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Circulating Tumor DNA Testing Informs Best Second-Line Treatment for Gastrointestinal Stromal Tumors

Liquid biopsy

NEW YORK – Testing for KIT resistance mutations in circulating tumor DNA may help inform the best second-line treatment for patients with gastrointestinal stromal tumors, researchers suggested based on data from a Phase III study.

Sebastian Bauer, the director of the Sarcoma Center at the University Hospital Essen in Germany, presented a ctDNA analysis that his team conducted as part of the Phase III INTRIGUE study during a special session hosted by the American Society of Clinical Oncology. They found that the presence of KIT mutations in the ctDNA of patients with GIST tumors can indicate whether they are more likely to respond to Pfizer's Sutent (sunitinib) or Deciphera Pharmaceuticals' Qinlock (ripretinib).

Within INTRIGUE, researchers were initially interested in comparing progression-free survival outcomes in patients receiving Sutent and Qinlock in the second-line treatment setting. Both drugs are US Food and Drug Administration-approved to treat GIST. Sutent is for GIST patients after they progress on first-line treatment with Novartis' Gleevec (imatinib). Qinlock, meanwhile, is limited to patients who have had three or more prior targeted agents. To be eligible for INTRIGUE, patients had to have progressed on or become intolerant to Gleevec.

INTRIGUE showed that second-line Qinlock didn't improve progression-free survival versus Sutent, at least not in the all-comer patient population. To try to understand why Qinlock failed to beat the standard of care in this earlier setting, researchers decided to look at patients' ctDNA for resistance mutations using Guardant Health's Guardant360 liquid biopsy assay.

Secondary mutations in the KIT kinase domain are the most common reason patients relapse on first-line Gleevec. Roughly 90 percent of Gleevec-relapsed patients develop such mutations. But the ctDNA analysis presented Tuesday showed that the specific exon that secondary mutation affects could be an important consideration when deciding which treatment to prescribe next.

Bauer and colleagues homed in on patients who had both primary KIT exon 11 mutations as well as secondary resistance mutations in the ATP binding pocket or the activation loop. When researchers considered patients' outcomes according to the secondary mutations they harbored, distinct groups emerged in terms of treatment benefit. Specifically, patients with KIT exon 13/14 mutations in the ATP binding pocket responded better to Sutent, and those with KIT exon 17/18 mutations in the activation loop appeared to do better with Qinlock.

Among patients with KIT mutations in the ATP binding pocket of exon 13/14, the median progression-free survival time was 15 months with Sutent versus just 4 months with Qinlock. The median overall survival wasn't reached for Sutent-treated patients in this biomarker subgroup, versus 24.5 months for those on Qinlock. The overall response rate was 15 percent with Sutent versus 9.5 percent with Qinlock.

Meanwhile, for patients with activation loop mutations in KIT exon 17/18, the median progression-free survival was 1.5 months with Sutent versus 14.2 months with Qinlock. The median overall survival was 17.5 months for patients on Sutent versus not yet reached for those on Qinlock. There were no objective responses among Sutent-treated patinets versus 44.4 percent with Qinlock.

In both groups, all patients had primary mutations in KIT exon 11. In a subset with both KIT exon 13/14 as well as the KIT exon 17/18 mutations, second-line Sutent outperformed Qinlock. These patients with co-occurring mutations had a median progression-free survival of 10.9 months on Sutent and 8.1 months on Qinlock and a median overall survival of 20.3 months versus 14.7 months, respectively. However, since only 22 patients had co-occurring mutations, researchers couldn't draw definitive conclusions.

According to Bauer, the INTRIGUE trial is the largest global Phase III trial in second-line Gleevec-resistant advanced GIST patients to demonstrate the importance of ctDNA NGS analysis when it comes to characterizing KIT mutations. His group is now planning a Phase III pivotal trial dubbed INSIGHT that Deciphera Pharmaceuticals has designed with the FDA's input and plans to launch in the second half of 2023.

That trial will compare Sutent's and Qinlock's activity in advanced GIST patients who have received Gleevec and whose tumors harbor KIT exon 11 and KIT exon 17/18 secondary mutations. In this trial, Deciphera is hoping to confirm the finding from INTRIGUE that this subset of patients will benefit more from second-line treatment with Qinlock than Sutent. Patients in INSIGHT will be prospectively screened and enrolled based on the presence of a KIT exon 17/18 mutation in ctDNA. Patients on Sutent will be able to crossover to Qinlock upon progression.

Liquid biopsy advantages, limitations

In a discussion of the INTRIGUE sub-analysis data, Breelyn Wilky, the director of sarcoma medical oncology at the University of Colorado Medicine, spoke to the importance of biomarker testing in GIST. The INTRIGUE study and a prior trial dubbed VOYAGER in a later-line GIST setting both suggested that tracking resistance mutations can inform treatments for these patients. In VOYAGER, Blueprint Medicines' Ayvakit (avapritinib) failed to best Bayer's Stivarga (regorafenib) in the third- or later-line setting, although similar to INTRIGUE, patients with certain KIT resistance mutations appeared to have better progression-free survival on Ayvakit.

When it comes to ctDNA, however, Wilky highlighted a key limitation, which is that GIST tends to shed less ctDNA than other cancer types. "The sensitivity [of ctDNA] is uniformly low in GIST that is non-metastatic, non-progressing, or low tumor burden," she said. While both the INTRIGUE and VOYAGER studies were able to detect ctDNA using Guardant360 in 77 percent of the samples, only 44 percent of patients were found to have KIT exon 11 primary mutations as well as KIT secondary mutations.

"This suggests that the sensitivity of ctDNA with Guardant360 is still relatively low to detect underlying secondary mutations, and these data, which could be critical for treatment selection, may still be under-captured," Wilky said, adding that further confirmation in the proposed INSIGHT trial could address this uncertainty and more work may be needed to set a ctDNA threshold for detecting resistance mutations. 

With these caveats, these data could potentially change practice, Wilky said, "and suggest that patients progressing on imatinib should consider mutation testing with ctDNA prior to selecting a second-line treatment regimen."