Patrick Schöffski, MD, MPH, discussed the key findings from the CREATE trial, the next steps for research into inflammatory myofibroblastic tumor, and the regulatory challenges for approval of drugs for rare cancers.
Patrick Schoffski, MD
In findings presented during the 2018 Annual Meeting of the Connective Tissue Oncology Society, the ALK inhibitor crizotinib (Xalkori) showed promise for the treatment of inflammatory myofibroblastic tumor (IMFT), a rare soft tissue sarcoma that usually occurs in children and young adults.
Results from the CREATE trial, a phase II study of crizotinib in advanced inoperable IMFT, were presented by lead study author Patrick Schöffski, MD, MPH. Findings from the study showed a 50% objective response rate in this patient population (95% CI, 21.1%-78.9%).
The study enrolled 35 patients across 13 sites in 8 European countries. Of those patients, 20 had centrally confirmed IMFT and were treated with crizotinib. Among 12 evaluable patients with ALK+ disease, 6 patients achieved a confirmed partial response (PR) or complete response, 1 achieved a non-confirmed PR and 5 had stable disease as best response.
In an interview withTargeted Oncology, Schöffski, of the Catholic University of Leuven, in Leuven, Belgium, discussed the key findings of the trial, the next steps for research into IMFT, and the regulatory challenges for approval of drugs for rare cancers.
TARGETED ONCOLOGY: What are the key findings from your study of crizotinib in patients with inoperable IMFT?
Schöffski:In our CREATE trial, we wanted to assess the activity of an oral targeted agent called crizotinib in patients with a very rare disease called IMFT. We documented a high objective response rate in patients with this disease characterized by positivity for an ALK rearrangement. Fifty percent of our patients had an objective response to crizotinib.
TARGETED ONCOLOGY: Do these results point to a new standard of care inALK-positive patients with IMFT?
Schöffski: This disease is so extremely rare that it is impossible to run big, randomized prospective trials. Actually, the study I am presenting here is the very first prospective phase II trial ever performed in this disease. All other data in the literature come from dose-finding studies in adult patients or pediatric patients from a mixed population of cancer patients with ALK-positivity of their tumors, so this is the very first attempt to study the activity in a rigorous way. It is impossible to do bigger, more definitive 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.
TARGETED ONCOLOGY: What did this trial demonstrate aboutALK-negative tumors?
Schöffski: Interestingly, we allowed the entry of bothALK-positive andALK-negative patients in this trial. We believe this was ethical because there is no standard of care for both subsets of this disease.
For theALK-negative subset of patients, we treated and evaluated 7 patients exposed to crizotinib, and interestingly, 3 of these 7 patients had shrinkage of their target lesions according to the standards that we used in this trial; 1 of these patients even had an objective partial response.
TARGETED ONCOLOGY: What are the next steps in your research?
Schöffski: Well first of all, this was a cohort of a multitumor study. I managed over the past year to publish 5 full papers related to this trial, so we put data into the literature for 5 very rare diseases, all coming from the same study with the same study design, and all patients treated with the same agent.
The next step has to be to work further on the biology of the tumors that we treated in this trial. When I wrote the protocol several years ago, I decided to collect tissue blocks from every tumor that was included in this trial. We have these tumor blocks, which Is a wonderful resource for doing translational research. We have built what we call tissue microarrays; we have put tiny little pieces of tumor from every patient in this trial in 1 paraffin block, which allows us to studyin a very rapid way—the biology, the expression of certain molecular targets, for example, in all patients simultaneously by just doing 1 staining.
This is something that’s currently ongoing. We are trying to understand what might be prognostic or predictive factors for response to crizotinib. Furthermore, we are trying to understand the difference betweenALK-positive andALK-negative cases. Of course, we are very interested in looking at theALK-negative patients who had some shrinkage of the target lesions or even a sporadic response, so we are doing a lot of tissue-based work at this time.
Furthermore, we have not only collected tissue blocks, but also scans from all of these patients, from the start of treatment until the end of treatment. I’m currently stimulating a number of radiology substudies. These diseases are so rare that even the radiological presentation of these tumors has not been described very well in the literature, so there is still a lot that can be done with materials collected in this study.
Futhermore, [in] the cohort that I’m presenting today, the myofibroblastic patients, about a third of these patients were still receiving active treatment when I first published data from this trial. Of course, we are still following them. We are still updating our database. We know at this point that the response rate will ultimately be even higher than what I’m reporting here today because we have seen some patients who had only stable disease on the treatment, converting to partial responses later on. It’s very likely that the objective response rate that I’m reporting as the primary endpoint will even increase over time.
TARGETED ONCOLOGY: Given the rarity of this cancer, what are some of the unmet research needs in IMFT?
Schöffski: It’s very difficult to perform research if you only have a sporadic case to perform some translational work. The beauty of our trial is that we did not only use it for establishing the response rate for a given treatment but to collect material in a prospective way, which is really a goldmine for further research.
Apart from the promising efficacy findings in this trail, further papers that will come out of this trial will teach us a lot about the biology about the spontaneous course of this disease, the natural evolution of the disease, and even survival.
If you look at the data that I’m presenting here, you will see that we provide very mature overall survival data. There is no data in the literature on how long a patient can actually live with advanced IMFT. We are providing data in a prospective way from a well-done, investigator-initiated academic trial.
TARGETED ONCOLOGY: Are there challenges related to approval of a drug for a rare indication in which a large, randomized study is not feasible?
Schöffski: The problem in rare diseases such as IMFT or the other cancers that we have treated in this prospective trial is that we will never generate the randomized level of evidence that is routinely required to get drugs approved by regulatory bodies. So far, with a tumor like IMFT, we have to be very creativeand regulators have to be very flexible—to broaden the label of such a drug in this disease.
Crizotinib is approved for NSCLC, which is a very common malignancy, as you know, but only for a tiny little subset of NSCLC patients, the ALK- andROS1-positive patients. Still, this is a considerable number of patients to do a more definitive study. In a disease like IMFT, it would be impossible.
We need a lot of flexibility on the side of regulators to bring the drug to the patients in need of such agents. At this point, we have already 3 generations of ALK inhibitors on the market for other indications. Critozinib was the prototype agent, and we need a way to bring this drug to the patients outside of clinical trials.
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.” Paper 017#3016595. Presented at the 2018 Annual Meeting of the Connective Tissue Oncology Society, November 14-17, 2018; Rome, Italy.