Nancy Berezin and Becky Owens attended the 2018 American Society for Clinical Oncology Annual Meeting as representatives of GSI. Following is a summary of the GIST-related news from the ASCO meeting, written by Nancy.
Blueprint Medicines’ BLU-285 now has a name — avapritinib — and is on track for new drug application filing in the first half of 2019 for GIST patients with the hard-to-treat PDGFRA D842V mutation. Enrollment in the Phase I “NAVIGATOR” study is complete in this population, but there are slots remaining for other patients with KIT- or PDGRFA-mutated GIST who have progressed on imatinib. Meanwhile, Blueprint’s randomized Phase III “VOYAGER” trial is about to begin enrollment. It is designed to test the safety and clinical activity of avapritinib vs regorafenib and is open to patients with advanced GIST who have progressed on imatinib and up to two other TKIs. The safety profile of this drug is similar to that of imatinib, with patients typically encountering gastrointestinal effects, periorbital edema, etc. Hand-foot syndrome has not been observed. However, up to 30% of study patients have experienced dose-dependent cognitive symptoms — mostly Grade 1 or 2 — which the company is following closely. Blueprint is also getting ready to roll out an educational campaign for both physicians and patients highlighting the importance of mutational testing as a prelude to targeted GIST therapy.
Another investigational drug that targets the PDGFRA D842V mutation is AROG’s crenolanib. Because it is so narrowly focused (crenolanib does not have activity against VEGFR, FGFR, or KIT), accrual into the randomized, placebo-controlled trial (ARO-012) has been slow, with approximately 20 patients enrolled thus far at sites in the U.S. and Europe. Patients must demonstrate advancing or metastatic GIST, but can have prior exposure to any of the TKIs.
At the sarcoma poster session on June 2, Dr. Suzanne George of Dana Farber Cancer Institute presented a broad analysis of mutational status in a large cohort of heavily pretreated GIST patients enrolled in the Phase I trial of Deciphera’s novel pan-KIT/PDGFRA switch-control inhibitor DCC-2618. Both tissue and liquid biopsies were performed and tested via next-generation sequencing. Sixty-two percent of patients with confirmed KIT mutations had secondary mutations at exon 17/18; exon 13/14 mutations were detected in 30%. Multiple patients had mutations at both exons 13/14 and 17/18. The majority of patients in this Phase I trial showed tumor shrinkage and durable progression-free survival. Side effects have been modest, although the company reports that there may be an increased incidence of squamous-cell skin carcinoma in this closely followed population. Currently, Deciphera is recruiting participants for its randomized Phase III “INVICTUS” trial, with the goal of approval as a fourth-line agent (after imatinib, sunitinib, and regorafenib). This is a placebo-controlled trial, with rapid crossover to the drug arm in cases of progression. The company anticipates launching a second-line Phase III randomized trial — comparing the efficacy and toxicity of DCC-2618 vs sunitinib in patients whose tumors have progressed on imatinib — by the end of 2018.
Additional ASCO posters of interest included a Phase Ib study of rapid alteration of sunitinib and regorafenib in patients with advanced GIST, presented by Dr. Cesar Serrano of the Vall d’Hebron University Hospital Institute of Oncology. This attempt to inhibit KIT secondary mutations by alternating drugs with complementary activity profiles did not accomplish its goal of disease stabilization. However, discussant Dr. Sebastian Bauer (West German Cancer Center) pointed out that the biological rationale remained valid and might prove successful given drugs with greater potency relative to their toxicity.
A useful study by a French group led by Dr. Olivier Mir examined the impact of proton pump inhibitors (PPIs) on sunitinib pharmacokinetics and activity. It already had been suspected that intake of PPIs might interfere with TKI bioavailability, and this proved to be the case: the amount of sunitinib dosage that actually was absorbed decreased by about 40% when PPIs were administered simultaneously. The authors concluded that either PPI discontinuation or sunitinib dose escalation should be considered in this setting.
Several studies sought to clarify the immunologic profile of GIST and other sarcomas, as a necessary step toward development of targeted immunotherapy. A team led by Dr. Armelle Dufresne of the French Sarcoma Group focused on the heterogeneous expression of immune check point (ICP) and membrane markers (MM), while Dr. Maria Pantaleo’s team from Italy demonstrated that GIST tumor samples contain significant immune infiltrate with abundant CD8+ T cells. The investigators noted that the microenvironment of GIST strongly resembles that of melanoma — important news, given the recent achievements of immunotherapy in slowing melanoma progression.
Finally, there is an unfortunate development that we need to share with you. On June 2, Dr. Andrew Wagner of Dana Farber Cancer Institute presented the results of a Phase I study of the investigational Plexxikon drug PLX9486, alone and in combination with another Plexxikon agent, pexidartinib (PLX3397), or sunitinib, in patients with advanced or unresectable GIST and non-GIST solid tumors with KIT mutations. Both combinations were designed to address a broad spectrum of mutations: primary mutations at KIT exons 9 or 11 and secondary mutations at exon 13/14 and exon 17/18. In the poster discussion that followed, Dr. Bauer described the results as promising — adding that there was good tolerability with very few Grade 3 or 4 adverse events with either combination. After hearing Dr Bauer’s talk, we met with Dr. Glenn Michelson, Plexxikon’s Chief Medical Officer, and Marguerite Hutchinson, Vice President, Business Development, to hear about next steps. To our shock, they informed us that the parent company, Daiichi Sankyo, was suspending development of drugs for this indication. Patients already enrolled in the Phase I trial would receive their medication as before; however, there would be no further trials, and PLX9486 would not reach market unless another backer could be found. That, sadly, is all we know at present. Those needing additional information are encouraged to contact Marguerite Hutchinson at firstname.lastname@example.org.