second-line chemotherapy (CTX) strategies in the unselected population. However, wild-type (wt) Kras patients treated with anti-epidermal growth factor receptor (EGFR) therapy plus CTX in first-line therapy showed significantly longer OS compared to those receiving only additional VEGF inhibition or no targeted therapy (p = 0.0056; mOS 46.8 vs. 20.4 months, respectively). wt Kras patients profited in trend (p = 0.076) from CTX combinations of first-line anti-EGFR followed by second-line anti-VEGF compared to first-line anti-VEGF followed by second-line anti-EGFR (mOS 46.8 vs. 19.2 months, respectively). CONCLUSIONS: Our results indicate successful allocation of the current mCRC treatment according to the Kras status. Differences in OS of wt Kras patients indicated the further need for randomized trials to define the potential benefit of sequential therapy with EGFR inhibition in first-line therapy followed by VEGFR inhibition vice versa.

[EGFR/HER1 inhibition: an example of new targeted therapies in non-small cell lung cancer]. / Neue molekulare Therapien beim nichtkleinzelligen Lungenkarzinom am Beispiel der EGFR/HER1-Inhibition.

BACKGROUND: Lung cancer is one of the most common forms of cancer in western industrialized countries. Patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and suffer many tumor-associated symptoms. Unfortunately, approximately 70% of patients with NSCLC present themselves with advanced poor-prognosis stage III and IV disease. In advanced disease, treatment is palliative and symptom-oriented. New less Adenotoxic drugs are urgently needed. One of the targets of new agents is the human epidermal growth factor receptor (EGFR/HER1), and agents targeting this receptor include erlotinib, gefitinib and cetuximab. CLINICAL STUDIES: Erlotinib, gefitinib and cetuximab have been investigated in different clinical studies and provided objective responses and symptom relief. A benefit in survival could only be observed in second- and third-line therapy with erlotinib. All new agents have been generally well tolerated. Erlotinib was recently approved in the USA and Europe for second- and third-line treatment of patients with locally advanced or metastatic NSCLC. CONCLUSION: Anti-EGFR has shown promising antitumor activity in NSCLC with a mild toxicity profile. However, some clinical issues such as screening for potentially responsive patients and optimal combination with other drugs should be the aim of future studies.