Although the sessions at the first ever GISTT Summit meeting in Essen Germany discussed many different topics, this article will focus on the theme of the summit, “removing roadblocks to a cure”. More than any other GIST conference that I have ever attended, the GISTT Summit had a much heavier focus on understanding what allows GIST tumor cells to survive treatment and less focus on resistance to treatments.
In some ways, the remarkable success of imatinib (Gleevec) as the initial treatment in GIST may have worked to slow progress in curing GIST. Imatinib has been described as the “unchallenged king” of drugs for GIST. Prior to the first use of imatinib in GIST and Chronic Myelogenous Leukemia (CML), benefit for systemic cancer treatments was measured in months, or sometimes even in weeks. In GIST, benefit is now measured in years, and in CML and a minority of GIST patients, benefit is measured in decades.
Yet, imatinib seems to cure very few GIST patients. Only about 10% of advanced GIST patients will have truly durable responses lasting more than 10 years. A more typical response for imatinib-sensitive GIST is two years (early clinical trial data that includes all GIST, not limited to imatinib-sensitive) to about 3 1/2 years (later real-world data for imatinib-sensitive GIST). Patients with KIT exon 9 mutations have intermediate sensitivity to imatinib with a dose-dependent benefit time (progression-free survival) ranging from about 8 to 19 months.
One of the roadblocks to a cure is that GIST seems to be stuck in a kind of circular “Catch-22”. Imatinib is such a good drug that the perception by the GIST community (patients, clinicians, researchers and pharma) is, “why try anything different”? Patients are not going to try anything else so why go to the considerable expense of offering an alternative? The simple answer is, because tumors become much more complex and aggressive in later stages of treatment. If you are going to cure GIST, the chances are much higher earlier in treatment. There are a number of different types of GIST. This article will focus on the most common type, GISTs driven by KIT mutations.
So, how do you challenge the king? Let’s lay out some of the steps that were discussed in the conference and then explore them.
1. Research must have progressed enough to offer reasonable hope for significantly improved responses.
2. Clinicians must develop protocols based on the best research available, provide funding for clinical trials (often, but not always from Pharma) and attract enough patients to fill those trials.
3. Patients need to have confidence that their treatment will be, at least as effective as imatinib, well tolerated and at least hope that the treatment will be better than imatinib alone.
4. Pharma has traditionally been the largest funder of trials. However, the design of a trial(s) will likely influence Pharma involvement. As a result, the role for Pharma is a little less clear.
Response in GIST can be measured in different ways: by tumor shrinkage or growth (CT or MRI), by metabolic response (PET scan) or by how many tumor cells die or remain viable (pathological response). In some cases, CT scans, regardless of a change in size, can also give some indication of the viability of tumor cells from the appearance of the tumors, especially a change in density. The percentage of tumor cell death versus remaining viable tissue does not strongly correlate with a change in tumor size (shrinkage or stable disease) or PET scans. Viable tumor cells remain in almost all imatinib-treated GISTs, although the percentage of viable cells varies from very few, to near 100%. Interruption of imatinib results in tumor regrowth in almost all cases, even in tumors with very few remaining viable cells.1
Dr. Jonathan Fletcher of Brigham and Women’s Hospital in Boston, Mass., presented new data of a possible mechanism keeping tumor cells alive. His lab has noted that, in some stable patients, KIT signaling is completely, or nearly completely inhibited, however, several key downstream signals (an intermediate signal) typical of receptor activation) remain activated. In, at least some cases (it’s unclear how many), these downstream signals may be activated by another receptor, EGFR, which appears to be stimulated by an EGFR ligand (growth factor). This intermediate signaling, (caused by EGFR) seems to be enough to keep the GIST tumor cells alive, but not enough to cause them to grow. If imatinib is interrupted however, tumor growth resumes through the re-activation of KIT signaling.
In a panel discussion, Dr. Peter Reichardt, raised the possibility of doing a trial that incorporated a window where the patient could be given a drug or drug combination with the intent of improving response. Although there was initially talk of targeting persistence in first-line advanced patients, the consensus seemed to be that trials in neoadjuvant treatment (imatinib given prior to surgery to make surgery easier) offered some advantages. One of the primary reasons for this was that you are looking for early signs that you are getting the desired effect. The bonus with neoadjuvant is that, after surgery, you get the entire remaining tumor for study of the effects of treatment.
There was discussion of how willing patients might accept/participate in such studies. In other words, would they be willing to forego imatinib. One possibility is that current state of the art seems more likely to be an imatinib-combination. So, perhaps the question won’t be foregoing imatinib, but accepting an addition to imatinib.
LRG is aware of several drug companies that have expressed an interest in first-line trials/up-front treatment. These include, but and not necessarily limited to, IDRX and Kura Oncology. Dr. Ciara Kelly of Memorial Sloan-Kettering Cancer Center (MSKCC) also presented plans for a trial combining imatinib and immunotherapy agent, GI102.
There was also discussion of continuing the conversation about these types of trials as well as bringing GIST patients back to referral centers. This was mentioned as a roadblock occurring in both Europe and the US. It is important for both patients and local doctors to understand that the local care team will always be a critical part of their care. However, referral centers may offer options that patients at all stages should be aware of.
It will be interesting to see how this apparent change in direction evolves. In the future, GIST patients may have more upfront options.
