Neeta Somaiah, MD, discusses the significance of the Peak study and what an approval of bezuclastinib plus sunitinib would mean for GIST.
Broad and selective targeting coupled with manageable toxicities are what make bezuclastinib (CGT0486) plus sunitinib (Sutent) compelling for the management of advanced gastrointestinal stromal tumors (GIST), according to Neeta Somaiah, MD.1
In an exclusive interview with OncLive®, Somaiah
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Somaiah is a professor and department chair of Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.
Somaiah: Sunitinib is a drug that has been around for a long time. It was first developed for other cancers and is a broad-spectrum TKI that has activity against KIT and other tyrosine kinases, including VEGFR, which contributes to some of the off-target effects and toxicities of sunitinib. In the context of GIST, it was tested after the breakthrough discovery of imatinib’s activity in GIST. A lot of other TKIs were also tested. Sunitinib showed activity, and the phase 3 study that compared sunitinib vs placebo after imatinib got the approval in the second-line setting.
For a long time, there have been other TKIs that have been tested and developed for other indications based on the target identification with activity in GIST. Thankfully, for the past couple of years, we have seen more broad-spectrum drugs that were developed with specific intent to the alterations seen in GIST, and we have identified what the primary driver alterations are. [Moreover,] over the years, experts have been working on [identifying] the secondary resistance mechanisms to these agents, and that has led to identification of drugs that might have activity not only against the primary alterations, but also secondary alterations.
Bezuclastinib is different. It is specific, unlike the broad-spectrum targeted inhibitor that sunitinib is. [Bezuclastinib] has more specific inhibition against alterations or mutations in the activation loop, which is exons 17/18 in the KIT gene. When disease progresses in exon 9, it could mean just less activity with imatinib, but with [alterations in] exon 11 and sometimes with exon 9, patients will have secondary alterations. Those secondary alterations are usually in exons 13 and 14, with exon 13 being the most common location since that’s the ATP binding pocket.
Interestingly, depending on the bulk of disease, some patients might have more than 1 alteration and have different clones within the tumor or different tumor metastases that might be driven by different secondary alterations. Bezuclastinib covers the exon 17/18 activation loop. Sunitinib, which we discovered later on, is the only approved drug so far that has activity against the ATP binding pocket alterations.
For a long time, we have known the drugs given after imatinib don’t seem to perform as well. In trials, the [median] progression-free survival [PFS] significantly drops after frontline therapy. But, when you look over the years, and including some other second-line studies, some patients benefit from sunitinib, and there are others who might benefit from more the activation loop [inhibition]. The thought [behind the Peak study] was: Do we need to come in with broader inhibitors, so we can get better activity in the second line and beyond? Or should we combine drugs?
The thought of combining drugs is not new because we have both regorafenib [Stivarga] and ripretinib [Qinlock] approved. We know that sunitinib works well against ATP binding alterations, but regorafenib also has activity against activation loop alterations. [Therefore,] there have been thoughts of combining both TKIs or alternating the sequencing of both those drugs to cover the broad spectrum of secondary mutations. However, due to the overlapping toxicities, that combination was not feasible at the drug dosing that is required for efficacy.
With bezuclastinib plus sunitinib, the beauty is that you can block that broad spectrum of secondary alterations you see post-imatinib without overlapping toxicities. You do not enhance the toxicities associated with sunitinib that we are worried about. For example, [sunitinib] can lead to palmar-plantar erythrodysesthesia, stomatitis, diarrhea, and some lab abnormalities. But, when you combine sunitinib with bezuclastinib, you do not see any enhancement of those adverse effects [AEs]. In fact, some of the AEs are better. Due to the way [the TKIs] combine, it lowers some of those sunitinib toxicities.
[In the Peak study], we had a combination that covers a broad spectrum of secondary alterations, and is tolerable. After we saw data from prior studies, it was the next obvious step to run a randomized study of bezuclastinib plus sunitinib vs sunitinib alone in patients who had progressed after imatinib in the second-line setting when they had measurable disease. The majority of patients had progressed on imatinib, and even the small percentage of the population that is intolerant to imatinib were also allowed on the study.
The study had a 1:1 randomization, with approximately 200 patients on each arm. [The study was also] a little different than the prior study with sunitinib since the sunitinib dosing was 37.5 mg daily.1 This dosing is something that I have used in the past and to me is easier to manage compared with the 50-mg dose that’s usually given for 4 weeks on and 2 weeks off. The 37.5-mg continuous dose is easier, and you don’t get breaks that can allow for tumor growth. In the combination arm, the same dose of sunitinib was combined with bezuclastinib, with that starting dose being 600 mg once daily.
Bezuclastinib Plus Sunitinib in the Phase 3 PEAK Study: Need to Knows
The primary end point was PFS by blinded independent central review, and OS and ORR were the key secondary end points. Circulating tumor DNA [ctDNA] collections also happened all through the study to help us identify what subsets might benefit the most. [The study] also looked at time of progression. We need to learn from these trials as we move along.
In the combination arm, the median PFS was 16.5 months [95% CI, 13.8-19.2], and for sunitinib monotherapy, it was 9.2 months [95% CI, 7.2-11.0]. [These data are] significant in terms of the difference with the combination vs sunitinib, and [the combination] outperforms what we have seen with most drugs post-imatinib. [These data] were encouraging; they translate to a 50% reduction in the risk of progression or death on the combination vs sunitinib alone.
The sunitinib arm [median PFS data] were also good, higher than what the phase 3 study of sunitinib vs placebo reported. There are a lot of explanations for that. We are [now] more well-versed with the AEs associated with sunitinib, and in this particular dosing schema, we were able to manage it better. [Thus,] patients stayed on sunitinib longer. Also, in that initial study, there were no other treatments after imatinib, and patients who were moving on or entering the study were patients with advanced disease and more disease bulk, thus the benefit was more short lasting. Now, as soon as we see progression, we treat it; we don’t just continue [with the current therapy].
[These data] match what we see in our regular practice of many years with sunitinib, but the combination arm outperformed. The other key secondary end point, ORR, was also impressive. [The ORR rates were] 45.6% [95% CI, 38.6%-52.7%] for the combination and 25.8% [95% CI, 20.0%-32.3%] for sunitinib alone. Response rates with imatinib [alone] are also in the 50% to 60% range; now, we’re coming to the second line and seeing a response rate not far from that. [Similar responses with sunitinib] are impressive because with frontline imatinib, we have seen patients who have great responses. If patients have residual disease and surgery, they tend to do better in terms of PFS on imatinib. [There’s] not a randomized study; there are some randomized data, but it’s mostly with retrospective data that we have seen this.
Also, patients who have focal progression can get the focal progression treated and continue the TKI because we’re taking care of the resistant clone. It provides a longer time on the drug. If you switch that to the second-line setting and you have a more dramatic response, patients will have a better chance of keeping the disease suppressed, especially if they have low-volume disease. When you keep that disease suppressed, the chance of having additional secondary alterations is lower; that allows them to stay on the drug longer. Even though survival end points are way more powerful than response, in this setting, the patients who have bulky disease or who might get converted to a resectable disease also [have] a high response rate in the second-line setting. The OS data are not mature between both arms, but regarding efficacy, we have a definite improvement in PFS and ORR [with the combination].
The all-grade treatment-emergent AEs [TEAEs] were balanced between both arms. The toxicities that were higher in the combination arm, included alanine aminotransferase level [ALT] increases. [Therefore,] liver function monitoring is important, especially in the first 2 months of the treatment, because any TKI can increase liver function test levels. There was a slightly increased risk with the combination, but most of those, at least in my experience, and as reported in the study, could be managed easily. [These TEAEs] just needs monitoring so they do not go unnoticed.
Other AEs that were slightly higher were taste alterations and hair color changes. You do see hair whitening with sunitinib, but with a combination, you see it a little more. In terms of some of the toxicities we worry about, like palmar-plantar erythrodysesthesia and stomatitis, those rates were lower in the combination arm compared with sunitinib alone, including rates of thrombocytopenia.
Overall, [the combinations] was well tolerated. The grade 3 or higher toxicities that were reported on the study were balanced between both the arms. The [toxicity rate] that was slightly higher on the combination arm was the ALT/aspartate aminotransferase level increase, with some anemia being higher on the combination arm. [Using the combination] would take a bit of adjustment because it is 2 drugs. We will have to get more comfortable treating with [the combination]. It is 8 pills of bezuclastinib to get the 600-mg dose, in addition to the 1 tablet of sunitinib. Patients have to swallow 9 oral medications at the same time, pretty much every day. Although I was initially worried about that, I have seen that patients have adopted this and haven’t had as much resistance to taking those medications because the tolerance is manageable. [Adherence to the combination] takes good education upfront, good supportive care measures, and, when needed, dose reductions to make sure patients can stay on the highest, most tolerable dose of both the drugs.
In my practice, it’s always important to know what the secondary driver alterations are, either through the ctDNA analysis or otherwise, because knowing the mutation that’s driving most of a patient’s disease also helps with some of the dose alterations. For example, if it’s exon 13, you don’t want to discontinue the sunitinib; you want to adjust the dose down so the patient can stay on it.
If the combination is FDA approved, [the indication will] likely be [in the post-imatinib progression setting]. [The combination] is mostly for KIT-mutated disease, which is most GIST tumors. We don’t necessarily need to know the secondary mutations; we need to know the primary alterations. For these patients, once [the combination is] approved, it would be important to start thinking about changing second-line practice.
In the absence of a clinical trial, this combination will be compelling, not only for us who see the data and who are treating patients with GIST, but also for patients who are gathering this information through various groups. In terms of patients who are already on second-line therapy or maybe even beyond, if they’re doing well on their second-line regimen, I don’t necessarily think [this approval] will lead to an immediate change because in the study, [there was crossover between the arms]. Patients who were receiving sunitinib alone did get to [switch to receive] the sunitinib-plus-bezuclastinib combination, and they also did well on that combination. Even in part 1 of the Peak study, we did treat patients well beyond the second line, and they benefited quite a bit. Experts and patients are all excited [for this approval], because it is another drug available and a combination that is tested, which patients can have access to depending on their stage of disease.
In the second line, [bezuclastinib plus sunitinib] has to be considered, but patients who have missed that second-line boat and are beyond might still be able to get access to the combination because it is a reasonably well-tolerated and efficacious regimen. As the field evolves, this question of the best way to sequence drugs is still going to keep coming up. Maybe it’s not one-size-fits-all for all patients; [this decision] might be a little different based on their [disease] makeup. For now, when a patient is progressing on imatinib, and you don’t know much else, the combination would be the best way to go.
Efforts [in GIST research] should be focused on coming together and pulling data to figure out what happens after using these broad-spectrum drugs. What comes next, and what are the outcomes? It’s great that these patients are doing so well, but if they’re not getting cured of their disease, they will need an option after. [The field should] focus on what’s driving resistance, so we can start looking at the best way to target it after these great options.
[Another focus should be] sequencing. Should [sequencing] be different for a different set of patients, or should we be treating all patients with this combination until we get more data? Invariably, some cells with some alterations or clones will eventually emerge. What do we do to get rid of those persistent cells, other than surgery? Is there a way to target that more upfront, so we can prevent this secondary disease resistance from emerging even further? That’s where the field for KIT-mutated GIST will be focusing on mostly, in addition to novel mechanisms of targeting these tumors. The more you understand the disease, the more excited you get about. What do we take into the frontline setting so we get even better activity there? We have to be cognizant of how well imatinib is tolerated and for how long. [Imatinib] is a tough drug [for investigational agents] to go up against [in clinical trials], but there might be ways to [do that]. For certain patients who have a high risk of progression on imatinib, we might need to think of alternate ideas up front; there’ll be a lot happening in that realm. When we talk about GIST in general, there are also other subsets of GIST that need attention because they have different mechanisms of progression.
