Crizotinib in Chinese Patients with ROS1-Rearranged Advanced Non‒Small-Cell Lung Cancer in Routine Clinical Practice

Lung cancer remains the leading cause of cancer-related deaths worldwide, and non‒small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers [1]. In the past decade, the treatment of NSCLC has undergone tremendous changes based on newly characterized key molecular alterations that drive lung carcinogenesis. The development of epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK)-targeted TKIs represent examples of individualized treatments for advanced NSCLC [2].

The c-ros oncogene 1 (ROS1) is also a molecular target in lung cancer. It encodes for an orphan receptor tyrosine kinase of the insulin receptor family and is related to ALK and leukocyte receptor tyrosine kinase [3]. In 2007, chromosomal rearrangements involving the ROS1 gene, leading to fusions of the ROS1 tyrosine kinase domain with one of several partner proteins, were reported [4, 5]. Since then, oncogenic ROS1 rearrangements have become an established therapeutic target in lung cancer. Bergethon et al. [6] identified ROS1 rearrangements in 18 of 1073 patients (1.7%) with NSCLC using fluorescence in situ hybridization (FISH), and suggested that ROS1 rearrangements define a unique molecular subset of NSCLC with distinct clinical characteristics, including younger patients (median age approximately 50 years) and never smokers, similar to those observed in patients with ALK-rearranged NSCLC.

Crizotinib, a multitargeted mesenchymal-epithelial transition/hepatocyte growth factor receptor (MET)/ALK/ROS1 inhibitor, has demonstrated remarkable efficacy in advanced ROS1-rearranged NSCLC and has consequently received approval from the US FDA and the European Medicines Agency (EMA) in 2016. This approval was based on efficacy and safety data from the expansion cohort of a phase I study (PROFILE 1001), which demonstrated an objective response rate (ORR) of 72% and a median progression-free survival (mPFS) of 19.2 months in patients with advanced ROS1-rearranged NSCLC [7].

Approximately 1–2% of patients with NSCLC harbor ROS1 rearrangements [4]. However, the incidence is slightly higher in East Asian populations, which report a frequency of 2–3% [8]. A phase II, open-label, single-arm, multicenter trial assessing the efficacy and safety of crizotinib in a cohort of 127 East Asian patients with ROS1-positive advanced NSCLC (study OO1201) reported an ORR of 71.7% and an mPFS of 15.9 months [9]. Thus, crizotinib was approved in China for ROS1-positive NSCLC in September 2017 based on the results of study OO1201. Our current retrospective analysis aimed to analyze the efficacy and safety of crizotinib treatment in Chinese patients with advanced NSCLC with ROS1 rearrangement in real-world clinical practice at the Fudan University Shanghai Cancer Center.

In the phase I PROFILE 1001 study, 50 patients with ROS1-rearranged NSCLC who were treated with crizotinib (14% as first-line therapy) achieved an ORR of 72% and a median PFS of 19.2 months [7]. On the basis of the efficacy and safety demonstrated in this study, crizotinib was granted full approval for the treatment of advanced ROS1-rearranged NSCLC by the FDA and the EMA in 2016 [7]. In a French phase II study [10] and in the EUROS1 retrospective analysis [11], the median PFS with crizotinib therapy for ROS1-rearranged NSCLC was 9–10 months, although both these studies enrolled only approximately 30 patients. The largest study of crizotinib conducted to date, an East Asian phase II study (OO1201), achieved a median PFS of 15.9 months among 127 patients with ROS1-rearranged NSCLC and an ORR of 71.7% [9], which led to the subsequent approval of crizotinib for patients with NSCLC with ROS1 rearrangement in Japan, China, and Korea [9]. In this study, 18.9% of patients received crizotinib as first-line therapy.

Our retrospective study analyzed the efficacy and safety of crizotinib in real-world clinical practice in Chinese patients, as few real-world studies have offered data on the efficacy and safety of crizotinib in Chinese patients with ROS1-rearrangement NSCLC (except for Chinese individuals in the published clinical trials). We demonstrated that crizotinib was effective in Chinese patients with ROS1-positive advanced NSCLC, achieving an ORR of 71.4%, a median PFS of 11.0 months (with 12 [34.3%] patients still in follow-up for PFS) and a median OS of 41.0 months, with 23 patients (65.7%) still alive. The median PFS with crizotinib therapy in our study was shorter than that reported in the PROFILE 1001 and OO1201 studies. This may reflect the inclusion of non-trial patients, limited sample sizes, and differences in patient demographics among the studies. However, the PFS values reported in the French phase II study and the EUROS1 study were comparable to those achieved in our study. Because 23 patients (65.7%) were still alive, the OS data in our study were not mature. However, this is one of the few studies to produce OS data to date.

Several factors were explored for their ability to predict PFS with crizotinib therapy. However, the clinical efficacy of crizotinib might be irrespective of age, sex, smoking history, the presence of brain metastases at baseline, or line of crizotinib treatment, which is consistent with the findings of the OO1201 study. Responses were achieved in patients independently of prior lines of therapy, which indicates that crizotinib is beneficial in both first- and later-line settings. The patients’ characteristics in our study were consistent with those of the China cohort of the OO1201 study, including a median age of 51.0 years in our study compared with 49.5 years, 65.7% female compared with 54.1%, and 100% adenocarcinoma compared with 95.9% in the OO1201 study.

The safety profile of crizotinib in our study was consistent with that reported in previous studies of crizotinib [7, 9, 12‐14]. No unexpected AEs were observed. Crizotinib-related AEs occurred in 94.3% of patients in our study. However, most AEs reported in our study were of grade 1 or 2 severity, and no grade 4 or higher crizotinib-related AEs were observed, which indicates that crizotinib is well-tolerated in Chinese patients with ROS1-positive advanced NSCLC in real-world clinical practice. The most commonly reported crizotinib-related AEs in the OO1201 study [9] were elevated transaminases (55.1%), vision disorder (48.0%), nausea (40.9%), diarrhea (38.6%), and vomiting (32.3%). The incidence and severity of AEs in our study were comparable to those in the OO1201 study [9]. The AEs attributed to crizotinib were manageable with dosing interruptions or reductions, with a low rate of permanent treatment discontinuations due to crizotinib-related AEs.

Very few studies currently focus on progression patterns with crizotinib and sequential treatments after crizotinib failure in patients with ROS1-positive advanced NSCLC. Among the 21 patients who experienced disease progression in our study, the most common progression site was the brain (10/21 [47.6%]), which is consistent with known data regarding poor crizotinib penetrance to the brain. Of the ten patients who experienced disease progression in the brain, six (60%) had brain metastasis at baseline. Of the 11 patients who experienced disease progression at other sites, one (9.1%) had brain metastasis at baseline. We postulated that patients with brain progression were more likely to have brain metastasis at baseline (p = 0.024). Poor penetration of crizotinib in the central nervous system (CNS) may account for both the short PFS and the high CNS progression rate. Furthermore, treatments beyond disease progression were diverse. The estimated median PFS2 was 21 weeks for all 21 patients experiencing PD after crizotinib. The estimated median PFS2 of 25.0 weeks in 13 patients who received CBPD was numerically longer than that of 21.0 weeks in eight patients who did not receive CBPD (p = 0.386). Seven patients who received both CBPD and local therapy had a longer PFS2 time of 82.0 weeks than the other 14 patients (21.0 weeks), although the differences were not statistically significant (p = 0.272). Despite the small sample size and the short follow-up time, we can infer that CBPD and local therapy after failure of crizotinib treatment were feasible and effective in clinical practice. Similarly, the prospective ASPIRATION study [15] supported the efficacy of first-line erlotinib therapy in Asian patients with EGFR mutation-positive NSCLC, and the feasibility of continuing erlotinib therapy beyond PD. Yang et al. [16] found that patients with local progression could benefit from continuation of EGFR-TKIs as systemic treatment plus local intervention after EGFR-TKI failure in clinical practice. In terms of failure after ALK-TKIs, Ou et al. [17] found that continuing ALK inhibition with crizotinib after PD may provide a survival benefit for patients with advanced ALK-positive NSCLC. As radiotherapy can control brain tumors and improve CNS symptoms rapidly, to some extent compensating for poor penetration of crizotinib in the CNS, Hong et al. [18] found that continuation of both crizotinib and local therapy may contribute to disease control in patients with ALK-positive NSCLC and CNS progression during crizotinib treatment. Thus, our study highlights the need for further verification of the effectiveness of CBPD and local therapy after failure of crizotinib treatment, especially for locoregional progression in patients with ROS1-positive NSCLC in clinical practice.

This study is significant for several reasons. First, it provided first-hand real-world data on the efficacy of crizotinib in patients with advanced NSCLC with ROS1 rearrangement. As ROS1-positive NSCLC is rare, it is difficult to perform large-scale, randomized, controlled, phase III clinical studies. Second, the safety profile noted in our study suggested that crizotinib is well-tolerated in Chinese patients with ROS1-positive advanced NSCLC in real-world clinical practice. In addition, we compared the safety profile between our study and the OO1201 study, which will help oncologists gain a better understanding of the possible adverse effects of crizotinib in real-world clinical practice. Third, we obtained information on disease progression at different sites in patients receiving crizotinib therapy and on treatment beyond disease progression in patients with ROS1 rearrangement NSCLC in real-world clinical practice. In the 21 patients who experienced disease progression, both the progression lesions and treatments beyond disease progression were diverse.

Our study has several limitations. First, as it was a single-center retrospective study with a relatively small sample size, possible information bias could have affected our outcomes. Second, the short follow-up time means the OS data were immature. Third, positivity for ROS1 rearrangements in our study was determined in about half our patients using the FISH detection method (18/35 [51.4%]). Although the break-apart FISH assay is the only assay clinically approved by the FDA to detect ROS1-rearranged NSCLC, it has both advantages and disadvantages. FISH can be performed even if the exact fusion partner is unknown, as it has the potential to identify all fusions for ROS1 in NSCLC and other solid tumors. On the other hand, the FISH assay cannot identify exact fusion partners, which can be confirmed by subsequent sequencing of the RT-PCR assay [19]. ROS1 fusion partners were identified in only 12 patients (34.3%) in our study. The most frequent ROS1 fusion partner was CD74 (CD74-E6; ROS1-E34), which was identified in eight patients (8/12 [66.6%]). When fusion partners are unknown, the effects of different fusion partners on the efficacy of crizotinib and on drug resistance cannot be analyzed, and this is the focus of current research on crizotinib resistance mechanisms in ROS1-rearranged NSCLC. Recently, one study that evaluated the roles of ROS1 fusion partners on the treatment response found that patients with non-CD74 ROS1-positive NSCLC were less likely to have brain metastases and to have a trend towards an improved PFS [20].