Murine double minute 2 (MDM2) inhibitors are moving to late-stage clinical trials, representing an exciting opportunity to target p53 in both solid tumors and hematologic malignancies.

“Tumor p53 (TP53), the gene that encodes p53, [a protein deemed] ‘the guardian of the genome,’ has been consider[ed] undruggable for a long time,” said Ecaterina E. Dumbrava, MD, an assistant professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in an interview with Targeted Therapies in Oncology™. Encouragingly, recent results suggest that “p53 is becoming actionable and druggable with direct p53-targeting drugs and with MDM2 inhibitors.”

“The human transcription factor p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, playing a critical role in protecting cells from malignant transformation,” Dumbrava explained further.^1,2 Activation of p53 target genes leads to cell cycle arrest, DNA repair, and, in cases of severe damage, apoptosis, allowing for damaged or potentially tumorigenic cells to be repaired or culled.^3,4 However, TP53 is the most commonly mutated gene in all cancers, with mutations occurring in approximately 50% of cancer types.^4,5

Activation of the p53 pathway is summarized in the FIGURE⁶ (p.54). MDM2 is an E3 ligase and a negative regulator of p53^7,8; some human tumors downregulate the p53 pathway by upregulating MDM2,⁹ which “results in impaired p53 activity, leading to accelerated cancer development and growth,” said Dumbrava. Therefore, “blocking MDM2 with targeted therapies leads to p53 reactivation and p53-mediated cell-cycle arrest or apoptosis that can be translated into clinically significant tumor shrinkage.” This is considered an attractive therapeutic strategy for cancers with wild-type or functional p53.^2,10

Raajit K. Rampal, MD, PhD, an associate attending physician at Memorial Sloan Kettering Cancer Center, agreed in an interview with Targeted Therapies in Oncology™, noting “this has been studied extensively and shown efficacy in preclinical studies and has been tested in solid tumors and hematologic malignancies with some degree of efficacy.”

However, stabilizing p53 signaling is not without concerns, as this results in an increase in apoptosis. In fact, treatment with MDM2 inhibitors is associated with gastrointestinal and bone marrow toxicities, which are thought to be on-target effects of MDM2 inhibition on normal cells.^11,12 “Patients can develop anemia and thrombocytopenia, as well as nausea, vomiting, and diarrhea. These [toxicities] can limit the utility of the drugs,” said Rampal.

Although there are no FDA-approved MDM2 inhibitors on the market, “various MDM2 inhibitors have been developed and are currently under investigation in clinical trials. MDM2 inhibitors have shown promising clinical efficacy in patients with liposarcoma and relapsed/refractory solid tumors, and acute myeloid leukemia; however, primary and acquired resistance have limited their potential clinical benefit,” said Dumbrava.

Recent Advances With MDM2 Inhibitors

MDM2 inhibitors have shown efficacy in both solid tumors and hematologic malignancies with several MDM2-p53 antagonists in development.

“In the myeloid malignancy space, [MDM2 inhibitors have] been well studied in myeloproliferative neoplasms [MPNs], including patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, where preclinical data has demonstrated that the inhibition of MDM2 increases cell death. This has been validated in clinical studies in which [treatment with] MDM2 inhibitors [has resulted in a decrease in] splenomegaly, a marker of disease in patients with myelofibrosis, for example; and some patients [had an improvement in] symptom profiles,” said Rampal. “There can also be a decrease in driver mutations. A key example is the JAK2 V617F mutation; sometimes there is a decrease in this variant when patients are exposed to MDM2 inhibitors.”

BI 907828

At the 2022 American Society of Clinical Oncology Annual Meeting (ASCO 2022), preliminary results of a phase 1 trial (NCT03449381) of treatment with BI 907828 in patients with advanced solid tumors showed partial responses (PRs) or stable disease (SD) in 88.9% of patients with dedifferentiated liposarcoma (DDLPS) and in 92.9% of patients with well-differentiated LPS (WDLPS). The progression-free survival for patients with LPS was over 10.5 months.¹³ “All patients who achieved an objective response had MDM2 amplifications,” Dumbrava noted.

An open-label, phase 2/3 study (Brightline-1; NCT05218499) comparing BI 907828 with doxorubicin in the first-line treatment of patients with advanced DDLPS is now recruiting participants.¹⁴

BI 907828 has also shown a manageable safety profile and encouraging preliminary efficacy in patients with advanced biliary tract cancer both as monotherapy (NCT03449381) and in combination with ezabenlimab, an anti–PD-1 antibody (NCT03964233). Five of 8 patients achieved a PR and 2 had SD.¹⁵ The combination of BI 907828 with immune checkpoint inhibitors (ezabenlimab and BI 754111) in patients with TP53–wild type advanced/metastatic solid tumors has shown preliminary signs of antitumor activity with a manageable toxicity profile (NCT03964233). Thus far with the combination of BI 907828 and ezabenlimab, 4 patients have achieved a confirmed PR, 1 had an unconfirmed PR, and 4 had SD.¹⁶

Milademetan

Milademetan (RAIN-32) is an oral MDM2 inhibitor that has shown encouraging results among 3 patients with no liposarcoma in a phase 1 trial of patients with advanced solid tumors or lymphomas (NCT01877382),¹⁷ including a disease control rate of 62% and a median progression-free survival of 7.4 months in patients with DDLPS who received intermittent dosing of the agent.¹⁸ These encouraging results prompted a randomized phase 3 trial (MANTRA [RAIN-3201]; NCT04979442) that aims to evaluate the efficacy and safety of milademetan compared with trabectedin (Yondelis) in patients with unresectable or metastatic DDLPS with disease progression on at least 1 prior systemic therapy.¹⁹ Milademetan monotherapy is also being evaluated for patients with locally advanced, incurable, or metastatic solid tumors that are refractory to standard therapy, are TP53–wild type, and have MDM2 amplification (copy number ≥ 12) in the phase 2 MANTRA-2 trial (RAIN-3202; NCT05012397).¹⁷

Navtemadlin

Promising results with navtemadlin (previously AMG-232 and KRT-232) were presented at ASCO 2022 in patients with TP53–wild type soft tissue sarcoma when given concurrently with preoperative radiotherapy (NCT03217266),²⁰ and in patients with Merkel cell carcinoma (NCT03787602).²¹ In the Merkel cell carcinoma study, both confirmed and unconfirmed responses were seen across dose levels. At the recommended phase 2 dose level, the overall response rate, both confirmed and unconfirmed, was 38% and the disease control rate was 63% with a median duration of response that was not reached.²¹

Data from an ongoing phase 1b/2 study (NCT04113616) of navtemadlin in patients with relapsed/refractory acute myeloid leukemia (AML) secondary to MPNs,22 and from an ongoing phase 2 study (NCT05027867) in patients with TP53–wild type relapsed/refractory small cell lung can cer23 also were presented at the meeting. When navtemadlin was added to dabra fenib (Tafinlar) and trametinib (Mekinist), however, it did not confer additional clinical benefit in patients with TP53–wild type, MAPK inhibitor–naïve metastatic mela noma, even although responses were seen with the combination in 11 patients.24

Siremadlin

A phase 1, doseescalation study (NCT02143635) of siremadlin in patients with TP53–wild type advanced solid or hematologic cancers identified a manage able safety profile and preliminary activity, particularly in patients with AML. Overall, the response rate was 3.5% and the disease control rate was 36.5%, yet among patients with AML, 5 achieved a complete response (CR) with an overall response rate of 13.2%.²⁵

Other recently published findings from a phase 1b, dose-escalation study showed that a combination of siremadlin and ribociclib (CDK4/6 inhibitor; Kisqali) demonstrated manageable toxicity and preliminary antitu mor activity in patients with advanced WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy. Three patients achieved a PR and 38 had SD.²⁶

Idasanutlin

Idasanutlin in combination with venetoclax (Venclexta) has shown manageable safety and encouraging efficacy in patients with relapsed/ refractory AML who are ineligible for cytotoxic chemotherapy (NCT02670044). The CR plus CR with incomplete blood recovery or incomplete platelet count recovery rate was 34.3% and the morphologic leukemia-free state rate was 14.3%. In patients with TP53 mutations, the CR rate was 20.0%.²⁷

Possible Drawbacks of MDM2 Inhibitors

Dumbrava explained that “cytopenia, and especially thrombocytopenia, and gas trointestinal toxicities have limited the development of MDM2 inhibitors in combi nations with other cytotoxic drugs.”

Rampal added that “a number of different things are being explored [to limit the toxicities associated with MDM2 inhibitors], and a lot of this has to do with altered dosing. In many studies, the drug is given for a limited duration of time to begin with. The question is, can that be reduced in terms of the number of days that a patient is dosed, and can we reduce the dose of the actual drug? Those are 2 of the things that are being explored in terms of trying to attenuate the toxicities of these drugs.”

The other caution with MDM2 inhibitors, at least in patients with MPN, is the expan sion of previously undetected TP53mutant clones, according to Rampal: “We have to be aware that our sequencing technologies have limits of detection. Nextgeneration sequencing can have a 3% to 5% limit of detection, and there may be TP53-mutant clones below those limits of detection.”

He explained that “these were likely sub clonal [populations] that emerged under the selective pressure of the MDM2 inhibitor. We’ve actually seen the fractions of those cells rise to quite high numbers, and that is a potential concern. On the other hand, we have not seen these patients progress—at least in MPNs—to the next stage of disease because of exposure to the MDM2 inhibitor. So the question is, what does it mean? I don’t think we know for certain. The data that we have at hand say that the TP53 mutant fraction may increase, but we don’t see progression of disease.”

Conclusions and Implications for Practice

“MDM2 inhibitors have shown both preclinical and clinical efficacy. The challenge now is how to mitigate the toxicities of the drugs, and also how to utilize them in combination with other targeted agents,” said Rampal. “I think it’s unlikely that these drugs will be used predominantly as a monotherapy. The more likely approaches we will see is that it will be combined with currently established therapies to extend their efficacy.”

Dumbrava noted that “additional research is needed to understand the role of MDM2 inhibitors in different solid tumors and the mechanisms or resistance.” She added that we may see FDA approvals, depending on the results of the phase 3 trials (Brightline-1 and MANTRA) presented at ASCO 2022.

She added that “while there is still a large gap between the FDA approvals and updated cancer treatment guidelines and what is done in community oncology practice, precision oncology is rapidly becoming a reality.” In fact, Dumbrava rec ommends molecular testing for all patients with solid tumors.

Although price may be a limitation, as there is “variable coverage across the country and by insurance [companies],” admitted Rampal, “there is an increasing realization that sequencing is not an acces sory. It’s an absolute necessity for diagnosis, prognosis, and treatment. I think that’s the way we have to think about it, and so I think the barriers to this should be lowered.”

REFERENCES:

1. Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14(5):359-370. doi:10.1038/nrc3711

2. Koo N, Sharma AK, Narayan S. Therapeutics targeting p53-MDM2 interaction to induce cancer cell death. Int J Mol Sci. 2022;23(9):5005. doi:10.3390/ijms23095005

3. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408(6810):307-310. doi:10.1038/35042675

4. Joerger AC, Fersht AR. The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem. 2016;85:375-404. doi:10.1146/annurev-biochem-060815-014710

5. Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15(1):13-30. doi:10.1038/nrclinonc.2017.151

6. Trino S, De Luca L, laurenzana I, et al. P53-MDM2 pathway: evidences for a new targeted therapeutic approach in B-acute lymphoblastic leukemia. Front Pharmacol. 2016;7:491. doi:10.3389/fphar.2016.00491

7. Brooks CL, Gu W. p53 ubiquitination: Mdm2 and beyond. Mol Cell. 2006;21(3):307-315. doi:10.1016/j.molcel.2006.01.020

8. Manfredi JJ. Mdm2 and MdmX: partners in p53 destruction. Cancer Res. 2021;81(7):1633-1634. doi:10.1158/0008-5472.CAN-21-0145

9. Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26(15):3453-3459. doi:10.1093/nar/26.15.3453

10. Konopleva M, Martinelli G, Daver N, et al. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020;34(11):2858-2874. doi:10.1038/s41375-020-0949-z

11. Khurana A, Shafer DA. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther. 2019;12:2903-2910. doi:10.2147/OTT.S172315

12. Chawla SP, Blay JY, Italiano A, et al. Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS). J Clin Oncol. 2013;31(suppl 15):10514. doi:10.1200/jco.2013.31.15_suppl.10514

13. Gounder MM, Yamamoto N, Patel MR, et al. A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS). J Clin Oncol. 2022;40(suppl 16):3004. doi:10.1200/JCO.2022.40.16_suppl.3004

14. Schöffski P, Schuetze S, Broto JM, et al. A phase II/III, randomized, open-label, multicenter study of BI 907828 compared to doxorubicin in the first-line treatment of patients with advanced dedifferentiated liposarcoma (DDLPS): Brightline-1. J Clin Oncol. 2022;40(suppl 16):TPS11586. doi:10.1200/JCO.2022.40.16_suppl.TPS11586

15. Yamamoto N, Tolcher AW, Hafez N, et al. Efficacy and safety of the MDM2–p53 antagonist BI 907828 in patients with advanced biliary tract cancer: data from two phase Ia/Ib dose-escalation/expansion trials. J Clin Oncol. 2023;41(suppl 4):543. doi:10.1200/JCO.2023.41.4_suppl.543

16. Yamamoto N, Hafez N, Tolcher AW, et al. A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 (ezabenlimab) and BI 754111 in patients (pts) with advanced solid tumors. J Clin Oncol. 2022;40(suppl 16):3095. doi:10.1200/JCO.2022.40.16_suppl.3095

17. Dumbrava EE, Hanna GJ, Cote GM, et al. A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2). J Clin Oncol. 2022;40(suppl 16):TPS3165. doi:10.1200/JCO.2022.40.16_suppl.TPS3165

18. Gounder MM, Bauer TM, Schwartz GK, et al. A first-in-human phase I study of milademetan, an MDM2 inhibitor, in patients with advanced liposarcoma, solid tumors, or lymphomas. J Clin Oncol. Published online January 20, 2023. doi:10.1200/jco.22.01285

19. Gounder MM, Schwartz GK, Jones RL, et al. MANTRA: a randomized, multicenter, phase 3 study of the MDM2 inhibitor milademetan versus trabectedin in patients with de-differentiated liposarcomas. J Clin Oncol. 2022;40(suppl 16):TPS11589. doi:10.1200/JCO.2022.40.16_suppl.TPS11589

20. Welliver MX, Torres-Saavedra PA, Van Tine BA, et al. NRG-DT001 phase Ib trial of neoadjuvant navtemadlin (previously AMG232 and KRT232) concurrent with preoperative radiotherapy in wild-type p53 soft tissue sarcoma of the extremity and body wall. J Clin Oncol. 2022;40(suppl 16):11521. doi:10.1200/JCO.2022.40.16_suppl.11521

21. Wong MKK, Burgess MA, Chandra S, et al. Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients (pts) with TP53WT Merkel cell carcinoma (MCC). J Clin Oncol. 2022;40(suppl 16):9506. doi:10.1200/JCO.2022.40.16_suppl.9506

22. Rampal R, Ramanathan S, Papayannidis C, et al. An open-label, multicenter, phase 1b/2 study of navtemadlin (KRT-232) in patients with relapsed/refractory acute myeloid leukemia secondary to myeloproliferative neoplasms. J Clin Oncol. 2022;40(suppl 16):TPS7063. doi:10.1200/JCO.2022.40.16_suppl.TPS7063

23. Dowlati A, Juan-Vidal O, Hiret S, et al. An open-label, multicenter, phase 2 study of the safety and efficacy of navtemadlin (KRT-232) in patients with TP53 wild-type relapsed/refractory small cell lung cancer. J Clin Oncol. 2022;40(suppl 16):TPS8600. doi:10.1200/JCO.2022.40.16_suppl.TPS8600

24. Moschos SJ, Sandhu S, Lewis KD, et al. Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in metastatic melanoma; a phase 1 study. Invest New Drugs. 2022;40(5):1051-1065. doi:10.1007/s10637-022-01253-3

25. Stein EM, DeAngelo DJ, Chromik J, et al. Results from a first-in-human phase I study of siremadlin (HDM201) in patients with advanced wild-type TP53 solid tumors and acute leukemia. Clin Cancer Res. 2022;28(5):870-881. doi:10.1158/1078-0432.CCR-21-1295

26. Abdul Razak AR, Bauer S, Suarez C, et al. Co-targeting of MDM2 and CDK4/6 with siremadlin and ribociclib for the treatment of patients with well-differentiated or dedifferentiated liposarcoma: results from a proof-of-concept, phase Ib study. Clin Cancer Res. 2022;28(6):1087-1097. doi:10.1158/1078-0432.CCR-21-1291

27. Daver NG, Dail M, Garcia JS, et al. Venetoclax and idasanutlin in relapsed/refractory AML: a non-randomized, open-label phase 1b trial. Blood. Published online October 20, 2022. doi:10.1182/blood.2022016362