Milademetan Shows Early Activity in MDM2-Amplified Advanced Solid Tumors

Published on: 

Milademetan monotherapy demonstrated preliminary antitumor activity in patients with MDM2-amplified and p53 wild-type advanced solid tumors.

Milademetan monotherapy demonstrated preliminary antitumor activity in patients with MDM2-amplified and p53 wild-type advanced solid tumors, according to data from the interim analysis of the phase 2 MANTRA-2 (RAIN-3202) trial (NCT05012397).1

As of the data cutoff date of October 26, 2022, 15 of 17 patients enrolled to the trial received the MDM2 inhibitor. Of the 10 patients who were evaluable for efficacy, 2 experienced unconfirmed partial responses (PRs) to treatment. One of the patients, who had pancreatic cancer, experienced a tumor regression rate of 34%; the other patient, who had lung cancer, had a regression rate of 30%. The patient with pancreatic cancer is pending response confirmation is still receiving milademetan, but the patient with lung cancer died from COVID-19.

The agent also demonstrated activity in 2 other patients with biliary tract cancer and breast cancers; the tumor regression rates in these patients were 29% and 27%, respectively. Both are still receiving treatment with milademetan.

Notably, activity with the MDM2 inhibitor was observed in patients with heavily pretreated, refractory disease.

“We are encouraged by the preliminary observations from the MANTRA-2 trial,” Avanish Vellanki, co-founder and chief executive officer of Rain Therapeutics, Inc., stated in a press release. “Treatment with milademetan led to tumor regression in patients previously treated with a multitude of therapies across a range of cancers. We look forward to expanding this dataset as the trial continues to enroll.”

Milademetan is a potent inhibitor of interaction between MDM2 and p53; the agent reactivates p53 with a heightened therapeutic index for the treatment of cancer.2 The agent was observed to inhibit the growth of TP53 wild-type/MDM2-amplified cell lines and patient-derived xenograft models from several cancer types.3

An intermittent dosing schedule of the agent at 260 mg once daily on days 1 to 3 and 15 to 17 every 4 weeks was determined to be optimal in a first-in-human phase 1 trial (NCT01877382).4 In 3 patients with non-liposarcoma and a MDM2 copy number of 12 or higher who received the recommended intermittent dosing schedule of the agent, all experienced tumor regression.3

MANTRA-2, a multicenter, single-arm, open-label, basket trial, enrolled patients with locally advanced or metastatic, TP53 wild-type solid tumors and MDM2 amplification. To be eligible for enrollment, patients were required to have received all standard treatments suitable for their disease type and stage.


Patients are excluded if they previously received a MDM2 inhibitor, had well-differentiated or dedifferentiated liposarcoma or intimal sarcoma, other primary malignancies in need of systemic antineoplastic treatment in the 2 years before the trial, primary brain tumor, or untreated brain metastases, among other criteria.

The target enrollment for the trial is 65 patients. Study participants are administered milademetan at the recommended dosing schedule and are receiving treatment until they experience disease progression, intolerable toxicity, or they meet other discontinuation criteria.

The primary end point of the trial is objective response rate. Secondary end points include duration of response, progression-free survival, growth modulation index, disease control rate, overall survival, safety, and patient-reported health-related quality of life.

Of the 15 patients who received their first dose of the agent, the median age was 54.0 years (range, 33.0-75.0).5 Most patients were female (67%) and White (73%). Forty-seven percent of patients had an ECOG performance status of 0 at baseline, and the remaining 53% had a status of 1. The median number of prior lines of treatment received was 4.0 (range, 1.0-11.0).

Evaluable patients had lung cancer, breast cancer, biliary tract cancer, and pancreatic cancer, among others.

The safety profile of milademetan proved to be consistent with what had previously been reported in the phase 1 study of the agent.

In the safety population (n = 15), 46.7% experienced hematologic adverse effects (AEs) of any grade, with 20.0% reporting effects that were grade 3 or higher in severity. The most common hematologic toxicities experienced with milademetan included thrombocytopenia (any grade, 33.4%; grade 3 or higher, 20%), anemia (any grade, 6.7%), increased blood creatinine (any grade, 6.7%), leukocytosis (any grade, 6.7%), leukopenia (any grade, 6.7%), and neutropenia (any grade, 6.7%; grade 3 or higher, 6.7%).

Non-hematologic AEs of any grade were reported in 66.7% of the 16 patients; 33.3% experienced toxicities that were grade 3 or higher. The most common non-hematologic toxicities comprised fatigue (any grade, 46.7%), diarrhea (any grade, 33.3%; grade 3 or higher, 6.7%), vomiting (any grade, 33.3%), abdominal pain (any grade, 26.7%), and nausea (any grade, 20.0%).


  1. Rain Therapeutics provides interim analysis of phase 2 basket trial of milademetan for MDM2-amplified advanced solid tumors (MANTRA-2). News release. Rain Therapeutics, Inc.; November 4, 2022. Accessed November 9, 2022.
  2. 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
  3. Tirunagaru VG, Xu F, Doebele RC, et al. Abstract 1174: exploration of MDM2 gene amplification, co-mutation status, and prognosis in solid tumors. Cancer Res. 2022;82(suppl 12):1174. doi:10.1158/1538-7445.AM2022-1174
  4. Gounder MM, Bauer TM, Schwartz GK, et al. Milademetan, an oral MDM2 inhibitor, in well-differentiated/dedifferentiated liposarcoma: results from a phase 1 study in patients with solid tumors or lymphomas. Presented at: 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 24-25, 2020; Barcelona, Spain. LBA 7