patient care perspectives
Late-line Dose Escalation in Patients With Advanced Gastrointestinal Stromal Tumors
Late-line tyrosine kinase inhibitor (TKI) dose escalation may benefit a subset of patients with gastrointestinal stromal tumors (GIST), allowing for a longer duration of disease stability. Nonetheless, strategies are needed to better address the secondary resistance mutations that lead to progression.
Richard F. Riedel, MD
Associate Professor of Medicine With Tenure
“All of this speaks to the fact that secondary mutations do develop, and we need to either have a way to prevent them from developing or have a more significant therapeutic effect on them.”
Imatinib dose escalation is a strategy that has been a part of clinical practice for quite some time. Previously published data showed that a subgroup of patients with metastatic GIST, who were progressing on standard-dose imatinib, benefited from an increase from once-daily to twice-daily dosing. As a result, nationally recognized cancer guidelines include this strategy for consideration, and I have been incorporating it in my clinical practice for many years.
More recently, a dose-escalation strategy has been explored with ripretinib, a novel oral switch-control TKI. Ripretinib was approved by the US Food and Drug Administration in May 2020 for adults with advanced GIST who had received prior treatment with 3 or more TKIs, including imatinib.
Ripretinib showed preliminary efficacy in a phase 1 study across a range of doses, and results were confirmed in the phase 3 INVICTUS study, which led to the approval of ripretinib 150 mg once daily. An analysis of the phase 1 trial data showed that 67 patients, who were receiving ripretinib and developed progression, underwent dose escalation from 150 mg once daily to 150 mg twice daily. Benefit was observed across all lines of therapy. In the INVICTUS trial, patients who were progressing on once-daily ripretinib also had the option to escalate to twice-daily dosing. Among 43 patients who underwent dose escalation, median progression-free survival (PFS) for once-daily dosing was 4.6 months, while the median PFS after dose escalation was 3.7 months. Ripretinib dose escalation, in the fourth-line setting, was well tolerated, with no significant worsening of toxicity.
Although dose escalation can be effective, it may also be associated with increased toxicity. Imatinib is generally well tolerated, but increasing the dose from 400 mg per day to 800 mg per day is associated with increased fatigue, diarrhea, nausea, and fluid retention. Despite encouraging—albeit limited—data on the role of dose escalation with ripretinib, it is unclear whether increased toxicity in a large population of patients will be observed. Clinicians need to be aware of the potential for increased side effects and be prepared to treat patients with appropriate supportive care measures.
Overall, these data suggest that dose-escalation strategies can be effective in some patients. It must be noted, however, that the benefits are somewhat limited, with fairly short PFS durations. The average time that patients are on standard-dose imatinib is just under 2 years, in the frontline setting. PFS becomes further shortened in the second- and third-line settings. This is, in part, attributed to the development of secondary mutations and the challenges associated with the ability of these therapies to effectively target them. The shortened response duration also highlights the need to leverage novel therapies to improve outcomes. All of this speaks to the fact that secondary mutations do develop, and we need to either have a way to prevent them from developing or have a more significant therapeutic effect on them.
Bauer S, George S, von Mehren M, Heinrich MC. Early and next-generation KIT/PDGFRA kinase inhibitors and the future of treatment for advanced gastrointestinal stromal tumor. Front Oncol. 2021;11:672500. doi:10.3389/fonc.2021.672500
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. 2008;26(4):626-632. doi:10.1200/JCO.2007.13.4452
George S, Chi P, Heinrich MC, et al. Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour. Eur J Cancer. 2021;155:236-244. doi:10.1016/j.ejca.2021.07.010
Heinrich MC, Jones RL, Gelderblom H, et al. INTRIGUE: a phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib. J Clin Oncol. 2022;40(suppl 36):359881. doi:10.1200/JCO.2022.40.36_suppl.359881
Janku F, Chi P, Heinrich MC, et al. Ripretinib intra-patient dose escalation (IPDE) following disease progression provides clinically meaningful progression-free survival (PFS) in gastrointestinal stromal tumor (GIST) in phase I study. Ann Oncol. 2020;31(suppl 4):S974–S975. doi:10.1016/j.annonc.2020.08.1849
Zalcberg JR, Heinrich MC, George S, et al. Clinical benefit of ripretinib dose escalation after disease progression in advanced gastrointestinal stromal tumor: an analysis of the INVICTUS study. Oncologist. 2021;26(11):e2053-e2060. doi:10.1002/onco.13917
Zalcberg JR, Verweij J, Casali PG, et al; EORTC Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, Australasian Gastrointestinal Trials Group. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005;41(12):1751-1757. doi:10.1016/j.ejca.2005.04.034