FDA Approves Komzifti (ziftomenib) for the Treatment of Adults with Relapsed or Refractory NPM1-Mutated Acute Myeloid Leukemia

Kura Oncology, Inc. (Nasdaq: KURA) and Kyowa Kirin Co., Ltd. (TSE: 4151)  announced the U.S. Food and Drug Administration (FDA)   approval of Komzifti™ (ziftomenib) for adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. Komzifti is the first and only once-daily, oral menin inhibitor approved for R/R NPM1-mutated (NPM1-m) AML, a devastating blood cancer with limited treatment options.

“Komzifti combines compelling efficacy, a favorable safety profile, compatibility with concomitant medications, and convenient once-daily oral administration in a population with few effective treatment options. These features highlight Komzifti’s potential to serve as the menin inhibitor of choice in its approved indication,” said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. “Together with our partner, Kyowa Kirin, we remain committed to advancing development of Komzifti across the treatment continuum for AML, where its best-in-class profile offers potential for even greater impact in combination regimens and earlier lines of therapy. We are fully prepared to launch Komzifti today and deliver this new medicine to patients in need.”

NPM1 mutations are among the most common founder mutations in AML, occurring in approximately 30% of cases. Historically, approximately 20% of patients with NPM1-m AML do not respond to front-line therapy. Of those who do respond, 70% will relapse within 3 years, most within 12 months. Early relapse and declining survival with each recurrence underscore the urgent need for treatment approaches that deliver lasting remission.

Approval is supported by the pivotal KOMET-001 trial (NCT04067336), which evaluated Komzifti’s safety and efficacy in 112 R/R NPM1-m AML patients. The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 21.4% (95% CI: 14.2, 30.2). The median duration of CR+CRh was 5.0 months (95% CI: 1.9, 8.1) and the median time to first response in patients who achieved a CR or CRh was 2.7 months (range: 0.9 to 15 months). 88% of patients who achieved CR or CRh did so within 6 months of initiating Komzifti. These data from the Prescribing Information are generally consistent with findings recently published in the Journal of Clinical Oncology.1

“Komzifti addresses a critical need for adult patients with R/R NPM1-m AML, many of whom are older and unable to tolerate intensive chemotherapy or transplant,” said Eunice Wang, M.D., Chief of the Leukemia Service and Professor of Oncology at Roswell Park Comprehensive Cancer Center. “The clinical data demonstrate deep and durable responses with a manageable safety profile, including no drug-drug interactions and no Boxed Warnings for QTc prolongation or Torsades de Pointes – key advantages for patients on multiple concurrent medications. This approval equips physicians with a new oral therapy to integrate into care and improve outcomes for this vulnerable patient population.”

The most common adverse reactions (≥20%), including laboratory abnormalities, were aspartate aminotransferase increased, infection without an identified pathogen, potassium decreased, albumin decreased, alanine aminotransferase increased, sodium decreased, creatinine increased, alkaline phosphatase increased, hemorrhage, diarrhea, nausea, fatigue, edema, bacterial infection, musculoskeletal pain, bilirubin increased, potassium increased, differentiation syndrome, pruritus, febrile neutropenia, and transaminases increased. Komzifti includes a Boxed Warning for differentiation syndrome, a well-studied mechanism-based risk in drugs that restore differentiation. Absence of clinically meaningful drug-drug interactions can ease the use of Komzifti with concomitant therapies, including those that cause QTc interval prolongation. QTc interval prolongation was ≤ Grade 3 in 12% of patients and no Grade 4 or Grade 5 QTc interval prolongation was reported. QTc interval prolongation of any cause occurred in 10% of the 70 patients 65 years of age or older.

“The approval of Komzifti underscores our commitment to advancing precision medicines to address the genetic drivers of disease in hematology and oncology,” said Takeyoshi Yamashita, Ph.D., Executive Vice President and Chief Medical Officer of Kyowa Kirin. “In AML, where many patients face severe disease progression and limited treatment options, the evolution toward targeted therapies such as Komzifti represents a major step forward and offers potential to transform existing standards of care. We are proud to partner with Kura Oncology in bringing this important therapy to patients and their families.”

In November 2024, Kura Oncology and Kyowa Kirin entered into a global strategic collaboration to develop and commercialize Komzifti. The collaboration builds on Kyowa Kirin’s leadership and expertise in hematologic malignancies. Under the terms of the collaboration, Kura leads development, regulatory and commercial strategy in the U.S. and is responsible for manufacturing Komzifti. The companies will jointly perform certain commercialization activities in accordance with a co-created U.S. territory commercialization plan. Outside the U.S., Kyowa Kirin leads development, regulatory and commercial strategy and is responsible for commercializing Komzifti.

As part of its commitment to helping patients access Komzifti, Kura has established a support program, Kura RxKonnect™, to minimize barriers to access and reimbursement for appropriate patients prescribed Komzifti. Kura RxKonnect is available 8:00 am – 8:00 pm ET by phone at (844) KuraPSP (844-587-2777) or online at www.KuraRxKonnect.com.

https://en.wikipedia.org/wiki/Ziftomenib

FDA Approves Komzifti (ziftomenib) for the Treatment of Adults with Relapsed or Refractory NPM1-Mutated Acute Myeloid Leukemia

FDA Grants Accelerated Approval for Ojemda (tovorafenib) for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma

Day One Biopharmaceuticals, Inc. (Nasdaq: DAWN) (“Day One” or the “Company”), a commercial-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved Ojemda (tovorafenib), a type II RAF inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This indication is approved under accelerated approval based on response rate and duration of response. With the approval, Day One received a rare pediatric disease priority review voucher from the FDA.

“Ojemda ushers in a new day for children living with relapsed or refractory pLGG, and we are pleased that we can deliver a new medicine for these patients in desperate need of new treatment options. Moreover, Ojemda is the first and only FDA-approved medicine for children with BRAF fusions or rearrangements, which are the most common molecular alteration in pLGG,” said Jeremy Bender, Ph.D., chief executive officer of Day One. “We are very proud that our first approved medicine addresses this serious and life-threatening disease of childhood and adolescence. We are grateful to the pLGG community, including patients and their families, study investigators, non-profit organizations, and advocacy groups, for their collaboration and support as we strive to close the innovation gap for children with cancer awaiting new treatments.”

pLGG is the most common brain tumor diagnosed in children, with patients suffering profound tumor- and treatment-associated morbidities that can impact their life trajectory. BRAF is the most commonly altered gene in pLGG, with up to 75 percent of children having a BRAF alteration. Until now, there had been no medicines approved for patients with pLGG driven by BRAF fusions.

“pLGG is a chronic and relentless cancer that can devastate children and their families, often stealing their vision, balance and speech,” said Dr. Sabine Mueller, pediatric neuro-oncologist, University of California San Francisco Benioff Children’s Hospitals. “The goal of pLGG treatment is to stabilize or shrink the tumor without further disrupting the child’s and family’s life. Historically, there has been no standard of care for children with pLGG who have relapsed. We are excited to welcome a new targeted treatment option with once-weekly oral dosing designed specifically for these kids and their families.”

Ojemda is the only systemic therapy for pLGG that offers once-weekly dosing, with or without food, as a tablet or oral suspension.

REF: https://en.wikipedia.org/wiki/Tovorafenib

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FDA Grants Accelerated Approval for Ojemda (tovorafenib) for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma

FDA Approves Jaypirca (pirtobrutinib) for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma

Loxo@Lilly, the oncology unit of Eli Lilly and Company (NYSE: LLY),  announced the U.S. Food and Drug Administration (FDA) approved Jaypirca™ (pirtobrutinib, 100 mg & 50 mg tablets) for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton's tyrosine kinase (BTK) inhibitor. Jaypirca was approved under the FDA's Accelerated Approval pathway based on response rate from the open-label, single-arm, international, Phase 1/2 study, called the BRUIN trial.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Jaypirca, a highly selective kinase inhibitor, utilizes a novel binding mechanism and is the first and only FDA approved non-covalent (reversible) BTK inhibitor. Jaypirca can reestablish BTK inhibition in MCL patients previously treated with a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the BTK pathway.

"The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent BTK inhibitor," said Michael Wang, M.D., Puddin Clarke Endowed Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center. "These data indicate that Jaypirca can provide efficacy in patients previously treated with a covalent BTK inhibitor, potentially extending the time patients may benefit from BTK inhibition therapy. Jaypirca offers a new approach to targeting the BTK pathway following treatment with a covalent BTK inhibitor and has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients."

The labeling for Jaypirca contains warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, second primary malignancies, and embryo-fetal toxicity. See Important Safety Information below and full Prescribing Information for additional information, including dosing modifications.

"We are pleased to bring a meaningful new therapeutic option to patients with MCL that can reestablish the benefit of targeting the BTK pathway after receiving multiple prior therapies, including a covalent BTK inhibitor," said Jacob Van Naarden, chief executive officer, Loxo@Lilly. "We are grateful to the patients, investigators, and other members of the clinical care teams for their contributions. Our team has been committed to rapidly advancing the development of Jaypirca for patients with MCL, and we look forward to building on this milestone by continuing to bring forward important new treatments for people with hematologic malignancies."

The FDA approval is based on data from a subset of patients in the BRUIN Phase 1/2 trial. The assessment of efficacy was based on 120 patients with MCL treated with Jaypirca 200 mg once daily until disease progression or unacceptable toxicity. Patients with active central nervous system lymphoma or allogeneic hematopoietic stem cell transplantation or CAR T-cell therapy within 60 days were excluded. Patients had received a median of three prior lines of therapy (range: 1 to 9), with 93% having two or more prior lines; all patients received one or more prior lines of therapy containing a covalent BTK inhibitor. Eighty-three percent (83%) of patients discontinued their last BTK inhibitor due to refractory or progressive disease. Efficacy was based on overall response rate (ORR) and duration of response (DOR) as assessed by an independent review committee (IRC) using 2014 Lugano criteria.

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https://en.wikipedia.org/wiki/Pirtobrutinib#/media/File:Pirtobrutinib.svg

FDA Approves Jaypirca (pirtobrutinib) for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma

Ibrutinib ‘new standard’ for relapsed, refractory mantle cell lymphoma

In continuation of my update on Ibrutinib and Temsirolimus

Temsirolimus

Phase III trial findings suggest that patients with relapsed or refractory mantle cell lymphoma derive significantly greater benefits from ibrutinib than from temsirolimus therapy.

Ibrutinib

The results of this direct comparison of the two treatment options approved in the European Union for this patient population “clearly establish ibrutinib as a new standard for treatment” of relapsed or refractory mantle cell lymphoma, says Peter Martin (Weill Cornell Medical College, New York, USA) in a comment accompanying the report in The Lancet.

He adds: “Many clinicians expect that, within the next 2 years, ibrutinib will find its way into the front-line setting for treatment of mantle cell lymphoma in combination with standard chemotherapy”.

In the trial, a total of 280 patients with relapsed or refractory disease who had previously been treated with at least one rituximab-containing regimen were followed up for a median of 20 months.

Median progression-free survival (PFS) was 14.6 months for the 139 patients randomly assigned to receive open-label oral ibrutinib and 6.2 months for the 141 patients given intravenous temsirolimus, a significant difference with a hazard ratio for progression or death of 0.43. The corresponding 2-year PFS rates were 41% and 7%.

Significantly more patients given the Bruton’s tyrosine kinase inhibitor ibrutinib achieved an overall response compared with those given the mammalian target of rapamycin antagonist temsirolimus, with rates of 72% versus 40%. And complete responses were observed in 19% and 1% of patients, respectively.

Ibrutinib ‘new standard’ for relapsed, refractory mantle cell lymphoma

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

In continuation of my update on carfilzomib

Carfilzomib significantly improves outcomes in previously treated patients with relapsed or refractory multiple myeloma, shows a head-to-head comparison with bortezomib.

In the ENDEAVOR phase III trial, published in The Lancet Oncology, median progression-free survival (PFS) was 18.7 months for the 464 patients randomly assigned to receive open-label carfilzomib plus dexamethasone. This was significantly longer than the 9.4 months for the 465 participants treated with bortezomib and dexamethasone, and equated to a 47% risk reduction in favour of carfilzomib.

Moreover, a significantly higher proportion of carfilzomib- than bortezomib-treated patients achieved an objective response, at 77% versus 63%, and the duration of response was also longer in the former group, at a respective 21.3 and 10.4 months.

The most common side effects of grade 3 or worse that occurred more frequently in the carfilzomib than the bortezomib treatment arm were anaemia and hypertension, with rates of 14% versus 10% and 9% versus 3%, respectively.

However, peripheral neuropathy of grade 3 was observed in 2% of carfilzomib-treated patients and there were no grade 4 events, compared with 8% of patients in the bortezomib arm who experienced events of grade 3 or 4.

Serious adverse events occurred in 48% of patients in the carfilzomib group and in 36% of those given bortezomib, but Meletios Dimopoulos (National and Kapodistrian University of Athens, Greece) and team note that the number of discontinuations and deaths attributable to adverse events were comparable between the groups.

They conclude that carfilzomib plus dexamethasone could be considered for multiple myeloma patients for whom bortezomib is indicated.

Role for carfilzomib in relapsed, refractory multiple myeloma treatment