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A Win for Trabectedin in High-Grade Myxoid Liposarcoma?

<ѻý class="mpt-content-deck">— Statistics support noninferiority versus more toxic chemotherapy, but results far from definitive
MedpageToday
 A photo of a vial of Yondelis over a microscope image of myxoid liposarcoma

Neoadjuvant trabectedin (Yondelis) for high-grade myxoid liposarcoma (HG-MLPS) demonstrated noninferiority to the long-time standard of anthracycline-ifosfamide (AI), according to new data from a previously completed trial.

Standard therapy was associated with twice as many recurrences as compared with trabectedin, translating into a 40% reduction in the hazard for disease-free survival (DFS) in favor of trabectedin. The prespecified margin for noninferiority for relapse was HR >1.25, and two separate analyses showed that the probability of a true HR >1.25 was <5%, satisfying the prespecified range for noninferiority.

The findings suggest that trabectedin might be an alternative to standard neoadjuvant chemotherapy for HG-MLPS of the extremities or trunk, reported Alessandro Gronchi, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and co-authors in the .

"The noninferiority of trabectedin versus AI would be valuable since trabectedin has a far better acute tolerability profile, with lower hematologic toxicity, no hair loss ... and no long-term cardiac toxicity," the authors stated. "Patients with HG-MLPS are usually 10 years younger than patients with other common adult-type STS [soft-tissue sarcoma], making the avoidance of anthracyclines even more relevant for them in the long run."

Taking into account the study's limitations, "one might argue that the data from the final analysis of this expanded cohort support the choice of trabectedin, possibly in combination with radiation therapy, when neoadjuvant treatment is a consideration for HG-MLPS," they added. "Additionally, we believe it is essential to further explore the prognostic correlation of current pathologic grading of HG-MLPS to improve prognostic risk stratification for these patients."

The findings came from a randomized trial that failed to demonstrate the superiority of histology-tailored therapy (HTT) versus AI. The trial, conducted by sarcoma research networks in Italy, Spain, France, and Poland, compared the two neoadjuvant strategies in the five most common types of STS. AI prevailed across four of the five tumor types.

Investigators observed a trend toward improved DFS with trabectedin in patients with HG-MLPS, and trial enrollment was reopened to accrue more patients with that one type of STS.

As originally designed, the trial tested the hypothesis that HTT would lead to superior outcomes versus standard AI, JCO Associate Editor Robert Maki, MD, noted in an . Instead, the that the reverse was true, as AI led to better DFS (the primary endpoint) and survival as compared with HTT.

When the trial was reopened to enrollment of more patients with HG-MLPS, investigators also changed the primary endpoint to whether the probability that HTT was noninferior to AI for an odds ratio of >1.25 was less than 5%. The new analysis showed that HTT did meet the statistical requirements of noninferiority.

"The implications of such a finding are important, specifically that patients with one of the more common sarcoma subtypes can benefit from the less toxic trabectedin than AIM [anthracycline-ifosfamide-mesna]," said Maki, of Memorial Sloan Kettering Cancer Center in New York City. "The concerns regarding the trial design are equally clear. It was not possible to determine type 1 or type 2 error from a study in which patients were enrolled with two different endpoints and two different study designs."

"Are this study sample size and small number of events enough to provide convincing evidence of the noninferiority of trabectedin compared with AIM for high-grade myxoid-round cell liposarcoma?" he added. "While the survival curves and the result of a prospective, randomized trial indicate noninferiority of the less toxic treatment, the study design issues complicate the interpretation."

Clinicians will be left to their own devices to interpret and apply the data from the trial or discard them, "as it is unlikely that a sizable study of neoadjuvant therapy will be examined again in this diagnosis in the foreseeable future, unless new drugs that are very active in metastatic disease are found."

Randomized trials are still feasible for rare cancers with poor outcomes, but trial design must be customized to account for challenges of accrual and expectations for outcomes, Maki concluded.

Gronchi and colleagues reported results for 101 patients with localized HG-MLPS originating in an extremity or the trunk wall. They were randomized to trabectedin or standard AI. The primary endpoint was 5-year DFS, and 5-year overall survival (OS) was a secondary endpoint.

During a median follow-up of 66 months, the trial had 22 recurrences, 15 in the AI arm and seven in the trabectedin arm. The absolute numbers translated into a DFS probability 0.86 for trabectedin and 0.73 for standard therapy, and the OS probabilities were 0.88 and 0.90, respectively.

The posterior probability of an HR >1.25 for DFS was 4.93%, meeting the Bayesian monitoring cutoff of <5%. A per-protocol analysis involving 97 randomized patients yielded a posterior probability of HR >1.25 of 3.63%, also supporting trabectedin noninferiority.

For OS, the overall analysis yielded an estimated HR of 1.20 for trabectedin versus AI, decreasing to 1.03 in the per-protocol analysis.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ѻý in 2007.

Disclosures

The study was supported by the European Union, the LYriCAN program of the French NCI, NetSarc, and DEPGYN.

Gronchi disclosed relationships with Novartis, Pfizer, Lilly, PharmaMar, Deciphera, Bayer, Nanobiotix, SpringWorks Therapeutics, and Boehringer Ingelheim.

Maki is an associate editor of the Journal of Clinical Oncology but was recused from peer review of the manuscript. He disclosed relationships with PEEL Therapeutics, Bayer, Deciphera, Ipsen, Regeneron, Daiichi, Bayer, SpringWorks Therapeutics, Amgen, Astex Pharmaceuticals, Boehringer Ingelheim, Rain Therapeutics, BioAtla, C4 Therapeutics, Exelixis, Inhibrx, Presage Biosciences, SARC, SynOx, and TRACON Pharma, as well as patent/royalty/intellectual property interests.

Primary Source

Journal of Clinical Oncology

Gronchi A, et al "Neoadjuvant chemotherapy in high-grade myxoid liposarcoma: Results of the expanded cohort of a randomized trial from Italian, Spanish, French, and Polish sarcoma groups" J Clin Oncol 2024; DOI: 10.1200/JCO.23.00908.

Secondary Source

Journal of Clinical Oncology

Maki R "Trials and tribulations in rare cancer clinical research" J Clin Oncol 2024; DOI: 10.1200/JCO.23.02137.