Clinical trial data show that adjuvant imatinib improves recurrence-free survival as well as overall survival, when administered for at least 3 years, among patients who undergo a macroscopically complete resection of a primary gastrointestinal stromal tumor (GIST), Chandrajit P. Raut, MD, MSc, told participants at the Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care, which was again held virtually this year.1 Yet even knowing there is a survival benefit, “patients [often] come off the drug early,” Dr. Raut noted. “Tolerance of even minor side effects tends to be challenging, and treatment discontinuation rates are high.”
The entire multidisciplinary team needs to work together, Dr. Raut emphasized, “to help patients navigate through minor side effects and keep them on the drug for as long as possible, because there is a survival benefit.” Dr. Raut is Chief of the Division of Surgical Oncology at Brigham and Women’s Hospital, Boston.
Tolerance of even minor side effects [of imatinib] tends to be challenging, and discontinuation rates are high.— Chandrajit P. Raut, MD, MSc
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Surgery Remains Principal Treatment
“GIST is the most common mesenchymal tumor of the gastrointestinal (GI) tract, but it accounts for less than 1% of all GI malignancies—3,000 to 4,000 cases per year in the United States,” Dr. Raut stated.
“Most [GIST-related] mutations are found in the KIT proto-oncogene, which encodes the KIT receptor tyrosine kinase. Approximately 70% involve KIT exon 11, and another 10% involve KIT exon 9. The second most commonly mutated gene is PDGFRA, encoding another receptor tyrosine kinase,” he explained. Imatinib, an oral drug, is a tyrosine kinase inhibitor targeting these receptor tyrosine kinases.
“Surgery is the principal treatment and the only potentially curative therapy for localized, resectable primary disease,” Dr. Raut reported. “Yet outcomes can be quite poor in the absence of adjuvant therapy” in a subset of patients at high-risk for recurrence.
“It is important to highlight that curative surgical resection is the cornerstone of management, yet for those patients [in whom surgery fails], we are fortunate that the molecular drivers are known in GIST, and this impacts the response to imatinib, the targeted agent, as well as its dosing,” commented Rebecca A. Gladdy, MD, PhD, invited discussant for the session on evidence-based sarcoma care. Dr. Gladdy is a surgeon/scientist at Mount Sinai Hospital and Princess Margaret Cancer Centre in Toronto.
Before imatinib therapy is initiated, mutation testing should be done for all patients ideally to ascertain whether they might benefit from the therapy, Dr. Raut said. “Most of us can get mutation testing done and covered by insurance, so it is not a burden on the patient,” or use in-house or other means to get sequencing done, he noted, while acknowledging that mutation testing might not be available in all institutions and areas.
Rebecca A. Gladdy, MD, PhD
“Imatinib remains the only drug that has been tested in phase III trials as an adjuvant therapy for GIST,” Dr. Raut said. These trials demonstrated “a consistent improvement in recurrence-free survival with the use of adjuvant therapy, and one study found a benefit in terms of overall survival as well.”
In 2009, Dematteo et al reported 1-year recurrence free survival of 98% among patients randomly assigned to imatinib following complete resection of a primary GIST, compared with 83% of those assigned to placebo following surgery.2 “This difference was statistically significant, although no overall survival difference was seen [which was not surprising given the crossover design]. The study led to the approval of imatinib in the adjuvant setting by both the U.S. Food and Drug Administration and the European Medicines Agency,” Dr. Raut stated.
“The second critical phase III trial,” he continued, was a Scandinavian and German collaboration reported by Joensuu et al in 2012.3 Following GIST resection, “patients defined as high risk were randomly assigned to receive adjuvant imatinib daily for 1 or 3 years. The primary endpoint was recurrence-free survival, and there was a benefit in favor of the 3-year arm in terms of recurrence,” Dr. Raut said.
“Importantly, this is the only study that has also demonstrated a benefit in terms of overall survival favoring 3 years of adjuvant therapy,” Dr. Raut noted. There was also a “trend toward disease-specific survival favoring the longer-duration therapy, but it did not reach statistical significance. Nonetheless, this led to the approval of imatinib in the adjuvant setting for at least 3 years for high-risk patients,” he stated.
“This past year, the authors reported their 10-year follow-up, and again, there was a sustained benefit with longer-duration therapy in terms of both recurrence-free and overall survival.4 The majority of patients who died in both arms, more than 80%, had confirmed metastatic disease at the time of death,” Dr. Raut said. “The benefit of longer-duration adjuvant therapy seems largely confined to patients with KIT exon 11 deletion or insertion-deletion mutations. Those with KIT exon 9 mutations and those with PDGFRA mutations do not seem to derive the same benefit.”
A 2015 study reported by Casali et al randomly assigned patients at intermediate or high risk to daily imatinib for 2 years or observation.5 “As expected, there was a benefit in terms of relapse-free survival but no benefit in terms of overall survival with just 2 years of adjuvant therapy,” Dr. Raut said.
“The primary endpoint was changed during the course of this study to imatinib failure–free survival, and in the overall cohort, no benefit was seen in this endpoint either. This is an interesting endpoint because it determines whether the time to second-line therapy—after recurrence and development of drug resistance—is improved with the use of imatinib in the adjuvant setting, compared with waiting until the time of first recurrence,” Dr. Raut remarked. “In the subset of patients with high-risk disease, there was a trend favoring the use of adjuvant imatinib. The authors published their 10-year follow-up in January 2021 and again found a trend favoring the use of adjuvant imatinib in imatinib failure–free survival, but again, this did not reach statistical significance.”
High Treatment Discontinuation Rates
A 5-year single-arm phase II study, PERSIST-5, reported by Raut et al in 2018, included patients who underwent complete resection of primary GIST and were at intermediate or high risk of recurrence.6 Patients received daily imatinib for 5 years or until treatment discontinuation due to intolerance or disease progression.
The use of adjuvant imatinib improved recurrence-free survival at any duration, [but] improved overall survival was only seen with 3 years of therapy.— Chandrajit P. Raut, MD, MSc
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“The 5-year recurrence-free survival was 90%, and the 5-year overall survival was 95%,” Dr. Raul noted. “Only seven patients had a recurrence at the time we reported these data, and only one patient had a recurrence while on the drug. That patient had a PDGFRA P842V mutation, which we now know is insensitive [to imatinib]. The other six patients had a recurrence when they stopped the drug, and only one of them had actually finished 5 years of therapy,” Dr. Raut reported. Overall, 49% of patients did not complete therapy. “The time from treatment discontinuation to relapse ranged from 7 to 24 months,” Dr. Raut noted.
“With the 5-year study, nearly half the patients stopped the drug early, and in the phase III studies, nearly one-quarter of patients stopped the drug early,” Dr. Raut pointed out. “This suggests that, even with a drug that is well tolerated and has relatively mild side effects (most of the patients had grade 1 or 2 adverse events), it is still hard to convince patients to stay on this drug for a longer duration.” The results of the 3-year study showing improved overall survival with imatinib were already known at the time of the 5-year study, “and yet it was still hard to get patients to continue on the trial,” Dr. Raut remarked.
The National Institutes of Health’s MedlinePlus lists the top five most frequent side effects of imatinib as “diarrhea, nausea, vomiting, change in the way things taste, and mouth sores or swelling inside the mouth.” The top five serious side effects (“If you experience any of these symptoms, call your doctor immediately”) are “swelling around the eyes; swelling of the hands, feet, ankles, or lower legs; sudden weight gain; shortness of breath; and fast, irregular, or pounding heartbeat.”
Although the studies have shown that “the use of adjuvant imatinib improved recurrence-free survival at any duration, improved overall survival was only seen with, at minimum, 3 years of therapy,” Dr. Raut recapped. “We do not know if longer-duration therapy will lead to even better results. Disease-specific survival rates were not consistently reported, though likely are favored with adjuvant imatinib. The imatinib failure–free survival showed a favorable trend with 2 years of adjuvant imatinib, but only in the high-risk subset.”
In terms of risk stratification, “patients at high risk had improved outcomes with adjuvant therapies, but those with intermediate risk had results that were somewhat uncertain, and they were variably included. In terms of molecular subsets, benefits seem to be seen in patients who had KIT exon 11 deletion or insertion-deletion mutations.”
Dr. Raut listed several take-home points:
DISCLOSURE: Dr. Raut and Dr. Gladdy reported no conflicts of interest.
1. Raut CP: Adjuvant therapy in GIST: Yes/no and how long? Society of Surgical Oncology (SSO) 2021 International Conference on Surgical Care. Presented March 19, 2021.
2. Dematteo RP, Ballman KV, Antonescu CR, et al: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial. Lancet 373:1097-1104, 2009.
3. Joensuu H, Eriksson M, Hall KS, et al: One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: A randomized trial. JAMA 307:1265-1272, 2012.
4. Joensuu H, Eriksson M, Hall KS, et al: Survival outcomes associated with 3 years vs 1 year of adjuvant imatinib for patients with high-risk gastrointestinal stromal tumors: An analysis of a randomized clinical trial after 10-year follow-up. JAMA Oncol 6:1241-1246, 2020.
5. Casali PG, Le Cesne A, Velasco, AP, et al: Time to definitive failure to the first tyrosine kinase inhibitor in localized GI stromal tumors treated with imatinib as an adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup randomized trial in collaboration with the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol 33:4276-4283, 2015.
6. Raut CP, Espat NJ, Maki RG, et al: Efficacy and tolerability of 5-year adjuvant imatinib treatment for patients with resected intermediate- or high-risk primary gastrointestinal stromal tumor: The PERSIST-5 clinical trial. JAMA Oncol 4:e184060, 2018.