Liposarcoma

MDM2 Inhibitor Breaks Through in Trial of Liposarcoma, Other Advanced Malignancies

Posted by

0


Intermittent dosing dramatically reduced myelosuppression that has hindered drug class

A computer rendering of MDM2 bound to tumor protein p53

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.

What’s New in Liposarcoma?

Posted by

0


Close-up of medical oncologist Mark Dickson attending a presentation.Medical oncologist Mark Dickson is one of the MSK specialists who treats sarcomas, a rare family of cancers.

Summary

In this Q&A, medical oncologist Mark Dickson discusses how people with liposarcoma are cared for at Memorial Sloan Kettering, what’s new in diagnosis and treatment, and the research he and his colleagues are conducting to improve patients’ treatment options.

Highlights
  • Liposarcoma is a rare cancer of the fat tissue.
  • MSK doctors have a lot of experience diagnosing and treating it.
  • They are conducting several clinical trials of new treatments.
  • Genomic testing is now making personalized treatment possible.

Liposarcomas are tumors that arise in the body’s fat tissue. They are relatively rare, affecting only about 2,000 people each year in the United States. But it’s not an unusual disease at Memorial Sloan Kettering: Our doctors and researchers specialize in this and about 50 other types of soft tissue sarcoma.

Mark Dickson is a medical oncologist who specializes in liposarcoma as well as other sarcomas of the soft tissue and bone and Kaposi sarcoma. In a recent interview, Dr. Dickson discussed the challenges of treating liposarcoma and the research he is doing to improve the lives of people living with the disease by finding treatments that are more effective and less toxic.

How are liposarcomas detected and diagnosed?

Symptoms vary depending on the location of the tumor.  For patient with a tumor in the abdomen, a common symptom is weight gain. A patient can gain ten to 20 pounds because some tumors can be very large [between 30 and 50 centimeters in diameter]. Patients who have tumors on their thighs or arms usually notice them right away. But a tumor in the abdomen might not be diagnosed as quickly since people often think their bellies have grown bigger due to normal weight gain.

Doctors use imaging tests, typically MRIs, to determine how far the disease has spread and to aid in assessing the stage of the tumor. The next step is a biopsy. Since sarcomas are rare, it is important that a surgeon or radiologist who is highly experienced with sarcomas does the biopsy.

Why are liposarcomas so difficult to treat?

Sarcomas are rare, and liposarcomas even rarer. The average oncologist might see one sarcoma in a year. That’s why patients are best off coming to a center such as MSK, where sarcomas are routine, not exceptional.

There are four types of liposarcoma. The most common is well-differentiated liposarcoma, low-grade tumors whose cells look like normal fat cells and grow slowly. Myxoid/round cell liposarcomasare intermediate to high-grade tumors, with the round cell being the high-grade form. Pleomorphic liposarcoma is the rarest but sometimes is a very aggressive disease type. And a dedifferentiated liposarcoma is a high-grade tumor that occurs when a lower-grade tumor changes and creates new high-grade cells.

Patients with well-differentiated liposarcoma can survive for decades, but recurrence is a problem. Simple well-differentiated tumors can be removed surgically and the prognosis is often good, but recurrent tumors are more challenging because the cancer can spread to other parts of the body and surgery may not be an option. Radiation has to be used sparingly to avoid side effects, and chemotherapy does not work well for many liposarcomas.

The five-year survival rate for patients with a high-grade liposarcoma is less than 50 percent. That’s why we’re seeking better treatments.

Back to top

What follow-up do patients need after they’re done with active treatment?

Because recurrence can occur from months to decades after the initial diagnosis, people who have been treated for liposarcoma need to be monitored for the rest of their lives. Patients will have follow-up testing — which typically consists of a physical exam and imaging tests to detect metastasis — on a schedule determined by their physician.

Patients are best off coming to a center such as MSK, where sarcomas are routine.
Mark A. Dickson
Mark A. Dickson,Medical oncologist

Are there any clinical trials for liposarcoma drugs taking place?

There are several clinical trials being conducted at MSK that are centered on well-differentiated and dedifferentiated liposarcomas.

We are testing drugs that will turn off certain genes that become overexpressed in liposarcomas, including the genes CDK4 and MDM2. Ideally we will find a drug as effective as imatinib (Gleevec™), which was developed to target the cancer cells that cause chronic myelogenous leukemia and blocks the production of the abnormal protein that causes cancer. Gleevec is also very effective against somegastrointestinal stromal tumors.

We are seeing particularly promising results with the CDK4-targeting drug PD0332991 (palbociclib). To date, 90 patients have taken part in a phase II trial that looks at the drug’s efficacy. In 2013, wepublished a preliminary study in the Journal of Clinical Oncology that found that 70 percent of the 30 patients given PD0332991 for 12 weeks did not have their disease progress during that time. This was a higher percentage than expected. In addition, some patients had significant shrinking of their tumors.

Trials for drugs that can inhibit the overexpression of MDM2 are just under way. We are doing phase I trials with the goal of seeing whether a drug is safe to use — and hopefully showing some efficacy. One of the trials involves SAR405838, an investigational anticancer drug. The purpose of this study is to find the highest dose of SAR405838 that can be given safely in patients with liposarcoma and other advanced cancers that have either continued to grow despite standard therapy or for which no standard treatments exist.

What other research efforts aimed at liposarcoma are happening at MSK?

Among the challenges of treating sarcomas is that they are not one disease but have different subtypes, so there is a lot of variety between different people’s tumors. For comparison, in melanoma, you’ll find a common type of mutations in the gene BRAF that can be targeted with a drug in approximately 60 percent of patients. We will not find these high percentages in sarcomas. However, even finding a clinically relevant mutation present in a smaller number of patients is helpful. I believe that genomic research will be key in helping patients with liposarcomas.

We are utilizing a test known as MSK-IMPACT™, a targeted tumor-sequencing test that can detect gene mutations and other critical genetic aberrations in both rare and common cancers. The goal is to find aberrations that make cancers vulnerable to particular drugs and to match individual patients with available therapies or clinical trials that will most benefit them. To date, we have done sequencing on about 300 soft tissue sarcomas.