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Most patients ( n = 22 ; 69 %) had received a prior antineoplastic therapy , including four ( 13 %) whose disease progressed after receiving midostaurin – the only U . S . Food and Drug Administration – approved treatment for SM .

Patients were treated in seven dosing cohorts ranging from 30 to 400 mg once-daily in fourweek cycles .

Unlike the multikinase inhibitor midostaurin , which “ hits a lot of targets and has some off-target toxicity ,” Dr . DeAngelo explained to ASH Clinical News , avapritinib is a highly selective and highly potent inhibitor of KIT activation loop mutants , including D816V .

The specificity may have contributed to the low toxicity observed in this trial . “ Thirty of 32 patients remain on study after a median treatment duration of nine months [ range = 4-19 months ], which is kind of unusual for patients in a phase I study ,” he added . Two patients discontinued treatment because of progressive disease ( acute myeloid leukemia ) and investigator decision .

The most common non-hematologic adverse events ( AEs ) were :

• periorbital edema ( any-grade , n = 19 [ 52 %] and grade ≥3 , n = 2 [ 6 %])

• fatigue ( any-grade , n = 13 [ 41 %] and grade ≥3 , n = 2 [ 6 %])

• peripheral edema ( any-grade , n = 11 [ 34 %])

Hematologic AEs included :

• anemia ( any-grade , n = 9 [ 28 %] and grade ≥3 , n = 3 [ 9 %])

• thrombocytopenia ( any-grade , n = 9 [ 28 %] and grade ≥3 , n = 2 [ 6 %])

• neutropenia ( any-grade , n = 4 [ 13 %] and grade ≥3 , n = 4 [ 13 %])

Overall , 16 patients ( 50 %) experienced grade ≥3 AEs , and there were no deaths on study . “ Most of the toxicities were lower-grade ( grade 1 or 2 ) and were easily controlled with dose delays or reductions ,” Dr . DeAngelo said .

No dose-limiting toxicities were observed and the MTD was not reached . Based on the results from the dose-escalation phase , the recommended phase II dose is avapritinib 300 mg once-daily .

Ten patients with advanced SM were excluded from the efficacy analysis for not meeting WHO diagnostic criteria , and 18 patients with advanced

TABLE 1 . Outcomes at Baseline Versus at Best Response

Measure

Evaluable Patients

Median at Baseline

Bone marrow ( BM ) mast cell burden

23 20 % ( range = 2-95 )

Blood / BM D816V allele burden

BLQ = below level of quantification

23 4.5 % ( range = 0.1-47 )

SM were evaluable for response ( measured by International Working Group criteria ).

The preliminary overall response rate was 72 percent , including two complete responses ( 11 %), eight partial responses ( 44 %), and three “ clinical improvements ” ( 17 %). Seventeen of these patients remain on treatment .

“ Avapritinib demonstrated significant clinical activity across all dose levels , with rapid and durable reductions in mast cell ( MC ) burden and D816V mutant allele fraction relative to baseline ,” the authors noted ( see TABLE 1 ).

They observed reductions in MC burden , and D816V mutant allele fraction were durable in 28 of the 30 patients who remain on study , seven of whom have completed one or more years of treatment . These observations occurred regardless of advanced SM subtype , prior therapy , concomitant mutations , and performance status . Marked reductions in MC burden were noted in two patients with mantle cell lymphoma whose disease had progressed on midostaurin and in two patients with advanced SM who were intolerant to midostaurin . These four patients are still on therapy at five , 12 , seven , and 14 months , respectively .

In a secondary analysis of neoplastic activity among patients treated with avapritinib , all patients achieved at least a 50 percent reduction in serum tryptase levels from baseline . “[ Serum tryptase ] is a good marker of MC burden ,” Dr . DeAngelo explained . “ To our excitement , 60 percent of patients had complete remission with respect to their marrow disease .”

All 25 patients with splenomegaly at baseline also experienced a decrease in spleen volume , including 15 patients ( 60 %) who achieved a reduction of at least 35 percent from baseline .

“ The KIT D816V mutation is present in 90 percent of patients with advanced SM , and these data validate this as a key disease driver ,” Dr . DeAngelo said . The data are preliminary , and safety and efficacy will need to be confirmed in dose-expansion cohorts , he noted . There are several planned investigations of avapritinib , including in indolent and smoldering SM .

The corresponding authors report receiving financial support from Bristol-Myers Squibb , Incyte , Immunogen , Blueprint Medicines , ARIAD , Shire , GlycoMimetics , Celgene , Novartis , Amgen , Pfizer , and Takeda .

REFERENCE

DeAngelo DJ , Quiery AT , Radia D , et al . Clinical activity in a phase 1 study of Blu-285 , a potent , highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis ( AdvSM ). Abstract # 2 . Presented at the 2017 American Society of Hematology Annual Meeting , December 10 , 2017 ; Atlanta , GA .

Median at Best Response

11 µ g / L ( range = 3-251 )

5 % ( range = 0-60 )

505 mL ( range = 143-1,757 )

1.1 % ( range = BLQ-41 )

Number with > 50 % Reduction ( 35 % for Spleen Volume )

28 ( 93 %)

17 % ( 74 %)

13 ( 54 %)

15 ( 63 %)

Results from the first randomized , phase III trial to evaluate frontline use of a monoclonal antibody in transplant-ineligible patients with newly diagnosed multiple myeloma ( MM ) show that daratumumab added to standard of care reduced the risk of disease progression or death by 50 percent , compared with standard of care alone . People who received the daratumumab combination also experienced deeper responses , according to lead author María Victoria-Mateos , MD , PhD , of the University Hospital of Salamanca in Spain , who presented the findings in a late-breaking abstract at the 2017 ASH Annual Meeting . Results were also published in the New England Journal of Medicine .

“ Daratumumab is an anti-CD38 monoclonal antibody that has shown high activity as a single agent in highly refractory patients , and is extremely active in combination with other drugs – but always in the relapsed setting ,” said co-author Jesús San-Miguel , MD , PhD , from Clínica Universidad de Navarra in Pamplona , Spain , who spoke with the press about results of the ALCYONE trial .

In this study , 706 patients were randomized 1:1 to receive bortezomib , melphalan , and prednisone ( VMP ; standard of care ), with or without the anti-CD38 monoclonal antibody daratumumab ( D-VMP ). Participants received a maximum of nine , six-week cycles of VMP or D-VMP in the following dosing :

• VMP : bortezomib 1.3 mg / m 2 subcutaneously on days 1 , 4 , 8 , 11 , 22 , 25 , 29 , and 32 of cycle 1 , and days 1 , 8 , 22 , and 29 thereafter ; melphalan 9 mg / m 2 twice-daily ; and prednisone 60 mg / m 2 twice-daily on days 1-4

• D-VMP : VMP regimen plus daratumumab 16 mg / kg intravenously once-weekly during cycle 1 , every 3 weeks for cycles 2-9 , and once-monthly thereafter

All patients ( median age = 71 years ; range = 40-93 years ) had newly diagnosed disease and were 65 years or older or were ineligible for high-dose chemotherapy with autologous hematopoietic cell transplantation ( AHCT ). Patients were stratified by International Staging System ( ISS ; I , II , III ), region ( Europe vs . other ), and age (< 75 vs . ≥75 years ).

This patient population represented “ real-life patients with active , advanced disease ,” Dr . San-Miguel noted . Most patients ( 74.9 %) had an Eastern Cooperative Oncology Group performance status score of ≥1 , 29.9 percent were 75 years or older , and 80.8 % had ISS stage II or III disease . Of the 616 patients with cytogenetic information available , 15.9 percent were high risk ( positive for del ( 17p ), t [ 14 ; 16 ], or t [ 4 ; 14 ]).

By June 12 , 2017 ( prespecified date of analysis ), patients had received a median of 12 treatment cycles ( range = 1-24 cycles ) in the D-VMP group and nine cycles ( range = 1-9 cycles ) in the VMP group . At a median follow-up of 16.5 months ( range not provided ), patients who received the daratumumab combination had a 50 percent reduction in the risk of progression or death , compared with standard care alone ( hazard ratio [ HR ] for progression-free survival [ PFS ] = 0.50 ; 95 % CI 0.38-0.65 ; p < 0.0001 ).

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