Crizotinib Demonstrates Important Clinical Activity in Advanced, Inoperable IMFT

Patrick Schoffski, MD

Patrick Schoffski, MD

Half of the patients with inflammatory myofibroblastic tumor (IMFT) demonstrated a response to crizotinib (Xalkori), according to results from the EORTC phase II study 90101, known as CREATE, that were reported at the 2018 CTOS Annual Meeting.¹

Crizotinib treatment met all predefined success criteria of this study, including a 50% objective response rate and long-lasting disease control inALK-positive patients, as well as demonstrating sporadic activity inALK-negative patients. These results were also previously published in theLancet Respiratory Medicinejournal.²

IMFT, a rare soft tissue sarcoma, is most commonly found in the thorax, retroperitoneal, or pelvic region and often occurs in children as well as adults. Surgical resection remains the mainstay of treatment, since IMFT has shown only limited sensitivity to chemotherapy and radiotherapy. To date, no drug has been approved specifically for this indication.

IMFT is so rare that it is not possible to accrue enough patients for large, randomized prospective trials, according to Patrick Schöffski, MD, of the Catholic University of Leuven, in Belgium.

“This is the very first prospective phase II trial ever performed in this disease; it is not possible to conduct larger trials, so I strongly believe that the data we provide here should serve as the reference and should be the basis for using crizotinib in clinical routine,” he commented.

The rationale to target the ALK receptor with crizotinib was based on the presence ofALKtranslocations in approximately 50% of patients with IMFT. Apart from ALK, crizotinib also targets ROS1, and MET. Further support for conducting this study came from a study reporting crizotinib response in 1 patient withALK-rearranged IMFT.³

CREATE is a multicenter, biomarker-driven, open label, 2-stage phase II study, which included 6 independent disease-specific cohorts.

Schöffski presented final results from the IMFT cohort of CREATE, which evaluated crizotinib activity in patients with advanced inoperable, metastatic IMFT with alterations in the ALK or MET pathways. Of the 35 patients enrolled across 13 sites in 8 European countries, 24 had centrally confirmed, advanced inoperable IMFT, ECOG performance status of 0-2, and measurable disease by RECIST 1.1. These patients were eligible for screening, yet only 20 patients started treatment.

BothALK-positive andALK-negative patients were included in this cohort, yet prior treatment with crizotinib or other ALK inhibitors was not allowed.

Adult patients received oral crizotinib at 250 mg twice daily; children were dosed according to a newly developed protocol. The median patient age was 45.5 years (range, 15 to 78); 50% of patients had undergone surgery and 40% had received prior systemic therapy, with just 1ALK-positive patient demonstrating a partial response (PR).

Tumor assessment by local investigator was done every other treatment cycle andALKwas assessed by immunohistochemistry and fluorescence in situ hybridization (FISH);ALKpositivity was defined as staining in 15% of tumor cells.

The primary endpoint was objective response rate (ORR) inALK-positive patients with IMFT. Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free (PFS), overall survival (OS), and other translational endpoints. This Simon 2-stage trial required a response in 2 of the first 12 treated patients to proceed.

Of the 24 screened patients, 16 (66.7%) wereALK-positive and 8 (33.3%) wereALK-negative. Nineteen patients were evaluable for the key endpoints of the trial.

Although the recruitment was discontinued early in June 2017 due to slow enrollment, the success criteria of the trial had already been met: 2 object responses among the first 12 patients and 6 responses in the stage 2 population had been demonstrated.

A high objective response rate was observed among 12 evaluable patients withALK-positive disease. Two patients (16.7%) achieved a complete response (CR), 4 (33.3%) had a PR, and 5 (41.7%) had stable disease (SD); no progressive disease (PD) was observed in theALK-positive subset following crizotinib. The ORR was 50% (95% CI, 21.1%-78.9%) and the DCR was 100% (95% CI, 73.5%-100%). The 1-year PFS rate was 73.3% (95% CI, 37.9%-90.6%). The DOR was 9.0 months (range, 1.4-41.6).

In the 7 patients comprising theALK-negative subset, no patient achieved a CR, 1 (14.3%) showed a PR, and 5 (71.4%) had SD; only 1 patient (14.3%) had PD. The ORR was 14.3% (95% CI, 0%-57.9%), and the DCR was 85.7% (95% CI, 42.1%-99.6%). The 1-year PFS rate was 53.6% (95% CI, 13.2%-82.5%). Among the 1 responding patient, the DOR was 7.6 months.

Overall, for all evaluable patients, the ORR was 36.8% (95% CI, 16.3%-61.6%) and the DCR was 94.7% (95% CI, 74.0%-99.9%).

Several reasons were offered for the observed antitumor activity inALK-negative patients. “The defined cut-off of 15%ALK-positive cells may have led to a false-negative result in tumors with a borderline percentage of positive cells,” Schöffski explained. “FISH may miss complex rearrangements that generate an atypical signal, and atypical breakpoints inALKfusions may not be covered by the FISH assay used;ALKactivation may be due to a point mutation, as seen in non—small cell lung cancer.”

The investigators pursued another plausible explanation, the presence of another crizotinib-sensitive alteration, such as aROS1rearrangement, which is known to be present in some IMFT. However, the exploratory analysis ofROS1as a potential alternate driver using FISH found noROS1rearrangement in 23 evaluable patients.

AllALK-positive patients demonstrated tumor shrinkage and 3 patients withALK-negative tumors showed shrinkage of their target lesions.

As of November 2017, the median follow-up was 863 days; at this time, 35% of patients (n = 7) remained on crizotinib. The mean dose intensity was 94.4% and mediation treatment duration was 7.2 months inALK-positive patients and 4.1 months inALK-negative patients. Five patients required dose reduction and 9 discontinued treatment due to disease progression, adverse events, patient decision, and surgery.

The safety analysis showed no new safety signals. The most commonly reported treatment-related adverse events (AEs) included nausea in 55% of patients, fatigue in 45%, blurred vision in 45%, and 35% of patients each had vomiting and diarrhea. Eight serious AEs occurred in 5 patients, including pneumonia, fever of unknown cause, heart attack, abdominal abscess, and QT prolongation. No death occurred on study or within 4 weeks of crizotinib discontinuation.

“Based on 1 response in 1 case treated in a phase I trial, the US National Comprehensive Cancer Network has recommended use of crizotinib in IMFT since 2012,” Schöffski noted. “CREATE now provides prospective evidence for this recommendation; this is likely the best type of evidence that can be generated in this indication.”

References

1. Schöffski P, Sufliarsky J, Gelderblom H, et al. Prospective trial of crizotinib (c) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 “CREATE”. Presented at: 2018 CTOS Annual Meeting; November 14-17, 2018; Rome, Italy. Paper 017.
2. Schöffski P, Sufliarsky J, Gelderblom H, et al. Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.Lancet Respir Med.2018;6(6):431-441. doi: 10.1016/S2213-2600(18)30116-4.
3. Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor.N Engl J Med.2010;363(18):1727-1733. doi: 10.1056/NEJMoa1007056.