Addressing Myelotoxicity as a Consequence of Treatment for Extended-Stage Small Cell Lung Cancer

EP. 3: Management of Extensive-Stage Small Cell Lung Cancer Treatment-Related Events

This article reviews the impact of chemotherapy-induced myelosuppression associated with current standard-of-care management of extensive-stage small cell lung cancer and examines new and emerging therapies that may have the potential to address unmet needs.


Current Management of Chemotherapy-Induced Myelosuppression

Patients with extensive-stage small cell lung cancer (ES-SCLC) receiving standard-of-care chemotherapy regimens are at risk for the development of chemotherapy-induced myelosuppression, which can result in serious clinical consequences.1 One treatment strategy often employed for the management of chemotherapy-induced myelosuppression is adjustment of the chemotherapy regimen.1,2 However, reduced dose intensity of chemotherapy due to dose delays or reductions can potentially impact the efficacy of treatments and compromise patient outcomes.1,2

Other traditional interventions for the management of chemotherapy-induced myelosuppression are typically administered after clinical manifestations present, but they are associated with limitations.3,4 Current strategies for the management of chemotherapy-induced anemia include transfusion of red blood cells (RBCs), administration of erythropoiesis-stimulating agents (ESAs), and iron supplementation.3,5 Although RBC transfusion provides the most effective way of rapidly correcting anemia in symptomatic patients, its use can lead to rare but potentially serious adverse events.6,7 Transfusion-related reactions, transfusion-associated circulatory overload, and infections are among the risks associated with RBC transfusions.6 For patients receiving chemotherapy, ESAs can help to reduce the need for RBC transfusions.3 However, ESAs increase the risk for thromboembolic and cardiovascular events as well as mortality, and thus, they only should be used after careful consideration in select patients.3,6

Beyond chemotherapy regimen modifications, the only treatment options for the management of chemotherapy-induced thrombocytopenia are platelet transfusion and off-label use of the thrombopoietin receptor agonist romiplostim.6 Improvement of thrombocytopenia with platelet transfusion is only temporary, and thus this intervention is impractical as a long-term treatment strategy.8 Additionally, although rare, platelet transfusion can lead to adverse events such as acute transfusion reactions (allergic and febrile non-hemolytic reactions), infection, transfusion-mediated immunomodulation, and thrombosis.4,9

Primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) reduces the incidence of febrile neutropenia resulting from chemotherapy-induced myelosuppression.6,10 However, use of G-CSFs is often associated with the development of bone pain, with up to 50% of patients who receive this treatment reporting any-grade bone pain, and up to 28% of patients reporting moderate-to-severe bone pain.11 While G-CSFs are otherwise well tolerated, the occurrence of bone pain can have a negative impact on the quality of life of patients.12

Impact of Chemotherapy-Induced Myelosuppression

Clinical complications

The clinical complications of chemotherapy-induced myelosuppression, including anemia, neutropenia, and thrombocytopenia as well as their corresponding treatments, create substantial burdens on patients and the health care system.5,13-16 Anemia can result in suboptimal response to chemotherapy, fatigue, and reduced quality of life.5,14 Severe neutropenia can lead to serious infections and febrile neutropenia, while thrombocytopenia increases the risk of life-threatening bleeding.13,17

Financial burden

The financial burden associated with these complications is substantial, as some patients may require hospitalization for optimal management.15,16 A retrospective study using a health care database in the United States showed that among patients with lung cancer, total costs per episode of hospitalization related to febrile neutropenia were $32,964 when taking into account hospital stay, emergency department visits, and office-based visits.16 Data from another retrospective study noted that among patients with solid tumors or non-Hodgkin lymphoma the total costs of care related to chemotherapy-induced thrombocytopenia, including inpatient care, were $2179 per patient episode, which was $1908 more than the costs associated with cycles without thrombocytopenia.15

Unmet Need in the Management of Chemotherapy-Induced Myelosuppression

Given the limitations associated with the current management strategies for chemotherapy-induced myelosuppression, an unmet need remains for alternative treatments that can act proactively to minimize or prevent myelosuppression.4 Trilaciclib and ALRN-6924 are promising agents in this setting.18,19 Trilaciclib, a transient inhibitor of CDK 4/6, was approved by the United States Food and Drug Administration in February 2021 to decrease the incidence of chemotherapy-induced myelosuppression in patients with ES-SCLC who receive treatment with a platinum/etoposide-containing or topotecan-containing regimen.20 Trilaciclib provides myeloprotection across multiple cell lineages by proactively protecting hematopoietic stem and progenitor cells from chemotherapy-induced damage.18,20,21

Trilaciclib

Results from a pooled analysis of phase 2 data among patients with ES-SCLC demonstrated that compared with placebo, administration of trilaciclib prior to chemotherapy significantly decreased the incidence of severe neutropenia (P < .0001).18 Significant improvements in most secondary myelosuppression end points, including the incidence of grade 3/4 anemia, RBC transfusions, and grade 3/4 thrombocytopenia, were also demonstrated with the administration of trilaciclib compared with placebo.18 Additionally, the proportion of patients requiring chemotherapy dose reductions was lower in the trilaciclib group compared with the placebo group.18 National Comprehensive Cancer Network guidelines have incorporated trilaciclib as a prophylactic option to be given prior to a platinum/etoposide-containing regimen or topotecan-containing regimen to reduce the incidence of chemotherapy-induced myelosuppression in patients with ES-SCLC.6,22

ALRN-6924

ALRN-6924 is a cell-permeating, stabilized alpha-helical peptide and dual inhibitor of MDMX/MDM2 that induces cell arrest in wild-type p53 cells.19 In a preclinical study, ALRN-6924 led to a transient, reversible cell cycle arrest in bone marrow cells in vitro and in vivo, and it reduced topotecan-induced DNA damage in healthy human bone marrow cells ex vivo.23 Additionally, when administered prior to chemotherapy, ALRN-6024 protected against neutrophil depletion in a mouse model of topotecan-induced neutropenia, while preserving or enhancing the anti-tumor efficacy of topotecan in p53-mutant tumors.23

A phase 1b trial (NCT04022876) is evaluating the use of ALRN-6924 for the prevention of topotecan-induced hematological toxicities in patients with p53-mutated ES-SCLC receiving second-line topotecan.24 Patients will receive topotecan on days 1 to 5 of 21-day cycles and will be randomized to receive 1 of 2 initial ALRN-6924 dose levels prior to each topotecan administration.24 This trial will also include a phase 1b cohort of patients with p53-mutated advanced non-small cell lung cancer receiving first-line treatment with carboplatin plus pemetrexed, with or without immunotherapy.24 Recruitment for the cohort of patients with ES-SCLC is complete, and plans for randomized expansion cohorts have been announced.4,24 Preliminary phase 1b data indicate that administration of ALRN-6924 treatment 24 hours prior to topotecan led to lower rates of severe anemia, neutropenia, and thrombocytopenia in patients with p53-mutated ES-SCLC when compared with historical data.19

Conclusions

Patients with ES-SCLC receiving standard-of-care chemotherapy regimens are at risk for serious clinical consequences of chemotherapy-induced myelosuppression.1 This creates substantial burdens on patients and health care systems because traditional management strategies are associated with limitations.4,14-16 New and emerging agents that are administered prior to chemotherapy are promising treatments that can potentially address this unmet therapeutic need by acting proactively to minimize or prevent myelosuppression.4,19,21


References

  1. Hussein M, Maglakelidze M, Richards DA, et al. Myeloprotective effects of trilaciclib among patients with small cell lung cancer at increased risk of chemotherapy-induced myelosuppression: pooled results from three phase 2, randomized, double-blind, placebo-controlled studies. Cancer Manag Res. 2021;13:6207-6218. doi:10.2147/CMAR.S313045
  2. Crawford J, Denduluri N, Patt D, et al. Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer. Support Care Cancer. 2020;28(2):925-932. doi:10.1007/s00520-019-04875-1
  3. Bohlius J, Bohlke K, Castelli R, et al. Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH Clinical Practice Guideline update. J Clin Oncol. 2019;37(15):1336-1351. doi:10.1200/JCO.18.02142
  4. Lyman GH, Kuderer NM, Aapro M. Improving outcomes of chemotherapy: Established and novel options for myeloprotection in the COVID-19 era. Front Oncol. 2021;11:697908. doi:10.3389/fonc.2021.697908
  5. Bryer E, Henry D. Chemotherapy-induced anemia: etiology, pathophysiology, and implications for contemporary practice. Int J Clin Transfus Med. 2018;6:21-31. https://doi.org/10.2147/IJCTM.S187569
  6. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic growth factors, version 4. 2021. Accessed September 9, 2021. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf
  7. Delaney M, Wendel S, Bercovitz RS, et al. Transfusion reactions: prevention, diagnosis, and treatment. Lancet. 2016;388(10061):2825-2836. doi:10.1016/S0140-6736(15)01313-6
  8. Al-Samkari H, Parnes AD, Goodarzi K, Weitzman JI, Connors JM, Kuter DJ. A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies. Haematologica. 2021;106(4):1148-1157. doi:10.3324/haematol.2020.251900
  9. Stolla M, Refaai MA, Heal JM, et al. Platelet transfusion - the new immunology of an old therapy. Front Immunol. 2015;6:28. doi:10.3389/fimmu.2015.00028
  10. Lee J, Lee JE, Kim Z, et al. Pegfilgrastim for primary prophylaxis of febrile neutropenia in breast cancer patients undergoing TAC chemotherapy. Ann Surg Treat Res. 2018;94(5):223-228. doi:10.4174/astr.2018.94.5.223
  11. Xu H, Gong Q, Vogl FD, Reiner M, Page JH. Risk factors for bone pain among patients with cancer receiving myelosuppressive chemotherapy and pegfilgrastim. Support Care Cancer. 2016;24(2):723-730. doi:10.1007/s00520-015-2834-2
  12. Moore DC, Pellegrino AE. Pegfilgrastim-induced bone pain: a review on incidence, risk factors, and evidence-based management. Ann Pharmacother. 2017;51(9):797-803. doi:10.1177/1060028017706373
  13. Li Y, Klippel Z, Shih X, Reiner M, Wang H, Page JH. Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies. Support Care Cancer. 2016;24(10):4377-4383. doi:10.1007/s00520-016-3277-0
  14. Epstein RS, Aapro MS, Basu Roy UK, et al. Patient burden and real-world management of chemotherapy-induced myelosuppression: results from an online survey of patients with solid tumors. Adv Ther. 2020;37(8):3606-3618. doi:10.1007/s12325-020-01419-6
  15. Weycker D, Hatfield M, Grossman A, et al. Risk and consequences of chemotherapy-induced thrombocytopenia in US clinical practice. BMC Cancer. 2019;19(1):151. doi:10.1186/s12885-019-5354-5
  16. Kawatkar AA, Farias AJ, Chao C, et al. Hospitalizations, outcomes, and management costs of febrile neutropenia in patients from a managed care population. Support Care Cancer. 2017;25(9):2787-2795. doi:10.1007/s00520-017-3692-x
  17. Barreto JN, McCullough KB, Ice LL, Smith JA. Antineoplastic agents and the associated myelosuppressive effects: a review. J Pharm Pract. 2014;27(5):440-446. doi:10.1177/0897190014546108
  18. Weiss J, Goldschmidt J, Andric Z, et al. Effects of trilaciclib on chemotherapy-induced myelosuppression and patient-reported outcomes in patients with extensive-stage small cell lung cancer: pooled results from three phase II randomized, double-blind, placebo-controlled studies. Clin Lung Cancer. 2021;22(5):449-460. doi:10.1016/j.cllc.2021.03.010
  19. Andric Z, Ceric T, Stanetic M, Rancic M, Jakopovic M, Ponce Aix S, et al. Abstract 96LBA. Prevention of chemotherapy-induced myelosuppression in SCLC patients treated with the dual MDMX/MDM2 inhibitor ALRN-6924. Eur J Cancer. 2020;138(suppl 2):S5. doi:10.1016/S0959-8049(20)31081-9
  20. Cosela. Prescribing information. G1 Therapeutics, Inc; 2021. Accessed September 9, 2021. https://www.g1therapeutics.com/cosela/pi/
  21. Daniel D, Kuchava V, Bondarenko I, et al. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled phase II trial. Int J Cancer. 2020;148(10):2557-2570. doi:10.1002/ijc.33453
  22. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 1.2022. Accessed September 9, 2021. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf
  23. Carvajal LA, Sutton D, Mounir M, McClanaghan J, Guerlavais V, Aivado M, et al. Abstract C064: The investigational peptide drug ALRN-6924, a dual inhibitor of MDMX and MDM2, is an effective myelopreservation agent. Mol Cancer Ther. 2019;18(12):C064. doi:10.1158/1535-7163.TARG-19-C064
  24. A study of ALRN-6924 for the prevention of chemotherapy-induced side effects (chemoprotection). ClinicalTrials.gov. Updated July 1, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/NCT04022876?term=NCT04022876&draw=2&rank=1