Long-Term Efficacy and Safety (5 Years) in RESPONSE, a Phase 3 Study Comparing Ruxolitinib (rux) with Best Available Therapy (BAT) in Hydroxyurea (HU)-Resistant/Intolerant Patients (pts) with Polycythemia Vera (PV)
Authors: Kiladjian Jean-Jacques , Zachée Pierre , Hino Masayuki , Pane Fabrizio , Masszi Tamas , Harrison Claire N. , Mesa Ruben A. , Miller Carole B. , Passamonti Francesco , Durrant Simon , Griesshammer Martin , Kirito Keita , Besses Carles , Moiraghi Beatriz , Rumi Elisa , Rosti Vittorio , Blau Igor W. , Francillard Nathalie , Dong Tuochuan , Wroclawska Monika , Vannucchi Alessandro M. , Verstovsek Srdan 
Published: October 2019

Abstract
Background
RESPONSE is a randomized (1:1), open-label, phase 3 study of rux vs BAT in pts with PV who are resistant/intolerant of HU. In RESPONSE, significantly more pts achieved the primary composite end point (hematocrit control [Hct] and a ≥ 35% reduction in spleen volume [SVR]) with rux compared to BAT (23% vs 1%; P ˂ .0001). The 4-year (y) follow-up confirmed that primary and clinicohematologic (CLHM) responses were sustained with the rux treatment, and the safety profile was consistent with previous reports. Here, we report the long-term efficacy and safety after 5 ys (256 weeks [wks]) of treatment (after last pt first treatment visit) in RESPONSE.
Methods
PV pts resistant/intolerant of HU (per modified ELN criteria) with splenomegaly requiring phlebotomy (PBT) for Hct control were randomized to rux 10 mg BID or BAT (selected based on investigator's choice). The primary response was a composite end point of achieving both Hct control without PBT (defined as no PBT eligibility between wks 8 to 32 with no more than 1 PBT eligibility from randomization to wk 8) through wk 32 and a ≥ 35% SVR by imaging at wk 32. Key secondary endpoints were durability of the primary response, overall CLHM (Hct control without PBT, platelet count ≤ 400 × 109/L, WBC count ≤ 10 × 109/L, SVR ≥35% by imaging), and long-term safety. Overall survival (OS) was an exploratory end point. Pts randomized to BAT could cross over (CO) to rux after wk 32.
Results
Pts were randomized to rux (n = 110) and BAT (n = 112). Baseline characteristics were mostly balanced between arms. At baseline, pts randomized to rux were reported to have longer prior exposure to HU compared to BAT (162.9 vs 145.6 wks) and higher frequency of prior nonmelanoma skin cancer (NMSC) or pre-cancerous skin conditions (10.9 vs 6.3%). No pt remained on randomized BAT treatment after wk 80 and median CO time was 34.7 wks. At study completion, 72 pts (66%) in the rux arm and 64 of the 98 pts (65%) who crossed over from BAT completed 5 ys of on-study treatment. Main reason for discontinuation in the BAT arm was lack of efficacy (89%). Adverse events (AEs; 15% and 16%), disease progression (11% and 9% ) and pt decision (6% and 6%) primarily led to treatment discontinuations in the rux arm and CO population, respectively.
At final analysis, the KM estimated probability of maintaining primary response for 224 wks (starting from wk 32) in the rux arm was 0.74 (95% CI: 0.51, 0.88) (Figure 1); 6/25 primary responders had progressed by the time of study completion. The probability of maintaining CLHM response for 224 wks (starting from wk 32) was 0.67 (95% CI: 0.54, 0.77) with 21/70 pts who achieved CLHM at wk 32 had progressed. Median duration of primary and CLHM responses had not been reached. In the intent-to-treat analysis not accounting for CO, KM estimates for OS at 5 ys in the rux and BAT arms were 91.9% (95% CI: 84.4, 95.9) and 91.0% (95% CI: 82.8, 95.4), respectively (HR = 0.95 [95% CI: 0.38, 2.41]). There were 2 on-treatment deaths in the rux arm (adenocarcinoma gastric [n = 1, investigator suspected event to be related to study drug] and neoplasm malignant [n = 1, not related to study drug]). In the CO population, 4 pts had fatal AEs leading to 4 on-treatment deaths (not related to rux). No pt died while on BAT.
With longer exposure of rux, there was no notable increase in rate of AEs. The most common AEs (exposure-adjusted rate ≥ 5) in the rux arm and CO population were anemia (8.9 and 8.8), pruritus (7.0 and 6.1), diarrhea (7.0 and 3.6), weight increased (6.1 and 4.2), headache (5.8 and 5.2), arthralgia (5.6 and 3.3), fatigue (5.1 and 3.9) and muscle spasms (5.1 and 3.3). Rates (per 100 pt-y) of thromboembolic events were lower in rux-treated pts (1.2) and the CO population (2.7) compared to BAT pts (8.2). The exposure adjusted rates of second malignancies were 7.0 (rux) vs 4.5 (CO) vs 4.1 (BAT). The exposure-adjusted rate of NMSC was 5.1 (rux) vs 2.7 (CO) vs 2.7 (BAT). Rates of transformation to myelofibrosis and acute myeloid leukeimia in the rux arm were 2.1 and 0.2 per 100 pt-y, 1.8 and 0.6 per 100 pt-y in CO population, and 1.4 and 0.0 per 100 pt-y in BAT arm, respectively.
Conclusion
In HU resistant/intolerant PV pts, clinical benefits of rux treatment (Hct control and CLHM) were durable with long-term therapy. Considering that the OS findings from this analysis are confounded by extensive CO, the observed HR from this analysis represents a conservative estimate of rux benefit. The long-term safety was consistent with previous findings.

Disclosures
Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Hino:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Novartis: Research Funding. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau. Masszi:Pfizer: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Harrison:Celgene: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; CTI BioPharma: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Miller:Gilead: Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI: Research Funding; Novartis: Honoraria, Speakers Bureau. Passamonti:Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy. Durrant:Novartis: Honoraria, Speakers Bureau. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kirito:Novartis Pharma KK: Honoraria. Besses:Novartis: Honoraria, Research Funding; Shire: Honoraria. Francillard:Novartis: Employment. Dong:Novartis: Employment, Equity Ownership. Wroclawska:Novartis: Employment, Equity Ownership. Verstovsek:Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees.