Ripretinib for advanced gastrointestinal stromal tumor: Plain language summary of the INVICTUS study

The purpose of this summary is to help you understand the results of the INVICTUS study originally published in the journal Lancet Oncology. INVICTUS is a clinical study which looked at ripretinib as a potential treatment for advanced gastrointestinal stromal tumor, also known as GIST. GIST is a type of cancer that starts in the digestive tract, also known as the gastrointestinal tract. In the study, all participants had advanced GIST and needed a fourth-line (or greater) treatment following the failures of three previous treatments. The study looked at how well ripretinib worked compared with a nonactive medicine (known as a placebo) and at the side effects. Participants were given ripretinib at a dose of 150 mg once a day or a placebo. The results of the INVICTUS study showed ripretinib increased the length of time participants survived before their cancer got worse. Treatment with ripretinib was associated with side effects that varied in severity. The results of this study led to ripretinib, also known by the brand name Qinlock®, being approved in the USA by regulators as the only medication for adults with advanced GIST who have previously been treated with 3 or more types of treatment called tyrosine kinase inhibitors. ClinicalTrials.gov NCT number: NCT03353753 .

Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor

The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.

Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG).

11524 Background: Pimitespib (PIM) is a novel class of orally active selective HSP90 inhibitors. KIT and PDGFRA are clients of HSP90 for their functional stability; therefore, HSP90 is a rational therapeutic target on GIST in pts with acquired resistance, such as secondary mutation in KIT, to approved tyrosine kinase inhibitors. A phase II trial showed clinical activity of PIM in pts with advanced GIST refractory to standard treatments whose medical need remains unmet. This phase III trial evaluated the efficacy and safety of PIM for this unmet clinical need. Methods: Eligible pts had histologically confirmed advanced GIST refractory to IM, SU, and REG, ≥1 measurable lesion, and ECOG performance status 0 or 1. Pts were randomized 2:1 to receive either PIM 160 mg once daily on a 5-days-on/ 2-days-off schedule or PL. Pts eligible for unblinding at the time of progressive disease were allowed to crossover to open-label PIM. The primary endpoint was progression-free survival (PFS) by blinded central radiological review based on modified RECIST 1.1. Secondary endpoints included overall survival (OS), PFS in the pts crossed over to PIM (secondary PFS), and safety. Crossover-adjusted OS was derived using the rank preserving structural failure time (RPSFT) model. Exploratory endpoints included pharmacogenomics (PGx). Results: From Oct 2018 to Apr 2020, 86 pts were randomized to receive either PIM (n = 58) or PL (n = 28). Baseline characteristics were well balanced between the two arms. Median PFS was 2.8 months (mo) (95% CI: 1.6–2.9) for PIM vs. 1.4 mo (95% CI: 0.9–1.8) for PL. The hazard ratio (HR) for PFS was 0.51 (95% CI: 0.30–0.87) ( p = 0.006, stratified log-rank test). Median OS was 13.8 mo (95% CI: 9.2–not reached) for PIM vs. 9.6 mo (95% CI: 5.5–not reached) for PL (HR for OS 0.63; p = 0.081), with 60.7 % of PL pts crossed over to PIM; secondary PFS was 2.7 mo (95% CI: 0.7–4.1). The RPSFT-adjusted median OS of PL was 7.6 mo (adjusted HR for OS 0.42; p = 0.007). Furthermore, the results of PGx analysis suggested that PIM was also effective in pts with secondary KIT mutation detected from blood samples. The most common ( > 5%) grade 3 or higher adverse events (AEs) in PIM/PL were diarrhea (13.8%/0%), anemia (6.9%/10.7%), decreased appetite (6.9%/0%), and tumor hemorrhage (5.2%/0%). AEs leading to PIM/PL study discontinuation were observed in 4/2 pts (6.9%/7.1%), respectively. Conclusions: This randomized trial demonstrated that PIM significantly improved PFS with OS prolongation in pts with advanced GIST refractory to IM, SU, and REG, as a HSP90 inhibitor for the first time. PIM was tolerated and AEs were manageable. With a mechanism of action different from that of standard therapies, PIM has the potential to be a new standard treatment in GIST. Clinical trial information: JapicCTI-184094.

Ripretinib for the treatment of advanced gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract yet represent the most common GI sarcomas. Most GISTs are driven by activating mutations of the KIT and/or PDGFRA genes. Prior to the development of tyrosine kinase inhibitors (TKIs), GISTs were associated with a poor prognosis because conventional cytotoxic chemotherapy was relatively ineffective. However, TKIs that inhibit the most common driver mutations in KIT or PDGFRA have revolutionized the treatment of GISTs over the past two decades. Notwithstanding, ongoing management challenges relate to the development of secondary mutations in these genes, resulting in tumor progression. Due to both the intra- and inter-patient heterogeneity of these secondary mutations in GISTs, optimal treatment requires an agent that blocks as many mutant genes as possible. Ripretinib – a novel switch-control TKI – inhibits many of the most common primary and secondary activating KIT and PDGFRA mutants involved in GIST progression through a dual mechanism of action. In the pivotal INVICTUS phase III trial, patients with advanced GIST that had progressed on at least imatinib, sunitinib, and regorafenib and who received ripretinib experienced significantly longer progression-free survival (primary endpoint) as well as prolongation of overall survival, compared with those receiving placebo. Treatment with ripretinib was associated with durable improvements in quality-of-life indices and a manageable toxicity profile. The most frequent side effects were common to the class of TKIs used in the management of GIST. These results led to the approval of ripretinib for treatment of advanced GIST in adults who have received three or more TKIs, including imatinib. Ripretinib is also under investigation in the second-line treatment of advanced GIST in a phase III trial (INTRIGUE) comparing ripretinib with sunitinib in patients with advanced GIST after treatment with imatinib. Plain language summary Use of ripretinib for the treatment of gastrointestinal stromal tumors (GISTs) Gastrointestinal stromal tumors (GISTs) are a rare type of tumor most commonly located in the stomach and small intestine but can develop anywhere throughout the gastrointestinal tract. The symptoms of GISTs vary in extent depending on location of the primary tumor and include a feeling of fullness, abdominal pain, intestinal bleeding, and fatigue. Since these symptoms are nonspecific, making a diagnosis can be challenging. Most GISTs carry initial mutations in genes that control specific enzymes called tyrosine kinases. Historically, treatment of GISTs was limited because traditional chemotherapy is ineffective against these tumors. However, with the introduction of drugs that inhibit tyrosine kinases [i.e., tyrosine kinase inhibitors (TKIs)], survival has been extended substantially. However, many GISTs go on to develop secondary mutations that render them resistant to a given TKI. Prior to the approval of ripretinib, four TKIs were available for the treatment of GIST: imatinib; sunitinib; regorafenib; and, recently, avapritinib. Each drug is used until resistance develops or patients are unable to tolerate the side effects of treatment, after which the next drug is started. Ripretinib was recently approved by the FDA as the fourth drug in the usual treatment sequence recommended for patients with advanced GIST who have progressed (or are treatment intolerant) after receiving three or more TKIs, including imatinib. Approval of ripretinib was based on the results of the INVICTUS trial, which demonstrated that the drug significantly improves the time patients have without progression of the disease or death compared with placebo. The most common side effects related to ripretinib were hair loss, muscle pain, nausea, fatigue, hand-foot syndrome, and diarrhea, although most events were not very severe. Ripretinib is being further studied as the second TKI used in patients with GIST who have progressed on or could not tolerate first-line treatment with imatinib.

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

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.

Identification and Validation of Aurora Kinase A (AURKA) Involved in the Progression and Imatinib Resistance of Advanced Gastrointestinal Stromal Tumors

Background: Gastrointestinal stromal tumor (GIST) is a common tumor originating from mesenchyme in the alimentary system. GISTs exhibit unique malignant behavior compared to typical carcinomas. Here, we explored genes that drive the progression and imatinib resistance of GISTs by bioinformatic tools and experiments. Methods: We analyzed gene expression profiles of GISTs and identified a key gene, AURKA, which regulated the progression of GISTs. We further determined the clinical significance of AURKA by immunohistochemical (IHC) staining assays and survival analysis. A series of in vitro experiments were performed to investigate in detail the effect of AURKA on the aggressiveness and imatinib resistance of GIST cells.Results: Our results showed that AURKA was higher in advanced GIST tissues than in non-advanced GIST tissues. AURKA mainly involved in cell cycle related biological processes as revealed by GSEA. AURKA was positively related with GIST progression and could be an independent prognostic marker of GISTs. It was also found to exhibit consistent expression patterns in several human malignancies. Additionally, AURKA influenced gene mutations associated with imatinib resistance. Overexpression of AURKA in GIST cells promoted cell proliferation and apoptosis, even after administration of imatinib. But imatinib significantly inhibited the effects of AURKA overexpression on the migration of GIST cells. Conclusions: Bioinformatics analyses and subsequent experiments identified AURKA as a key gene in GIST progression. AURKA showed a contribution to imatinib resistance and could be a candidate therapeutic target for GISTs.

Ripretinib (DCC-2618): a new tyrosine kinase inhibitor for the treatment of metastatic gastrointestinal stromal tumors

Ripretinib (DCC-2618) is a novel tyrosine kinase inhibitor designed to broadly inhibit primary and secondary mutations in KIT (exons 9,11, 13, 14,17,18) and PDGFRA (exon 18). Here in our article we describe clinical trials of ripretinib for patient with advanced gastrointestinal stromal tumors (GIST). The clinical trial INVICTUS-randomized phase III study of ripretinib for patient with advanced GIST in 4 lines therapy; it is the most important results, because there are currently no approved drugs for such patients. Median PFS was significantly improved with ripretinib compared with placebo 6,3 и 1 months (p0,0001) and median OS was significantly improved with ripretinib compared with placebo 15,1 и 6,6 months (p0,004). High efficacy of ripretinib was accompanied with favorable profile of toxicity, only 8,2% patients experienced treatment discontinuations due to adverse events.

Ripretinib: First Approval

Ripretinib (QINLOCK™) is a novel type II tyrosine switch control inhibitor being developed by Deciphera Pharmaceuticals for the treatment of KIT proto-oncogene receptor tyrosine kinase (KIT)-driven and/or platelet derived growth factor receptor A (PDGFRA)-driven cancers, including gastrointestinal stromal tumour (GIST). Ripretinib inhibits KIT and PDGFRA kinase, including wild-type, primary and secondary mutations, as well as other kinases, such as PDGFRB, TIE2, VEGFR2 and BRAF. In May 2020, oral ripretinib received its first approval in the USA for the treatment of adult patients with advanced GIST who have received prior treatment with ≥ 3 kinase inhibitors, including imatinib. The US FDA, Health Canada and the Australian Therapeutic Goods Administration collaborated on the review of the ripretinib new drug application in this indication as part of Project Orbis; regulatory review in Australia and Canada is ongoing. Clinical development for GIST, solid tumours and systemic mastocytosis is underway in several countries worldwide. This article summarizes the milestones in the development of ripretinib leading to this first approval for the treatment of advanced GIST.

A phase II study of MEK162 (binimetinib [BINI]) in combination with imatinib in patients with untreated advanced gastrointestinal stromal tumor (GIST).

11508 Background: ETV1 and KIT are lineage-specific master transcriptional and signaling survival factors in GIST. In preclinical models, dual lineage targeting of ETV1 by MEK inhibition with BINI and KIT by imatinib are synergistic in suppressing GIST tumorigenesis and progression. This single-arm phase II study is designed to test the efficacy of the BINI+imatinib as a first-line treatment in patients (pts) with advanced GIST. Methods: Adult pts with untreated advanced GIST received imatinib (400mg daily) plus BINI (30mg twice daily), 28-day cycles. The primary endpoint (EP) was RECIST1.1 objective response rate (ORR) (complete response [CR]+partial response [PR]). The study was designed to detect a 20% improvement in the ORR of imatinib alone (unacceptable rate of 45%; acceptable rate of 65%). A sample size of 44 patients was required, using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1. Confirmed PR in > 24 pts would be considered positive. Secondary EPs included RR by Choi and EORTC criteria, resectability conversion rate (RCR), progression free survival (PFS), overall survival (OS) and long-term AEs. Correlatives included characterization of tumor genomics by MSK-IMPACT, cfDNA by MSK-ACCESS, ETV1 protein levels and transcriptomes and signaling inhibition. Results: At data cutoff of Jan 31, 2020, 38/39 pts with advanced GIST of all genotypes, including 3 KIT/PDGFRA-wild type GIST pts, were evaluable for primary EP. Median age 60 (range 29-78), 29% female. 26/38 pts with confirmed PR; Best ORR was 68.4% (two-sided 95% CI, 51-83%; one-sided 90% CI, 57-100%). 8/9 pts became resectable after treatment; RCR was 88.9% (95% CI, 52-100%). 13 pts remain on trial (2-159 weeks [wks]). 9 pts discontinued trial due to disease progression (11-159 wks); one pt progressed within 3 months, indicating primary resistance. Grade 3/4 toxicity included CPK elevation (asymptomatic, 61%), neutrophil decrease (11%), maculopapular rash (8%), anemia (8%). No unexpected toxicities observed. Correlation of outcome with MSK-IMPACT, MSK-Access and paired tumor biopsies will be presented. Conclusions: This study met its primary endpoint. BINI plus imatinib is highly effective in treatment-naive advanced GIST, with expected and manageable long-term treatment-associated toxicities. The combination strategy warrants further evaluation in direct comparison with imatinib in the frontline treatment of GIST. Clinical trial information: NCT01991379 .