Sapanisertib Not Active in Patients With TSC1/TSC2-Mutated mUC


In an interview with Targeted Oncology™, Joseph Kim, MD, an associate professor of internal medicine at the Yale School of Medicine, discuss the lack of clinical benefit of sapanisertib for the treatment of TSC1/TSC2mutated mUC.

Joseph Kim, MD

Joseph Kim, MD

Sapanisertib, a potent mTOR complex 1 and 2 inhibitor, did not demonstrate clinical activity in a significant portion of patients with TSC1- or TSC2-mutated metastatic urothelial carcinoma (mUC) treated in the phase 2 study. This is despite the fact that everolimus (Zortress), a potent mTOR inhibitor, has shown to be clinically active in patients with mUC, including in patients with a deleterious TSC1 mutation.

Forty-one patients were screened for inclusion In the phase 2 study of sapanisertib, and of those screened, 17 were enrolled.The primary end point was overall response rate (ORR), and the secondary endpoints included incidence of toxicity, progression-free survival, and overall survival.

During the study, all patients were given sapanisertib on days 1-28 of each 28-day cycle in the absence of disease progression or unacceptable toxicity. The study found that of the 13 evaluable patients, no ORR was observed. Four patients were found to have stable disease at the first scan; however, no stable disease was confirmed with subsequent scans. 

In an interview with Targeted Oncology™, Joseph Kim, MD, an associate professor of internal medicine at the Yale School of Medicine, discuss the lack of clinical benefit of sapanisertib for the treatment of TSC1/TSC2mutated mUC.

TARGETED ONCOLOGY™: Regarding TSC1 and TSC2 mutations in urothelial carcinoma, how have these mutations been shown to impact outcomes for patients?

KIM: There is a report from the Memorial Sloan Kettering Cancer Center where they show the activity of everolimus in patients with UC that harbor TSC1 and TSC2 mutations, and this was the basis of our study. TSC1 and TSC2 is one of the key regulators of the mTOR pathway. From the data, it appears that this mutation is seen in about 8% to 10% of mUC cases, and what we wanted to do is to see whether we can accrue patients with a TSC1 OR TSC2 mutations and treat them with next generation mTOR inhibitor using sapanisertib. Unlike everolimus, sapanisertib is a competitive inhibitor of an AKT binding domain of the mTOR complex one and complex 2. Everolimus is an inhibitor of mTOR1. So, we thought that inhibiting both will be better than just TSC1 because, it is also believed that mTOR complex 2 is one of the mechanisms by which mTOR inhibitors actually develop resistance. We wanted to inhibit both pathways and see if it can really induce a good objective response in our patients. 

What we did is that we accrued patient with TSC1/TSC2. One of the challenges we learned from this process is that although the literature will say 8% to 10% of the tumors will harbor this mutation, in reality, it was really hard to find those patients. Around the time of study accrual, there are a lot of changes happening in the treatment landscape in mUC, including approval of immunotherapy with atezolizumab (Tecentriq), nivolumab (Opdivo) and other inhibitors. So, there were some patients who actually withdrew their consent to receive those agents, and by the time they came back to enroll in the trial, they were actually too sick to be enrolled. We had some trouble finding these patients in our screening process. We even offered prescreening. As I showed in the poster, we actually identified about 6 patients through the screening process, and there were some patients who were accrued through next generation sequencing as a set of care. So, if they identify the mutation they could also come into the trial as well.

Were there any unique characteristics you would like to note about this patient population?

Our study populations were heavily pretreated. Many of these patients already received a platinum-based chemotherapy, and some even received checkpoint inhibitors, and/or antibody drug conjugates. About 70% of the patients received all 3 of these agents. The median survival for our patient populations is actually very poor.

What is your key takeaway on the results?

Unfortunately, we did not see any object responses in patients with TSC1 or TSC2 mutations, and I think there are a couple of reasons for this. One is that maybe we should have looked at more biomarkers beyond TSC1and TSC2. Many of these patients had other mutations, maybe we should have looked at the mTOR activation biomarker in the setting of TSC1, TSC2 mutations and other mutations. And maybe we should have used a better agent that is more effective and better tolerated. There are some patients who could not continue on the treatment because of the toxicities.

What options currently exist for these patients with TSC1- and TSC2-mutated mUC?

Currently, there is no treatment available for patients with this mutation. There is a treatment available for patients with FGFR2- or FGFR3-mutated mUC. They could be treated with afatinib (Gilotrif), which has been shown to induce object responses in the 40% range. Clearly, there's an unmet need for precision medicine in metastatic urothelial carcinoma.

What other ongoing challenges do you face with this patient population?

I think that we should identify patients not just based on this mutation alone. Maybe we should look at the mutation and the impact of the mutation on the biology of the tumor. And, really be able to find the right drug for this group of patients. We tend to think that mutation equals initial response to treatment, but I think we should look at beyond the mutation status.

I think we should be smarter about designing a better trial. I think what we learned from this study is that we noted very different types of mutations in TSC1 and TSC2, as I show in the poster, most commonly occurring mutations were like frameshift mutations, termination mutations, mostly in TSC1 in the role binding domain, and that sort of what's out there in patient samples. And I think that once we understand the impact of these mutations, that's one take home point.

During ASCO GU, we a saw a good amount of positive data in mmUC, including nivolumab in the adjuvant setting showing an improvement in disease-free survival. That was very interesting. Also, we saw positive results with enfortumab. We were fortunate enough to participate in the phase 1 study here at Yale, and now we have level-one evidence saying that enfortumab improved survival, compared with patients receiving chemotherapy.

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