Crizotinib Activity in MET-Altered Non-Small Cell Lung Cancer Undetermined

While the remarkable activity of crizotinib (Xalkori) as treatment of patients with ROS1 fusion-positive advanced non–small cell lung cancer (NSCLC) was confirmed in a recent systemic review and meta-analysis, the efficacy of this small molecular inhibitor remains unknown in patients with MET-altered disease.¹

Several clinical trials have evaluated the efficacy and safety of crizotinib in the MET-altered and ROS1 fusion-positive patients with advanced NSCLC, but there remains inconsistencies regarding the associations between the positivity of either a ROS1 fusion or MET alteration and the clinical activity of crizotinib, as well as the prognosis of these patient populations. The meta-analysis aimed to explore the activity of this therapy in these 2 groups of patients.

Among 711 search results from PubMed and Web of Science for crizotinib data, 20 studies were selected for the review, which comprised of 719 patients with advanced NSCLC. Across all studies, the initial crizotinib dose was 250 mg administered twice daily, and the efficacy and response data were evaluated by RECIST classifications. Sixteen studies reported on the efficacy of crizotinib among patients with ROS1 alterations, while 6 studies reported on treatment responses for patients with MET alterations.

Complete responses (CRs) were observed among 4.2% of the ROS1 fusion-positive population (95% CI, 1.9-6.4), while partial responses (PRs) occurred in 71.2% (95% CI, 65.3-77.1) and stable disease (SD) in 13.4% (95% CI, 9.7-17.0). Progressive disease (PD) was observed in 5.8% of the ROS1-altered patients (95% CI, 3.8-7.8). The pooled disease control rate (DCR) was 93.2% (95% CI, 90.8-95.5), and the pooled ORR among this population was 77.4% (95% CI, 72.8-82.1).

The median progression-free survival (PFS) in the ROS1 fusion arm was 14.5 months, with a range from 5.5 to 22.8 months. Median overall survival (OS) was not reached in most studies, but among those where OS data were available, the median was 32.6 months (range, 17.2-51.4).

The pooled proportions of CRs and PRs in the MET-altered population were 3.1% (95% CI, 0.5-5.7) and 39.3% (95% CI, 25.8-52.7), respectively. The proportion of patients with SD was 36.9% (95% CI, 28.6-45.1), while PD was 17.5% (95% CI, 7.4-27.7). The DCR was found to be 78.9% (95% CI, 70.3-87.4), and the ORR 40.6% (95% CI, 28.3-53.0).

The median PFS was 5.2 months (range, 2.4-7.3), and the median OS was 12.7 months (range, 5.4-31.0). However, the survival data for MET-altered patients were insufficient for further analysis.

The most frequent adverse events (AEs) related to crizotinib included impairment in 43.7%, edema in 42.9%, and fatigue in 40.1%, which were followed by gastrointestinal symptoms like nausea (39.7%), vomiting (36.2%), and diarrhea (36.9%). The most common severe AEs of grade 3 or higher included neutropenia (5.7%) and elevated transaminase (4.2%).

Overall, patients with NSCLC who harbored a ROS1 fusion has significant improvements in response rates with crizotinib compared with those who received platinum-pemetrexed chemotherapy. The most common variant in ROS1-positive NSCLC is CD47, but findings evaluating the survival outcomes between ROS1-positive subgroups indicated no statistical difference among the different groups of patients.

The investigators also noted that responses to crizotinib tended to occur early on, and about 50% of patients had an objective response following 2 cycles of therapy. However, these dramatic responses to initial treatment tend to be short-lived as acquired resistance to the agent typically develops at some point in this population. About 50% of patients had developed disease progression or died at the end of follow-up.

A potential explanation for the resistance to crizotinib may be variations in the mutation at baseline. ROS1rearrangements can occur concurrently with other mutations, such as EGFR, ALK, or TP53, but exclusive ROS1 fusions have been associated with a better prognosis, according to a real-world analysis that explored concomitant mutations in patients with ROS1-rearranged NSCLC who were treated with the ROS1 protein inhibitor.2 The study ultimately demonstrated that concomitant mutations may deteriorate PFS in this population. However, more research is necessary to explore the mechanism of resistance to crizotinib in this patient population.²

Several phase 3 clinical trials have demonstrated results that were discouraging for the use of crizotinib in this patient population, but those trials did not target tumors with MET exon 14 alterations specifically. The results from this analysis demonstrate the agent had a lower response rate, as well as a shorter survival as treatment of patients with MET alterations compared with ROS1 fusions.

The high rate of AEs may also limit use of this agent in the MET-positive NSCLC population, but the study authors suggest a number of potential explanations for the efficacy discrepancies between the ROS1 and METgroups. The activation mechanisms, for instance, are different among the 2 groups, whereas the ROS1 fusion may signal tumorigenesis to promote cell growth and survival, particularly through the MAPK/ERK, PI3K/AKT, JAK/STAT3, and Src homology region 2 domain-containing phosphase-1 and 2. In tumors harboring a METalteration, the MET exon 14 mutation prevents ubiquitination, which further promotes stabilization of the MET protein. The clinicopathological characteristics of MET exon 14-positive NSCLC are distinct from ROS1-positive disease.

The level of heterogeneity, in terms of response rate and survival, was significant among the studies used for this analysis of patients with MET-altered NSCLC, and it has been previously reported that higher levels of MET amplification are more likely to respond to crizotinib.³

The findings from this report are encouraging for both patients with ROS1- or MET-positive advanced NSCLC. Although the data from this analysis further supports the use of crizotinib as treatment of patients with advanced NSCLC who harbor ROS1 fusions, more research is necessary to understand the impact of crizotinib therapy in patients with MET-altered disease. Additional studies evaluating other tyrosine kinase inhibitors with longer follow-up are expected to optimize the treatment of this patient population.

_References

_{1. Vyong HG, Nguyen TQ, Nguyen HC, et al. Efficacy and safety of crizotinib in the treatment of advanced non-small cell lung cancer with ROS1 rearrangement or MET alteration: a systemic review and meta-analysis. Targeted Oncology. Published Online: August 31, 2020. doi: 10.1007/s11523-020-00745-7}

_{2. Zeng L, Li YZ, Xiao LL, Xiong Y, Liu L, Jiang WJ, et al. Crizotinib presented with promising efficacy but for concomitant mutation in next-generation sequencing-identified ROS1-rearranged non-small-cell lung cancer. Oncotargets Ther. 2018;11:6937–45. doi: 10.2147/ott.s1762 73}

_{Moro-Sibilot D, Cozic N, Pero M, Mazieres J, Otto J, Souquet PJ, et al. Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSe phase II trial. Ann Oncol. 2019;30(12):1985–91. doi: 10.1093/annon c/mdz40 7}