Avapritinib—a therapeutic breakthrough for PDGFRA D842V mutated gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal (GI) tract and represent approximately 1–2% of primary GI cancers. GIST tumors express a broad spectrum of mutations but the majority (85%) is driven by activating mutations in the genes encoding for KIT or platelet-derived growth factor receptor A (PDGFRA) (1). Targeting these genes with tyrosine kinase inhibitors (TKIs) dramatically improved the outcome of these patients. However, 5–6% of GIST harbor activating mutations of PDGFRA involving a substitution of an aspartic acid (D) with a valine (V) at position 842, also known as D842V. This mutation stabilizes the PDGFRA activation loop in the active conformation and prevents binding of type II TKIs, providing primary resistance to all previously approved TKIs (2).

In preclinical models, the type I TKI, avapritinib, already demonstrated antitumor activity in KIT and PDGFRA mutated GIST (3,4). These results prompted the initiation of the multicenter phase I NAVIGATOR trial which assesses the safety and antitumor activity of avapritinib in GIST. This study by Heinrich et al. (5) included 3 groups: patients without a PDGFRA D842V mutation who progressed following imatinib plus ≥2 other approved TKIs, patients with PDGFRA D842V mutated GIST regardless of previous therapy and patients without a PDGFRA D842V mutation that only received previous imatinib.

In this report of the subgroup with PDGFRA D842V mutated GIST by Jones et al. (6), avapritinib demonstrated an objective response rate of 95% in patients with PDGFRA D842V mutated GIST receiving a 300/400 mg starting dose, regardless of previous therapy. Median time to response in this group was 60 days. Based on the results of this trial, the VOYAGER trial, comparing avapritinib versus regorafenib as ≥ 3rd line treatment in molecularly unselected GIST patients, was initiated (7). Avapritinib did not meet the primary endpoint of superior progression free survival (PFS) compared with regorafenib. However, the subgroup of 7 patients with PDGFRA D842V mutated GIST receiving avapritinib showed an overall response rate (ORR) of 42.9% [95% confidence interval (CI) 9.9–81.6; all partial respons (PR)].

Other TKIs assessed in PDGFRA D842V mutated GIST only showed low potency. Crenolanib blocked phosphorylation of PDGFRA D842V mutated cell lines, suggesting a possible activity in PDGFRA D842V mutated GIST patients (8). In a phase II trial, crenolanib showed a 31% clinical benefit rate with a partial response in 2/16 patients and stable disease in 3/16 patients (9). Inclusion in the phase III trial (CRENOGIST) is ongoing. In preclinical studies ripretinib, a type II switch-pocket kinase inhibitor, demonstrated activity in PDGFRA D842V mutated GIST. However, avapritinib is 10-fold more potent than ripretinib as shown in an enzymatic assay (10). In another preclinical trial, a PDGFRA D842V mutated GIST cell line was highly resistant to ripretinib (11).

The most frequently reported adverse events (AEs) of avapritinib, such as fatigue, gastro-intestinal complains, edema and anemia commonly also occur with other TKIs. However, cognitive side effects are of special interest in patients treated with avapritinib. Any grade cognitive effects were reported in 104/250 (41.6%) patients receiving any dose of avapritinib. In the NAVIGATOR trial, among patients treated with a 300 mg starting dose the majority (92.5%) of patients experienced grade 1 or 2 cognitive effects and no patients experienced grade 4 or 5 cognitive effects. Also, cognitive effects occur more frequently in elderly patients (≥65 years) than in younger patients [38/65 (58.5%) vs. 40/102 (39.2%); P=0.018]. After dose interruption 53.3% of patients with grade ≥2 cognitive effects showed improvement of the AE. Post hoc analysis of the NAVIGATOR trial showed a lower rate of cognitive effects with 300 mg (67/167, 40.1%) compared with 400 mg avapritinib (25/50, 50.0%) (12). Association between the avapritinib dose and the rate of cognitive effects was also seen in the combined VOYAGER and NAVIGATOR analysis, with 23% and 38% of patients reporting any grade cognitive effects in respectively the 300 and 400 mg dosing group (13). Pharmacokinetic (PK) data from both studies suggest a trend for a higher rate of grade 3 or 4 AEs in patients with higher concentrations of avapritinib, regardless of the prescribed dose. Given a high interpatient variability it is important to realize drug exposure is stronger related to these AEs than drug dose. Hence one could consider measuring avapritinib drug concentrations to guide treatment.

Avapritinib is the first drug that shows a prominent and durable response in patients with PDGFRA D842V mutated GIST. Response rates were similar between TKI-pretreated and TKI-naive patients. Treatment related adverse events, including cognitive effects, were generally well tolerated and manageable with dose modifications. Based on these results, in January 2020, avapritinib received FDA approval for the treatment of adults with unresectable or metastatic PDGFRA D842V mutated GIST. This registration is remarkable in different ways. First of all, due to the rarity of this subgroup of GIST the size of the combined cohort of PDGFRA D842V mutated GIST patients was limited to 45 patients receiving a starting dose of 300/400 mg and there was no control group. Also, registration was approved even before long term efficacy and safety data were obtained. However, treatment options are minimal and therefore the observed antitumor effect supports the use of avapritinib as first line therapy for PDGFRA D842V mutated GIST. Even though the fate of this subgroup of patients has changed with the introduction of avapritinib, treatment options are still limited when secondary resistance develops and further research is needed to overcome the development of resistance.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gastrointestinal Stromal Tumor. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-22-7/coif). NS provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma. NS received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, ADCtherapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric, Cresecendo, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, Genmab, Gilead, GlaxoSmithKline, Incyte, InteRNA, Janssen/Johnson&Johnson, Kinate, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Seattle Genetics, Servier, Taiho, and Takeda. NS serves as an unpaid editorial board member of Gastrointestinal Stromal Tumor from November 2020 to October 2022. ER has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ducimetière F, Lurkin A, Ranchère-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One 2011;6:e20294. [Crossref] [PubMed]
2. Cassier PA, Fumagalli E, Rutkowski P, et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res 2012;18:4458-64. [Crossref] [PubMed]
3. Evans EK, Gardino AK, Kim JL, et al. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med 2017;9:eaao1690.
4. Gebreyohannes YK, Wozniak A, Zhai ME, et al. Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors. Clin Cancer Res 2019;25:609-18. [Crossref] [PubMed]
5. Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 2020;21:935-46. [Crossref] [PubMed]
6. Jones RL, Serrano C, von Mehren M, et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer 2021;145:132-42. [Crossref] [PubMed]
7. Kang YK, George S, Jones RL, et al. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol 2021;39:3128-39. [Crossref] [PubMed]
8. Heinrich MC, Griffith D, McKinley A, et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res 2012;18:4375-84. [Crossref] [PubMed]
9. von Mehren M, Tetzlaff ED, Macaraeg M, et al. Dose escalating study of crenolanib besylate in advanced GIST patients with PDGFRA D842V activating mutations. J Clin Oncol 2016;34:11010. [Crossref]
10. Smith BD, Kaufman MD, Lu WP, et al. Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants. Cancer Cell 2019;35:738-51.e9. [Crossref] [PubMed]
11. Grunewald S, Klug LR, Mühlenberg T, et al. Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain. Cancer Discov 2021;11:108-25. [Crossref] [PubMed]
12. Joseph CP, Abaricia SN, Angelis MA, et al. Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors. Oncologist 2021;26:e622-31. [Crossref] [PubMed]
13. Joseph CP, Abaricia SN, Angelis MA. Avapritinib for the treatment of GIST: Analysis of efficacy, safety, and patient management strategies at the recommended phase 2 dose. Connective Tissue Oncology Society Annual Meeting 2019. Tokyo: CTOS, 2019.