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

EP. 7: Clinical Trial Evidence for Chemoprotectant Benefit of ALRN-6924 for Chemotherapy-Induced Myelosuppression

This article provides an overview of the role of MDM2 and MDMX as drivers of malignancy and examines the potential chemoprotectant benefit of the dual MDM2/MDMX inhibitor ALRN-6924 observed in 2 phase 1b clinical trials of patients with small cell lung cancer and non-small cell lung cancer.


The TP53 tumor-suppressor gene and its protein product, p53, play a central role in DNA damage repair and have been a focus of research for many years.1 Antitumor activity of p53 is negatively regulated by the MDM2 protein, which binds and destroys p53, and the MDMX protein, which inhibits p53 activity following protein sequestration.1 Although TP53 mutations continue to be the most commonly observed variants among human malignancies, many cancers retain wild-type TP53 status (WT TP53). Amplification of the MDM2 gene or overexpression of the MDM2 protein have been identified as major drivers of malignancy in WT TP53 tumor cells, which has highlighted the reactivation of natural p53 function as an appealing therapeutic strategy.1,2

First identified in the early 2000s, MDM2 inhibitors have been studied for their antitumor efficacy.2 Recently, evidence has emerged suggesting that dual inhibition of MDM2 and MDMX are needed to achieve a more complete p53 activation.2 Previous studies investigating monotherapy with MDM2 antagonists in various cancer types have often demonstrated neutropenia and thrombocytopenia as dose-limiting toxicities (DLTs).1,3 MDM2 plays a role in the process of hematopoiesis; these DLTs are believed to be on-target effects of MDM2 inhibition.1,3 Conversely, hematopoietic toxicities observed with early studies evaluating certain dual MDM2/MDMX inhibitors are nearly absent, which has prompted further investigation of these agents in combination therapy strategies and as chemoprotectants.1

ALRN-6924 is a stabilized α-helical peptide that binds to and inhibits the activity of MDM2 and MDMX, resulting in the initiation of p53 transcription and subsequent cell-cycle arrest.4 Previous studies investigating ALRN-6924 have demonstrated antitumor activity and potential synergistic effects in terms of tumor growth inhibition when used in combination with other chemotherapeutic agents.2,5,6 The high level of MDMX expression in bone marrow cells may help minimize the overall inhibition of MDM2 in bone marrow cells and the subsequent MDM2-mediated degradation of p53.1 Evidence demonstrating a lower occurrence of hematopoietic-related toxicities following treatment with ALRN-6924 further supports this hypothesis and may suggest a potential role for dual MDMX/MDM2 inhibitors as chemoprotectants.1 An ongoing, 2-part, phase 1b trial (NCT04022876) is currently investigating the use of ALRN-6924 to prevent chemotherapy-induced myelosuppression (CIM) in small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC).4,7,8


Part 1: Phase 1b Study of the Dual MDMX/MDM2 Inhibitor, ALRN-6924, for the Prevention of Chemotherapy-Induced Myelosuppression in SCLC

This phase 1b study (NCT04022876) of ALRN-6924 enrolled 39 patients with TP53-mutated, extensive-disease SCLC and an ECOG performance status of 0 to 2 who were being treated with 5 daily doses of topotecan.4,7 The study investigated treatment schedules and dose levels of ALRN-6924 for the mitigation of CIM.4 Results were presented in a poster at the 2021 European Society for Medical Oncology Virtual Congress.4

Patients were given ALRN-6924 at a dosing schedule of either 24 hours or 6 hours prior to each infusion of topotecan. In the 31 patients treated on a 24-hour schedule, ALRN-6924 was given at a dose of 0.2 mg/kg to 4 patients, 0.3 mg/kg to 16 patients, 0.6 mg/kg to 6 patients (5 evaluable), and 1.2 mg/kg to 6 patients.4 The median treatment duration was 64.5 days, 72 days, 16.5 days, and 41.5 days for each dosing group, respectively. The median number of cycles completed was 5, 4, 1, and 2.5, respectively. Topotecan dose reductions were observed in 3 patients (19%) in the 0.3 mg/kg group and 1 patient (17%) in the 1.2 mg/kg group.4 Adverse events (AEs) of at least grade 3 were reported during any cycle in 3 patients (75%), 14 patients (88%), 5 patients (83%), and 6 patients (100%) in the 0.2, 0.3, 0.6, and 1.2 mg/kg groups, respectively. The most common AEs of grade 3 or higher included neutropenia (3 [75%], 13 [81%], 5 [83%], and 6 [100%]), thrombocytopenia (2 [50%], 7 [44%], 2 [33%], and 2 [33%]), leukopenia (2 [50%], 3 [19%], 4 [67%], and 4 [67%]), anemia (0 [0%], 3 [19%], 1 [17%], and 1 [17%]), and fatigue (0 [0%], 1 [6%], 1 [17%], and 0 [0%]).4 Grade 4 neutropenia was observed during the first treatment cycle in 1 patient (25%), 5 patients (31%), 4 patients (67%), and 1 patient (17%) across the 0.2, 0.3, 0.6, and 1.2 mg/kg cohorts, respectively.4 Red blood cell (RBC) transfusions were required in 0 patients (0%), 1 patient (6%), 3 patients (50%), and 3 patients (50%) in the 0.2, 0.3, 0.6, and 1.2 mg/kg groups, respectively. In these groups, platelet transfusions were required in 0 patients (0%), 1 patient (6%), 2 patients (33%), and 1 patient (17%), respectively.4

A 0.3-mg/kg dose of ALRN-6924 was given to 7 patients 6 hours before topotecan was administered. The median treatment duration was 44 days, with a median of 3 completed cycles. Topotecan dose reductions occurred in 1 patient (14%).4 In this group of patients, AEs of grade 3 or higher reported in any cycle of treatment occurred in 7 patients (100%), with neutropenia (7 [100%]), thrombocytopenia (5 [71%]), leukopenia (3 [43%]), and anemia (1 [14%]) being the most common.4 Neutropenia was observed at a severity of grade 4 during the first cycle of treatment in 3 patients (43%) in the 6-hour schedule group.4 RBC and platelet transfusions were required in 1 patient (14%) and 1 patient (14%), respectively.4 Overall, the study demonstrated a chemoprotective effect of p53 activation by selective induction of cell cycle arrest, which may provide clinical benefit for patients harboring TP53 mutations.4


Part 2: Phase 1b Study Investigating the Chemoprotective Effects of ALRN-6924 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)

In July 2021, a phase 1b, randomized, double-blind, placebo-controlled trial (NCT04022876) to investigate the chemoprotective effects of ALRN-6924 was announced for patients with TP53-mutated, advanced NSCLC undergoing first-line treatment with carboplatin and pemetrexed.8

In this study, enrolled patients will be randomly assigned to receive carboplatin and pemetrexed plus either 0.3 mg/kg of ALRN-6924 or placebo during 4 treatment cycles of 21 days each. Investigators will assess the proportion of treatment cycles in which patients are free of severe hematologic or other toxicities (including neutropenia, thrombocytopenia, and anemia ≥ grade 3; neutropenia or febrile neutropenia of grade 4; duration of grade 4 neutropenia) as primary end points. Additional primary end points for the study include the proportion of treatment cycles completed without chemotherapy dose reductions or without transfusions or growth factor support. Also being assessed are the overall response rate, progression-free survival, quality of life, and the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events treatment-emergent AEs of grade 3 or 4.8

The trial is currently recruiting, and interim results of the first 20 enrolled patients are expected to be released during the second quarter of 2022; the release of topline results of the full enrollment is estimated to occur during the fourth quarter of 2022.7,9


Conclusions

With few advances in terms of molecular targeted therapies for SCLC, chemotherapy continues to be a mainstay of therapy for both limited- and extensive-stage disease.10 Chemotherapy-based treatment approaches can be effective in prolonging patient survival; however, multilineage CIM remains a challenge that presents a real-world burden on both patients with SCLC and the health care system and that highlights the need for further innovation for mitigation strategies.10 Primary and secondary management approaches using granulocyte-colony stimulating factor, erythrocyte-stimulating agents, and blood transfusions are available, but they are lineage-specific, and they have their own associated risks.11 ALRN-6924 offers a novel approach to CIM management with evidence as a potential chemoprotectant in SCLC patients treated with topotecan.4




References

  1. Saleh MN, Patel MR, Bauer TM, et al. Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53. Clin Cancer Res. 2021;27(19):5236-5247. doi:10.1158/1078-0432.CCR-21-0715
  2. Pairawan S, Zhao M, Yuca E, et al. First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models. Breast Cancer Res. 2021;23(1):29. doi:10.1186/s13058-021-01406-x
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  6. Sallman DA, Borate U, Cull EH, et al. Phase 1/1b study of the stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, as monotherapy or in combination with cytarabine for the treatment of relapsed/refractory AML and advanced MDS with TP53 wild-type. Blood. 2018;132(suppl 1):4066. doi:10.1182/blood-2018-99-118780
  7. A study of ALRN-6924 for the prevention of chemotherapy-induced side effects (chemoprotection). ClinicalTrials.gov. Updated July 1, 2021. Accessed March 31, 2022. https://clinicaltrials.gov/ct2/show/NCT04022876
  8. Aileron Therapeutics announces initiation of randomized, double-blind, placebo-controlled trial of ALRN-6924 in patients with advanced non-small cell lung cancer (NSCLC). Global News Wire. July 1, 2021. Accessed April 1, 2022. https://www.globenewswire.com/news-release/2021/07/01/2256463/28652/en/Aileron-Therapeutics-Announces-Initiation-of-Randomized-Double-Blind-Placebo-Controlled-Trial-of-ALRN-6924-in-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer-NSCLC.html
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  11. Weiss JM, Csoszi T, Maglakelidze M, et al; G1T28-02 Study Group. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019;30(10):1613-1621. doi:10.1093/annonc/mdz278