Intermittent dosing dramatically reduced myelosuppression that has hindered drug class

Almost half of patients with advanced solid tumors or lymphomas experienced disease control with a drug that reactivates the TP53 tumor suppressor, a first-in-human study showed.

Overall, the oral murine double minute-2 (MDM2) inhibitor milademetan produced a disease control rate (DCR) of 45.8% in 107 patients, including 58.5% in a subgroup with dedifferentiated liposarcomas (DDLPS). Notably, an intermittent dosing regimen reduced the incidence of grade 3/4 toxicity by 50% or more, with no drop-off in efficacy, reported Mrinal Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

The improved tolerability with intermittent dosing has helped jump-start a drug class that had been stalled for a decade by myelosuppression, they noted in the Journal of Clinical Oncologyopens in a new tab or window.

“It was really the intermittent dosing that has now allowed for a resurgence of this entire class of drugs, and many drug companies are now back in the space after many major pharmaceutical companies sort of abandoned it after evaluating continuous dosing,” Gounder told MedPage Today. “Intermittent dosing is the only way forward that many companies are pursuing.”

“It really depends on the pharmacokinetics and half-life of drugs,” he added. “If somebody else is choosing to do daily dosing, that doesn’t mean they are on the wrong track. That may be appropriate for that specific drug’s pharmacology, but in general, the field is moving towards an intermittent dosing schedule.”

MDM2 and Oncogenesis

The p53 protein encoded by TP53 corrects DNA damage by multiple mechanisms, acting as a tumor suppressor in normal cells by inducing cell-cycle arrest or repair, apoptosis, or senescence. Aside from TP53 mutations, multiple other mechanisms can inactivate wild-type p53, including overexpression of MDM2 by MDM2 amplificationopens in a new tab or window or other means.

MDM2 amplification occurs in 3.5% to 7.0% of human cancers, although no specific copy-number threshold for the alteration has been determined. In DDLPS, intimal sarcomas, and certain other tumors, MDM2 amplification occurs in the absence of TP53 mutationsopens in a new tab or window, making inhibition of the MDM2 protein a logical target to support p53’s suppressive activity, Gounder and co-authors noted in the introduction to the study.

In preclinical studies, milademetan induced p53-dependent apoptosis in cancer cell lines and antitumor activity in xenograft models with wild-type p53. Gounder and colleagues reported findings from a study designed primarily to evaluate the safety and tolerability of the drug with different dosing schedules, and determine the maximum tolerated dose or recommended phase II dose (RP2D). Investigators then evaluated the RP2D and an intermittent dosing schedule in patients with liposarcomas.

They initially evaluated 21-day and 28-day dosing, then two intermittent dosing schedules — days 1-7 or days 1-3 and then 15-17. A total of 69 patients received extended or continuous dosing, and 38 were treated on intermittent schedules.

The study involved a total of 107 patients: 53 with DDLPS, 22 with melanoma, four with lymphoma, three with osteosarcoma, and 25 with miscellaneous malignancies. Two-thirds of the patients had wild-type TP53, 13 had TP53 mutations, and the rest had indeterminate or unknown mutation status. Although enrollment focused on tumors with a high prevalence of MDM2 amplification or overexpression, testing for MDM2 status was not required. Patients with TP53 mutations were excluded.

Safety, Toxicity Data

Across all dosing schedules evaluated, the most common all-grade adverse events (AEs) were nausea (72%), thrombocytopenia (60.7%), fatigue (44.9%), and anemia (35.5%). Nonhematologic AEs were generally mild or moderate, whereas the severity of hematologic AEs, particularly thrombocytopenia, was associated with dose density.

Overall, the most common grade 3/4 drug-related AEs were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). Among patients who received the RP2D on the split intermittent dosing schedule, rates for the same AEs were 15.0%, 5.0%, and 0%. All-grade and grade 3/4 thrombocytopenia occurred in 69.6% and 36.2% of patients treated with extended-continuous dosing versus 44.7% and 15.8% with the two intermittent schedules combined.

No patients treated by intermittent dosing developed serious drug-related AEs versus 11.6% of patients who received milademetan by extended-continuous dosing.

Pharmacodynamic studies showed that levels of growth differentiation factor-15 increased with plasma concentrations of milademetan. Expression of p53, p21, and MDM2 increased in a handful of serum samples evaluable on day 8 of cycle 1.

With regard to antitumor activity in both parts of the study combined, two patients with DDLPS and one each with synovial sarcoma, small-cell lung cancer, and melanoma achieved partial responses. Additionally, 56 patients had stable disease. Response duration was not yet evaluable. Median duration of stable disease was 7.4 months, and median progression-free survival was 4.0 months.

“Despite almost two decades of research dedicated to the development of MDM2 inhibitors, none has progressed beyond early-phase clinical trials in patients with solid tumors,” the authors noted in the discussion of their findings. “The main reason for the apparent lack of progress is myelosuppression, an on-target class effect mediated by reactivation of p53.”

“In this first-in-human study of the MDM2 inhibitor milademetan, extended or continuous schedules led to unfavorable myelosuppression, particularly thrombocytopenia, as with other inhibitors in this class,” they added. “We found that intermittent dosing, allowing time for bone marrow recovery markedly reduced the occurrence and severity of thrombocytopenia and other hematologic events. Furthermore, even if toxicities occurred, patients were more likely to continue therapy with fewer dose reductions or prolonged interruptions and maintain clinical outcomes.”

Gounder said a phase III trial of the MDM2 inhibitor in DDLPS accrued its enrollment target in record time, and initial results are expected later this year. Additionally, Rain Oncology, which acquired milademetan from Daiichi Sankyo, has launched a basket trial to evaluate the MDM2 inhibitor in various tumor types associated with MDM2 amplification.