Circulating tumor DNA (ctDNA) analysis of KIT exon mutations may help to predict which second-line therapy is best for patients with advanced gastrointestinal stromal tumor (GIST), according to data presented during the ASCO Plenary Series: January 2023 Session.¹ Exploratory analysis of the phase III INTRIGUE study found that patients with resistance mutations in the KIT activation loop derived meaningful clinical benefit from ripretinib—but not sunitinib—whereas those with KIT ATP-binding pocket mutations had better responses to sunitinib vs ripretinib.

“This is the largest, global phase III trial in second-line imatinib-resistant GIST to demonstrate the significance of ctDNA next-generation sequencing–based analysis of the complex landscape of KIT mutations and to correlate mutational status with treatment response,” said presenting author Sebastian Bauer, MD, of the Department of Medical Oncology and Sarcoma Center/West German Cancer Center, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium, Partner Site University Hospital Essen, Germany. “Further research is needed to validate these findings, but if confirmed, it could lead to better quality of life and improved prognosis for patients suffering from this condition.”

This is the largest, global phase III trial in second-line imatinib-resistant GIST to demonstrate the significance of ctDNA next-generation sequencing–based analysis of the complex landscape of KIT mutations and to correlate mutational status with treatment response.

— Sebastian Bauer, MD

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As Dr. Bauer explained, GIST is the most common sarcoma of the gastrointestinal tract, and most GIST cases have activating mutations in KIT (approximately 80%) or PDGFRA (5%–10%). Although imatinib, a KIT/PDGFRA tyrosine kinase inhibitor, has been shown to induce objective responses or stable disease in most cases of advanced GIST, most imatinib-treated patients will experience tumor progression because of development of secondary resistance mutations in KIT or PDGFRA.^2,3

According to Dr. Bauer, the primary mechanism of imatinib resistance is the emergence of heterogenous KIT secondary mutations in the kinase domain, which occur in approximately 90% of patients. These KIT secondary mutations occur in exons 13/14 (ATP-binding pocket) or exons 17/18 (activation loop).

INTRIGUE Trial Design

The INTRIGUE trial was an open-label, phase III study that enrolled adults with advanced GIST who had previously experienced disease progression on or developed intolerance of imatinib. Participants were randomly assigned to receive either ripretinib (150 mg, once daily) or sunitinib (50 mg daily for a 4-week period followed by a 2-week break). Baseline peripheral whole-blood samples were analyzed using Guardant360, a 74-gene ctDNA next-generation sequencing–based assay. Only KIT mutations were reported.

Ripretinib and Sunitinib Yield Different Responses

Of 453 participants in the overall intent-to-treat population, 362 samples were analyzed. ctDNA was detected in 280 of 362 samples (77%), and 213 of 280 samples displayed KIT mutations (76%). 

Common resistance mutations were found in the KIT activation loop (42%) and ATP binding pocket (38%). In both populations, said Dr. Bauer, results showed efficacy consistent with primary analysis based on tumor data used for randomization. Additionally, subgroup safety profiles remained consistent across all parameters tested throughout the study duration.

In contrast, however, for patients who had a primary exon 11 mutation and a secondary exon 17/18 mutation, the median progression-free survival was 14 months with ripretinib vs 1.5 months with sunitinib. The median overall survival with ripretinib was not reached for this group of patients and was 17.5 months for patients on the sunitinib arm.

“Efficacy data in this cohort of patients with activation loop mutations showed no responses in patients who had received sunitinib,” said Dr. Bauer. “In contrast, 44% of patients in the ripretinib arm achieved a partial response, with a median duration of response of 16.7 months.”

According to Dr. Bauer, these findings demonstrate how valuable next-generation sequencing can be when predicting which treatment option will yield optimal results for patients with GIST. They also suggest that analyzing a patient’s unique tumor DNA may be essential to understanding which drug will be most effective.

Based on this subgroup analysis of the INTRIGUE trial, the phase III, randomized, multicenter, open-label ­INSIGHT trial will evaluate ripretinib vs sunitinib in patients with advanced GIST previously treated with imatinib harboring KIT exon 11 and 17/18 mutations. Unlike the INTRIGUE study, however, the INSIGHT trial will allow patients who have been randomly assigned to the sunitinib arm to cross over to ripretinib. 

DISCLOSURE: Dr. Bauer reported financial relationships with ADC Therapeutics, Adcendo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Daiichi Sankyo, Deciphera, Exelixis, GlaxoSmithKline, Janssen-Cilag, Lilly, Mundipharma, Nanobiotix, Novartis, Pfizer, and PharmaMar.

REFERENCES

1. Bauer S: Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE. ASCO Plenary Series: January 2023 Session. Abstract 397784. Presented on January 24, 2023.

2. Blanke CD, Rankin C, Demetri GD, et al: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626-632, 2008.

3. Grunewald S, Klug LR, Mühlenberg T, et al: Resistance to avapritinib in PDGFRA-driven GIST is caused by secondary mutations in the PDGFRA kinase domain. Cancer Discov 11:108-125, 2021.