The first patient has been enrolled on the phase 2 portion of the LIO-1 trial, which will examine the combination of lucitanib plus nivolumab in those with gynecologic cancers.
Erika P. Hamilton, MD
The first patient has been enrolled on the phase 2 portion of the LIO-1 trial (NCT04042116), which will examine the combination of lucitanib plus nivolumab (Opdivo) in those with gynecologic cancers, according to an announcement from Clovis Oncology.1
“The phase 2 part of the LIO-1 trial will advance our scientific understanding of the potential for an inhibitor for multiple tyrosine kinases, including VEGF, such as lucatinib, to be combined with a PD-1 inhibitor for the treatment of gynecologic cancers,” Erika P. Hamilton, MD, director of the Breast and Gynecologic Research Program at Sarah Cannon Research Institute at Tennessee Oncology, stated in a press release.
“It is estimated that nearly 100,000 women will be diagnosed with a gynecologic cancer in the United States this year alone, and it is vital that we identify new treatment options, in particular new combination, for these women,” Hamilton added.
Lucitanib is an investigational angiogenesis inhibitor of the tyrosine kinase activity of VEGFR 1-3, PDGFRα/β, and FGFR 1-3.2 The rationale to combine angiogenesis inhibitors with immunotherapy agents is based on clinical data that have suggested increased efficacy with this approach in several cancer indications.
Because angiogenic factors like VEGF are typically upregulated in tumors and produce an immunosuppressive tumor microenvironment, antiangiogenic agents could potentially reverse this effect and enhance response to immunotherapy, according to Clovis Oncology.
In the phase 1b portion of the trial, investigators wanted to determine the recommended dose of lucitanib in combination with nivolumab in patients with advanced solid tumors. In the phase 2 portion of the trial, the objective is to assess the safety and efficacy of the doublet in patients with advanced gynecological solid tumors.3
To be eligible for participation, patients had to be 18 years of age or older, have acceptable organ function, and a life expectancy of 3 months or longer. Additionally, patients had to have an advanced or metastatic solid tumor and tumor tissue available at the time of screening. To participate in the phase 2 portion, patients had to have measurable disease per RECIST v1.1 criteria, have an advanced, recurrent, or metastatic gynecological solid tumor, and have been willing and capable of providing another biopsy 4 weeks post treatment.
If they had received previous treatment with lucitanib, had an active second malignancy or active central nervous system brain metastases, they were not permitted. Moreover, if patients had duodenal stent or any gastrointestinal disorder, a known history of HIV or AIDS or if they tested positive for hepatitis B or C, they could not participate. Those with evidence of interstitial lung disease, active pneumonitis, myocarditis, or a history of myocarditis, were excluded, along with anyone with unstable or uncontrolled hypertension. Additionally, if patients received previous treatment with a PD-1/PD-L1 inhibitor or a VEGF TKI, they were not included in the phase 2 portion of the trial.
The primary end point of the phase 1b portion of the trial was to identify the recommended phase 2 dose of the combination by examining the incidence of adverse effects and clinical lab abnormalities defined as dose-limiting toxicities and maximum-tolerated dose. Confirmed best overall response rate per investigator assessment in accordance with RECIST v1.1 criteria served as the primary end point of the phase 2 portion.
Secondary end points included acute and long-term safety and tolerability of the doublet, further examination of preliminary efficacy of the combination, area under the curve at steady state, steady state minimum plasma concentration, steady state maximum plasma concentration, and total clearance of the drug following oral administration.
The trial is being done in the United States and Europe. The work is being done in collaboration with the European Network for Gynaecological Oncological Trial groups for the study sites in Europe. The phase 2 dose for the study is based on data from the phase 1b dose-escalation portion of the LIO-1 study, which was recently completed. Data from the first portion of the trial will be presented during the 2020 ESMO Virtual Congress.
“The initiation of the phase 2 stage of the LIO-1 clinical trial is an important milestone for the lucatinib development program, and I am grateful to our team and our investigators for their commitment to initiating this study safely and expeditiously in this new COVID-19 era,” Patrick J. Mahaffy, president and chief executive officer of Clovis Oncology, added in the release.
Previous results examining lucitanib in combination with immune checkpoint blockade showed that the agent augmented antitumor activity in syngeneic nonclinical models.4 Specifically, the addition of lucatinib to anti–PD-1 demonstrated similar or better antitumor activity than other angiogenesis inhibitors in this setting. The approach was found to encourage intratumoral T-cell infiltration and immune-associated gene expression changes that are critical for antitumor immunity.