Ripretinib inhibits polyclonal drug-resistant KIT oncoproteins: the next step forward in gastrointestinal stromal tumor therapy

Genetic alterations in KIT or PDGFRA kinase that are detected in >85% of gastrointestinal stromal tumors (GISTs), constitute the target for the current GISTs therapy (1). The FDA-approved KIT kinase inhibitors crucially improved the treatment of advanced GISTs (2). Yet, primary or secondary resistance to authorized therapies remains a major clinical challenge. The secondary resistance mutations inevitably emerge during targeted therapy, causing disease progression. These mutations usually occur in the kinase switch pocket (encoded by KIT exons 13 and 14 or PDGRA exons 14 and 15) or in the activation loop domain (encoded by KIT exons 17 and 18 and PDGFRA exon 18) (3,4). Importantly, most resistance mutations in GIST are quite heterogeneous, with majority of patients acquiring multiple subclonal mutations, with diverse tumor metastases carrying multiple distinct resistant mutations. An inhibitor that blocks only a subset of resistance mutations allows for the selection and growth of other resistant subclones.

A dual “switch-control” tyrosine kinase inhibitor, Ripretinib (formerly known as DCC-2618), was developed to restrain both internal kinase domains, to lock the KIT and PDGFRA kinases in the inactive conformation. As such, it was predicted to be effective against the full spectrum of mutant KIT and PDGFRA kinases found in cancers. Accordingly, ripretinib was a potent inhibitor of both wildtype and a wide range of mutant KIT and PDGFRA kinases, including intrinsically imatinib-resistant KIT D816V and PDGFRA D842V mutations, in the preclinical in vitro studies (5).

The efficacy of ripretinib was evaluated in a pivotal, double-blind, randomized, placebo-controlled, INVICTUS (ClinicalTrials.gov identifier: NCT03353753) phase 3 trial, in patients for whom treatment with so far approved kinase inhibitors had failed. A total of 129 eligible patients were randomized to either ripretinib (n=85) or placebo (n=44) (6). The median progression-free survival (PFS) and median overall survival (OS) for patients receiving ripretinib were significantly longer in comparison with patients receiving a placebo. For patients in the ripretinib arm, 9% had a partial response and 47% had stable disease at 12 weeks, compared with patients in the placebo arm, which showed 0 patients with a partial response and 5% with stable disease. In addition to highly promising efficacy, ripretinib had a well-tolerated safety profile. In May 2020, the US FDA approved ripretinib for the treatment of adult patients with advanced GISTs as a fourth-line or higher therapy (7). Thereafter, ripretinib was approved by EMA in the same indication (8). Thus, ripretinib has raised as a new standard of care for advanced, multi-resistant GIST patients. This constitutes an important step forward in the area of drug development in GIST.

The current report by Bauer and co-workers (9) presented the genomic analysis and the detailed characterization of the complex and extensive heterogeneity of KIT/PDGFRA mutations in patients from the INVICTUS phase 3 study. Of note, the authors used double approach to reveal tumor genotype, i.e., traditional one, based on sequencing of tumor tissue, and the novel liquid plasma ctDNA analysis. The material for both approaches were collected prior to study enrolment and analyzed by next-generation sequencing.

Notably, combining results from tissue and liquid biopsy, 115 out of 128 (89.9%) patients had detectable KIT/PDGFRA mutations. Within 80 patients with detectable KIT/PDGFRA mutations in both tissue and liquid biopsies, the high 93.75% concordance rate of primary mutation was observed; notably, liquid biopsy detected most of the mutations found in tissue biopsy and several additional distinctive mutations. Hence, the combination of these two methodologists revealed more complex range of mutations, providing a complete genomic picture of resistance phenotype in tumors of heavily pre-treated GIST patients. Furthermore, efficacy results in the INVICTUS trial were explored by mutation subgroup using combined tissue and liquid biopsy data. Patients were grouped into four subsets based on the presence of any KIT exon 9, exon 11, exon 13, and exon 17 mutations. Not adequate sample size did not allow for evaluation of other rare subgroups, such as KIT exon 14 or 18 mutations, PDGFRA mutations (particularly D842V substitution) or tumors without detectable KIT/PDGFRA mutations (WT). Importantly, patients receiving ripretinib showed PFS benefit over placebo across all tumors’ genotypes [hazard ratio (HR) 0.16, 95% confidence interval (CI): 0.10–0.27] and in all evaluated subsets in Kaplan-Meier PFS analysis.

More information on the activity of ripretinib on earlier stages of GIST and its mechanism of action to different molecular subtypes can give the final results of phase III INTRGUE trial (10), which outcomes published in press release indicate that ripretinib is not superior to sunitinib in a second-line therapy in terms of progression-free survival. Nevertheless, ripretinib had a better safety profile and induced fewer grade 3–4 toxicities, including arterial hypertension.

While ripretinib shows improved progression-free and overall survival in INVICTUS study, which keeps up with its predicted wide range of efficacy, patients continue to show disease progression. Potentially, the efficacy of ripretinib against every secondary KIT mutation is not equal and some mutations are insufficiently inhibited in a permanent manner; and/or novel resistant KIT mutations emerge under selective pressure with time. Alternatively, KIT-independent mechanisms may arise or some unknown yet mechanisms reduce the effect of ripretinib. A blend of all these mentioned above mechanisms might also be in place. Importantly, how the tumor dynamics evolve during ripretinib treatment and whether the changing tumor mutational landscape can predict the emerging resistance during treatment is an open question. These can be addressed on account of the cancer DNA samples gathered during the trial. Metastatic GIST is possibly a golden cancer prototype for the clinical application of ctDNA analysis, although not all GISTs shed DNA into the blood at the analytically optimal level (11). In the scenario of INVICTUS study, the results of ctDNA testing during treatment would be particularly interesting and are awaited by a broad research community. These might assist in drawing the firm conclusions on the ripretinib clinical efficacy and prognostic potential on ctDNA based monitoring of patients across this or possible future clinical trials.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gastrointestinal Stromal Tumor. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-22-5/coif). PR received payment or honoraria from MSD, BMS, Sanofi, Merck, Pierre Fabre, Philogen, and Novartis and he is on the Advisory Board of MSD, BMS, Sanofi, Merck, Pierre Fabre, Novartis, Blueprint Medicines and Philogen. MDR has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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