Michael Mark

Clinical Outcome of ALK-Positive Non–Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs)

Introduction NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and EGFR or KRAS mutations co‐occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly understood. Methods Outcomes of patients with metastatic NSCLC de novo co‐alterations of ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and sequencing (EGFR/KRAS) from six Swiss centers were analyzed. Results A total of 14 patients with adenocarcinoma were identified. Five patients had ALK/EGFR co‐alterations and nine had ALK/KRAS co‐alterations. Six of seven patients with ALK/KRAS co‐alterations (86%) were primary refractory to crizotinib. One patient has had ongoing disease stabilization for 26 months. Of the patients with ALK/EGFR co‐alterations, one immediately progressed after receiving crizotinib for 1.3 months and two had a partial response for 5.7 and 7.3 months, respectively. Three of four patients with ALK/EGFR co‐alterations treated with an EGFR TKI achieved one or more responses in different lines of therapy: four patients had a partial response, three with afatinib and one with osimertinib. One patient achieved a complete remission with osimertinib, and one patient was primary refractory to erlotinib. Median PFS during treatment with a first EGFR TKI was 5.8 months (range 3.0–6.9 months). Conclusions De novo concurrent ALK/KRAS co‐alterations were associated with resistance to ALK TKI treatment in seven out of eight patients. In patients with ALK/EGFR co‐alterations, outcomes with ALK and EGFR TKIs seem inferior to what would be expected in patients with either alteration alone, but further studies are needed to clarify which patients with ALK/EGFR co‐alterations may still benefit from the respective TKI.

Randomized phase III trial of erlotinib versus docetaxel in patients with advanced squamous cell non-small cell lung cancer failing first line platinum-based doublet chemotherapy stratified by Veristrat good versus Veristrat poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung trial.

Introduction Docetaxel and erlotinib are registered second‐line treatments for wild‐type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second‐line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS‐lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial. Methods EMPHASIS‐lung was a randomized phase III multicenter trial exploring the differential effect of second‐line erlotinib versus docetaxel on progression‐free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC. Results A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events. Conclusions The final analysis of EMPHASIS‐lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).

Orteronel Switch Maintenance Therapy in Metastatic Castration Resistant Prostate Cancer After First-Line Docetaxel: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (SAKK 08/11).

We tested whether a switch maintenance treatment with orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration‐resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel.

Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors

SummaryPurpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1–28) in combination with paclitaxel 80 mg/m2 on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4. Once the RP2D was defined, patients with advanced ovarian carcinoma were treated at this dose level in an expansion phase. Biomarkers of Hh signaling were assessed by immunohistochemistry in archival tissue and antitumor activity evaluated using RECIST 1.1. Results 18 patients were treated: 3 at 400 mg, 3 at 600 mg and 12 at 800 mg sonidegib. Only one patient treated at 800 mg presented a DLT (prolonged neutropenia resulting in failure to receive 75% of the planned sonidegib dose). However, 4 of 12 patients treated at 800 mg had their sonidegib dose reduced for toxicity after cycle 1. Hh biomarker (SHH, Patched, SMO and GLI1) staining did not correlate with clinical activity. Best response was partial response in 3 patients (2 ovarian, 1 breast cancer) and stable disease >4 cycles in 3 patients (2 ovarian, 1 anal cancer). Conclusions The combination of sonidegib and paclitaxel is tolerable and evidence of antitumor activity was identified. The RP2D of sonidegib was 800 mg in combination with paclitaxel 80mg/m2.

Multimodal Treatment in Operable Stage III Non-Small Cell Lung Cancer: A Pooled Analysis on Long Term Results of three SAKK trials (SAKK 16/96, 16/00, 16/01)

Introduction: Long‐term data on outcomes of operable stage III NSCLC are scarce. Methods: Individual patient data from 368 patients enrolled in one phase III and two phase II trials were pooled and outcomes after applying the eighth (denoted with an asterisk [*]) versus the sixth TNM staging edition were compared. Patients were treated with either preoperative radiotherapy following 3 cycles of induction chemotherapy (trimodal) or neoadjuvant chemotherapy alone (bimodal). Results: With the sixth version, the 5‐ and 10‐year survival rates were 38% and 28% for stage IIIA, respectively, and 36% and 24% for stage IIIB, respectively. Factors associated with improved 5‐year overall survival were younger age, R0 resection, and pathologic complete remission (pCR) (p = 0.043, p < 0.001 and p = 0.009). With the eighth TNM staging version, 162 patients were moved from stage IIIA to IIIB*. The 5‐ and 10‐year survival rates were 41% and 29% for stage IIIA*, respectively, and 35% and 27% for stage IIIB* patients, respectively. There was no difference in the bi‐ versus trimodal group with regard to median overall survival (28 months [95% confidence interval (CI): 21–39 months] and 37 months [95% CI: 24–51 months], p = 0.9) and event‐free survival (12 months [95% CI: 9–15 months] versus 13 months [95% CI: 10–22 months], p = 0.71). Conclusions: We showed favorable 10‐year survival rates of 29% and 27% in stage IIIA* and IIIB*, respectively. Younger age, R0 resection, and pathologic complete response were associated with improved long‐term survival. Outcomes using the sixth versus eighth edition of the TNM classification were similar in operable stage III NSCLC.

Combination of cisplatin and lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma: Report of two cases.

Malignant mesothelioma is an aggressive disease with dismal prognosis despite multimodal treatment including chemotherapy, surgery and radiotherapy. At progression it is possible to provide systemic second-line treatment but its effects are limited. Herein we report two patient cases with mesothelioma who received second-line chemotherapy with the combination of cisplatin and the novel compound lurbinectedin. The combination showed promising activity in both cases with manageable toxicity. We discuss the results of this regime in the light of historical as well as emerging data in mesothelioma.

Long-term tolerability of the BRAF inhibitor vemurafenib in patients with metastatic melanoma: current study data and real-life observations

Vemurafenib is a targeted therapy against metastatic melanoma. It specifically inhibits the V600 mutated BRAF kinase in the mitogen-activated protein kinase pathway. Only limited data are available on long-term tolerability and efficacy of this drug. Here, we report and discuss six patients from our own clinical practice who were treated with vemurafenib for 16–27 months. Overall, these long-term responders tolerated vemurafenib well during the prolonged period of therapy. Most of the side-effects occurred during the first 6 months of treatment and were transient. The most common persistent side-effect was phototoxicity, which was manageable by precautionary measures or with dose reduction. Interestingly, even permanent dose reductions of 50 % of the standard dose did not abrogate long lasting remissions but improved tolerability, which is a prerequisite of long-term therapy. In addition to our own clinical experience, this article reviews current study results regarding the tolerability and efficacy of long-term vemurafenib therapy.

Lung cancer screening: current evidence and recommendations

Lung cancer is the leading cause of cancer-related death in industrialized countries, especially among current and former smokers. Lung cancer survival is directly correlated to the stage of the disease. Cancer screening can detect cancer at an early stage of the disease. Screening in general should prevent cancer or reduce cancer-specific mortality. Clinical practice guidelines of major medical societies have not recommended routine screening for lung cancer so far. Recent publications of new studies raised interest in lung cancer screening again. In this article, we give an overview on the current evidence of lung cancer screening and discuss our personal recommendations for clinical practice.