A new approach to refractory gastrointestinal stromal tumours with diverse acquired mutations
Mené sur 129 patients atteints d’une tumeur stromale gastro-intestinale de stade avancé, cet essai de phase III évalue l’efficacité, du point de vue de la survie sans progression, et la toxicité du riprétinib (un inhibiteur de tyrosine kinase ciblant KIT et PDGFR alpha ; durée médiane de suivi : 6,3 mois)
Molecular targeted therapy has improved the prognosis for patients with advanced cancers with driver mutations as seen in lung adenocarcinomas, leukaemia, and gastrointestinal stromal tumours. Targeted agents include antibodies or small molecules that specifically bind to proteins coded by driver alterations. The clinical efficacy of these drugs, however, can be limited by the emergence of refractory clones with resistant mutations. These mutations have typically been seen in patients with gastrointestinal stromal tumours. Gastrointestinal stromal tumours are rare cancers that develop mainly in the gastrointestinal tract. The discovery of driver mutations in the KIT and PDGFRA genes has led to clinical development of three tyrosine kinase inhibitors (TKIs)—imatinib, sunitinib, and regorafenib—and has revolutionised treatment and prognosis of patients with advanced gastrointestinal stromal tumours. However, primary and secondary resistance to these drugs limit their activity and, eventually, almost all gastrointestinal stromal tumours progress, mainly due to acquired mutations. 1 These TKIs inhibit KIT and PDGFRA tyrosine kinases by competitively binding to their ATP-binding domains with ATP, thus, most acquired mutations are found in the ATP-binding pocket or activation loop of the KIT or PDGFRA gene, resulting in reactivation of the corresponding kinase. 2 Acquired mutations after TKI therapy are highly variable and are heterogeneous in a patient, even within a single lesion. Furthermore, refractory gastrointestinal stromal tumours might potentially have different resistance mechanisms other than acquired mutations. 3 Hence, the activities of TKIs with similar mode of action are limited after imatinib; median progression-free survival of sunitinib in the second-line is 6·8 months and that of regorafenib in the third-line is 4·8 months. 4 , 5 Since the approval of regorafenib in 2012, many agents have been evaluated for fourth-line therapy, but none of them were approved for patients with gastrointestinal stromal tumours that were refractory to three TKIs until the end of 2019.
The Lancet Oncology , commentaire, 2019