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Trent Shares Treatment Considerations in 2 GIST Patient Cases

Shannon Connelly
Published Online:2:03 PM, Fri August 4, 2017

Jonathan C. Trent, MD, PhD
Jonathan C. Trent, MD, PhD, recently discussed the treatment considerations he makes when treating patients with gastrointestinal stromal tumors (GIST). Trent, professor of medicine, and co-director of the Musculoskeletal Center, Sarcoma Medical Research Program at Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed his treatment decisions based on 2 case scenarios during a Targeted Oncology live case-based peer perspectives dinner.

Case 1 
 
August 2014

A 59-year-old Caucasian female presented to her physician with acute onset abdominal pain. Her past medical history was remarkable for hyperlipidemia managed on a statin. Her ECOG performance status was 1. Abdominal CT findings showed an 11-cm mass in the jejunum and a 3-cm lesion in the liver. Biopsy confirmed primary GIST in the jejunum. Immunohistochemistry was positive for c-KIT (CD117); molecular analysis showed an exon 11 mutation. Mitotic activity was high with >5 mitoses/50 high-power fields. Based on tumor size and presence of liver metastases, systemic therapy with imatinib (Gleevec) was recommended over surgery.

TARGETED ONCOLOGY:  What role does mutational analysis play in therapy selection?

Trent: Mutation analysis plays a critical role in therapy selection for any patient with GIST who is going to be treated with a targeted receptor tyrosine kinase inhibitor (TKI), such as imatinib, sunitinib (Sutent), or regorafenib (Stivarga). The reason is that the specific mutation that the patient has determines the therapy.

If a patient, for instance, has a KIT exon 11 mutation, the initial therapy would be with imatinib 400 mg per day. But if that patient were to have an exon 9 mutation, one could consider treating the patient with imatinib at a higher dose, such as 800 mg per day. Alternatively, a patient may have a GIST that has an unusual or rare mutation, such as RAS. A RAS mutation would be resistant to imatinib and would be treated with a RAS inhibitor. Additionally, there are GIST patients whose tumor may have a PI3K mutation, and one could consider an MTOR inhibitor.

There are some GIST patients who don't have KIT mutations or PDGFR mutations at all. These patients include the so-called succinate dehydrogenase (SDH)–deficient GIST, where loss of a metabolic enzyme called succinate dehydrogenase drives the GIST tumor phenotype. These SDH-deficient GIST patients have tumors that are relatively resistant to the standard receptor TKIs, like imatinib.

Additionally, a patient with a GIST may have a mutation in a PDGFR gene called D842V. This gene is also relatively resistant to imatinib, and a patient would generally be referred for a clinical trial, of which there are several ongoing in the United States, including of crenolanib or BLU-285. These are targeted directly towards the D842V PDGFR-resistant mutation. Additionally, a patient may have a condition called neurofibromatosis that can contribute to GIST. These tumors are also relatively resistant to imatinib. Understanding the molecular profile of an individual patient's GIST helps us determine the optimal therapy for that patient.

Treatment was initiated with imatinib 400 mg daily. No further progression was noted on follow-up imaging.

TARGETED ONCOLOGY:  Are there any additional tests you would recommend for this patient?

Trent: After mutation testing, we generally obtain a baseline CT of the abdomen and pelvis, a chest X-ray, and routine laboratory testing. Once the patient is, in this case, being treated with imatinib at 400 mg per day, this patient would have another CT scan, chest X-ray, and laboratory testing every 2 months initially. 

October 2016

Two years later, during routine follow-up, the patient complained of recurring abdominal pain. An abdominal CT scan showed a slight increase in the primary tumor size and the appearance of another small lesion in the liver. Her ECOG performance status was still 1.

TARGETED ONCOLOGY:  How do you define progression in a patient with GIST?

Trent: Progression in a patient with GIST is viewed differently than many other situations of progression in oncology. The reason we view progression differently is that there can be different types of progression. A GIST patient treated with a TKI, such as imatinib, sunitinib, or regorafenib can have a spectacular response to therapy, in which tumors become necrotic or hypoattenuating on CT scan and don't enhance with contrast. At the time of progression, a patient may have a limited type of progression where there's only 1 nodule enlarging in size. All the other nodules in the liver could still be responding to the TKI, whereas the solitary lesion is progressing. We call this limited progression. It's important because limited progression can be treated with a localized therapy, such as hepatic arterial embolization, or radiofrequency ablation, or NanoKnife. This allows the patient to continue on the therapy for which the majority of the lesions are still responding. The solitary lesion that's enlarging has been ablated with one of these procedures.

Another type of progression could be nodular progression, where there's a small nodule at the rim of a previously treated lesion. This is something that we may monitor for a little while initially, but if it's growing within the treated nodule, we would also consider treating with a localized therapy.

There is a third type of progression we consider, called widespread progression, where the majority, if not all, of the tumor nodules and tumor lesions throughout the patient's body could be growing at the same time. This situation of widespread progression is not practical for treating with localized therapy, and so we would consider switching to a different therapy in that setting. 

TARGETED ONCOLOGY:  Could this patient have developed secondary resistance to imatinib treatment?

Trent: Secondary resistance is quite common in patients with metastatic GIST treated with kinase inhibitors. Secondary resistance to imatinib often involves a site in exon 13 or exon 17 that mutates in such a way that the imatinib does not bind to, nor inhibit, the KIT receptor effectively. These mutations are commonly in exon 13 and exon 17 of the KIT gene. 

TARGETED ONCOLOGY:  Would mutation testing impact therapy?

Trent: Mutation testing, at this point, could be useful, but may not be. The issue is that in the setting of widespread progression, secondary mutations could be different in different lesions. And some lesions may not even have secondary mutations. They could have a different mechanism of resistance.

However, in limited progression, if there's 1 or 2 nodules enlarging that are resistant to imatinib, a biopsy could be informative in understanding the type of secondary mutation. The most common types are exon 13 and 17. It appears that sunitinib is most effective in exon 13 secondary mutations, while regorafenib seems to have more activity in exon 17 and 18 secondary mutations. This has not been validated in prospective clinical trials, and there is very limited data from a small number of patients. If a solitary lesion was growing and there was an exon 17 mutation, one could consider treating that patient with regorafenib, rather than sunitinib, since we know sunitinib has a low binding affinity for secondary mutations in KIT exon 17. 
The patient was switched to sunitinib 37.5 mg daily and showed stable disease on follow-up imaging.
                  
March 2017

At her 6-month follow-up, an abdominal CT revealed new metastases in the liver. Her ECOG performance status had changed to 2. She was subsequently referred to an academic center for treatment and was switched to regorafenib 160 mg on days 1-21 every 28 days.

Approximately 3 weeks after initiating treatment with regorafenib, she complained of increased fatigue and presented with hand-foot skin reaction, which presented as tingling, burning sensations on the palms and decreased tolerance for touching hot objects.

TARGETED ONCOLOGY: What efficacy data do we have for regorafenib in terms of its benefits on overall survival, disease control, and progression-free survival (PFS) in patients with GIST?

Trent: Regorafenib is an orally bioavailable TKI that inhibits a number of receptors, including KIT, PDGF receptor, FGF receptor, VEGF receptor, and RAS, and it's been studied in the GRID study in progressive disease. In the GRID study, the majority of patients had progression to imatinib and sunitinib, and 199 patients were randomized 2:1 to either regorafenib in 133 patients, or placebo plus best supportive care in 66 patients. The patients were followed until disease progression. This was a multi-center randomized international phase III study that provided a clear PFS benefit over placebo for those patients with metastatic GIST who were resistant to imatinib and sunitinib. 

TARGETED ONCOLOGY:  What are the expected toxicities with regorafenib and how can they be proactively managed?

Trent: Regorafenib does provide a PFS benefit over placebo in patients with metastatic GIST; however, it is associated with several side effects that are manageable. One of the common side effects is hypertension, which is easily managed with anti-hypertensive medications. Another can be hand-foot syndrome, where patients get sickening of the keratin on the palms and soles. This can be managed with urea-containing lotions, and occasionally podiatry for patients’ feet. Patients may get diarrhea, which can be managed with a standard over-the-counter or prescription anti-diarrheal agent. 

Case 2 

A 44-year-old male presented with severe abdominal discomfort. He had a past medical history of mild back pain and joint pain managed with nonsteroidal anti-inflammatory drugs (NSAIDs). Abdominal CT findings showed a large mass with a diameter of 14 cm involving the cardia, fundus, and body of the stomach; splenic involvement was also noted. A biopsy and histological examination confirmed that the mass was a GIST. IHC tests indicated that the tumor was positive for c-KIT. Genetic analyses showed a mutation in exon 11 of c-KIT. His diagnosis was GIST of the stomach with liver and spleen metastases.

TARGETED ONCOLOGY:  What is the role of a multidisciplinary team for the management of this patient?

Trent: Multidisciplinary teams are critical in management with any sarcoma patient, and particularly patients with GIST, because of the multimodality management. Even a patient with metastatic GIST who responds to therapy could benefit from surgical resection of the primary tumor and, potentially, resection or eradication of the metastatic lesions. In this case, a patient had a 14-cm GIST tumor of the stomach and also a small lesion of the liver. A KIT exon 11 mutation was detected, and with a primary tumor and a solitary liver lesion, one could raise the question as to the role of surgical resection of the primary tumor and the metastatic lesion.

Published data from several series suggest that patients with metastatic GIST who are benefitting from a kinase inhibitor, such as imatinib or regorafenib, are the subset of patients who are most likely to benefit from surgical resection of metastatic disease. For this patient, treatment options include surgical resection of the primary tumor and the liver metastases. Another option would be to initiate therapy with imatinib 400 mg per day.

This decision is best made by a multidisciplinary GIST team in discussion at a conference where there can be clear communication. In this case, it's critical because we know that patients who are not responding to a kinase inhibitor are less likely to benefit from surgical resection. Whereas, patients who are responding to therapy are more likely to benefit from a surgical resection. In our practice at Sylvester, we would discuss this patient at clinic and make the decision to initiate therapy with imatinib. If the patient responds to therapy, we would discuss the patient's situation again at our multidisciplinary conference and potentially discuss resecting all radiographically visible disease. 

Treatment was initiated with neoadjuvant imatinib to achieve reduction of operative risk for the primary tumor and for functional preservation. Tumor size was reduced to 8 cm at 3 months and to 5 cm at 6 months. No further reduction was noted at 9 months. At 10 months, the patient underwent total gastrectomy, splenectomy, and partial hepatectomy.

TARGETED ONCOLOGY:  What factors should be considered when deciding on duration of neoadjuvant treatment?

Trent: When we see a patient with GIST who is being treated with neoadjuvant imatinib therapy, or sunitinib or regorafenib, several important factors have to be considered. One is the patient's performance status, another is the anatomic location of the primary tumor and/or metastatic tumors, and the best approach to eradicate or resect all radiographically visible disease.
In this case, it was decided to treat the patient with neoadjuvant imatinib or prior resection or eradication. The duration of treatment is really driven by how well the patient is responding to therapy. In our practice, we treat with neoadjuvant imatinib in order to shrink the GIST as much as possible, as well as kill as many tumor cells as possible in case there is tumor rupture or some other event at the time of resection. Additionally, neoadjuvant treatment initiates treatment of potential micrometastatic disease that might not be radiographically visible yet. In our practice, this duration ends up being anywhere from 9 to 12 months of neoadjuvant imatinib therapy prior to surgical resection or other localized therapy. 

TARGETED ONCOLOGY:  What is the risk of recurrence for this patient?

Trent: The risk of recurrence is very high because the patient already has a metastatic lesion and there's a high probability that there are other metastatic lesions, so after neoadjuvant imatinib, after resection, or other localized therapy, the patient would continue imatinib post-operatively and would resume a monitoring schedule of contrast CT scan of the abdomen and pelvis with and without contract, just X-ray and routine laboratory testing every 2 to 3 months. Adjuvant therapy would be given to this patient postoperatively and the patient with metastatic GIST would be treated indefinitely with kinase inhibitors. 

TARGETED ONCOLOGY:  In an event this patient develops severe toxicity following adjuvant therapy, what options are available?

Trent: If the patient develops severe toxicity while on postoperative therapy, options include aggressively managing the toxicity or transitioning to another kinase inhibitor, such as sunitinib or regorafenib.

 
 
Reference:
Demetri GD, Reichardt P, Kang Y-K, et al; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1.


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