Category Archives: Clinical Trial

Karyopharm Shares Data at ASH 2023 Showing Strong SVR and TSS Durability Observed from Phase 1 Study of Selinexor 60mg and Ruxolitinib in JAK Inhibitor (JAKi)-Naïve Myelofibrosis Patients, with no SVR or TSS Progressions Observed As of the Data Cutoff(1)

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Biomarker Data from Phase 1 Study of Selinexor in Combination with Ruxolitinib in Treatment-Naïve Myelofibrosis (MF) Suggestive of Disease Modification

Data Reinforce the Potential for Selinexor in Combination with Ruxolitinib to Become a Novel, First-Line Treatment for JAKi-Naïve Patients with MF

NEWTON, Mass., Dec. 10, 2023 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced long-term follow up of treatment-naïve patients with myelofibrosis (MF) who participated in the Phase 1 portion of its study evaluating once-weekly selinexor in combination with ruxolitinib (NCT04562389). The data, featured in an oral presentation at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023), show patients treated with 60mg selinexor, and who achieved ≥35% reduction in spleen volume (SVR35) at week 24, continued to remain in radiographic response. In addition, all patients who achieved TSS50 at Week 24 remained in response as of the data cut-off.

The data included in the oral presentation for ASH 2023 were based on the Phase 1 portion of the Phase 1/3 study evaluating the safety and efficacy of once-weekly selinexor in combination with ruxolitinib in patients with treatment-naïve MF (NCT04562389). As of August 1, 2023, 24 patients had been assigned to either selinexor 40mg (N= 10) or 60mg (N=14), in combination with ruxolitinib. The maximum duration of follow-up was 78 weeks with a median duration of 32 weeks for SVR35 durability, and a maximum duration of follow-up was 64 weeks with a median duration of 51 weeks for TSS50 durability.

An exploratory biomarker analysis showed a reduction of variant allele frequency (VAF) at week 24 for all three MF driver genes (CALR, MPL, and JAK2) and rapid and sustained reduction of pro-inflammatory cytokine production. Early cytokine reduction at Week 4 was associated with spleen volume reduction (SVR) at Week 24 and was sustained until the end of treatment. The clinical efficacy associated with biomarkers impacting MF biological hallmarks may suggest disease modification.

“The growing body of data from this study suggests that selinexor in combination with ruxolitinib may provide spleen reduction, symptom improvement, long-term durability and disease modification, expanding the benefit this combination may provide to patients with treatment-naïve myelofibrosis, ” said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. “We’re excited about the potential to change treatment paradigms for these patients – and expand the number of patients who benefit from first-line therapy.”

The safety profile was consistent with previous data cuts with no new safety signals observed as of Aug 1st.

“The current standard of care is not associated with consistent molecular or pathologic responses,” said Dr. Sri Tantravahi, University of Utah. “The long-term findings are very exciting as they underscore the potential for durable, clinically relevant responses and modification of disease course. The wait for new options has been long and difficult for the myelofibrosis community, and we welcome this important research to help advance the understanding of XPO1 and JAK inhibitor combinations as a meaningful treatment option for patients.”

“We are encouraged by the attention MPNs (Myeloproliferative Neoplasms) are getting in recent years from companies like Karyopharm,” said Kapila Viges, Chief Executive Officer of MPN Research Foundation. “With patients waiting for more answers to these chronic yet serious blood cancers, we look forward to the data readouts at ASH this year. Efforts to develop better therapies and now combinations of therapies bring hope to the myelofibrosis community and open the potential for more options in the treatment paradigm. For patients, options matter.”

About XPOVIO® (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade® (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO® in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Please refer to the local Prescribing Information for full details.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

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Navitoclax Combo Significantly Reduces Spleen Volume in Myelofibrosis

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Silas Inman

Combining navitoclax with ruxolitinib produced significant reductions in spleen volume by at least 35% at week 24 (SVR35W24) compared with ruxolitinib plus placebo but did not lead to significant changes in total symptom score (TSS) in those with myelofibrosis, according to data from the phase 3 TRANSFORM-1 study (NCT04472598) presented during the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.1

After a median follow-up of 14.9 months (range, 0.0-29.5), navitoclax and ruxolitinib elicited a SVR35W24 for 63.2% of patients compared with 31.5% for placebo plus ruxolitinib, marking a significant overall difference of 31.0% (95% CI, 19.5%-42.5%; P <.0001). At week 24, there was a mean -9.7 change in TSS with navitoclax/ruxolitinib from baseline (95% CI, -11.8 to -7.6) compared with a change of -11.1 for placebo plus ruxolitinib (95% CI, -13.2 to -9.1), which was not statistically significant (P = .2852).

“The spleen volume reduction was doubled and highly statistically significant. There’s no question there, but for the secondary end point, the total symptom score, both groups have the reduction, but it was not statistically significant,” said lead investigator Naveen Pemmaraju, MD, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “There may be multiple reasons for that. Ruxolitinib alone is a nice drug for symptom improvement, but when you add in a second drug, you’re improving the outcomes for the patient but maybe introducing a bit more toxicity. The statistical significance may not have come out because of that.”

Oral navitoclax is a BCL-XL, BCL-2, and BCL-W inhibitor, which may impart unique efficacy for myeloproliferative neoplasms (MPN). “It turns out in MPN and myelofibrosis that the BCL-XL pathway appears to be a bit more important than the BCL-2,” said Pemmaraju. “In myelofibrosis, BCL-XL appears to be upregulated and so in vitro studies showed that either the navitoclax by itself or even better in combination with the ruxolitinib can overcome JAK resistance and add benefit.”

In the combination arm, navitoclax was administered at a starting dose of 200 mg if platelet counts were above 150 x 109 per liter or, if not, at 100 mg, which was later escalated to 200 mg if tolerated and after platelet counts reached greater than 75 x 109 per liter. This methodology was implemented to avoid thrombocytopenia, which was observed in earlier trials with the agent. Ruxolitinib was administered at the standard dose in each arm, although Pemmaraju noted with necessary dose reductions the relative dose intensity was lower. There were 125 patients in the combination arm and 127 in the control group.

In the combination arm, the median age of patients was 70 years (range, 42-87) compared with 69 years (range, 37-85) in the control group. The time from diagnosis to study entry was 8 months (range, 0.3-181.6) in the combination arm and 6 (range, 0.3-198.8) in the control group. Most patients had primary myelofibrosis, at 50% in the investigational arm and 57% in the control group. Other types included transformed version of myelofibrosis, namely those post polycythemia vera and post-essential thrombocythemia. The median spleen volume at entry was 1441 cm3 (range, 419-8020) in the combination group and 1639 cm3 (range, 219-5664) in the control arm.

The median TSS in the combination arm was 21 (range, 0.1-60.6) compared with 24 (range, 6.7-61.6) in the control group. A minority of patients were transfusion dependent at baseline, at 4% in the combination group and 3% in the control arm. The most common risk score was intermediate-2, at 83% in the combination group and 87% in the control. JAK2 V617F was the most common driver mutation, with approximately two-thirds having this mutation in each group. Nearly half of patients had mutations associated with high molecular risk. “These high molecular risk mutations are very important,” said Pemmaraju. “Earlier studies may not have captured this, and we were fortunate to capture this in the majority of patients.”

There was a significantly higher rate of SVR35 with the combination at all time points throughout the study. Across the full-time scale of the study, 76.8% of those in the combination arm experienced a SVR35 compared with 41.7% with ruxolitinib plus placebo, which was a meaningful 34.6% reduction (95% CI, 23.6%-45.6%; P <.0001). The median time to first SVR35 response was similar between groups, at 12.3 (range, 10.1-48.3) vs 12.4 (range, 11.3-72.3) weeks, for the combination and control arms, respectively. Fewer patients lost SVR35 in the combination group (18.8%) compared with the control arm (26.4%). Nearly three-fourths of patients had a 12-month duration of SVR35 in each arm (76.7% vs 76.9%, combination and control, respectively).

The rate of any grade adverse effect (AE) was common between arms, with more patients in the combination arm having a grade 3 or higher AE (85% vs 70%). The most common grade 3 or higher AEs in the combination vs control arms, respectively, were thrombocytopenia (51% vs 15%), anemia (46% vs 39%), and neutropenia (38% vs 4%). For all grade events, diarrhea was more commonly seen with the combination vs control (34% vs 14%). Serious AEs were less common with the combination at 26% compared with 32% for the control arm. AEs that led to dose reduction or dose interruption were twice as common in the combination arm.

“Importantly, dose reductions and interruptions were mostly due to the thrombocytopenia, but importantly none of those were due to clinical bleeding,” said Pemmaraju.

In 2022, AbbVie, the company developing navitoclax noted plans for a submission to the FDA in 2023, pending pivotal study results.2 At this time, the agent is not approved.

References

  1. Pemmaraju N, Mead AJ, Somervaille T, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023;142(suppl 1):620.doi:10.1182/blood-2023-173509
  2. AbbVie presents positive investigational navitoclax combination data in phase 2 REFINE study suggesting anti-fibrosis activity for patients with myelofibrosis. News release. AbbVie. April 12, 2022. Accessed December 10, 2023. https://news.abbvie.com/2022-04-12-AbbVie-Presents-Positive-Investigational-Navitoclax-Combination-Data-in-Phase-2-REFINE-Study-Suggesting-Anti-Fibrosis-Activity-for-Patients-with-Myelofibrosis

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Study yields ‘encouraging’ preliminary data for navitoclax combination in myelofibrosis

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December 11, 2023

Key takeaways:

  • Navitoclax plus ruxolitinib led to improvement in spleen volume reduction in patients with untreated myelofibrosis.
  • Adverse events of thrombocytopenia and anemia appeared common but manageable.

SAN DIEGO — Navitoclax added to ruxolitinib led to a significant improvement in spleen volume reduction compared with placebo among patients with untreated myelofibrosis, study results presented at ASH Annual Meeting and Exposition showed.

Findings from the phase 3 TRANSFORM-1 study suggest the combination therapy has a manageable safety profile that appeared consistent with the use of both agents in previous studies, according to researchers.

“The is the first randomized trial in JAKi-naive [myelofibrosis] with a navitoclax and ruxolitinib combination, which led to a in spleen volume reduction 35% at week 24 twice as high as placebo plus ruxolitinib, with similar symptom response despite a lower average dose of ruxolitinib,” Naveen Pemmaraju, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation.

Background and methodology

The double-blind TRANSFORM-1 study assessed the efficacy and safety of navitoclax (AbbVie) — and investigational Bcl-2 inhibitor — plus the JAK2 inhibitor ruxolitinib (Jakafi, Incyte) compared with placebo plus ruxolitinib among adults with JAK2 inhibitor-naive myelofibrosis.

Inclusion criteria included adults with intermediate- or high-risk myelofibrosis with measurable splenomegaly, evidence of myelofibrosis-related symptoms, no prior JAK2 inhibitor treatment, and an ECOG performance score less than or equal to 2.

Researchers randomly assigned patients in a 1:1 ratio to ruxolitinib plus either navitoclax or placebo.

Spleen volume reduction 35% at week 24 served as the study’s primary efficacy endpoint. Secondary endpoints included change in total symptom score at week 24, spleen volume reduction 35% at any time, duration spleen volume reduction 35%, anemia response, reduction in marrow fibrosis, OS, leukemia-free survival, reduction in PROMIS Fatigue scale and improvement in EORTC QLQ-C30 physical functioning scale.

The study included 252 patients (125 received navitoclax and ruxolitinib, 127 received placebo plus ruxolitinib; median age, 69 years; 57% male) with a median follow-up of 14.9 months (0 – 29.5 months).

Results and next steps

Researchers reported that 79 patients (63.2%) in the investigative arm achieved spleen volume reduction 35% at week 24, compared with 40 patients (31.5%) in the control arm, thus meeting the study’s primary efficacy endpoint. Additionally, researchers noted that 96 patients (77%) in the investigative arm achieved spleen volume reduction 35% at any time, whereas 53 patients (42%) did so in the control arm.

Median duration of spleen volume reduction 35% had not been reached in the investigative arm compared with 19.4 months (95% CI, 16.8 months to not yet reached) in the control arm.

Researchers observed grade 3 or higher adverse events among 85% of patients in the navitoclax arm and for 70% of patients in the placebo arm. The most common adverse events among patients receiving navitoclax included thrombocytopenia, anemia, diarrhea, and neutropenia.

Additionally, 26% of patients in the navitoclax arm and 32% of patients in the placebo arm experienced serious adverse events, including anemia, thrombocytopenia and neutropenia.

With navitoclax treatment, adverse events led to a dose reduction of the agent in 101 patients (81%) and treatment interruption in 87 patients (70%).

Among enrolled patients, 83 (33%) discontinued study treatment. The most common reason for discontinuation included adverse events (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). Thirteen patient deaths occurred in each study arm.

“Adverse events of thrombocytopenia, anemia and neutropenia were common but manageable with dose modification without any clinically significant sequelae,” Pemmaraju said. “Preliminary data are encouraging and additional evaluations are ongoing to assess additional outcomes of overall survival and responses in subgroups.”

Source: 

Pemmaraju N, et al. Abstract 620. Presented at: ASH Annual Meeting and Exhibition; Dec. 5-9, 2023; San Diego.

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Navitoclax with Ruxolitinib Improves Myelofibrosis with Manageable Safety

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By Patrick Daly

December 6, 2023

Ruxolitinib combined with navitoclax induced spleen volume reduction of ≥35% at week 24 (SVR­35W24) at a rate twice as high as with ruxolitinib and placebo in Janus kinase (JAK) inhibitor–naïve patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF), according to authors of the ongoing phase III TRANSFORM-1 study.

The study, evaluated the doublet therapy to address “a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival” in patients with MF, according to lead author, Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston. Findings were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

The cohort included 252 patients with a median age of 69 (range, 37–87) and intermediate-2 or high-risk MF with splenomegaly, signs of MF-related symptoms, no prior JAK2 inhibitor therapy, and an Eastern Cooperative Oncology Group performance score of 2 or less.

The primary outcome was SVR­35W24, and secondary outcomes included change in Myelofibrosis Symptom Assessment Form total symptom score (TSS) at week 24, SVR­35 at any time, SVR­35 response duration, anemia response, reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in fatigue, and improvement in physical functioning at the data cutoff of April 13, 2023.

Investigators noted 79 of 125 (63.2%) patients in the navitoclax group achieved SVR­35W24 compared with 40 of 127 (31.5%) in the placebo group (P<0.0001). Furthermore, 96 (77%) patients on navitoclax achieved SVR­35 at any time compared with 53 (42%) patients on placebo.

The median time to SVR response was 12.3 weeks (range, 10.1–48.3) in the navitoclax group versus 12.4 weeks (range, 11.3–72.3) in the placebo group. Patients in the navitoclax group had a mean change from baseline in TSS of –9.7 (95% CI, –11.8 to –7.6) at week 24, whereas patients in the placebo group had a mean change of –11.1 (95%CI, –13.2 to –9.1; P=0.2852).

Adverse events (AEs) of grade 3 or higher occurred in 85% and 70% of navitoclax and placebo patients, respectively. The most common AEs in greater than 30% of patients on navitoclax were thrombocytopenia, anemia, diarrhea, and neutropenia.

Serious AEs occurred in 26% of patients in the navitoclax and 32% of patients in the placebo group, including anemia in two and one patients, respectively, as well as thrombocytopenia and neutropenia in two and one navitoclax patients. Overall, 39% of navitoclax or placebo discontinuations were due to AEs, and 17% were due to a physician’s decision.

Overall, “the responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae,” the authors summarized.

Reference

Pemmaraju N, Mead AJ, Somervaille TCP, et al. A randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Abstract #620. Presented at the 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

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Phase II Data on Pelabresib Combination for Myelofibrosis Leads to Launch of Phase III Double-Blind Trial

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By Patrick Daly

December 6, 2023

Pelabresib in combination with ruxolitinib exhibited significant clinical activity and disease-modifying potential without treatment-limiting toxicities among patients with myelofibrosis (MF) in the ongoing phase II MANIFEST study, according to lead author, Raajit Rampal, MD, PhD, of the Memorial Sloan Kettering Cancer Center in New York City.

Pelabresib is an investigational oral small-molecule agent that inhibits BET-driven gene transcription that contributes to MF pathogenesis.

Following the findings of MANIFEST, Dr. Rampal and colleagues initiated the phase III MANIFEST-2 trial to further evaluate pelabresib plus ruxolitinib. Primary findings from MANIFEST-2 were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

The global, double-blind, active control study screened 591 patients at 138 sites, and ultimately randomized 431 Janus kinase inhibitor (JAKi)-naïve patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF to either pelabresib plus ruxolitinib or placebo plus ruxolitinib.

Patients were eligible if they had a Dynamic International Prognostic Scoring System score of intermediate-1 or higher, platelet count of ≥100 × 109/L or greater, spleen volume of ≥450 cm3 or greater, two or more symptoms with an average score of three or greater on the Myeloproliferative Neoplasm Symptom Assessment Form (or a Total Symptom Score [TSS] of ≥10), peripheral blast count less than 5%, and an Eastern Cooperative Oncology Group performance status of two or less.

The primary endpoint was spleen volume reduction of ≥35% (SVR35) at week 24, and secondary endpoints included TSS changes, safety, pharmacokinetics, bone marrow fibrosis changes, progression-free survival, overall survival, and transfusion requirement and rates.

“MANIFEST-2 has completed recruitment and will provide definitive efficacy results of combination therapy in JAKi treatment-naïve pts with MF,” the authors stated, adding that “MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease.”

Reference

Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Abstract #628. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

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Ruxolitinib Treatment Outperforms Best Available Therapy in Pooled Analysis

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By Patrick Daly

December 6, 2023

Patients with polycythemia vera (PV) who received ruxolitinib treatment achieved sustained hematocrit control over 80 weeks and had improved symptom control at week 16 compared with patients who received best available therapy (BAT), based on a post hoc pooled analysis of data from the RESPONSE and RESPONSE 2 trials.

The efficacy data were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California, by lead author, Claire Harrison, MD, of the Guy’s and St. Thomas’ NHS Foundation Trust in London, United Kingdom.

“Reductions in JAK2V617F allele burden were consistently observed through Week 208 in patients treated with ruxolitinib, including those who crossed over from BAT,” Dr. Harrison and colleagues reported.

The analysis assessed 371 pooled patients from RESPONSE and RESPONSE 2, of which 184 were treated with ruxolitinib and 187 with BAT. The cohort had a median age of 61.8 ± 11 years and most patients were White (88.1%) and male (62.5%). Hematocrit control was defined as hematocrit maintained below 45% starting week 16 plus one or less phlebotomy between baseline and week four.

At week 28, the proportion of patients with hematocrit control was 62.0% (95% CI, 54.5-69.0) in the ruxolitinib group versus 18.2% (95% CI, 12.9-24.5) in the BAT group. Further, 47.3% (95% CI, 39.9-54.8) of patients in the ruxolitinib group had sustained hematocrit control through week 80; authors noted nearly all patients in the BAT group had crossed over to the ruxolitinib group by that point.

The proportion of patients who achieved a 50% or greater reduction from baseline in Myeloproliferative Neoplasms Symptoms Assessment Form Total Symptom Score at week 16 was 48.7% (95% CI, 40.7-56.8) in the ruxolitinib group compared with 18.0% (95% CI, 12.5-24.6) in the BAT group (odds ratio, 4.3; 95% CI, 2.6-7.2), and the mean change in score was -4.4 ± 10.0 and 0.6 ± 6.9, respectively.

Additionally, patients randomized to ruxolitinib had consistently decreased JAK2V617F allele burden through week 208, and mean JAK2V617F allele burden decreased from 66.1% to 41.4% at four years.

“Taken together, these results provide further evidence of the patient benefit of ruxolitinib in patients with PV with or without splenomegaly,” Dr. Harrison and colleagues concluded.

Reference

Harrison C, Kiladjian JJ, Palandri F, et al. Ruxolitinib treatment in polycythemia vera results in reduction in JAK2 allele burden in addition to improvement in hematocrit control and symptom burden. Abstract #4553. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

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New Developments in MPN Management Provide Additional Options for Patients

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December 5, 2023

Kyle Doherty

Although myeloproliferative neoplasms (MPNs), which are comprised of essential thrombocythemia, polycythemia vera (PV), and myelofibrosis, remain relatively rare— with estimated annual incidence rates of 1.03, 0.84, and 0.47 per 100,000 individuals, respectively—there remains an unmet need for effective treatment options for patients with these diseases who progress on standard of care therapies.1 However, significant progress has been made in terms of understanding this group of disorders and developing treatment strategies to combat them, with Naveen Pemmaraju, MD, saying the medical field has entered a “golden era” of MPN treatment.

During a recent OncLive Peer Exchange® video series titled “Expert Insights Into the Management of MPNs,” Jamile M. Shammo, MD, explained, “MPNs represent a heterogeneous group of hematopoietic stem cell neoplasms that share common features. Myeloid proliferation is certainly something that we see [in MPNs], as well as a propensity for thrombotic events, symptoms that are related either to constitutional symptoms or splenomegaly related. All 3 entities tend to progress to higher myeloid neoplasms; essential thrombocythemia [to] PV that goes to myelofibrosis and then myelofibrosis can evolve into acute leukemia. Of course, the rate of progression varies from one entity to the other, with essential thrombocythemia having the lowest risk [of progression].”

The development of MPNs is almost always associated with mutations in JAK2, making this family of genes an attractive treatment target. JAK2 mutations are observed in approximately 95% of patients with PV and approximately 50% of both patients with essential thrombocythemia and myelofibrosis. Notably, the emergence of additional treatment targets also has sparked the development of novel agents in recent years.1

During the discussion, expert oncologists reviewed updated findings from ongoing and completed clinical trials in the field. They primarily focused on studies evaluating emerging agents in PV and myelofibrosis.

MANAGING PV

Abdulraheem Yacoub, MD, began the discussion on PV by noting that the JAK1/2 inhibitor ruxolitinib (Jakafi) has been the standard-of-care agent in PV since 2015. Prior to this, PV was historically managed with phlebotomy, hydroxyurea, and/or interferons. Ruxolitinib became the first FDA-approved drug for the treatment of patients with PV in December 2014 when it received an indication from the agency for patients who had an inadequate response to or were intolerant of hydroxyurea.2

“The introduction of ruxolitinib to the treatment landscape of patients with myelofibrosis has truly been transformative,” Shammo commented. “We all remember the patients we had in the clinic [in the past] and how we had simply nothing but supportive care to offer. Ruxolitinib was approved based on the results of 2 phase 3 studies. COMFORT-I [NCT00952289] randomly assigned patients [with myelofibrosis] to receive ruxolitinib or placebo and examined [spleen] volume reduction and reduction in total symptom score from baseline at 24 weeks. COMFORT-II [NCT00934544], which ran mostly in Europe, randomly assigned patients to be treated with ruxolitinib or best available therapy [as selected by the investigator]. This study [also evaluated] spleen volume reduction, but at week 48. In either trial, ruxolitinib was statistically significantly more active in attaining the primary end point and for that reason it was approved. Some might say that the evidence is perhaps less compelling than what you would [typically] find in a phase 3 study, but when you have multiple studies showing the same thing, that treatment with ruxolitinib improves [outcomes] compared with placebo or best available therapy, I tend to feel like it’s reasonable enough to believe that actually is the case.”

Long-term data from 2 phase 3 trials, RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036), comparing the safety and efficacy of ruxolitinib with best available therapy in different patient populations with PV recently were published in The Lancet Haematology. RESPONSE enrolled adult patients with PV who were resistant to or intolerant of hydroxyurea and randomly assigned them 1:1 to receive either ruxolitinib (n = 110) or best available therapy (n = 112; hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide (Agrylin), approved immunomodulators, or observation without pharmacological treatment). RESPONSE-2 enrolled a higher-risk patient population; eligible patients had inadequately controlled PV without splenomegaly and were intolerant of or resistant to hydroxyurea with an ECOG performance status of 2 or less. They were randomly assigned to receive ruxolitinib (n = 74) or best available therapy (n = 75).3,4

Follow-up data from RESPONSE demonstrated that the 5-year overall survival (OS) rate was 91.9% (95% CI, 84.4%-95.9%) in the ruxolitinib group vs 91.0% (95% CI, 82.8%-95.4%) in the best available therapy arm. Most patients (88%) in the best available therapy arm crossed over to receive ruxolitinib, and no patients remained in this arm after week 80. There were 25 primary responders in the ruxolitinib arm, 6 of whom had progressed by the time of the final analysis. The 5-year probability of maintaining a primary composite response was 74% (95% CI, 51%-88%), the probability of maintaining complete hematological remission was 55% (95% CI, 32%-73%), and the probability of maintaining overall clinicohematological responses was 67% (range, 54%-77%).3

At a median follow-up of 67 months (IQR, 65-70), findings from RESPONSE-2 showed that the 5-year OS rate was 96% (95% CI, 87%-99%) in the ruxolitinib arm compared with 91% (95% CI, 80%-96%) in the best available therapy arm. In the ruxolitinib arm, 22% of patients (95% CI, 13%-33%) achieved durable hematocrit control with an estimated median duration of control not reached (NR) at week 260 (95% CI, 144-NR). Most patients in the best available therapy arm (77%) crossed over to ruxolitinib, no patients continued with best available therapy after week 80 per protocol, and the median duration of hematocrit control was not reported due to the small number of responders at week 80.4

In light of findings from RESPONSE and RESPONSE-2, investigators in both studies concluded that ruxolitinib is a safe and effective long-term treatment option for patients with PV for whom hydroxyurea proved ineffective.3,4

“Both studies have ong-term follow-up and have published 5-year data showing very durable responses,” Yacoub said. “There were very few late failures on ruxolitinib and no unexpected adverse effects were observed with longterm follow up. This has built a strong case for ruxolitinib as a standard treatment for patients [with PV] after hydroxyurea failure.”

Ropeginterferon Takes Center Stage

A more recent breakthrough for patients with PV was the emergence of the interferon ropeginterferon alfa-2b-njft (Besremi). In November 2021, ropeginterferon became the first agent to receive FDA approval for patients with PV regardless of their treatment history.5

Ropeginterferon was compared with hydroxyurea in the phase 3 PROUD-PV trial (NCT01949805) and its extension continuation study, CONTI-PV (NCT02218047). Eligible patients were 18 years or older and had earlystage PV with no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment. Patients could opt to enter CONTI-PV after 1 year of initial treatment in PROUD-PV.6

Findings from the studies revealed that at a median follow-up of 182.1 weeks (IQR, 166.3- 201.7) patients in PROUD-PV who received ropeginterferon (n = 122) achieved complete hematological response with normal spleen size at a rate of 21% compared with 28% of patients who received hydroxyurea (n = 123). However, in CONTI-PV, 53% of patients in the ropeginterferon arm (n = 95) had a complete hematological response with improved disease burden at 36 months vs 38% of patients in the hydroxyurea arm (n = 74; P = .044). Moreover, at 36 months in CONTI-PV, the complete hematological response rate regardless of spleen criterion was 71% vs 51% in the investigative and comparator arms, respectively (P = .012); at 12 months in PROUD-PV these rates were 43% vs 46%, respectively (P = .63).6

Study authors concluded that ropeginterferon was effective in inducing hematological responses. Although noninferiority to hydroxyurea in terms of hematological response and normal spleen size was not observed at 12 months, improved responses vs hydroxyurea were present at 36 months. Thus, the authors wrote that ropeginterferon offers an effective and “safe long-term avenue for treatment with distinct features from hydroxyurea.”6

“It’s wonderful to have options because we get patients with PV [who] could not be any more different,” Yacoub said. “They have different goals of care, and at the end of the day, we are treating individual patients, not diseases. For each patient, we have to define what we are trying to achieve. There are patients who are going to live with the disease a lot longer. They have more high-risk presentations and would benefit from the maximum data that we have with the application of the effective agents. There are patients who have relatively low-risk disease, and they’re likely going to live their natural lives with some medical management from our end. We have to individualize our choices.”

Looking ahead, the phase 3 VERIFY trial (NCT05210790) is underway with the aim of adding rusfertide (PTG-300), a novel and potent hepcidin mimetic, to the PV treatment landscape. Rusfertide previously demonstrated clinical activity in early-phase studies, characterized by good tolerability and consistent and durable hematocrit control, as well as improvements in iron deficiency among patients who required higher than normal amounts of phlebotomies even after standard-of-care therapy.7

VERIFY is enrolling patients with PV who have received at least 3 phlebotomies in the previous 6 months or at least 5 in the previous 12 months as a result of inadequate hematocrit control, with or without concurrent cytoreductive therapy. Eligible patients will be randomly assigned 1:1 to receive either placebo plus ongoing therapy or rusfertide plus ongoing therapy.

Part 1a of the trial is the double-blind, placebo- controlled, add-on phase that will enroll parallel groups and last 32 weeks. During part 1b, patients who complete part 1a will receive rusfertide for 20 weeks. Patients who successfully complete part 1b will enter the long term extension phase, part 2, and will continue to be treated with rusfertide for 104 weeks. The primary end point is the proportion of patients achieving a response in from week 20 to week 32 in part 1A. The study was initiated in January 2022 and has a target enrollment of 250 patients.7

Managing Myelofibrosis

Patients with myelofibrosis have more FDA-approved treatment options than those with PV. To date, 3 Janus kinase (JAK) inhibitors have been approved for the treatment of patients with myelofibrosis: ruxolitinib, fedratinib (Inrebic), and pacritinib (Vonjo).

Similar to PV, ruxolitinib became the first FDA-approved therapy for the treatment of patients with myelofibrosis, gaining an indication for patients with intermediate- and high-risk disease in November 2011. In August 2019, patients with intermediate- 2 or high-risk primary or secondary myelofibrosis gained fedratinib as an FDA-approved option. Finally, the FDA approved pacritinib in March 2022 for the treatment of adult patients with intermediate- or high-risk primary or secondary myelofibrosis with platelet levels below 50,000/μL.8-10

“The current NCCN [National Comprehensive Cancer Network] guidelines are really agnostic of the second-line therapy, which is interesting,” Raajit K. Rampal, MD, PhD, said. “You can start a patient who [at that time] has over 50,000 platelets on ruxolitinib or fedratinib. And if there is a need to change therapy, you could use any of these 3 agents. That’s an important message for our audience to remember, that the second line is not platelet restricted. We have an abundance of options.”

After summarizing updated data from pivotal trials of the already approved agents, the panelists shifted their focus to new findings from trials evaluating investigational therapies beyond JAK inhibitors in myelofibrosis. Updates from the studies were presented during the 2023 American Society of Clinical Oncology Annual Meeting in June.

Novel Agents Seek to Augment the Armamentarium

In the phase 2 ACE-536-MF-001 trial (NCT03194542), investigators examined the erythroid maturation agent luspatercept-aamt (Reblozyl) for the management of anemia in patients with myelofibrosis; it occurs in approximately 40% of patients. Investigators noted that luspatercept demonstrated anemia improvement across all cohorts of in the study, regardless of transfusion dependency and use of ruxolitinib. For example, 26.3% (95% CI, 13.4%- 43.1%) of patients who were red blood cell transfusion dependent and received prior ruxolitinib (n = 38) achieved transfusion independence following treatment with luspatercept.11

The phase 1/2 LIMBER study (NCT04455841) evaluated the safety and efficacy of the oral ALK2 inhibitor zilurgisertib alone and in combination with ruxolitinib in adult patients with intermediate 1 or 2 primary or secondary myelofibrosis. Among patients in the monotherapy group who were not transfusion dependent (n = 6), anemia improvement (hemoglobin increase of ≥ 1.5 g/ dL relative to baseline) occurred in 1 patient; this level of improvement was observed in 3 of 9 patients in the combination group. Zilurgisertib monotherapy or combination therapy with ruxolitinib was determined to be generally well tolerated and displayed the potential for therapeutic activity, the study authors concluded.12

Another phase 1/3 trial, XPORT-MF-034 (NCT04562389) evaluated a ruxolitinibcontaining combination, this time with the selective inhibitor of nuclear export selinexor (Xpovio) in patients with JAK inhibitor–naive myelofibrosis. At week 24, efficacy-evaluable patients (n = 22) achieved spleen volume reduction of at least 35% (SVR35) from baseline at a rate of 64%. Investigators noted that the combination displayed encouraging activity, and updated data will be made available at a future date.13

Finally, in a single-arm phase 2b study (NCT04217993) the oral, novel JAK/ACVR1 inhibitor jaktinib showed promising activity in patients with myelofibrosis who were intolerant to ruxolitinib. Efficacy-evaluable patients who received jaktinib (n = 44) achieved an SVR35 rate of 43% at 24 weeks, and the best spleen response rate was 55%. Notably, response was maintained for a minimum of 12 weeks in 80% of patients.14

“It’s exciting to have all these non-JAK inhibitors [in the pipeline],” Rampal said in conclusion. “Ultimately, hopefully, we can figure out what the best fit is for an individual patient. We’re not there yet, but with an abundance of data, we’ll get there. It’s also important to note that there are a number of agents that are earlier on [in development] that are moving along. Even beyond this next generation of non-JAK inhibitors already in the pipeline, there is a generation beyond that that is in clinical trial development.”

References

  1. McMullin MF, Anderson LA. Aetiology of myeloproliferative neoplasms. Cancers (Basel). 2020;12(7):1810. doi:10.3390/cancers12071810
  2. FDA approves ruxolitinib. News release. FDA. Updated February 22, 2016. Accessed October 18, 2023. bit.ly/3PVXObQ
  3. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera
    (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8
  4. Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus bestavailable therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480-e492. doi:10.1016/ S2352-3026(22)00102-8
  5. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed October 18, 2023. bit.ly/3rXAt1u
  6. Gisslinger H, Klade C, Georgiev P, et al; PROUD-PV Study Group. Ropeginterferon alfa-2b versus standard therapy for polycythaemia
    vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol.
    2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4
  7. Verstovsek S, Kuykendall A, Hoffman R, et al. Verify: a phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2022;140(suppl 1):3929-3931. doi:10.1182/ blood-2022-163755
  8. Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):3008-3014. doi:10.1158/1078-0432.CCR-11-3145
  9. FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed October 18, 2023. bit.ly/3s30OuX
  10. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed October 18, 2023. bit.ly/3S0PVVj
  11. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: results from the ACE-536-MF-001 study. J Clin Oncol.2023;41(suppl 16):7016.doi:10.1200/JCO.2023.41.16_suppl.7016
  12. Bose P, Mohan S, Oh S, et al. Phase 1/2 study of the activin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB000928,
    LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients (pts) with anemia due to myelofibrosis (MF). J Clin Oncol. 2023;41(suppl 16):7017. doi:10.1200/JCO.2023.41.16_suppl.7017
  13. Ali H, Kishtagari A, Maher KR, et al. Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with
    myelofibrosis: updated results from XPORT-MF-034. J Clin Oncol. 2023;41(suppl 16):7063. doi:10.1200/JCO.2023.41.16_suppl.7063
  14. Zhang Y, Zhou H, Xiao ZJ, et al. Jaktinib in patients (pts) with myelofibrosis (MF) who were intolerant to ruxolitinib (RUX): an open-label, single-arm phase 2b study. J Clin Oncol. 2023;41(suppl 16):7061.doi:10.1200/JCO.2023.41.16_suppl.7061

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Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis

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Zijian Fang, Giuditta Corbizi Fattori, Thomas McKerrell, Rebecca H. Boucher, Aimee Jackson, Rachel S. Fletcher, Dorian Forte, Jose-Ezequiel Martin, Sonia Fox, James Roberts, Rachel Glover, Erica Harris, Hannah R. Bridges, Luigi Grassi, Alba Rodriguez-Meira, Adam J. Mead, Steven Knapper, Joanne Ewing, Nauman M. Butt, Manish Jain, Sebastian Francis, Fiona J. Clark, Jason Coppell, Mary F. McMullin, et al.

Abstract

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.

Introduction

Myeloproliferative neoplasms (MPN) arise from mutations acquired by HSPCs, most frequently affecting the genes encoding the kinase JAK21,2,3,4 or the multi-functional protein CALR5,6. Currently JAK1/2 inhibitors can improve disease-related symptoms and overall survival but have a limited impact on clone size7,8, likely because they cannot discriminate between mutant and wild-type JAK2 or due to the acquisition of pharmacological resistance9,10,11. Allogeneic HSC transplantation remains the only curative treatment for MPN but can only be performed in a minority of patients due to its toxicity12, warranting investigation of new therapies.

Men exhibit a higher prevalence of myeloid neoplasia compared with women13,14. Furthermore, MPN subtypes with poorer prognosis (primary myelofibrosis and polycythemia vera, compared with essential thrombocythemia) have a higher prevalence in males than in females15,16,17. Additionally, the risk of secondary myelofibrosis, which worsens the outcomes of PV/ET, is higher for men than for women, regardless of their age17,18,19. However, the reasons underlying this gender difference are unclear. It is possible that sex-chromosome genes and gender-dependent differences in epigenetic regulation, metabolism or immune response partly account for sexual dimorphism in cancer20. Another explanation might be the loss of sex chromosomes with age, which preferentially occurs in males, perhaps suggesting a higher genomic instability in men21.

However, one key determinant of gender disparities in cancer might be the effect of sex hormones20. Estrogens regulate the self-renewal, proliferation, and apoptosis of mouse hematopoietic stem and progenitor cells (HSPCs)22,23. Estrogen receptors (ERs) are differentially expressed in mouse HSPC subsets22. ERα activation induces proliferation of mouse long-term HSCs22,23 and protects them from proteotoxic stress through the modulation of UPR24. The selective ER modulator (SERM) tamoxifen induces apoptosis of multipotent hematopoietic progenitors but spares normal HSCs22. In MPN mouse models, tamoxifen restores the physiological apoptosis levels in mutant HSCs and selectively eliminates these cells, but not their non-mutated counterparts22. Based on these preclinical studies, we conducted a Phase II, multicenter, single-arm A’herns design clinical trial assessing tamoxifen’s safety and activity in reducing molecular markers of disease burden in MPN (TAMARIN). Here we report the results of the TAMARIN study. In addition, we describe an exploratory analysis of HSPCs from study patients and associated laboratory research investigating the mechanism of action of tamoxifen in human MPN.

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MANIFEST-2 Meets Primary End Point With Pelabresib Plus Ruxolitinib in MF

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November 21, 2023

By Jordyn  Sava

The combination of pelabresib (CPI-0610), an investigational BET inhibitor, with the ruxolitinib (Jakafi), a JAK inhibitor, demonstrated a statistically significant and clinically meaningful improvement in the proportion of JAK inhibitor-naive patients with myelofibrosis (MF) achieving at least a 35% reduction in spleen volume (SVR35) at week 24 compared with placebo plus ruxolitinib, according to topline results from the phase 3 MANIFEST-2 study (NCT04603495).1

A total of 66% of patients treated with pelabresib plus ruxolitinib achieved SVR35 at week 24 vs 35% of patients given placebo plus ruxolitinib (95% CI, 21.6-39.3; P <.001), meeting the primary end point of the study.

Further, the key secondary end points of symptom improvement in patients achieving at least a 50% reduction in total symptom score (TSS50) and absolute change in total symptom score (TSS) from baseline at week 24 were also promising with a strong positive trend favoring pelabresib plus ruxolitinib combination with TSS reduced by 15.99 points at week 24 at baseline vs 14.05 points at week 24 in the placebo plus ruxolitinib arm (Δ -1.94; 95% CI, -3.92-0.04, P =.0545), using least square mean estimate.

“Pelabresib is a first-in-class oral inhibitor of BET proteins, primarily those containing the BD1 and BD2 domains. It’s being developed currently in myelofibrosis. It has been tested in other diseases, but it has shown significant activity in myelofibrosis,” said Joseph M. Scandura, MD, PhD, Weill Cornell Medicine,in an interview with Targeted OncologyTM.

“I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis,” said John Mascarenhas, MD, director of the adult leukemia program at The Tisch Cancer Institute at Mount Sinai, New York, in a press release.1 “The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume—the best prognostic indicator we have at our disposal for long-term myelofibrosis patient outcomes. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation.”

MANIFEST-2 is an ongoing, randomized, double-blind, phase 3 trial where 430 patients with JAK inhibitor-naive MF were randomly assigned in a 1:1 ratio to receive upfront pelabresib plus ruxolitinib vs ruxolitinib alone.2

Patients aged ≥ 18 years with a confirmed diagnosis of MF, adequate hematologic, renal, and hepatic function, and an ECOG performance status of ≤ 2 were eligible for inclusion in the trial. Enrollment was also open to patients who had at least 2 symptoms with an average score ≥ 3 or an average total score of ≥ 10 over the 7-day period prior to randomization using the MFSAF v4.0, a prognostic risk-factor score of intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) scoring system, and a spleen volume of ≥ 450 cm3.

If patients had splenectomy or splenic irradiation in the previous 6 months, chronic or active conditions and/or concomitant medication use that would prevent them from receiving treatment, or had previously been treated with any JAK or BET inhibitor for treatment of a myeloproliferative neoplasm, they were excluded from the study.

Additional findings showed that treatment with the combination also showed significant improvements in both key secondary end points within an analysis of patients classified as intermediate risk who made up over 90% of patients in MANIFEST-2. DIPSS Int-1 and Int-2 was a predefined stratification factor in the protocol for the MANIFEST-2 trial. Here, TSS was reduced by 15.18 points at week 24 with pelabresib plus ruxolitinib vs 12.74 points at week 24 in the placebo plus ruxolitinib arm (Δ -2.44; 95% CI, -4.48- -0.40; P <.02).1

Another key secondary end point, TSS50, was met among 52% of patients treated with pelabresib and ruxolitinib at week 24 vs 46% treated with placebo plus ruxolitinib (95% CI, -3.5-15.5; P =.216).1 Among patients at intermediate-risk, 55% of patients achieved TSS50 in the pelabresib and ruxolitinib treatment arm at week 24 compared with 45% in the placebo plus ruxolitinib arm (95% CI, 0.35-19.76; P <.05).

Following a Type C meeting with the FDA in September 2023, absolute change in TSS was included as a key secondary end point in the study. Per clinical protocol, this continuous end point was created to directly measure change in the average TSS from baseline to week 24 to help accurately estimate the magnitude of symptom burden reduction among patients with MF.

Findings from MANIFEST-2 also demonstrated that more patients achieved hemoglobin response (≥ 1.5 g/dL from baseline)in the pelabresib and ruxolitinib arm vs the placebo and ruxolitinib arm. For safety, the safety profile of pelabresib and ruxolitinib was consistent with what was previously observed with the combination and no new safety signals were observed. Adverse events of anemia were seen less frequently among patients in the pelabresib and ruxolitinib arm than those in the placebo and ruxolitinib arm.

Findings from the phase 3 MANIFEST-2 study will be further presented during an oral presentation at the 65th American Society for Hematology Annual Meeting and Exposition. Based on this encouraging data, continued conversations with regulatory agencies will occur with hopes of submitting a new drug application for combination of pelabresib and ruxolitinib in MF to the FDA in the middle of 2024.

“Myelofibrosis patients experience a severely diminished quality-of-life due to symptoms such as severe fatigue, night sweats, bone pain and fever—symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” said Ruben A. Mesa, MD, FACP, president and executive director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, in a press release.1 “Total symptom score assessment is a validated tool to document the challenges that patients encounter on a daily basis. The symptom reduction shown in MANIFEST-2 is an important result that should be strongly considered when evaluating the efficacy of the pelabresib and ruxolitinib combination therapy for myelofibrosis.”

REFERENCES:
  1. MorphoSys’ phase 3 study of pelabresib in myelofibrosis demonstrates statistically significant improvement in spleen volume reduction and strong positive trend in symptom reduction. News release. MorphoSys AG. November 20, 2023. Accessed November 21, 2023. https://tinyurl.com/2n9swrer
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated September 25, 2023. Accessed November 21, 2023. https://www.clinicaltrials.gov/study/NCT04603495

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Pelabresib Plus Ruxolitinib Improves Spleen Volume Reduction in JAK Inhibitor-Naive Myelofibrosis

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November 21, 2023

By Ryan Scott

Treatment with the combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) led to a statistically significant and clinically meaningful improvement in spleen volume reduction vs placebo plus ruxolitinib in patients with JAK inhibitor-naive myelofibrosis, meeting the primary end point of the phase 3 MANIFEST-2 trial (NCT04603495).1

Findings showed that 66% of patients treated with the combination of pelabresib and ruxolitinib experienced a spleen volume reduction of at least 35% (SVR35) at week 24 vs 35% of patients treated with placebo plus ruxolitinib (31% difference; 95% CI, 21.6%- 39.3%; P < .001).

Furthermore, patients in the pelabresib and ruxolitinib group experienced a median reduction in total symptom score (TSS) of 15.99 points at week 24, reduced from 28.26 at baseline, compared with a reduction of 14.05 points, reduced from 27.36, in those treated with placebo plus ruxolitinib (delta, –1.94; 95% CI, –3.92 to 0.04; P = .0545).

Notably, findings revealed that a higher percentage of patients experienced a hemoglobin response of an increase of at least 1.5 g/dL from baseline when treated with the combination of pelabresib and ruxolitinib compared with those given placebo and ruxolitinib.

Detailed findings from MANIFEST-2 will be presented at the 2023 ASH Annual Meeting in December. MorphoSys, the developer of pelabresib, will continue to review data and plans to submit a new drug application to the FDA and a marketing authorization application to the European Medicines Agency for pelabresib in combination with ruxolitinib in myelofibrosis by the middle of 2024.

“I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis,” John Mascarenhas, MD, director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai in New York, New York, said in a news release. “The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume—the best prognostic indicator we have at our disposal for long-term outcomes [for patients with myelofibrosis]. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation.”

The randomized, double-blind, placebo-controlled MANIFEST-2 trial enrolled patients at least 18 years of with a confirmed diagnosis of myelofibrosis with adequate hematologic, renal, and hepatic function. Furthermore, patients must have a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System; a spleen volume of 450 cm3 or more; and an ECOG performance status 2 or less. Exclusion criteria include splenectomy or splenic irradiation in the previous 6 months; medication use that would prohibit treatment; or prior administration of any JAK or BET inhibitor for treatment of a myeloproliferative neoplasm.2

Eligible patients were randomly assigned 1:1 to receive pelabresib in combination with ruxolitinib or placebo plus ruxolitinib.

TSS response from baseline at week 24 and the proportion of patients with at least a 50% reduction in TSS (TSS50) were key secondary end points.1

Patients with intermediate-risk disease comprised more than 90% of patients in the study population, and in this population, pelabresib plus ruxolitinib reduced by a median TSS by 15.18 points at week 24 from the baseline median TSS of 28.20, compared with a median reduction of 12.74 points at week 24 from a baseline TSS of 27.53 in the placebo plus ruxolitinib arm (delta, –2.44; 95% CI, –4.48 to –0.40; P < .02). This difference was statistically significant.

At week 24, 52% of patients in the pelabresib arm achieved at least a 50% reduction in TSS (TSS50) vs 46% in the placebo arm (6% difference; 95% CI, –3.5% to 15.5%; P = .216). In intermediate-risk patients, TSS50 was achieved by 55% of those in the pelabresib arm compared with 45% in the placebo arm (10% difference; 95% CI, 0.35%-19.76%; P < .05).

Regarding safety, pelabresib and ruxolitinib remained in line with the previously observed safety profile, and no new safety signals were reported. Notably, instances of anemia as an adverse effect were less frequent in patients treated with pelabresib plus ruxolitinib compared with those treated with placebo plus ruxolitinib.

“[Patients with] myelofibrosis experience a severely diminished quality of life due to symptoms such as severe fatigue, night sweats, bone pain and fever—symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, said in a news release.

References

  1. Morphosys’ phase 3 study of pelabresib in myelofibrosis demonstrates statistically significant improvement in spleen volume reduction and strong positive trend in symptom reduction. News release. Morphosys. November 20, 2023. Accessed November 21, 2023.
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2). ClinicalTrials.gov. Updated September 25, 2023. Accessed November 21, 2023.

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