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

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

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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/
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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