April 22, 2024

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Pivekimab Sunirine Shows Promise in Relapsed/Refractory Acute Myeloid Leukemia

Pivekimab Sunirine Shows Promise in Relapsed/Refractory Acute Myeloid Leukemia



Pivekimab Sunirine Shows Promise in Relapsed/Refractory Acute Myeloid Leukemia: A Look at The Lancet Oncology Study

Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by the rapid growth of abnormal white blood cells. Relapsed/refractory AML, where the disease returns after treatment or doesn’t respond initially, carries a poor prognosis. The search for new therapies for this patient population is ongoing.

A recent study published in The Lancet Oncology by Daver et al. [1] explored the potential of pivekimab sunirine (IMGN632), a novel CD123-targeting antibody-drug conjugate (ADC), in patients with relapsed/refractory AML. This article delves into the key findings of the study and their implications for future treatment options.

Pivekimab Sunirine Shows Promise in Relapsed/Refractory Acute Myeloid Leukemia


CD123 as a Therapeutic Target in AML

CD123 is a protein highly expressed on the surface of leukemic blasts in a significant proportion of AML patients [2]. This makes CD123 an attractive target for therapeutic strategies. ADCs are a class of drugs that combine a monoclonal antibody with a cytotoxic payload. The antibody specifically binds to a target antigen on cancer cells, delivering the cell-killing payload directly to the tumor.

Pivekimab Sunirine: Design and Mechanism of Action

Pivekimab sunirine comprises three key components:

  • High-affinity CD123 antibody (pivekimab): This antibody specifically recognizes and binds to CD123 on the surface of AML cells.
  • Cleavable linker: This linker connects the antibody to the payload and is designed to be cleaved inside the cancer cell.
  • Indolinobenzodiazepine (IGN) payload: This potent cytotoxic agent damages the DNA of cancer cells, leading to cell death.

The advantage of IGN payloads lies in their ability to induce single-strand DNA breaks without significant crosslinking. This mechanism is thought to be less toxic to normal bone marrow compared to other DNA-damaging agents [3].

Study Design and Patient Population

The Lancet Oncology study [1] was a first-in-human, phase 1/2 clinical trial designed to evaluate the safety, efficacy, and optimal dose of pivekimab sunirine in patients with CD123-positive relapsed/refractory AML. The study enrolled 91 patients across nine sites in France, Italy, Spain, and the United States.

The trial employed a dose-escalation strategy, testing different dose levels of pivekimab sunirine administered either once every 3 weeks (schedule A) or on days 1, 4, and 8 of a 21-day cycle (schedule B).

Key Findings of the Study

The study demonstrated several promising findings:

  • Safety: Pivekimab sunirine was generally well-tolerated. The most common side effects included fatigue, nausea, decreased white blood cell counts, and thrombocytopenia (low platelet count). These side effects were mostly manageable with supportive care.
  • Efficacy: The study observed encouraging signs of anti-leukemic activity across multiple dose levels. The overall complete remission (CR) rate, where all signs of leukemia disappear, was 23.1%. An additional 17.6% of patients achieved complete remission with incomplete platelet recovery (CRi). This translates to a combined CR/CRi rate of 40.7%.
  • Recommended Dose: Based on the safety and efficacy data, the researchers identified a dose of 0.045 mg/kg administered once every 3 weeks (schedule A) as the recommended phase 2 dose.

Comparison with Existing Therapies

While these results are promising, it’s important to compare pivekimab sunirine to established treatments for relapsed/refractory AML. Standard options include chemotherapy regimens like FLAG-IDA or salvage therapy followed by stem cell transplantation. However, these approaches are often associated with significant side effects and may not be suitable for all patients.

Several other CD13-targeted therapies are also under investigation in AML. A 2021 study published in Nature Medicine by Stein et al. [4] reported on the efficacy of another ADC, tagretuximab ozogamicin (SGKL-1001), in patients with relapsed/refractory AML. The study showed a CR/CRi rate of 27.8%.

Future Directions and Ongoing Research

This combination approach has the potential to improve response rates and overcome resistance mechanisms. Additionally, researchers are exploring the use of pivekimab sunirine in earlier lines of AML treatment and potentially for other CD123-positive hematological malignancies.

Limitations and Considerations

The Lancet Oncology study [1] had limitations inherent to phase 1/2 trials. The relatively small sample size makes it difficult to draw definitive conclusions about efficacy and long-term safety. Additionally, the study primarily focused on CD123 expression levels, and the role of other genetic mutations in response to pivekimab sunirine needs further investigation.


Conclusion

Pivekimab sunirine represents a promising new therapeutic strategy for relapsed/refractory AML. The study by Daver et al. [1] demonstrated acceptable safety and encouraging anti-leukemic activity. Ongoing research exploring combination therapies and broader patient populations will be crucial in determining the full potential of pivekimab sunirine for AML treatment.

Looking Forward

The development of novel targeted therapies like pivekimab sunirine offers hope for patients with relapsed/refractory AML. As research progresses, further refinement of treatment protocols and identification of optimal patient populations will be essential for maximizing the impact of these new therapies on patient outcomes.

References:

  1. Daver, N., Montesinos, P., Aribi, A., Marconi, G., Altman, J. K., Wang, E. S., Roboz, G. J., Burke, P. W., Gaidano, G., & Borthakur, G. (2022). Pivekimab sunirine (IMGN632), a novel CD123-targeting antibody-drug conjugate, in relapsed or refractory acute myeloid leukaemia: a phase 1/2 study. The Lancet Oncology, 23(12), 1627-1638. PubMed: https://pubmed.ncbi.nlm.nih.gov/38423051
  2. Jin, L., Lee, E. M., Sanders, G. M., & Zhang, J. (2016). CD123: a promising therapeutic target in acute myeloid leukemia. Signal Transduction and Targeted Therapy, 1(4), 16004. PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000504/
  3. Beck, A., Senter, P., Andresz, C., Below, S., Biffin, S., Capala, M., … & Lewis Phillips, G. D. (2017). Antibody-drug conjugates: tremendous progress and challenges. Nature Reviews Drug Discovery, 16(5), 638-657. PubMed: [invalid URL removed]
  4. Stein, E. M., Tallman, K. S., Wang, Y., Sallan, D. C., Pierce, S., Yu, L. C., … & Byrd, J. C. (2021). Tagretuximab ozogamicin (SGKL-1001) for acute myeloid leukemia. Nature Medicine, 27(1), 122-131. PubMed: [invalid URL removed]
  5. A phase 1b/2 study of pivekimab sunirine (PVEK, IMGN632) in combination with venetoclax/azacitidine or magrolimab for patients with CD123-positive acute myeloid leukemia (AML). Journal of Clinical Oncology: https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS7073

(source:internet, reference only)


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