Short-Term Goals and Long-Term Implications of 
the First U.S.-Based Clinical Trial on CIMAvax-EGF

Short-Term Goals and Long-Term Implications of 
the First U.S.-Based Clinical Trial on CIMAvax-EGF

Dr. Grace Dy
On October 17, 2016, the U.S. government eased restrictions on Cuba that had been in place since 1962. For the first time in more than 50 years, Cuban-made drugs and medical products were now allowed to enter the United States, facilitating cooperation between American and Cuban researchers.

But even before this important development, investigators at Roswell Park Cancer Institute made plans to test a promising Cuban-made vaccine for non–small cell lung cancer (NSCLC) called CIMAvax-EGF. CIMAvax-EGF is largely a result of Cuban health care’s focus on preventative care and innovation driven by limited economic resources. Developed at the Center of Molecular Immunology in Havana, the vaccine stimulates the body’s immune system to block the EGF protein by preventing it from attaching to EGF receptors. Without the interaction between EGF ligands and EGF receptors, cancer cells are starved, and tumor progression is hindered.

In January, roughly 3 months after the easing of restrictions, the first U.S.-based clinical trial of CIMAvax-EGF was initiated at Roswell Park. Leading the way for others to follow, this National Cancer Institute–designated comprehensive cancer center became the first U.S. research center to receive permission from the U.S. Food and Drug Administration to test a Cuban-made drug in American patients.

In an interview with the ASCO Daily News, researchers overseeing the trial at Roswell Park discussed the effectiveness of CIMAvax-EGF in NSCLC, the results of completed clinical trials in Cuba, and the long-term plans for additional testing of the vaccine.

CIMAvax-EGF’s Performance in the Clinical Setting

Researchers from Roswell Park Cancer Institute and the Center of Molecular Immunology in Havana, credit Roswell Park Cancer Institute.
“CIMAvax-EGF works by using the adaptive immune response to develop neutralizing antibodies to the growth factor EGF, which then deprives cancers that depend upon this growth factor to activate the EGFR pathway,” explained Grace Dy, MD, of Roswell Park and principal investigator of the phase I/II CIMAvax-EGF trial. Activation of the EGFR pathway is a critical step in tumorigenesis because it “promotes a number of protumorigenic effects, such as proliferation, anti-apoptosis, and angiogenesis.”

From 1995 to 2016, Cuban researchers tested CIMAvax-EGF in five pilot studies or phase I/II clinical trials, one randomized phase II trial, as well as one ongoing phase IV post-registration trial. This latest study is examining the use of CIMAvax-EGF in the primary health care setting in Cuba.

“In the clinical trials to date, the vaccine appears to be safe and well-tolerated,” Dr. Dy said. “In contrast to drugs that affect the EGFR pathway signaling at the receptor level, side effects were mild to moderate in severity.” Pain at the injection site, fever, vomiting, and headache were the most frequently reported side effects.

“Overall, CIMAvax-EGF has been very well-tolerated in more than 5,000 patients who have received it,” said Kelvin Lee, MD, of Roswell Park. “The phase II and phase III clinical trials have consistently shown a clinical benefit in terms of increased overall survival, as well as an improvement of the quality of life in patients with NSCLC.”

Dr. Lee further noted that in a recently completed phase III clinical trial involving 270 patients in the vaccine arm, the majority of reported adverse events were grade 1-2 (injection-site pain, fever, vomiting, and headache), 3.6% of adverse events were grade 3 (headache, dyspnea, injection-site reaction, eosinophilia, fevers, chills, tremor, and arthralgia), and there were no grade 4 or 5 adverse events.1

Dr. Kelvin Lee
According to Dr. Dy, translational studies performed on CIMAvax-EGF in Cuba found that patients with high pretreatment serum levels of EGF who received the vaccine derived survival benefit in comparison to similar patients who received a placebo. This finding may be “explained by the concomitant reduction in levels of circulating EGF once antibody titers increased,” she said.

Due to its promising results in Cuban trials, the therapeutic applications of CIMAvax-EGF in the past decade have spread far beyond the Cuban borders. “CIMAvax-EGF has been approved/registered for the treatment of advanced NSCLC in Cuba and Peru since 2008, in Paraguay since 2012, and, most recently, in Colombia [in February 2016],” Dr. Lee said. “It is also an approved therapy in the Czech Republic, Germany, Malaysia, the Philippines, Thailand, and the United Kingdom.”

The CIMAvax-EGF/Nivolumab Phase I/II Trial

The CIMAvax-EGF/nivolumab phase I/II trial at Roswell Park will enroll between 60 and 90 patients with advanced (stage IIIB/IV) NSCLC whose disease has progressed during or after first-line systemic chemotherapy, including targeted therapy. CIMAvax-EGF is being tested in combination with the checkpoint inhibitor nivolumab, the second-line therapy for NSCLC.

“As nivolumab is being utilized in this study as the standard-of-care backbone agent, eligibility criteria are similar to the inclusion/exclusion trial of various phase III trials that led to the approval of nivolumab as a second-line treatment in patients with NSCLC, which required that patients have disease progression after no more than one line of platinum-based first-line treatment for inclusion,” Dr. Dy said. Additional eligibility criteria include a life expectancy of at least 6 months and a patient performance status (ECOG) equal to or less than 2.

Dr. Dy further explained that the phase I portion of the trial will evaluate the safety and optimal scheduling of the combination of CIMAvax-EGF with nivolumab as second-line treatment for metastatic NSCLC.

“The dose-escalation phase I portion may take 12 to 18 months or longer to complete,” she said. “Subsequently, the expansion cohort will enroll patients to receive different maintenance schedules of vaccination, and antibody titers will be closely monitored. Once the recommended dose schedule is determined, the single-arm phase II portion of this trial will ensue.”

It is expected that the accrual for phase II of the trial will take approximately 18 months.

Long-Term Implications

While the oncology community eagerly awaits the results of the first U.S.-based CIMAvax-EGF trial, researchers overseeing the study are hopeful that insights obtained will be applicable to future clinical trials, as well as other types of cancer. “We hope to be able to optimize and validate the EGF and anti-EGF antibody assays for future clinical trials and to investigate various blood- and tissue-based biomarkers to help us understand predictive biomarkers of response and resistance to the CIMAvax-EGF/nivolumab combination,” Dr. Dy said.

Furthermore, Dr. Lee noted that Roswell Park is considering additional clinical trials of CIMAvax-EGF in NSCLC and other cancers. “CIMAvax-EGF has not been widely tested in other types of cancer, although there are clinical trials ongoing in Cuba in prostate cancer,” he said. “The vaccine definitely could be used in other cancers, in particular those cancers where there is evidence that targeting EGFR with small-molecule inhibitors or antibodies is effective.”

For now, the immediate focus is on NSCLC and the vaccine’s potential use in lung cancer prevention. “We are planning a trial of CIMAvax-EGF for the prevention of lung cancer in individuals at high risk for the disease, such as those who have had NSCLC that has been surgically removed,” Dr. Lee said.

He explained that this would require a large phase II trial in high-risk individuals, and in particular, those patients who have had an early-stage NSCLC tumor surgically resected but are at very high risk to develop a second NSCLC tumor, as well as heavy smokers with evidence of chronic obstructive pulmonary disease.

“We envision this CIMAvax-EGF phase II prevention trial being a component of low-dose CT screening for lung cancer that is being done as standard of care in the United States,” Dr. Lee said.

With this exciting study underway and a promising research scenario in place, new hope for patients with lung cancer is on the horizon.