Each year, 4,000-6,000 people in the US are diagnosed with gastrointestinal stromal tumor (GIST), one of the most prevalent soft tissue sarcomas. GIST cases often occur with mutations in c-Kit or PDGFRA, two tyrosine kinases frequently mutated in other types of cancer as well. As such, the standard of care for GIST cases is surgical resection of the tumor and treatment with the tyrosine kinase inhibitor (TKI), imatinib. However, this intervention is often not curative for patients with metastatic disease, and imatinib resistance is common. Other TKIs have been approved for second- and third-line therapies, however the side effects of TKIs can severely decrease quality of life. Other lines of therapies for GIST patients are needed.
Bolstering the immune system of cancer patients with immune checkpoint inhibitors has been successful in treating many cancers with poor prognosis. Programmed death ligand-1 (PD-L1), an immune suppressive molecule, is often expressed by tumor cells and interacts with PD-1 on immune cells, limiting their function against cancer. Blocking this interaction can allow immune cells to evade this suppressive signal and kill cancer cells. With a patient suffering from metastatic GIST whose cancer had progressed despite multiple rounds of TKI treatment, Dr. Seth Pollack (Clinical Research Division) decided to give immunotherapy a shot. The results of one patient’s battle with GIST was described in a brief report in OncoImmunology.
The patient presented with GIST without mutations in the often-mutated tyrosine kinase genes. Nonetheless, she was treated with various TKIs for 8 years despite side effects including fatigue, rash, and diarrhea. Eventually, the patient developed hand-foot syndrome, a debilitating side effect of TKIs where patients experience swelling, pain, and sometimes blisters all over their hands and feet. Despite these interventions, the patient’s cancer progressed, and she did not want to continue TKI use. Compassionate use of nivolumab, a PD-1 inhibitor, was pursued, as it has been successful in treating other difficult cancer types with limited toxicity. Nivolumab was administered every two weeks. During the first month, the patient experienced transient joint pain and edema, but much higher quality of life than during TKI treatment. Amazingly, over the course of 64 cycles (approximately 2 years, 8 months) of nivolumab treatment, the patient showed an overall decrease in liver metastases and no new metastases. Sadly, after 71 cycles of treatment, the cancer once again started to progress.
While this study is only one patient, it shows that use of immune checkpoint inhibitors, like nivolumab, could be beneficial in some GIST patients. Other clinical trials have shown stable disease in approximately 33% of metastatic GIST patients treated with immune checkpoint inhibitors. Additionally, analysis of GIST tissues showed that 69% were positive for PD-L1, while 90% were positive for IDO, an immune checkpoint enzyme that is overexpressed in some cancers. Since TKIs have some activity against IDO, it remains to be determined clinically whether TKIs and PD-1/PD-L1 blockade combination therapies are beneficial for this patient population desperately in need of new treatment options.
This work was supported by Bristol-Myers Squibb Co in providing Nivolumab.
Fred Hutch/UW Cancer Consortium members Ryan O’Malley, Robert Pierce, and Seth Pollack contributed to this work.
This work was supported by Bristol-Myers Squibb Co in providing Nivolumab.
Fred Hutch/UW Cancer Consortium members Ryan O’Malley, Robert Pierce, and Seth Pollack contributed to this work.
Schroeder B, Kohli K, O’Malley R, Kim T, Jones R, Pierce R, Pollack S. 2020. Durable tumor regression in highly refractory metastatic KIT/PDGFRA wild-type GIST following treatment with nivolumab. OncoImmunology.