The bispecific antibody CDX-527 is now under investigation in patients with advanced or metastatic solid tumors who have progressed during or following standard-of-care treatment with the recent initiation of a phase 1 trial (NCT04440943), according to an announcement from Celldex Therapeutics, Inc.

“CDX-527 builds on our prior clinical experience where the combination of CD27 activation and PD-1 blockade was well tolerated and demonstrated biological and clinical activity when the individual agents were dosed together,” Tibor Keler, PhD, executive vice president and chief scientific officer of Celldex Therapeutics, stated in a press release. “We believe this bodes well for the potential safety and activity profile of CDX-527, which incorporates the 2 mechanisms into 1 molecule.”

CDX-527 combines blockade of the PD-1 pathway with T-cell co-stimulation through CD27 into 1 molecule through the use of an IgG1-ScFv format, according to Celldex Therapeutics, Inc, the drug developer.

In the open-label, non-randomized, multicenter phase 1 trial, investigators will examine the safety, tolerability, and activity of CDX-527.

In the dose-escalation portion of the trial, participants will be assigned to different dose levels of the agent to establish its toxicity profile and which dose level will be examined in the expansion portion of the research. Up to 90 patients with select solid tumors will be enrolled to the expansion phase of the trial to receive the established dose. These patients will be closely monitored for response and adverse effects.

To be eligible for participation, patients had to have a recurrent, locally advanced, or metastatic solid tumor other than microsatellite instability–low colorectal cancer, glioblastoma multiforme, prostate cancer, pancreatic cancer, mucosal or ocular melanoma. Patients had to have received all standard options for their disease, have measurable disease per iRECIST criteria, and be willing to undergo a pre- and on-therapy biopsy, if needed.

If they had a history of severe hypersensitivity reactions to other monoclonal antibodies, previously received an anti-CD27 antibody, underwent major surgery within 4 weeks before study treatment, received immunosuppressive medications within 4 weeks or systemic corticosteroids within 2 weeks before study treatment, they were not permitted to enroll.

Additionally, if patients had a previous malignancy, other than treated basal or squamous skin cancer or in situ cancers, they could not participate. If they experienced any thrombotic events within the past 6 months before the study treatment, had active, untreated central nervous system metastases, or active autoimmune disease, they were excluded from the analysis.

The primary end point of the trial is safety and tolerability of the bispecific antibody, while key secondary end points included objective response rate, clinical benefit rate, duration of response, progression-free survival, and overall survival, as well as immunogenicity and pharmacokinetic evaluation of the agent.

Preclinical data have shown stronger T-cell activation and antitumor activity with the investigational agent compared with a PD-L1 antibody in combination with a CD27 antibody.

 Moreover, the agent has demonstrated direct antibody-dependent cellular cytotoxicity against tumor cells that express either CD27 or PD-L1. In preclinical models, the bispecific antibody has been found to have an antibody-like pharmacokinetic profile, without any concerning safety signals observed.

“Importantly, preclinical studies of CDX-527 also demonstrated greater activity than the combination of individual antibodies, adding to our enthusiasm that this next-generation checkpoint inhibitor could be an important addition to the Celldex pipeline,” added Keler.

Celldex Therapeutics initiates phase 1 study of new bispecific product candidate CDX-527 in solid tumors. News release. Celldex Therapeutics, Inc. August 24, 2020. Accessed September 16, 2020. 

A study of PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies. ClinicalTrials.gov. Updated August 26, 2020. Accessed September 16, 2020. 

https://clinicaltrials.gov/ct2/show/NCT04440943.

Vitale LA, He L-Z, Thomas LJ, et al. Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy. Published online May 25, 2020. 

Articles

The bispecific antibody CDX-527 is now under investigation in patients with advanced or metastatic solid tumors who have progressed during or following standard-of-care treatment with the recent initiation of a open-label phase 1 trial.

Bispecific Antibody CDX-527 Enters Phase 1 Trial in Solid Tumors

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.

“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.

 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.

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.

 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.

Clovis Oncology announces first patient enrolled in the phase 2 portion of the LIO-1 trial evaluating the combination of lucitanib and Opdivo in gynecologic cancers. News release. Clovis Oncology. August 5, 2020. Accessed September 11, 2020. 

Lucatinib clinical development overview. Clovis Oncology. Accessed September 11, 2020. 

A study to evaluate lucitanib in combination with nivolumab in patients with a solid tumor. ClinicalTrials.gov. Updated December 13, 2019. Accessed September 11, 2020. 

https://www.clinicaltrials.gov/ct2/show/NCT04042116.

Dusek RL, Robillard L, Harding TC, et al. Combination of the angiogenesis inhibitor lucitanib with immune checkpoint blockade augments antitumor activity in syngeneic models. Presented at: 2019 Society for Immunotherapy of Cancer Meeting; November 6-10, 2019; National Harbor, MD. Accessed September 11, 2020. 

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.

Lucitanib/Nivolumab Combo Enters Phase 2 Evaluation for Gynecologic Cancers

A multi-year, multi-study research collaboration between Daiichi Sankyo and Gustave Roussy Cancer Center will support the clinical, translational, and preclinical evaluation of 2 of the company’s lead antibody-drug conjugates (ADCs): DS-1062 in advanced non–small cell lung cancer (NSCLC), and patritumab deruxtecan in metastatic breast cancer.

The partnership will commence with 2 Gustave Roussy-led, 2 Daiichi-funded adaptive phase 2 trials to evaluate the safety and efficacy of the investigational agents, as well as potential markers of response and resistance to the respective therapies.

The adaptive study designs are expected to expedite the identification of individuals who benefit from treatment with the ADCs. Furthermore, in their incorporation of repeated clinical and biomarker assessments, the studies will also aid efforts to recognize factors associated with individual patient response and subsequently refine development.

Characterizing markers of response and resistance will be a crux of the collaboration, according to Fabrice André, MD, PhD, director of research at Gustave Roussy Cancer Center, Villejuif, France, who explained that investigators will use 3 different approaches to identify these distinguishers. The first method involves performing a biopsy before and after treatment to derive biomarkers from patients’ cellular content.

“The second strategy will be to predefine a hypothesis about the biomarkers based on what we observe on the basic science side,” André told 

. “For example, we would investigate the journey of the ADC in lysosome and the role of the DNA repair protein for resistance. Our third strategy will be to use screening of the cancer cell to identify mechanisms of resistance, thanks to a system of screening to knockout gene or induce gene expression.”

Both studies will be open label and will enroll up to 100 patients each across various sites in France. The first trial will evaluate DS-1062 in patients with advanced NSCLC who progressed on prior anti–PD-1/PD-L1 therapy and platinum-doublet chemotherapy. The second trial will examine patritumab deruxtecan in patients with HER3-expressing metastatic breast cancer. The primary end point, shared by the 2 trials, is objective response rate assessed by independent central review. Key secondary end points, which will also remain consistent across the 2 studies, include clinical benefit rate, progression-free survival, duration of response, overall survival, and safety measures.

Although the safety and efficacy of DS-1062 and patritumab deruxtecan have yet to be established, mechanistically, the agents are known to deliver cytotoxic chemotherapy to cancer cells via a linker attached to a monoclonal antibody (mAb) that binds to a specific target expressed on the malignant cells. Specifically, DS-1062 uses a humanized anti-TROP2 mAb affixed to a topoisomerase I inhibitor payload by a tetrapeptide-based linker. Patritumab deruxtecan has the same payload and linker as DS-1062 but comprises a human anti-HER3 antibody.

Immunotherapies, administered to patients who express PD-L1, and targeted therapies, given to those with a genomic alteration that predicts sensitivity to precision interventions, dominate the NSCLC landscape, André said, adding that cytotoxic agents have also been shown to have activity in NSCLC, albeit modest.

The development of DS-1062 represents the potential for a new class of agents, ADCs, in the treatment of this tumor type. “What we expect to have is a third innovative [set of] drugs in this disease; that will be ADCs,” André said, adding that Gustave Roussy investigators similarly “expect to develop a drug that will synergize with immunotherapeutics, and perhaps a targeted therapy, to prolong survival.”

By contrast, ADCs are less new to the breast cancer landscape, but approvals have typically favored HER2-positive or triple-negative disease. At present, no therapies are specifically indicated for the treatment of patients with HER3-expressing breast cancer, thus providing a rationale for pursing a HER3-targeted treatment.

Beyond the phase 2 studies to be led by Gustave Roussy, DS-1062 and patritumab deruxtecan are under investigation in other clinical trials, including a phase 1 (NCT03401385) evaluation of the former agent in patients with advanced solid tumors that are relapsed on or refractory to standard treatment or for whom no standard treatment is available.

 This study is currently enrolling 350 patients with unresectable/advanced NSCLC or metastatic triple-negative breast cancer.

Meanwhile, patritumab deruxtecan is being studied in the phase 1 setting in patients with previously treated metastatic or unresectable NSCLC; this trial continues to enroll patients with this disease (NCT03260491). The ADC is also the subject of study in an ongoing phase 1/2 trial (NCT02980341) in patients with HER3-expressing breast cancer.

These established research initiatives will later be joined by additional studies under Daiichi and Gustave Roussy’s collaboration, which will explore DS-1062 and patritumab deruxtecan in combination with other agents.

Daiichi Sankyo and Gustave Roussy enter innovative research collaboration for Dxd ADCs DS-1062 and patritumab deruxtecan. News release. Gustave Roussy. July 22, 2020. Accessed September 8, 2020. 

Liu X, Liu S, Lyu H, Riker AI, Zhang Y, Liu B. Development of effective therapeutics targeting HER3 for cancer treatment. 

. 2019;21:5. doi:10.1186/s12575-019-0093-1

A multi-year, multi-study research collaboration between Daiichi Sankyo and Gustave Roussy Cancer Center will support the clinical, translational, and preclinical evaluation of 2 of the company’s lead antibody-drug conjugates: DS-1062 in advanced non–small cell lung cancer, and patritumab deruxtecan in metastatic breast cancer. 

Pipeline Report: September 2020

Articles

Bispecific Antibody CDX-527 Enters Phase 1 Trial in Solid Tumors

Lucitanib/Nivolumab Combo Enters Phase 2 Evaluation for Gynecologic Cancers