Fourth-Line Ripretinib Elicits Significant Responses in Advanced GIST

Ripretinib (Qinlock) provides meaningful benefit as a fourth- and later-line therapy in patients with advanced gastrointestinal stromal tumor (GIST) who harbor KIT or PDGFRA mutations, even after crossover in the phase 3 INVICTUS trial, according to César Serrano-García, MD, PhD.

“The addition of ripretinib to this repertoire of treatments in these patients is important,” said Serrano-García. “First, because it's something new in terms of its design and it's very selective against KIT. Its level of toxicity is actually lower than any other multikinase inhibitors approved after imatinib (Gleevec).”

In the trial, patients were randomized to ripretinib (n = 85) or placebo (n = 44) and after being treated with imatinib, sunitinib (Sutent), or regorafenib (Stivarga). Those in the placebo arm were allowed to crossover and receive ripretinib. Updated results showed that ripretinib significantly improved progression-free survival (PFS), yielding a median PFS of 6.3 months in patients who were initially given the agent versus 1.0 month in the placebo arm (HR, 0.15; 95% CI, 0.09-0.25; P < .0001). The median overall survival (OS) was 15.1 and 6.6 months in the initial ripretinib and placebo arms, respectively (HR, 0.36; 95% CI, 0.21-0.62).

Approximately 29 patients on placebo crossed over to receive ripretinib, in which the median PFS was 4.6 months (95% CI, 1.8–not estimable [NE]). Also in the crossover arm, the median OS was 11.6 months (95% CI, 6.3–NE).

These results suggest that patients should receive ripretinib early on in their treatment due to aggressive nature of the disease, explained Serrano-García.

In an interview with OncLive, Serrano-García, principle investigator of the Translational Sarcoma Research Program and faculty member of the Sarcoma Unit at Vall d’Hebron Hospital in Barcelona, Spain, further discussed the crossover analysis of the INVICTUS trial, as well as next steps with ripretinib.

OncLive: What was the rationale for the INVICTUS trial?

Serrano-García: GIST is actually the most common sarcoma subtype—there are up to 70 or more sarcoma subtypes. The interesting part of GIST is that there is an oncogene addiction to a type of kinase that is activated and drives the growth of the tumor. Most of these have driver mutations in KIT or PDGFRA and they are targeted by similar drugs or treatments, such as imatinib, sunitinib, and regorafenib. These are the 3 drugs that we have approved so far, but these patients eventually progress on all of them. [However], they are still suitable for more therapies, [although] since 2012, we [haven’t had any others approved].

The rationale [for the INVICTUS study] was fantastic in the sense that we have a good drug that is able to target KIT or PDGFRA—particularly all types of KIT or secondary mutations that emerge during resistance. Despite this being a rare cancer, the sarcoma community was able to come together for this trial, which demonstrated that ripretinib is an effective drug in these patients who have progressed on all drugs approved so far.

Could you further discuss how KIT and PDGFRA mutations drive GIST?

About 90% of these tumors are driven by primary mutations in KIT or PDGFRA. These are receptor tyrosine kinases that are in the membrane of the cells. They're normally everywhere—every [patient with GIST] has these in their cells—but in these patients [who] are mutated, they govern the growth of these tumors throughout the entire disease.

Back in 2000, imatinib was approved as first-line therapy for these patients and was actually 1 of the first examples of a targeted therapy approved in cancer overall—right after chronic myelogenous leukemia and breast cancer. These patients do very well with imatinib; they stay on it for 2 years or 3 years, but eventually they progress. The main mechanism of progression in GIST is KIT secondary mutations. This means that the tumor figures out how to escape the binding of imatinib to the KIT receptor or the PDGFRA receptor and they modify their structure and the shape of the protein by the secondary mutation. [Therefore], imatinib cannot bind anymore and novel therapies are needed. That has been the latest step of development from 2000 until now.

How have imatinib, sunitinib, and regorafenib performed thus far in this patient population?

Sunitinib was approved back in 2006 and regorafenib in 2012. Sunitinib and regorafenib are multikinase inhibitors, meaning that they broadly inhibit several types of KIT secondary mutations. They also inhibit other kinases or protein molecules that are important in cancer overall. The difference with ripretinib is that it was specifically designed to bind to KIT mutations, regardless of the type of KIT secondary mutations. This is important because something that we have seen is that sunitinib or regorafenib often bind to some KITsecondary mutations, but not all of them. In the context of heterogeneity of KIT secondary mutations or PDGFRA secondary mutations, there are some that are correctly inhibited, but there are others that are not; the tumors eventually progress in a median time of 4 to 6 months, irrespective of sunitinib and regorafenib.

Could you discuss the design of the INVICTUS study?

The design of this study was a phase 3, international, multicenter trial that randomized patients with GIST who have progressed on all types of therapies—not just imatinib, sunitinib, and regorafenib—to ripretinibversus placebo in a 2:1 fashion. [Patients were able to] crossover afterwards. We knew beforehand that at this stage, the disease progressed rapidly, so there was a first CT scan of reevaluation right after 4 weeks of treatment initiation.

If patients at that time were progressing—[the study] was unblinded—and if they were on placebo, they were offered to be treated with ripretinib at the standard dose. Patients who, at some point, progressed while on ripretinib were offered to have a doubled dose increase, as well. The regular dose of ripretinib is 150 mg daily, so they were offered up to 300 mg per day.

The primary end point was PFS, but other measures included OS and response rate. There are also some molecular analyses, such as circulating tumor DNA trials, that will be reported [at a later date].

What did prior findings of this study reveal?

The phase 1 trial is still unpublished, but was reported during some meetings, such as the 2020 ASCO Virtual Scientific Program or the 2020 AACR Annual Virtual Meeting. This trial already showed promising activity [with the agent] in these patients who are completely resistant to all other types of [approved[ therapies; [results] also showed a good safety profile. Taking all [of these data into consideration], the next step was to go directly to the phase 3 trial.

What were the updated results that were presented at the 2020 ESMO World Congress on Gastrointestinal Cancer?

The patients who were first randomized to placebo and at the time of progression were unblinded. These patients were then offered the opportunity to receive ripretinib. For patients who were randomized to placebo, 29 [of them] eventually received treatment with ripretinib, though some couldn’t because their disease worsened quickly. From these 29 patients, it was interesting to see how they eventually obtained benefit from ripretinib despite being initiated with some delay. The PFS from the original INVICTUS trial was 6.3 months and placebo was 1.0 month. In the population who were first on placebo and then started ripretinib the PFS was 4.6 months, which means that these patients had benefit, despite being initiated a little bit later.

[Additionally], something interesting from INVICTUS was that the original results showed that ripretinib in the fourth-line [setting] and beyond benefited OS, which is the first TKI to [show] that after progression on imatinib. The benefit at that time was 15 months for ripretinib and 6.6 months for placebo. The patients who received ripretinib after placebo [experienced] an OS of 11.6 months. This means that patients treated with ripretinib, even if it is given later on still benefit, but [the benefit is not as high compared with] if they were initiated on treatment at the beginning of the trial. This somewhat highlights that this disease is progressing quite quickly and [these patients] actually need to initiate ripretinib early on.

How would you describe the safety profile of ripretinib?

The safety profile [of ripretinib] is actually quite similar to imatinib. Since this is a very targeted agent against KIT, it didn’t have any other [off-target effects]. There is some myasthenia and very little nausea, but most of the patients were uneventful. Something that is probably a little bit different from any other type of TKIs [is that ripretinib has a] somewhat higher degree of alopecia in about 30% to 40% of patients. Serious adverse effects (AEs) occurred in less than 10% of patients. Only a small number of patients had to discontinue therapy due to AEs.

What are the next steps for this research?

Right now, there is an ongoing trial called the Intrigue trial [NCT03673501], which is basically a study with ripretinib in combination with sunitinib in the second-line [setting]. Given the good activity and the good safety profile of ripretinib, this [is worth exploring]. The trial is currently ongoing and is also a worldwide, multicenter, phase 3 study [where patients are] randomized 1:1. We are really looking forward to the results of this trial. Since ripretinib was recently approved, there will probably be ongoing discussions about combining ripretinib with [other agents], as the rationale will be very appealing.

I truly appreciate that a drug can be approved for a rare cancer, which is completely remarkable. We have shown that there are drugs that are active [in this subtype], especially if the tumors have a specific biology that is suitable for targeted therapy. Additionally, the sarcoma community can come together [and move] these drugs toward approval for our patients.

Reference

Serrano C, Heinrich M, George S, et al. Efficacy and safety of ripretinib as ≥4th-line therapy for patients with gastrointestinal stromal tumor (GIST) following crossover from placebo: analyses from INVICTUS. Paper presented at: ESMO World Congress on Gastrointestinal Cancer 2020. July 1-4, 2020; Virtual. O-13.