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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NCCN Guidelines Update Adds Momelotinib for High-, Low-Risk Myelofibrosis

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November 21, 2023

By Pearl Steinzor

Momelotinib has been added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for the treatment of patients with high- and low-risk myelofibrosis (MF) and myelofibrosis with anemia.

MF is part of a group of heterogeneous disorders of the hematopoietic system collectively knowns as Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs). MPNs are considered a rare disease, with the prevalence of MF in the United States estimated to be approximately 13,000, respectively.

Furthermore, MPNs are associated with symptom burdens that result in worse quality of life, functional status, and activities of daily living. Patients with MF are more likely to report symptoms such as fever, night sweats, and weight loss compared with patients with polycythemia vera (PV) or essential thrombocythemia (ET).

Momelotinib is an oral Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with a recommended dosage of 200 mg orally once daily with or without food. Special considerations for the use of momelotinib also includes risk of major adverse cardiovascular events, thrombosis, and development of malignancies, especially in patients who currently smoke or previously smoked.

The treatment approach for MF is currently identical for primary MF (PMF), post-PV MF, or post-ET MF.

Treatment for lower-risk MF includes momelotinib as a category 2B drug in symptomatic patients. Symptomatic patients may be treated with category 2A drugs, including ruxolitinib, peginterferon alfa-2a, or hydroxyurea, or category 2B momelotinib.

The treatment pathway requires monitoring the response and signs/symptoms of disease progression every 3 to 6 months. For those who respond to the treatment, the guidelines recommend continuing treatment and monitoring. For those with no response or loss of response, the guidelines recommend an alternative option not used for initial treatment, such as momelotinib. The guidelines recommend that patients with disease progression are moved to a higher-risk and accelerated/blast phase MF status.

In patients with high-risk MF, momelotinib was given category 2A status for those with higher platelets (≥50 x 109/L) who were not a transplant candidate; other drugs include ruxolitinib (category 1), fedratinib (category 1), or pacritinib (category 2B). Similarly, the guidelines recommend monitoring patients every 3 to 6 months, continuing treatment for those with a response, recommending a clinical trial or alternative JAK inhibitor not used before for those with no response or loss of response, and accelerated/blast phase MF status for those with disease progression.

For the management of MF-associated anemia, the guideline recommends ruling out coexisting causes, such as bleeding; iron, vitamin B12, or folate deficiency; and hemolysis. After treating coexisting causes, preferred regimens in patients with higher serum erythropoietin (≤500 mU/mL) include clinical trials or momelotinib. Other drugs that may be useful in certain circumstances include danazol, lenalidomide with or without prednisone, thalidomide with or without prednisone, or luspatercept (category 3). Those with a response are recommended to continue treatment, and those with no response or loss of response are recommended to select a treatment other than the one they initially began.

Reference

NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2023. Accessed November 21, 2023. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf\

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JAK2 Inhibition’s Role in Newly Diagnosed Myelofibrosis

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November 20, 2023

Targeted Oncology Staff

At a live virtual event, Jeanne Palmer, MD, provided commentary on the development of myeloproliferative neoplasms in patients, particularly those with newly diagnosed aggressive myelofibrosis. She highlighted the importance of the Janus kinase (JAK)-STAT pathways and how mutations in genes such as JAK2 can change a prognosis and a physician’s approach to treatment. Furthermore, she discussed the data behind the use of JAK inhibitors in this patient population and how they benefit patients in multiple ways but present a challenge in certain subsets of patients.

DEVELOPMENT AND INHIBITION TARGETS OF MYELOPROLIFERATIVE NEOPLASMS

The pathogenesis of the myeloproliferative neoplasms [MPNs], particularly the ones that are BCR-ABL1 negative, [occurs] primarily through the JAK-STAT pathway.1 This is where we find what we call the driver mutations, which are the mutations that are critical in making the disease progress. There are 3 different mutations that we more commonly see, with the first being JAK2 V617F.2 So JAK1 and JAK2…are right below the cell membrane, [and with this mutation], JAK2 is the one that is mutated, and when it is mutated, it keeps the 2 receptors it’s attached to on, which keeps it constitutively activated. Therefore, it goes on and continues to signal throughout the cell to make the cell grow disproportionally to what it should be.

In polycythemia vera [PV], most mutations are JAK2 V617F; however, there is a small percentage [of mutations in patients with PV] that are JAK2 exon 12, which is a mutation in another part of the JAK2 gene.2 The [other 2] driver mutations, which are less common, are MPL and calreticulin.1

The MPL mutation is in the thrombo-poietin receptor…and the CALR mutation is in calreticulin, and what happens is the calreticulin sits outside of the cell membrane.1 The CALR mutation is interesting because it is extracellular. There are currently different therapeutics that target that because it is outside of the cell. The calreticulin is divided into type 1 or type 2. The type 1 is associated with a good prognosis, [whereas] type 2 isn’t necessarily [tied to a good prognosis].2

There are many factors that influence the production of MPNs, and this is an area of a lot of research, but there are a couple of [factors] that are prominent. First, the JAK2 mutant clone provides a survival advantage, and any of the mutations that are present in these myeloproliferative cells make them grow a lot.3 They’re extremely tough, they’re difficult to kill, and they try to predominate. There’s also evidence that some of the inflammation can drive these so that you have the cells that create inflammation because of the mutations and then that further drives for the replication and reproduction of the cells.3

There are also higher incidences of prior autoimmune conditions in patients with MPNs, and there’s a genetic predisposition to some of the MPNs as well as to the JAK2 mutation. Disruption of the JAK-STAT pathway can also affect NF-κB signaling, and there’s defective negative feedback regulation, hence what I talked about before about the signal being constitutively on.3

PATHWAYS INVOLVED IN MYELOFIBROSIS

One of the things that we’re learning with myelofibrosis is that there are a number of different pathways involved. We all know about the JAK-STAT pathway, but there are a couple of other pathways that we think are probably important and help us differentiate the [use] of different JAK inhibitors. One of them is IRAK1 and the other one is ACVR1.4 IRAK1 primarily involves a lot of the inflammatory cytokines…whereas ACVR1 [affects] the hepcidin pathway. We all remember hepcidin…from medical school when we learned about that iron metabolism pathway that you thought you’d never have to learn again. Well, hepcidin has made a resurgence not only in anemia of chronic disease but also in myelofibrosis and PV. However, one of the problems in myelofibrosis is that patients’ hepcidin [levels] can be too high, so if you can suppress it, they may benefit [from that kind of treatment]. The ACVR1 pathway reduces hepcidin transcription, which is thought to help anemia…and [researchers] found that this also appears to be a target of pacritinib [Vonjo].4

PERSIST-2 FINDINGS DEMONSTRATE PACRITINIB’S ROLE IN TREATMENT

[The baseline characteristics of the PERSIST-2 (NCT02055781) study] showed that there were fairly equivalent patient populations [between the study arms].5 One thing to note about the baseline demographics…is that in the control arm, almost half the patients had ruxolitinib [Jakafi] as their best available therapy and were allowed to continue it at the dosing level appropriate [for them]… depending on their platelet level. Again, [for those with] 50 × 109/L to less than 100 × 109/L platelet count, the dose recommended was 5 mg twice a day, which is what most patients were on [in the control arm].5

When we look at the spleen volume reduction rate in PERSIST-2 [findings]…it is a 35% decrease, and this spleen volume reduction is not as impressive in this [study]. The [spleen volume reduction] percentage is less [with] pacritinib as we would see [with] ruxolitinib.5 I also want to point out that these patients [in this study] have lower platelet [count], have a lower JAK2 allele burden, and maybe are less likely to respond well to JAK inhibitors. However, it is important to note that in PERSIST-2 [findings], the spleen volume reduction was greater in the patients who received treatment compared with those who did not.5

People have looked at JAK2 burden and response to JAK inhibitors, but they were more compiled data rather than split. You need a lot more patients to be able to note that difference. I would not use JAK2 allele burden as a decision point of whether to give somebody a JAK inhibitor or not. But there are some circumstantial data that [suggest] if somebody has a higher JAK2 allele burden then they’re more likely to respond to treatment.6

But that’s more likely because [the patient] probably has a proliferative variant, they have the hyperproliferative disease rather than cytopenic disease, and those patients tend to be more likely to respond to therapy because you can dose them adequately because their counts are high enough.

When using pacritinib, it’s important to remember that we don’t expect to see platelet [count] improvement, but sometimes we [see it] because the spleen shrinks, and when the spleen shrinks, you have less sequestration. But in general, I’ve seen platelet [count] go down a lot, so it’s very important not to give this drug [while] thinking, “Oh, my patients’ platelet [levels] are going to go up.” And then [you see the platelet levels go down and think] the drugs [are] not working, because what you hope for is that this will flatline.

When we look at the hematologic response [to pacritinib in the PERSIST-2 study findings], you do see that change in platelet count.5 Although 400 mg daily is not the prescribing dose, [their platelet counts went up]. Although those 400-mg data are not included in a lot of analyses because the dosing that’s found to be the best is 200 mg twice a day, you’ll see that the platelet [count] for those who were on 200 mg of pacritinib twice a day is flat. I don’t have a good explanation why the platelet [count] went up in the 400-mg once-a-day [group], because the responses weren’t that great, so [it] wasn’t the dose that was chosen to move forward. In terms of the red blood cell transfusions over time, they went down in patients, so the lower the red blood cell transfusion, the better it is in patients who are on 200 mg of pacritinib twice a day.5

When you look at patients with low platelet [count], the impressive thing about pacritinib is that you can maximize the dose and maximize the spleen volume reduction. If you took patients [with low platelet count] who got ruxolitinib at 5 mg twice a day, about 10% of them will have a spleen volume reduction of greater than 35%, so this is an extremely low rate of spleen volume reduction.5 One of the things that’s important to remember about this is pacritinib allows maximal JAK inhibition for patients with low platelet [count]. If you have somebody with normal platelet [count] and give them pacritinib, you’re not going to see the same benefit as you would with ruxolitinib, but a big part of that is [due to] the limitations with the cytopenias. For patients who have thrombocytopenia, pacritinib provides a significant advantage because you can maximize the dose.

TOXICITIES TO CONSIDER WITH JAK INHIBITION

[In the PERSIST-2 trial findings], all the adverse events [AEs] were expected, but I want to point out diarrhea is a major AE with pacritinib [Figure5]. Whenever using pacritinib, it’s extremely important to give [the patient] antidiarrhea and antinausea [medicine] when you start this medication. The majority of patients will have diarrhea, and it can be a significant AE.5

[Researchers in this study also looked at]…viral infections [and saw that] zoster can be activated in these patients through fungal infection.7 That’s something of interest to me, especially because I live in Arizona, where we have a lot of valley fever, which is a fungal infection.

What they had found…was that [in] these infections, especially if you look at pacritinib vs best available therapy or when best available therapy is ruxolitinib, we don’t see as [many cases], and in…[other] secondary [malignant tumors], it was even [fewer with] pacritinib compared with best available therapy with ruxolitinib.7

Frankly, there’s a lot of focus on these numbers that…when you look at the absolute numbers of these events, [they] are extremely low, but this is one area that they are trying to highlight where there is less of an infection risk [with pacritinib].7

References

1. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390. doi:10.1056/NEJMoa1311347

2. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405. doi:10.1056/NEJMoa1312542

3. Mendez Luque LF, Blackmon AL, Ramanathan G, Fleischman AG. Key role of inflammation in myeloproliferative neoplasms: instigator of disease initiation, progression. and symptoms. Curr Hematol Malig Rep. 2019;14(3):145-153. doi:10.1007/s11899-019-00508-w

4. Chifotides HT, Verstovsek S, Bose P. Association of myelofibrosis phenotypes with clinical manifestations, molecular profiles, and treatments. Cancers (Basel). 2023;15(13):3331. doi:10.3390/cancers15133331

5. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

6. Vannucchi A, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment. Ther Adv Hematol. 2011;2(1):21-32. doi:10.1177/2040620710394474

7. Pemmaraju N, Harrison C, Gupta V, et al. Risk-adjusted safety analysis of the oral JAK2/IRAK1 inhibitor pacritinib in patients with myelofibrosis. EJHaem. 2022;3(4):1346-1351. doi:10.1002/jha2.591

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Ad hoc: MorphoSys’ Phase 3 Study of Pelabresib in Myelofibrosis Demonstrates Statistically Significant Improvement in Spleen Volume Reduction and Strong Positive Trend in Symptom Reduction

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MANIFEST-2 met primary endpoint,
nearly doubling SVR35 response rate (66% versus 35%) 

The key secondary endpoints assessing symptom reduction, TSS50 and absolute change in TSS, showed significant improvements for intermediate-risk patients (p<0.05, p<0.02, respectively) and strong numerical improvements for overall population 

Pelabresib plus ruxolitinib showed clinically meaningful anemia improvement versus placebo and ruxolitinib 

Safety results were consistent with prior clinical trials, with no new safety signals

MorphoSys intends to submit for approval in the U.S. and Europe in mid-2024

MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announces strong topline results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib compared with placebo plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis.

MANIFEST-2 met its primary endpoint, as the combination therapy demonstrated a statistically significant and clinically meaningful improvement in the proportion of patients achieving at least a 35% reduction in spleen volume (SVR35) at week 24. The key secondary endpoints assessing symptom improvement – proportion of 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 – showed a strong positive trend favoring the pelabresib and ruxolitinib combination. In an analysis of patients classified as intermediate risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2) – constituting more than 90% of patients in MANIFEST-2 – the combination therapy demonstrated significant improvements in both key secondary endpoints. DIPSS was a pre-defined stratification factor in the MANIFEST-2 study protocol.

MANIFEST-2 Topline Results Overview

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study that randomized 430 JAK inhibitor-naïve adult myelofibrosis patients, making it one of the largest myelofibrosis studies conducted to date.

Significant Improvement in Spleen Volume Reduction

In MANIFEST-2, 66% of patients receiving pelabresib in combination with ruxolitinib achieved SVR35 at week 24, the primary endpoint, versus 35% of those receiving placebo and ruxolitinib, nearly doubling SVR35 response rates (95% CI [21.6; 39.3], p<0.001).

Meaningful Improvements to Myelofibrosis Symptoms

In a key secondary endpoint, TSS was reduced by 15.99 points at week 24, from 28.26 at baseline, in the pelabresib and ruxolitinib treatment arm and by 14.05 points at week 24, from 27.36 from baseline, in the placebo plus ruxolitinib arm (Δ -1.94, 95% CI [-3.92; 0.04], p=0.0545), using least square mean estimate.

In intermediate-risk patients (DIPSS Int-1 and Int-2), TSS was reduced by 15.18 points at week 24, from 28.20 at baseline, in the pelabresib and ruxolitinib treatment arm versus 12.74 points at week 24, from 27.53 at baseline, in the placebo plus ruxolitinib arm, which was significant (Δ -2.44, 95% CI [-4.48; -0.40], p<0.02). DIPSS is an established prognostic system used to predict patient survival, classifying myelofibrosis patients into the following risk categories: low, intermediate-1, intermediate-2 or high.

Absolute change in TSS was included as a key secondary endpoint to directly measure change in the average TSS from baseline to week 24. It is a continuous endpoint that provides a meaningful, detailed assessment of symptom score reductions, thereby enhancing precision in estimating the magnitude of symptom burden reduction in patients with myelofibrosis. This endpoint was added to the MANIFEST-2 clinical trial protocol following a Type C meeting with the U.S. Food and Drug Administration (FDA) in September 2023.

TSS50, another key secondary endpoint, was achieved by 52% of patients in the pelabresib and ruxolitinib treatment arm at week 24 compared with 46% in the placebo plus ruxolitinib arm (95% CI [-3.5; 15.5], p=0.216). In intermediate-risk patients, TSS50 was achieved by 55% of patients 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<0.05).

Improvements in Anemia

The MANIFEST-2 results show a greater proportion of patients achieved hemoglobin response (≥ 1.5 g/dL from baseline) with the pelabresib and ruxolitinib combination than with placebo and ruxolitinib.

Pelabresib and Ruxolitinib Combination Was Well-Tolerated

At the time of this analysis, the safety of pelabresib and ruxolitinib was consistent with the previously observed safety profile of this combination therapy; no new safety signals were observed. Importantly, adverse events of anemia were reported less frequently with pelabresib and ruxolitinib than with placebo and ruxolitinib.

Planned Regulatory Next Steps

Based on the strong and comprehensive data generated from the MANIFEST-2 study, MorphoSys will continue conversations with regulatory agencies, with intention to submit a New Drug Application for pelabresib in combination with ruxolitinib in myelofibrosis to the FDA and a Marketing Authorization Application to the European Medicines Agency in the middle of 2024. The combination therapy received Fast Track designation for this disease from the FDA in 2018.

***

END OF AD HOC RELEASE

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CHA2DS2-VASC Predicted Thrombotic Risk in Patients With MPNs and Atrial Fibrillation

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November 16, 2023

Andrea S. Blevins Primeau, PhD, MBA

Although CHA2DS2-VASC does not account for myeloproliferative neoplasms (MPNs), it accurately predicted thrombotic risk in this patient population with atrial fibrillation (AF). However, HAS-BLED did not predict bleeding risk, according to the results of a retrospective study.

“Further investigation is needed to refine risk scores in MPN,” the authors wrote in their report. The study, which was published in the Journal of Thrombosis and Thrombolysis, analyzed data from 1617 patients with and 24,185 matched patients without MPNs from the National Readmission Database. All patients had AF. The primary outcomes were in-hospital or 30-day readmission for bleeding or thrombosis.

Characteristics were balanced between the cohorts. Overall, 29% of patients were on long-term anticoagulation, 25% were on long-term antiplatelet therapy. Comorbidities were common, with 76% of patients with hypertension, 42% with congestive heart failure, 35% with anemia, 33% with coronary artery disease, 24% with chronic lung disease, and 22% with diabetes.

However, patients with MPN were not at an increased risk of bleeding, with 2.60% experiencing a bleed compared with 2.98% of patients without MPNs (OR, 0.87; 95% CI, 0.63-1.19). Risk of bleeding was not accurately predicted by HAS-BLED, with a c-statistic of 0.55 (95% CI, 0.46-0.64) among patients with MPNs. For patients without MPN, the HAS-BLED was moderately predictive (c-statistic, 0.56; 95% CI, 0.54-0.58).

Patients with MPN were more likely to experience bleeding if their MPN type was essential thrombocythemia (P =.009), if they had anemia (P <.001), peripheral vascular disease (P =.024), or chronic kidney disease (P =.047). However, after multivariate analysis only ET remained independently associated with bleeding (adjusted OR, 3.08; 95% CI, 1.04-9.16).

Any hospital readmission within 30 days occurred among 18.6% of patients with MPN compared with 11.9% of patients without MPNs (P <.001). Within 90 days, 26.4% and 20.4% of patients with and without MPNs had a hospital readmission (P <.001).

Cardiovascular (CV)-related hospital readmission, which included arterial thrombosis, heart failure, and arrythmia, was also more common among patients with MPNs, occurring among 6.2% compared with 5.0% without MPN within 30 days (P =.046). However, there was no significant difference in CV readmission rates during the 90-day period.

Reference
Leiva O, How J, Grevet J, et al. In-hospital and readmission outcomes of patients with myeloproliferative neoplasms and atrial fibrillation: insights from the National Readmissions Database. J Thromb Thrombolysis. Published online October 15, 2023. doi: 10.1007/s11239-023-02900-z

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Allogeneic HCT Provides OS Benefit Independent of TP53 Allelic Status in MDS

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November 18, 2023

By Kyle Doherty

Patients with myelodysplastic syndrome (MDS) harboring a TP53 mutation experienced a survival benefit with allogeneic hematopoietic cell transplantation (HCT) compared with non-HCT treatment regardless of TP53 allelic status, according to findings from an analysis of the phase 2 Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 study (NCT02016781) published in the Journal of Clinical Oncology.1

Findings from a univariate analysis showed that, irrespective of treatment strategy, patients with a TP53 mutation (n = 87) experienced a 3-year overall survival (OS) rate of 21% (standard error [SE] ± 5%) compared with 52% (SE ± 4%) among patients who were TP53 wild-type (n = 222; HR, 2.55; 95% CI, 1.86-3.50; P < .001). Additionally, the 3-year OS rate among patients with a single TP53 mutation (n = 39) was comparable with that of patients with a TP53 multi-hit mutation (n = 48), at 22% (SE ± 8%) vs 20% (SE ± 6%), respectively (HR, 1.29; 95% CI, 0.79-2.11; P = .31).

When HCT was used as a time-dependent covariate, patients with a TP53 mutation who received HCT (n = 48) experienced a 3-year OS rate of 23% (SE ± 7%) vs 11% (SE ± 7%) in patients who were treated with non-HCT therapy (n = 32; HR, 1.76; 95% CI, 1.02-3.06; P = .04). Moreover, the 3-year OS rate among patients with very high-risk MDS per the Molecular International Prognostic Scoring System per molecular International Prostate Symptom Score (IPSS-M) without a TP53 mutation who received HCT (n = 22) was significantly improved compared with those with the same risk profile and mutational status who received non-HCT therapy (n = 8), at 68% (SE ± 10%) vs 0% (SE ± 12%), respectively (P = .001).

“The absence of a non-HCT control group in [other] retrospective analyses has called into question whether the long-term survival observed in these studies was reasonably attributable to the transplantation intervention,” investigators wrote. “In this study, we directly addressed this question and now conclude definitively that reduced intensity transplantation mediates long-term survival for patients with TP53-mutated MDS compared with non-HCT treatment. Moreover, we show that the benefit of HCT over non-HCT treatment was independent of TP53 allelic state and not restricted to specific subgroups of TP53-mutated MDS.”

Previously published findings from the primary analysis of BMT CTN 1102 showed that patients who received reduced intensity conditioning HCT (n = 260) achieved a 3-year OS rate of 47.9% (95% CI, 41.3%-54.1%) compared with 26.6% (95% CI, 18.4%-35.6%) among those who were treated with non-HCT therapy or best supportive care (n = 124), for an absolute difference of 21.3% (95% CI, 10.2%-31.8%; P = .0001). The 3-year leukemia-free survival rates were 35.8% (95% CI, 29.8%-41.8%) vs 20.6% (95% CI, 13.3%-29.1%), respectively (absolute difference, 15.2%; 95% CI, 13.3%-29.1%; P = .003).2

BMT CTN 1102 was a multicenter prospective trial that evaluated the efficacy of reduced intensity conditioning HCT (donor arm) vs that of hypomethylating therapy or best supportive care (no donor arm) in patients with IPSS intermediate-2 or high-risk de novo MDS who were 50 to 75 years old. To perform their genetic analysis of BMT CTN 1102, study authors performed targeted DNA sequencing on frozen whole blood samples collected at the time of enrollment, which were available for 229 patients in the donor arm and 80 patients in the no donor arm. Baseline patient characteristics did not differ significantly between those in the donor and no donor arms.1

Patients included in the genetic analysis (n = 309) had a median age of 66.9 years (range, 50.1-75.3), with most patients being over 65 years old (61.8%). Most patients were female (62.1%), had IPSS intermediate-2 disease (66.7%), and complex karyotype (65.0%). At baseline, the median hemoglobin was 9.3 g/dL (range, 8.1-10.7) and the median platelet count was 70 x 109/L (range, 34-132).

In addition to a univariate analysis, investigators constructed 2 multivariable models adjusted for age at enrollment, performance status, IPSS risk status, MDS disease duration, and clinical and genetic variables. One model was based on random assignment on the basis of donor availability and the other compared HCT vs non-HCT treatment with HCT representing a time-dependent covariate.

Additional findings from the univariate analysis showed that, outside of TP53 mutations, the presence of KMT2Apartial tandem duplications was associated with a decrease in 3-year OS rate compared with those who did not have these duplications (HR, 2.21; 95% CI, 1.22-3.99; P = .009). However, patients with a germline DDX41 mutation (HR, 0.39; 95% CI, 0.17-0.87; P = .022) and somatic mutations in STAG2 (HR, 0.57; 95% CI, 0.34-0.96; P = .034) displayed superior OS compared with those who did not have these mutations.

Results from the donor vs no donor analysis revealed that patients in the donor arm experienced an OS improvement compared with those assigned to the no donor arm (HR, 1.60; 95% CI, 1.10-2.32; P = .013). Among patients with a TP53 mutation, assignment to the donor arm did not significantly improve OS compared with the no donor arm (HR, 1.76; 95% CI, 0.95-3.26; P = .073).

In the model that compared HCT with non-HCT treatment, patients who received HCT (n = 197) experienced a significantly lower risk of death compared with those treated with non-HCT therapies (n = 78; HR, 2.31; 95% CI, 1.53-3.49; P < .001). Findings from this model showed that patients with a TP53 mutation had a much greater risk of dying if they did not receive HCT vs those who did (HR, 3.89; 95% CI, 1.87-8.12; P < .001), which study authors noted could signify that, “…HCT might improve long-term survival in patients with mutated TP53, independent of other risk factors.” Investigators also found molecular clearance of TP53 mutation before HCT not to be predictive of long-term survival.

“Together, these data indicate that no patient with TP53-mutated MDS should be excluded from consideration for HCT a priori on the basis of TP53 status alone. Despite the relative benefit of HCT over non-HCT treatment, however, the absolute survival benefit remains modest, meriting value-based discussions between physicians and patients on the appropriateness of transplantation,” study authors concluded.

Reference

  1. Versluis J, Saber W, Tsai HK, et al. Allogeneic hematopoietic cell transplantation improves outcome in myelodysplastic syndrome across high-risk genetic subgroups: genetic analysis of the blood and marrow transplant clinical trials network 1102 study. J Clin Oncol. 2023;41(28):4497-4510. doi:10.1200/JCO.23.00866
  2. Nakamura R, Saber W, Martens MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol. 2021;39(30):3328-3339. doi:10.1200/JCO.20.03380

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Increased Understanding of the Mechanisms of Myelofibrosis Helps Usher in New Treatments and Novel Agents

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November 16, 2023

By Ryan Scott

Research providing a growing understanding of the molecular mechanisms of myelofibrosis has helped facilitate the development of new treatments for this patient population, and novel agents are poised to continue emerging in this space, according to Gaby Hobbs, MD.

In February 2022, the FDA approved pacritinib (Vonjo)for the treatment of patients with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L.1 Additionally, the regulatory agency approved momelotinib (Ojjaara) for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia in September 2023.2 Both agents inhibit ACVR1, and their approvals are examples of how the growing understanding of the biology of myelofibrosis is informing drug development.

“We have a better understanding of several mechanisms that are involved in the development and the pathophysiology of myelofibrosis,” Hobbs said in an interview with OncLive® following a State of the Science Summit™ (SOSS) on hematology, which she chaired.

In the interview, Hobbs discussed how further research into the biology of myelofibrosis has propelled the development of novel therapies for this patient population, expanded on ongoing and upcoming investigations of various agents, and highlighted the role that biomarkers play in the diagnosis, prognosis, and treatment response evaluation for these patients. Hobbs is a hematology-oncology physician, the clinical director of Leukemia Service, and an assistant in medicine at the Massachusetts General Hospital in Boston.

OncLive: Your presentations at the SOSS centered around the evolving treatment landscape of myelofibrosis and current standards of care. What were the key points you aimed to highlight during these discussions?

Hobbs: There have been a lot of changes in the therapies available for [patients with myelofibrosis] over the last couple of years. The first presentation focused on providing a brief overview of the current standard of care and new therapies that are available for [treating patients with] myelofibrosis.

The second talk [focused] an area where there’s still a lot of unmet need, which is anemia, [and I wanted to] give the audience an idea or approach on how to manage anemia for these patients, especially [after] the approval momelotinib.

What is the current understanding of the molecular mechanisms of myelofibrosis? How has this influenced the development of personalized treatment strategies for this patient population?

[The increased understanding of the mechanisms of myelofibrosis] has helped with some of the new drug approvals, including pacritinib and momelotinib. We were [previously] focused mostly on the JAK/STAT signaling pathway; now we appreciate that there are other signaling pathways that may also be involved in the pathophysiology of this disease.

For example, momelotinib and pacritinib also inhibit the ACVR1 pathway, which leads to an improvement in anemia. That’s a very clear way in which we’ve had improvement in therapies based on better understanding of the biology of [myelofibrosis].

Beyond momelotinib and pacritinib, are there any other agents currently under investigation in myelofibrosis that are intriguing?

There are many different agents that are currently being studied. The one that is most likely closest to being available to patients is luspatercept-aamt [Reblozyl], as that is already approved for patients with myelodysplastic syndrome, and that specifically will help patients with anemia. With regards to other novel therapeutics, there are many agents that are currently under development, including drugs like the telomerase inhibitor imetelstat, the BCL-2/BCL-XL inhibitor navitoclax, the BET inhibitor pelabresib [CPI-0610], the MDM2 inhibitor navtemadlin [formerly KRT-232], and the XPO1 inhibitor selinexor [Xpovio].

There are many agents under development now that [could] change the field of myelofibrosis from just having single-agent JAK inhibitors to having combination therapies that could hopefully help our patients live with less symptoms and also live longer.

What role do biomarkers play in the diagnosis, prognosis, and treatment response evaluation for patients with myelofibrosis?

When you say biomarkers in myelofibrosis, we rely significantly on genetic mutations and a variety of different risk scores to prognosticate for our patients. We know that patients with JAK2 mutations have different outcomes than those with CALR mutations. More specifically, we know that having additional mutations outside of JAK/STAT mutations also contribute to a negative prognosis, and those include mutations such as ASXL1, IDH, SRSF2, and EZH1. Those genetic mutations help us to understand prognosis with these patients, when taken into conjunction with other clinical variables that are included in [risk] scores.

References

  1. CTI BioPharma announces FDA accelerated approval of VONJO™ (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. CTI BioPharma Corp. News release. February 28, 2022. Accessed November 8, 2023. https://www.prnewswire.com/news-releases/cti-biopharma-announces-fda-accelerated-approval-of-vonjo-pacritinib-for-the-treatment-of-adult-patients-with-myelofibrosis-and-thrombocytopenia
  2. Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed November 8, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia

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Dr. Lucia Masarova Discusses Indirect Comparison of Pacritinib and Momelotinib in Myelofibrosis

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November 16, 2023

By Patrick Daly

Dr. Masarova of The University of Texas MD Anderson Cancer Center in Houston, spoke with HemeToday on findings from a matched indirect treatment comparison of pacritinib and momelotinib in patients with mild myelofibrosis.

“I think it’s fantastic that we have a fourth inhibitor. It’s really good that [momelotinib] has a very broad indication for patients with myelofibrosis and anemia, where we haven’t had actually any drug,” Dr. Masarova said.

She detailed the mechanism of action of momelotinib and highlighted the relative benefits in safety and anemia response compared with pacritinib.

“The anemia responses that we have seen all seem to be little higher than those we’ve seen before although the mechanism of these agents is reported to be very similar. So that’s something that we’ll have to learn in clinical practice how to best sequence these patients and these agents in terms of patients responses,” Dr. Masarova said.

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$72 Million Funds Neoantigen-based Cancer Vaccine Candidates

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November 14, 2023

(Precision Vaccinations News)

Nouscom recently announced the completion of its Series C equity financing, raising $72 million that will be used to continue advancing and expanding Nouscom’s wholly-owned clinical pipeline to achieve multiple clinical value catalysts.

As of November 13, 2023, the funding proceeds will support the following initiatives:

Readout from Nouscom’s ongoing randomized Phase 2 clinical trial for NOUS-209, an off-the-shelf vaccine targeting 209 shared neoantigens, in combination with pembrolizumab for the treatment of Mismatch Repair/Microsatellite Instable Metastatic Colorectal Cancer.

Final readout from the ongoing Phase 1b study and advancement of NOUS-209 monotherapy in Lynch Syndrome carriers investigating the potential to intercept, prevent, or delay cancer before it occurs. LS carriers have a genetic predisposition to and, consequently, a higher risk of developing certain cancers. Promising initial results from this study were reported on October 31, 2023.

Completion of a Phase 1b study evaluating NOUS-PEV, a personalized cancer immunotherapy, in combination with a checkpoint inhibitor in patients with advanced melanoma and entry into randomized Phase 2 trials in indications with high unmet medical needs.

Nouscom has also exclusively out-licensed VAC-85135, an off-the-shelf immunotherapy developed under a multi-project agreement, which is currently under evaluation in a Phase 1 clinical trial for the treatment of Myeloproliferative Neoplasms sponsored by Janssen Research & Development and Bristol Myers Squibb.

Dr. Marina Udier, Chief Executive Officer of Nouscom, commented in a press release, “…. This financing will allow us to further accelerate development across our wholly-owned clinical portfolio reporting multiple clinical trial readouts, including from our ongoing randomized Phase 2 clinical trial with NOUS-209.”

“These Phase 2 data, if positive, have the potential to position Nouscom’s neoantigen-based cancer vaccines amongst the most thrilling developments in the field.”

According to a Review Article published by the journal Frontiers in Immunology in February 2023, Neoantigen vaccines are based on epitopes of antigenic parts of mutant proteins expressed in cancer cells. These highly immunogenic antigens may trigger the immune system to combat cancer cells.

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