CPI-0610 Shows Practice-Changing Potential in Myelofibrosis

The novel BET inhibitor CPI-0610 demonstrated clinical activity with or without ruxolitinib (Jakafi) in patients with JAK inhibitor-naïve and JAK inhibitor-exposed or -intolerant myelofibrosis, according to findings from 3 arms of the global phase 2 MANIFEST trial (NCT02158858) that were presented at the 2020 European Hematology Association Congress.^1-3

The results showed that, at the time of data cutoff on April 17, 2020, CPI-0610 as monotherapy, as an add-on to ruxolitinib, or in combination with ruxolitinib elicited a significant reduction in spleen volume of at least 35% (SVR35) and total symptom score reduction of at least 50% (TSS50).

“We continue to see signals of disease modification, such as increases in hemoglobin, conversions of transfusion-dependent patients to transfusion independence, and bone marrow fibrosis improvements. If corroborated in further testing, these data suggest that CPI-0610 could potentially change the treatment paradigm in myelofibrosis,” study author, Claire Harrison, MD, DM, FRCP, FRCPath, of the Guy’s and St. Thomas’ NHS Foundation Trust in London, England, stated in a press release.⁴

Patients treated in arm 1 of the trial (n = 43) had advanced myelofibrosis and were refractory to, intolerant of, or ineligible for ruxolitinib. CPI-0610 was given as monotherapy. Patients in arm 2 (n = 70) had experienced a suboptimal response to ruxolitinib or developed disease progression on the JAK inhibitor, and these patients received CPI-0610 as an add-on to ruxolitinib. In arm 3, patients with JAK inhibitor­-naïve myelofibrosis received the combination of CPI-0610 and ruxolitinib.

Arm 1:

On arm 1, patients were split into 1 of 2 cohorts: transfusion dependent (TD; cohort 1A; n = 16) and transfusion independent (TI; Cohort 1B; n = 27).

Among response-evaluable patients in cohort 1A (n = 14), 28.6% experienced SVR35 (95% CI, 8.4%-58.1%) at 12 weeks and 0% at 24 weeks (n = 10; 95% CI, 0%-30.9%). Evaluable patients in cohort 1B (n = 23) had an SVR35 rate of 17.4% at 12 weeks (95% CI, 5.0%-38.8%) and 23.8% at 24 weeks (n = 21; 95% CI, 8.2%-47.2%).

At 12 weeks, the rate of TSS50 was 42.9% of patients in cohort 1A (n = 14; 95% CI, 17.7%-71.1%) and 30% in cohort 1B (n = 20; 95% CI, 11.9%-54.3%). At 24 weeks, the rates were 8.3% (n = 12; 95% CI, 0.21%-38.5%) and 47.4% (n = 19; 95% CI, 24.5%-71.1%), respectively.

The conversion rate from TD to TI among 14 evaluable patients in cohort 1A was 21.4%. Additionally, 57.9% of patients in cohort 1B (n = 19) had at least a 1.5 g/dL increase in hemoglobin from baseline.

Improvement in bone marrow fibrosis within the first 6 months of treatment was also observed in this arm.

Patients in arm 1 had a median age of 69.6 years, and more than half (58.1%) were male. According to the Dynamic International Prognosis Scoring System (DIPSS), 14% of patients were intermediate-1 risk, 58.1% were intermediate-2 risk, and 27.9% were high risk.

Additionally, 67.4% of patients had primary myelofibrosis while 16.3%, 9.3%, and 7% had post–polycythemia vera (PV) myelofibrosis, post–essential thrombocythemia (ET) myelofibrosis, and an unidentified subtype, respectively.

Over half of patients (55.8%) had prior JAK inhibitor therapy for at least 6 months, while 27.9% and 16.3% had JAK inhibitor therapy for less than 6 months or were ruxolitinib naïve, respectively.

At least 3 mutations were present in 60.5% of patients. Moreover, 53.5%, 44.2%, and 65.1% of patients had HMR, ASXL1, or JAK2 V617F mutations, respectively.

Patients had a median hemoglobin level of 9.2 g/dL, the majority of which (74.4%) had a level that was less than 10 g/dL. Additionally, patients had a median platelet count of 178 x 109/L, a median spleen volume of 1954 cc, and a median TSS of 21.7.

Regarding safety, CPI-0610 monotherapy was generally well tolerated. The most common all-grade treatment-emergent adverse effects (TEAEs) included nausea, diarrhea, thrombocytopenia, anemia, respiratory tract infection, dysgeusia, cough, and fatigue.

Grade 3 hematologic TEAEs included thrombocytopenia (14%) and anemia (9.3%).

Six TEAEs led to treatment discontinuation. One patient experienced grade 4 blood bilirubin increase, acute kidney injury, and sepsis. Other TEAEs that led to discontinuation included grade 3 blood creatinine, grade 3 pulmonary mass, grade 3 diarrhea and weigh decrease, grade 2 fatigue and pleuritic pain, and grade 1 diarrhea, dizziness, transient hearing loss, vision loss, and weight decrease.

Although grade 3/4 hyperuricemia was observed in 7% of patients, it was deemed unrelated to CPI-0610 treatment.

Based on these findings, the study has been expanded to 60 patients with TD myelofibrosis who are refractory to, intolerant of, or ineligible for ruxolitinib.

Arm 2:

As in arm 1, patients on arm 2 were grouped into 1 of 2 cohorts: TD (n = 44; cohort 2A) and TI (n = 26; cohort 2B).

In cohort 2A, SVR35 was observed in 12% (n = 25; 95% CI, 2.6%-31.2%) and 20.8% of patients (n = 24; 95% CI, 7.1%-42.2%) at 12 weeks and 24 weeks, respectively. In cohort 2B, these rates were 9.1% (n = 22; 95% CI, 1.1%-29.2%) and 22.2% (n = 18; 95% CI, 6.4%-47.6%), respectively.

In cohort 2A, 54.8% (n = 31; 95% CI, 36.0%-72.7%) of patients at 12 weeks and 46.2% (n = 26; 95% CI, 26.6%-66.6%) of patients at 24 weeks experienced TSS50. Patients in cohort 2B had 12- and 24-week TSS50 rates of 30% (n = 20; 95% CI, 11.9%-54.3%) and 36.8% (n = 19; 95% CI, 16.3%-61.6%), respectively.

Moreover, 34.4% of evaluable patients (n = 32) converted from TD to TI.

Patients had a median age of 67.7, and 60% were male. According to DIPSS, 11.4% of patients were intermediate-1 risk, 64.3% were intermediate-2 risk, and 24.3% were high risk.

As in arm 1, the majority of patients, 68.6%, had primary myelofibrosis. Additionally, 12.9%, 17.1% and 1.4% of patients had post–PV myelofibrosis, post–ET myelofibrosis, or had an unidentified subtype, respectively.

Prior ruxolitinib exposure of at least 6 months was reported in 75.7% of patients. Conversely, 12.9% of patients had received less than 6 months of ruxolitinib, and 11.4% of patients had unidentified pretreatment information.

Regarding mutational profile, 77.1% of patients had at least 3 mutations. Moreover, 61.4% had HMR mutations, 52.9% had ASXL mutations, and 64.3% had JAK2 V617F mutations.

Patients had a median hemoglobin level of 9.0 g/dL, and 74.3% of patients had a level that was less than 10 g/dL. Additionally, patients had a median platelet count of 178 x 109/L, a median spleen volume of 1946 cc, and a median TSS of 19.5.

Regarding safety, the addition of CPI-0610 to ruxolitinib was generally well tolerated and displayed similar TEAEs as CPI-0610 monotherapy. Drug discontinuations due to TEAEs occurred in 10% of patients (n = 70).

Grade 3 hematologic TEAEs included thrombocytopenia (22.9%) and anemia (7.1%). Grade 4 thrombocytopenia and anemia occurred in 1.4% of patients.

Fatal TEAEs included acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage, and disease progression.

Arm 3:

Moreover, in arm 3, the safety population included 64 patients. A total of 30 patients were evaluable for the primary end point of SVR35.

At 12 weeks, 72.5% of patients (n = 51; 95% CI, 58.3%-84.1%) had SVR35 and 58% (n = 50; 95% CI, 43.2%-71.8%) had TSS50. At 24 weeks, these rates were 63.3% (n = 30; 95% CI, 43.9%-80.1%) and 58.6% (n = 29; 95% CI, 38.9%-76.5%), respectively.

Evaluable patients had a median age of 65.6 years, and 73.3% of patients were male. Additionally, 33.3%, 56.7%, and 10% of patients had a DIPSS risk of intermediate-1, intermediate-2, and high, respectively.

Half of the patients had a diagnosis of primary myelofibrosis. One-third of patients had post-ET myelofibrosis, and 10% had post-PV myelofibrosis.

Regarding mutational status, 56.7% of patients had at least 3 mutations. Moreover, 56.7% had an HMR mutation, 43.3% had an ASXL1 mutation, and 66.7% had a JAK2 V617F mutation.

Patients had a median hemoglobin level of 9.4 g/dL, and 56.7% of patients had a level of less than 10 g/dL. Additionally, patients had a median platelet count of 350.5 x 109/L, a median spleen volume of 1740.5 cc, and a TSS of 15.6.

Patient demographics were fairly comparable in the efficacy and safety populations.

The combination of ruxolitinib and CPI-0610 was generally well tolerated among patients in the safety population. All-grade and grade 4 thrombocytopenia were observed in 20.3% and 3.1% of patients, respectively. Similarly, all-grade and grade 4 anemia was observed in 23.4% and 1.6% of patients, respectively.

Common non-hematologic TEAEs included diarrhea, nausea, respiratory tract infection, and abdominal pain.

Two TEAE-related deaths were reported, due to multiorgan failure resulting from sepsis secondary to bacterial endocarditis and multiorgan failure due to sepsis, but secondary to community acquired pneumonia.

Based on these findings, a randomized phase 3 trial of ruxolitinib plus CPI-0610 versus ruxolitinib plus placebo has been initiated in JAK inhibitor‑naïve patients with advanced myelofibrosis.

References

1. Talpaz M, Rampal R, Verstovsek S, et al. CPI-0610, a bromodomain and extraterminal domain protein (BET) inhibitor, as monotherapy in advanced myelofibrosis patients refractory/intolerant to JAK inhibitor: update from phase 2 MANIFEST study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract EP1091.
2. Verstovsek S, Mascarenhas J, Kremyanskaya M, et al. CPI-0610, bromodomain and extraterminal domain protein (BET) inhibitor, as “add-on” to ruxolitinib (RUX), in advanced myelofibrosis patients with suboptimal response: update of phase 2 MANIFEST study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract EP1083.
3. Mascarenhas J, Harrison C, Patriarca A, et al. CPI-0610, a bromodomain and extraterminal domain protein (BET) inhibitor, in combination with ruxolitinib, in JAK inhibitor treatment naïve myelofibrosis patients: update of phase 2 study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract EP1084.
4. Constellation pharmaceuticals provides updates of MANIFEST study for CPI-0610 and EZH2 Franchise. News release. June 12, 2020. Accessed June 16, 2020. bit.ly/3e2FtWm.