Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial

Abstract

Introduction: ROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS). Conclusions: Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-coaberrant patients had a significantly worse outcome compared to TP53 wild-type patients.

ALK inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis

“…Few prospective non-randomized studies have assessed outcomes with the use of ALK inhibitors in this population, although several small single-arm phase II studies have reported 12 month survival of 83%-85% (median progression-free survival of at least 15 months) with crizotinib. [46][47][48] Current recommendations from the American Society of Clinical Oncology [49] and the European Society of Medical Oncology [45] support the use of crizotinib as first-line treatment for patients with ROS1 rearrangements; additional research is needed to assess the benefits of other ALK inhibitors in this population.…”

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

“…Although break-apart FISH has traditionally been the criterion standard test for detection of ROS1 rearrangements, the ROS1 FISH is especially difficult to interpret and may be prone to both false negatives and false positives. 9,11,19,[36][37][38][39][40] To increase the robustness of the results, we decided to repeat all FISH tests in house and score them with an outstanding automated FISH scanning system using a high threshold for positivity. The mean and median numbers of positive cells in positive tumors were very high (>80%, which is well above the threshold) and obviously contributed to the excellent correlation with FISH, but it must be emphasized that some rare fusion partners ([GOPC], which is also known as FIG, occurs in 3% of ROS1 patients and is not represented in the present study) are a well-known source of false-negative FISH results.…”

“…Overall, the variety and prevalence of ROS1 partners identified were similar to those described. 24,37,45 The percentage of cases in which the suboptimal RNA quality and/or quantity resulted in low sequencing coverage highlights the need for an evidence-based algorithmic approach. 39,46,47 The fusion partner can influence both the IHC staining and the FISH pattern, with the EZR variant usually being associated with a membranous accentuation and isolated 3 0 signals, respectively.…”

“…24,48 Unfortunately, this is still a controversial topic that would need larger multicenter series with longer follow-up and standardized NGS to draw definitive conclusions. 22,37 A review of published studies in the light of our findings suggests that there are two scenarios that can have important clinical consequences when ROS1 IHC is to be used as the primary screening method for ROS1 therapy: (1) a ROS1 FISH-false-positive result in a patient with another druggable alteration that is causing the ROS1 IHC positivity (awareness of the FISH potential pitfalls is essential [i.e., percentage of positive nuclei around the cutoff, 3 0 isolated pattern], and if the result is inconsistent, it is sensible to use a third methodology [i.e., NGS], which will potentially discover the reason for the IHC positivity) and (2) a ROS1 NGSnegative or failed report in a ROS1-rearranged sample that exhibited intense and homogeneous IHC staining. 38,44 The choice of RNA-based NGS can reduce the risk of false negatives, and using another sample or a third technology (i.e., FISH) when the initial NGS approach fails is mandatory to confirm those positive IHC results.…”

Immunhistochemische und molekularpathologische Diagnostik von Lungenkarzinomen

“…Wir empfehlen ein primäres Screening von NSCLC mittels IHC [8] und bei Progress nach primärer TKI-Therapie in jedem Fall eine Rebiopsie/ Liquiddiagnostik zur Ermittlung einer möglichen Zweitlinientherapie. Es gibt wahrscheinlich kaum andere Tumortypen als ROS1-translozierte Adenokarzinome, die so stark von einer zielgerichteten Therapie mit TKI profitieren, wie diese zahlenmäßig beträchtliche Patientengruppe [24].…”