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New Medicines

Ayvakyt (EU), Ayvakit (US)Gastrointestinal stromal tumours (GIST) - advanced; fourth-line treatment

Information

Ayvakyt (EU), Ayvakit (US)
New molecular entity
Blueprint Medicines Corporation
Blueprint Medicines Corporation

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Not approved
Yes
Yes
Aug 21The company has informed NICE that it will be withdrawing its evidence submission for this appraisal, so NICE has suspended its appraisal. UK launch now seems unlikely any time soon [12].
Sep 20The EC has granted conditional marketing authorization to avapritinib as a monotherapy for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation [11].
Jul 20Recommended for EU conditional approval by CHMP - the full indication is "as monotherapy for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) harbouring the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation. It is proposed that the medicine be prescribed by physicians experienced in the treatment of anticancer therapy." [10] Conditional approval indicates that the information available is less than would usually be required, but that the medicine fulfils a significant unmet need and the benefit to risk balance is considered to be acceptable under those circumstances; the manufacturer will normally be expected to provide further clinical data to retain the marketing authorisation.
May 20The US FDA has issued a complete response letter (CRL) for the new drug application of avapritinib for the treatment of adults with unresectable or metastatic fourth-line gastrointestinal stromal tumor (GIST). The CRL states that the FDA cannot approve the application [9].
Jan 20Approved in US for "the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations." [7]
Oct 19US FDA, following its New drug Application (NDA) mid-cycle review meeting, informs Blueprint Medicines that it intends to split the proposed indications for avapritinib into two separate NDA for PDGFRA Exon 18 mutant GIST regardless of prior therapy and fourth-line GIST. The FDA also requested top-line results from the VOYAGER trial to make a informed review of the proposed fourth-line indication and potential clinical benefit in this population including evaluation of response rate and safety for the fourth-line indication [6].
Aug 19Filed in US, with priority review, for the treatment of adult patients with PDGFRa Exon 18 mutant GIST, regardless of prior therapy, and fourth-line GIST, a decision is expected 14/2/20 [5].
Jul 19 Filed in EU for treatment of adult patients with PDGFRα D842V mutant GIST, regardless of prior therapy, and fourth-line GIST [4].
Jan 19Has orphan drug status in EU & US [3].
Jun 17Granted breakthrough therapy designation from the US FDA for treatment of patients with unresectable or metastatic PDGFRa D842V-driven GIST. Blueprint Medicines also received feedback from the US FDA in a end-of-PI meeting, stating that, the additional data from the expansion cohort of the PI NAVIGATOR trial in GIST is sufficient to support a New Drug Application of avapritinib which company plans to file for the treatment of PDGFRa D842V-driven GIST [3].

Category

Tyrosine kinase inhibitor designed to selectively inhibit PDGFRa and KIT, targeting their gene mutations including the PDGFRa D842V and KIT exon 17 mutations.
GISTs are rare. They represent 0.1-3% of all gastrointestinal cancers. However GISTs are the most common primary mesenchymal tumours of the gastrointestinal tract. The estimated incidence of GISTs is around 15 per million of population per annum. There are approximately 900 new cases per year in the UK [1].
Gastrointestinal stromal tumours (GIST) - advanced; fourth-line treatment
Oral

Further information

Yes

Trial or other data

Aug 21PIII VOYAGER RCT (n=476) found no significant improvement in progression free survival for avapritinib compared to regorafenib (4.2 vs 5.6 months, HR 1.25, 95%CI 0.99-1.57) [9].
May 20Apr 20: top-line results from the Phase 3 VOYAGER clinical trial of avapritinib versus regorafenib in patients with locally advanced unresectable or metastatic GIST found that the trial did not meet the primary endpoint of an improvement in progression-free survival (PFS) for avapritinib versus regorafenib [8].
Mar 18Pivotal VOYAGER PIII trial in patients with locally advanced unresectable or metastatic GIST of avapritinib versus regorafenib in patients previously treated with imatinib and one or two other TKIs starts (NCT03465722; BLU285-1303). 460 patients will be recruited in the US, UK, South Korea, European Union, Australia and Asia. The primary efficacy endpoint is progression free survival determined by central radiologic assessment per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Collection of primary outcome data due to complete Apr 21 [2].
Feb 18Enrolment of a third-line or later (KIT-driven) GIST cohort was completed in the PI NAVIGATOR study (NCT02508532), and enrolment of the second-line GIST cohort was initiated. Earlier, Blueprint had announced an expansion of the trial, wherein the recruitment target for patients previously treated with imatinib and at least one additional tyrosine kinase inhibitor (TKI) was increased from 50 to 100 patients, and a new cohort was added, to investigate avapritinib in second-line GIST. The NAVIGATOR trial is designed to investigate the safety and tolerability of multiple ascending doses of avapritinib in patients with unresectable, treatment resistant GIST. The trial intends to evaluate pharmacokinetics, pharmacodynamics, and preliminary antineoplastic activity of avapritinib in patients with GIST whose cancer is driven by PDGFRa D842V and KIT Exon 17 mutants. Approximately 200 patients are expected to enrol into this trial in the US, the UK, the EU and Asia. In November 2017, data from the trial (n=116), demonstrated robust clinical activity and a favourable safety profile of avapritinib. Dosing began at 30mg per day and increased in a stepwise fashion to 400mg per day. Blueprint selected 300mg qid as the recommended part 2 dose (RP2D) for the expansion portion of the clinical trial, with an option to escalate patients to the maximum tolerated dose (MTD) of 400mg qid following two treatment cycles [3].

Evidence based evaluations

Ayvakyt (EU), Ayvakit (US)Advanced systemic mastocytosis, including patients with aggressive SM (ASM), SM with associated haematologic neoplasm (SM-AHN), and mast cell leukaemia (MCL)

Information

Ayvakyt (EU), Ayvakit (US)
Licence extension / variation
Blueprint Medicines Corporation
Blueprint Medicines Corporation

Development and Regulatory status

None
Approved (Licensed)
Launched
Yes
Yes
Mar 22approved in the EU [11]
Jan 22Recommended for EU approval by CHMP – the extension to the existing indication is “as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL), after at least one systemic therapy”. Approval of 25 mg and 50mg film coated tablets is also recommended [10].
Jun 2130-day list price in the US will be $33,568 [8].
Jun 21Approved in US [7].
Mar 21EMA validates Type II variation MAA for avapritinib for treatment of advanced SM [6].
Dec 20supplementary NDA submitted to the U.S. Food and Drug Administration (FDA) for avapritinib for the treatment of adult patients with advanced systemic mastocytosis [5].
Feb 19Has breakthrough therapy status for treatment of advanced systemic mastocytosis [3].
Oct 18has orphan drug status in EU & US [3]
May 18Blueprint Medicines receives positive feedback from the US FDA in support of its registration plan for avapritinib in patients with advanced, smoldering and indolent systemic mastocytosis (SM). In accordance with the feedback, the company intends to initiate the PII PATHFINDER trial in patients with advanced SM and the PII PIONEER trial in smoldering SM [3].

Category

Tyrosine kinase inhibitor which selectively inhibits activated KIT and platelet-derived growth factor receptor A (PDGFRA) mutant kinases. By blocking these enzymes, avapritinib is expected to control the growth of mast cells, slowing down the progression of disease
This is a rare and heterogeneous group of disorders, of which urticaria pigmentosa is the most common manifestation. It affects under 1 in 1,000 patients attending dermatology clinics. Estimated incidence is 1 in 150,000 [1].
Advanced systemic mastocytosis, including patients with aggressive SM (ASM), SM with associated haematologic neoplasm (SM-AHN), and mast cell leukaemia (MCL)
Oral

Trial or other data

Mar 20Results from part 1 of the PII PIONEER trial showed a statistically significant improvement in patient-reported outcomes with avapritinib. Patients treated with avapritinib showed a statistically significant mean decline of approximately 30% in total symptom score (TSS) at 16 weeks, as measured by the Indolent SM Symptom Assessment Form (ISM-SAF). In addition, patients treated with avapritinib achieved consistent improvements across objective measures of mast cell burden and patient-reported quality of life. Avapritinib was well-tolerated with no patients discontinuing treatment due to adverse events. Based on the full Part 1 data, 25 mg once daily has been selected as the recommended Part 2 dose [4].
Jan 19PII PIONEER trial to assess the safety and efficacy of avapritinib in patients with with indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) whose symptoms are not adequately controlled by best supportive care (BSC) starts (NCT03731260; BLU-285-2203). The randomised, double-blind, placebo-controlled trial intends to recruit 112 patients in the US [2].
Oct 18PII registration-enabling PATHFINDER trial to assess the safety and efficacy of avapritinib in patients with advanced systemic mastocytosis including patients with aggressive systemic mastocytosis and systemic mastocytosis with associated haematologic neoplasm and mast cell leukaemia starts (BLU-285-2202; NCT03580655). The primary efficacy endpoint is the objective response rate. The open-label trial will enrol 60 patients in the US. Collection of primary outcome data due to complete Dec 20 [2].

Evidence based evaluations