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.