Switch Control Inhibition of KIT and PDGFRA in Patients With Advanced Gastrointestinal Stromal Tumor: A Phase I Study of Ripretinib

Abstract

PURPOSE In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations. PATIENTS AND METHODS This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated. RESULTS At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed. CONCLUSION Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.

Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward

“…The safety profile of ripretinib in the phase III trial was consistent with previous evaluations ( Table 1 ), 22 , 23 and was overall favorable, with most side effects being low grade and manageable. Common treatment-related adverse events occurring in more than 20% of the patients were alopecia (49–63% in women), myalgia (28%), nausea (26%), fatigue (26%), HFSR (21%) and diarrhea (20%).…”

“…A phase I, open-label, first-in-human, clinical trial studied the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity in 258 patients with cancer, including 184 GIST. 23 GIST patients had experienced progression or intolerance to at least one line of systemic therapy. Patients in the dose-escalation part of the trial ( n = 68) received ripretinib 20–200 mg twice a day or 100–250 mg once daily in repeated 28-day cycles.…”

“…Phase I and phase III studies demonstrated that ripretinib is a very well-tolerated drug, also showing higher activity in the second line compared with the historical sunitinib data. 23 These results triggered the ongoing phase III INTRIGUE trial, which is currently comparing ripretinib with sunitinib in patients with advanced GIST after front-line imatinib failure (NCT03673501). Although the rationale behind this trial seemingly favors the ripretinib arm, there are several nuances that mean we await the results with bated breath: first, although ripretinib is a pan-KIT inhibitor, sunitinib is very potent against the KIT exon 13 V654A mutation, the most common secondary mutation emerging after imatinib failure; 14 , 16 second, the multikinase inhibitory nature of sunitinib, compared with ripretinib, may account as an extra aid by inhibiting several other kinases that can be somewhat relevant for GIST cell survival; and third, current GIST disease extension and volume after imatinib failure is less bulky than it was back in 2006 when sunitinib was first tested—meaning that current sunitinib mPFS may be higher than that described in the original trial.…”

“…Basically, there is a very simple observation: patients with KIT/PDGFRA mutation keep progressing to a pan-KIT inhibitor after initial response or disease stabilization. 23 , 24 Additionally, ripretinib is still a type II TKI that does not bind irreversibly to the kinase. Potentially, KIT-independent mechanisms may arise as the main driver of resistance 28 —something that can be addressed thanks to the tumor biopsies and plasma samples for ctDNA analysis collected across the trials.…”

“…Likewise, although dermatologic examinations have been present across the phase I and III trials, no keratoacanthomas/squamous cell carcinomas have been reported so far. 23 , 24 …”