TABLE 2.
Selected Investigational Therapeutic Strategies for Advanced GISTs
| Therapeutic Agent | Indication | Efficacy | Safety |
|---|---|---|---|
| Targeted therapies | |||
| Cabozantinib 61 | KI used in thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma; tested in third‐line GIST | PFS at 12 wk, 60%; mPFS, 6.0 mo; 80% of patients achieved a PR or SD | The most common treatment‐related AEs ≥ grade 3 were diarrhea, PPES, fatigue, and hypertension. |
| Sorafenib 62 | KI used in kidney, liver, and thyroid cancer; tested in ≥third‐line GIST | PR or SD achieved in 40% of patients; mPFS, 7.2 mo | Treatment‐related AEs were reported in 72% of patients; none of the patients discontinued. |
| Nilotinib 63 , 64 | KI used to treat Philadelphia chromosome CML; tested in ≥first‐line GIST | First line: PFS at 24 mo with nilotinib, 51.6%; with imatinib, 59.2% | First line: The study's rates of discontinuation due to AEs were 8.0% with nilotinib and 5.3% with imatinib; frequently reported AEs in the nilotinib arm were rash, nausea, and abdominal pain. |
| Second/third line: 4 of 12 patients achieved SD | Second/third line: The most common AEs were fatigue, anemia, and anorexia; 1 patient experienced grade 4 anemia. | ||
| Dasatinib 65 | KI used to treat CML and ALL; tested in second‐line GIST | mPFS, 2.9 mo; PR reported in 25% of patients | Serious AEs occurred in 24% of patients and included pleural effusion, nausea/vomiting, and muscle weakness. |
| Pazopanib 66 | KI used in advanced renal cell cancer and metastatic soft tissue sarcoma; tested in third‐line GIST | mPFS with pazopanib, 3.4 mo; mPFS with supportive care only, 2.3 mo | Grade 3 or higher AEs were reported in 72% of pazopanib‐treated patients; the most common was hypertension. |
| Ponatinib 67 | KI used to treat CML and ALL; tested in ≥third‐line GIST | CBR at ≥16 wk for patients with a primary KIT exon 11 mutation, 55%; without a primary KIT exon 11 mutation, 22% | Seventeen of 35 patients discontinued treatment; the most common AEs were rash, fatigue, myalgia, and dry skin. |
| Immunotherapy | |||
| Pembrolizumab 68 | Anti–PD‐1 antibody used to treat multiple forms of cancer | 6‐mo nonprogression rate, 11.1% | AEs were mild and included fatigue, diarrhea, and anemia. |
| Nivolumab + ipilimumab 69 | Anti–PD‐1 antibody used to treat multiple forms of cancer; tested in ≥second‐line GIST | mPFS with nivolumab only, 8 wk; with nivolumab + ipilimumab, 8.43 wk | Grade 3 fatigue (1 patient in the nivolumab‐only arm) and diarrhea (1 patient in the nivolumab + ipilimumab arm). |
| Combination therapy | |||
| Imatinib + peginterferon α‐2b 70 | Interferon given to promote antitumor activity; used to treat hepatitis C and melanoma; tested in ≥third‐line GIST | All 7 patients had a CR or PR; OS at 3.6‐y follow‐up, 100% | All patients experienced temporary low‐grade fever and flu‐like symptoms; grade 3 neutropenia (3 patients) and skin rash (2 patients). |
| Imatinib + buparlisib 71 | Phosphoinositide 3‐kinase inhibitor used experimentally to treat breast cancer; tested in third‐line GIST | No PR or CR; mPFS, 3.5 mo | Treatment‐related AEs were reported in 98.3% of patients; 45% of these patients had grade 3‐4 AEs; the most common were nausea and fatigue. |
| Imatinib + binimetinib 72 | MAPK inhibitor used to treat metastatic melanoma; tested in first‐line GIST | Of 38 patients, 26 had a PR; best objective response rate, 68.4% | Grade 3‐4 toxicities included CPK elevations, neutrophil decreases, rash, and anemia. |
| Cycling therapies | |||
| Imatinib/regorafenib (ALT‐GIST) 73 | Imatinib for 21‐25 d, 3‐ to 7‐d washout, regorafenib for 21 d, 7‐d washout; tested in first‐line GIST | Responses to imatinib only and the alternating therapy were similar; 1 patient on alternating therapy had a CR, 23 had a PR, and 15 had SD; PFS at 1 y, 86% | Seven patients on alternating therapy discontinued because of toxicity; 38% of patients on alternating therapy had serious AEs. |
| Sunitinib/regorafenib 74 | Sunitinib for 3 d, regorafenib for 4 d, no washout; tested in fourth‐line GIST | SD was achieved in 4 patients; mPFS, 1.9 mo; mOS, 10.8 mo | All patients experienced treatment‐related AEs, but the majority were mild (grades 1 and 2); 4 patients experienced grade 3 AEs of hypertension or PPES. |
| Imatinib rechallenge (RIGHT) 75 | Imatinib rechallenge for patients who progressed on imatinib and sunitinib; tested in third‐line GIST | mPFS with imatinib, 1.8 mo; with placebo, 0.9 mo | Grade 3 or higher toxicities included anemia, fatigue, and hyperbilirubinemia. |
Abbreviations: AE, adverse event; ALL, acute lymphocytic leukemia; ALT‐GIST, alternating‐regimen gastrointestinal stromal tumor; CBR, clinical benefit rate; CML, chronic myeloid leukemia; CPK, creatinine phosphokinase; CR, complete response; GIST, gastrointestinal stromal tumor; KI, kinase inhibitor; MAPK, mitogen‐activated protein kinase; mOS, median overall survival; mPFS, median progression‐free survival; OS, overall survival; PD‐1, programmed cell death protein 1; PFS, progression‐free survival; PPES, palmar‐plantar erythrodysesthesia syndrome; PR, partial response; SD, stable disease.