Results from the 208-Week (4-Year) Follow-up of RESPONSE Trial, a Phase 3 Study Comparing Ruxolitinib (Rux) with Best Available Therapy (BAT) for the Treatment of Polycythemia Vera (PV)

BACKGROUND

RESPONSE is an ongoing, multicenter, open-label, phase 3 trial comparing the efficacy and safety of rux with BAT in patients (pts) with PV who are resistant to or intolerant of hydroxyurea (HU). Primary analysis and 80-week (wk) follow-up results from RESPONSE have been published previously. The 80-wk follow-up data confirmed that the probability of maintaining primary and hematocrit (Hct) responses with rux treatment was 92% and 89%, respectively, and hence, rux could be an effective long-term therapy option for hydroxyurea (HU)-resistant/intolerant (R/I) pts with PV. Here, we report the long-term efficacy and safety updates of rux treatment in RESPONSE trial after a follow-up of 208 wks (after last pt first treatment visit).

METHODS

This was a preplanned follow-up when all pts completed the wk 208 visit or discontinued. Pts who were R/I of HU per modified ELN criteria, were aged ≥ 18 years (y), with splenomegaly, and phlebotomy (PBT) requirement to control Hct were eligible. Pts were randomized 1:1 to receive open-label rux 10 mg bid or BAT (selected based on investigator's choice). Pts randomized to BAT could crossover (CO) to rux after wk 32. The primary response was a composite endpoint 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% of reduction in spleen volume (SVR) by imaging at wk 32. Durability of the primary response, overall clinicohematologic response (CLHM; Hct control without PBT, platelet count ≤ 400 × 10⁹/L, a WBC count ≤ 10 × 10⁹/L, SVR ≥ 35% by imaging) as well as the long-term safety were updated at wk 208 .

RESULTS

Overall, 222 pts were randomized (rux, 110; BAT, 112) and BL characteristics were overall similar between arms, though more pts randomized to rux had prior history of nonmelanoma skin cancer (NMSC) or pre-cancerous skin conditions (10.9 vs 6.3%) and longer prior exposure to HU (162.9 vs 145.6 wks) compared to BAT arm. At the wk 208 analysis, 41 pts (37%) originally randomized to rux arm were still receiving therapy (median exposure, 225 wks) vs no pts on BAT (median exposure, 34 wks). Among the pts in rux arm, 29% completed the treatment as per protocol. Of 98 pts who crossed over to rux after wk 32, 38% remained on rux (median exposure, 189 wks) and 31% completed treatment. Other main reasons for the study drug discontinuations (rux + CO pts) were disease progression (11% + 8%), pt decision (6% + 6%), and adverse events (AE, 14% + 14%).

At the time of analysis in rux arm, 6 of 25 primary responders and 21 of 70 pt who achieved overall CLHM have progressed. Median duration of primary and CLHM responses has not been reached (Figure 1). The KM estimate at 208 wks of duration of primary and CLHM responses for rux arm are 0.73 (95% CI: 0.49, 0.87) and 0.67 (95% CI: 0.54, 0.77), respectively. The KM estimates for overall survival at 5 y were 90.6% (95% CI: 80.1, 95.7) in the rux arm and 87.7% (95% CI: 74.8, 94.3) in the BAT arm. Since wk 80 in rux arm, there were 2 new on-treatment deaths (adenocarcinoma gastric [n = 1, investigator-suspected event to be related to study drug] and neoplasm malignant [n = 1, investigator assessed it not related to study drug]). In the CO population, there were 4 pts who died and had fatal AEs leading to 4 on-treatment deaths (not related to rux).

The most frequent AEs (> 20%) in the rux arm (wk 208 vs wk 80) were anemia (35% vs 27%), pruritus (27% vs 20%), diarrhea (26% vs 20%), headache (23% vs 22%), arthralgia (22% vs 13%), weight increased (21% vs 16%), and muscle spasms (20% vs 16%). The most frequent AE (> 20%) in CO pts (wk 208 vs wk 80) was anemia (29.6% vs 22.4%). In the rux arm and CO pts, incidence of thromboembolic events (wk 208 vs wk 80) was 4.5% vs 6% and 9.2% vs 6.1%. The exposure-adjusted rate of overall malignancies in rux was 6.8 (wk 208) vs 6.1 (wk 80) per 100 pt-ys and 4.5 per 100 pt-ys in CO pts (wk 208).The exposure-adjusted rate of NMSC in rux was 5.1 (wk 208) vs 4.4 (wk 80) per 100 pt-ys. In the CO pts, exposure-adjusted rate of NMSC was 2.6 (wk 208) vs 2.0 (wk 80) per 100 pt-ys. At wk 208, the rates of transformation to MF and AML in rux arm were 2.2 and 0.2 per 100 pt-yrs, respectively, and 1.9 and 0.3 in CO pts.

CONCLUSION

At wk 208 analysis of data from RESPONSE study, the overall safety profile remained consistent with the 80-wk data, and the response was durable. In both the rux arm and CO population, around 30% of pts completed the study treatment and 37% of pts were still receiving the treatment.

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