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Legubicin significantly improved PFS vs doxorubicin in advanced soft tissue sarcoma, with reduced cardiotoxicity and consistent benefit across subgroups.
Legubicin (QHL-108) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs doxorubicin (Adriamycin) in pretreated patients with advanced soft tissue sarcoma (STS), according to findings from a phase 2/3 trial (CTR20212527) presented at the
Regarding efficacy, median PFS was 10.4 months (95% CI, 6.0-12.6) with legubicin (n = 157) vs 4.9 months (95% CI, 2.8-6.6) with doxorubicin (n = 144), resulting in a 50% reduction in the risk of disease progression or death (HR, 0.50; 95% CI, 0.35-0.70; P < .0001). PFS benefit was also consistent across predefined subgroups and regardless of histology, anthracycline use, and legumain expression level.
“This study supports legubicin as a promising and safe STS therapy with long-term maintenance treatment potential, indicating the possibility of replacing doxorubicin across multiple STS subtypes, and provides clinical proof for legumain-activated albumin-drug conjugates,” Zan Shen, PhD, lead study author and director of the Department of Medical Oncology at Shanghai Sixth People’s Hospital, Jiaotong University in Shanghai, China, said.
Doxorubicin is part of the standard frontline therapy for patients with advanced or metastatic STS, but chronic use is associated with increased toxicity.2
Legubicin is a first-in-class albumin-drug conjugate activated by the tumor-specific protease legumain, which is overexpressed in the tumor microenvironment and malignant cells relative to normal tissues.1 Given the ability of the doxorubicin payload to remain inactive by the conjugated chemical linker, the agent effectively limits cardio- and hematotoxicity by remaining in an albumin complex form in normal tissues. Legubicin also targets the release of the activated doxorubicin payload to the tumor microenvironment through tumor-specific activation of legumain under acidic pH and the enhanced permeability and retention effect of serum albumin. Through this mechanism, legubicin provides enhanced drug concentration and efficacy, Shen noted.
A randomized, double-blind, pivotal, positive control trial was designed to evaluate the efficacy and safety of legubicin vs doxorubicin in patients with advanced STS. To be eligible for enrollment patients had to have received a diagnosis of unresectable, recurrent, or metastatic STS and been exposed to a cumulative anthracycline dose of no greater than 100 mg/m2 of doxorubicin or an equivalent. An ECOG performance status between 0 and 2 was required and patients with the following subtypes were excluded: alveolar soft part sarcoma, clear cell sarcoma, gastrointestinal stromal tumor, chondrosarcoma, extraosseous Ewing sarcoma, alveolar rhabdomyosarcoma, and embryonal rhabdomyosarcoma.
Study participants were randomly assigned 1:1 to 270 mg/m2 of legubicin every 3 weeks (Q3W) or 75 mg/m2 of doxorubicin Q3W. Shen noted that patients in the experimental arm would in essence be receiving a 1.9-times equimolar dose of doxorubicin. Of note, 306 patients were randomly assigned to therapy, but 5 patients who had been mistakenly enrolled with non-STS indications were excluded from the efficacy analysis.
The primary end point was PFS by independent review committee (IRC). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and the percentage of patients reaching cardiotoxicity indicators by cardiotoxicity IRC.
Overall (n = 301), the median age was 55.0 years (range, 18-75) and most patients were female (n = 155; 51.5%). All were Asian and most had an ECOG performance status of 1 (n = 201; 66.8%). Most patients had recurrent or metastatic disease at enrollment (n = 243; 80.7%), and the represented histologic subtypes were undifferentiated pleomorphic sarcoma (n = 35; 11.6%), synovial sarcoma (n = 30; 10.0%), liposarcoma (n = 40; 13.3%), leiomyosarcoma (n = 50; 16.6%), other (n = 145; 48.2%), and missing (n = 1; 0.3%). With respect to treatment history, most patients had received only first-line therapy (n = 252; 83.7%); 16.3% (n = 49) received second- or later-line therapy, which included an anthracycline in 6.3% (n = 19) of cases.
Legumain expression was either strongly positive (n = 30; 10.0%), weakly positive (n = 79; 26.2%), or unknown (n = 192; 63.8%).
Additional findings revealed that the median OS was not available (NA) in either arm but favored the legubicin (95% CI, NA-NA) vs the doxorubicin (95% CI, 24.3 months-NA) arm (HR, 0.49; 95% CI, 0.30-0.79). The ORR and DCR also favored legubicin, at 23.6% (95% CI, 17.2%-31.0%) and 80.9% (95% CI, 73.9%-86.7%), respectively, vs 18.1% (95% CI, 12.2%-25.3%) and 63.9% (95% CI, 55.5%-71.7%) with doxorubicin.
Grade 3 or greater hematologic treatment-related adverse effects (TRAEs) in the legubicin (n = 160) and doxorubicin (n = 146) arms, respectively, included neutropenia (15.0%; 78.8%), anemia (11.9%; 17.8%), myelosuppression (0.6%; 15.8%), and febrile neutropenia (0%; 0.7%). Grade 3 or greater gastrointestinal (GI) TRAEs in the legubicin and doxorubicin arms, respectively, included GI system disorders (0%; 2.7%), oral ulcer (0%; 1.4%), GI disorders (0%; 0.7%), and GI bleeding (0%; 0.7%).
Treatment-related alopecia occurred in 13.8% (n = 22) of patients in the legubicin arm vs 74.0% (n = 108) of those in the doxorubicin arm.
“A favorable safety profile in cardiac, hematologic, and other frequently reported toxicities was shown with legubicin, leading to clear reduction in toxicity and enhanced efficacy, and enabling longer cumulative treatment,” Shen added.
With respect to the latter secondary end point, Shen noted that cardiotoxicity was reduced by more than 20-fold in the rate of grade 3 or greater cardiac TRAEs, requiring significantly fewer treatment discontinuations (legubicin, 1.9%; doxorubicin, 43.8%; discontinuation rate difference, –42.0%; 95% CI, –50.2% to –33.4%).
Grade 3 or greater cardiotoxicities in the legubicin and doxorubicin arms, respectively, included elevated troponin I (0.6%; 24.0%), elevated troponin T (0%; 13.0%), myocardial injury (0.6%; 3.4%), cardiomegaly (0%; 0.7%), and heart failure (0%; 0.7%).
“[Legubicin] may reshape the chemotherapy and combination therapy paradigm by overcoming the dose limitations of anthracyclines, thereby enabling broader clinical application and benefiting more patients,” Shen concluded.
Disclosures: Shen reported no conflicts of interest.
