Expanding Options for Relapsed/Refractory Gastrointestinal Stromal Tumors - Episode 5
Andrew Wagner, MD: What are the standard first- and second-line treatments for patients with metastatic gastrointestinal stromal tumor [GIST]?
Shreyaskumar Patel, MD: The standard of care is imatinib in the frontline setting. Imatinib has set the bar quite high. The 2 large randomized studies conducted on both sides of the pond and their analysis put together, called the meta GIST analysis, has clearly given us an indication that the median overall survivals that used to be in the 1- to 1½-year range in the pre-TKI [tyrosine kinase inhibitors] era on imatinib have certainly gotten almost to 5 years. And there are long-term data with follow-ups approaching 10 years to support this.
The unfortunate reality is that unlike chronic myelogenous leukemia and imatinib, the tails to the curve seem to be drifting down. The slope is downward, we don’t see a flattening of the curve. The B2222, the registrational trial with the longest follow-up, gives us some hints that about 10% of patients with metastatic GIST will still have control of metastatic disease at 10 years with imatinib, implying that development of secondary resistance is fairly universal.
The median time to development of secondary resistance, aka median duration of response to imatinib in the frontline setting, happens to be close to 2 years, give or take a few months. Once patients have failed imatinib—or I should say, imatinib has failed the patient—the approved second-line agent tested in that setting is sunitinib, randomized to placebo. The median progression-free survival with sunitinib in the second-line setting appears to be approximately 6 months. That got the drug approved as the standard-of-care second-line therapy. Unfortunately again, resistance development is fairly common and the approved third-line agent is regorafenib.
That was approved based on the GRID trial, again randomized to regorafenib versus placebo. The median progression-free survival [PFS] for the regorafenib arm is a matter of diminishing returns, as you see PFS in the rego [regorafenib] arm going down to 4.8 months. These are the 3 standard approved agents until recently. We have a couple of new approvals that I’m leaving out for a reason; we can get back to them now or at a later point in time. For a long time, we had these 3 drugs and then we kept looking for clinical trials with newer agents or rechallenging these patients with sister analogs of some of these same drugs.
I just summarized the agent and their efficacy, I guess. Andy, maybe you can educate us with some more granular details as to their mechanisms of action. What exactly does each of these drugs do, and why they do what they do?
Andrew Wagner, MD: Imatinib and sunitinib and regorafenib are all tyrosine kinase inhibitors. Imatinib has what we would consider a pretty clean profile for inhibiting a relatively small number of kinases, which include KIT among a few others. This is probably why imatinib is generally pretty well tolerated: because it doesn’t have a lot of effects on other kinases. Sunitinib and regorafenib differ because they have much broader kinase activity, and really are broader-spectrum multitargeted kinase inhibitors.
Notably, in addition to KIT, they both inhibit the vascular endothelial growth factor [VEGF] receptor. That causes probably the biggest share of the toxicity those drugs can contribute. That differs from the toxicity of imatinib. Those toxicities can include palmar-plantar erythrodysesthesia, or hand-foot syndrome, hypertension, proteinuria, and some oral dysesthesias. All probably related to the VEGF receptor and inhibitor activity. They also probably are more potent KIT inhibitors than imatinib is. The 1 way of seeing that is that they are more likely to cause whitening of the hair than imatinib.
In addition to inhibiting the primary mutations that we described before in KIT, they also have broader activity across the resistance mutations that present after imatinib stops working. Typically, those mutations are occurring in either the ATP binding domain of KIT, which is encoded by exons 13 and 14. Or in the activation loop of KIT, which is encoded by exons 17 and 18. Sunitinib seems to have more activity against exons 13 and 14 mutations, in addition to the exon 9 or 11 mutations, which are the driver mutations. Regorafenib is used against the exon 17, 18 mutations. Each can cover perhaps different areas of resistance to imatinib.
That’s primarily how sunitinib and regorafenib differ from each other. They are similar in their KIT inhibitory activity and their VEGF receptor inhibitor activity. But they do have a slightly different spectrum of activity against different KIT resistance mutations. They have not been formally studied in the first-line setting. To be clear about that, there really is no good evidence for their use compared with imatinib for a typical KIT-mutant tumor.
The efficacy of imatinib, Shreyas, as you described earlier, is quite good, as is the tolerance of imatinib. Imatinib still remains the standard for those for those KIT-mutant tumors. It’s a little more difficult for the SDH-deficient tumors, which do not seem to respond to imatinib. Because the accumulation of succinate may drive production of vascular endothelial growth factor, there have been some reports of activity of the VEGF receptor antagonist sunitinib and regorafenib as well as some other drugs in controlling the SDH-deficient GIST.
That could be a situation where they are using an earlier line of therapy than imatinib. Other than that, they really are reserved for patients who either progressed on imatinib or who were intolerant of imatinib and could not maintain treatment on imatinib because of toxicity.
Transcript edited for clarity.
Andrew Wagner, MD, reports the following disclosures: Consulting with Deciphera, Daiichi-Sankyo, NanoCarrier. He also reports research funding to his institution with Daiichi-Sankyo, Eli Lilly, Karyopharm, Plexxikon, Aadi Biosciences.