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CIMAvax-nivolumab combination appears safe, demonstrates ‘good signals’ in advanced lung cancer
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The Cuban-developed immunotherapy CIMAvax-EGF in combination with nivolumab appeared safe for patients with advanced non-small cell lung cancer, according to results from the first portion of a phase 1/phase 2 trial.
The combination also demonstrated more effectiveness than either agent alone.
“[Although] this is a small study and we will need to verify that these conclusions hold true when we move on to our phase 2 study, these early hints of clinical activity encourage us to continue exploring this combination approach,” lead investigator Grace Dy, MD, division chief for thoracic oncology at Roswell Park Comprehensive Cancer Center, said in a press release.
Researchers in Cuba developed CIMAvax, a recombinant anti-human epidermal growth factor immunotherapy. Studies conducted there showed a survival benefit for patients with advanced NSCLC who received CIMAvax as maintenance therapy following combination chemotherapy.
CIMAvax now is being studied in the United States as part of a collaboration between Roswell Park and the Centro de Inmunología Molecular (CIM) in Havana.
In the dose-escalation phase 1 portion of their trial, Dy and colleagues evaluated CIMAvax in combination with the anti-PD-1 antibody nivolumab (Opdivo, Bristol-Myers Squibb), a standard therapy for treatment-resistant or recurrent NSCLC.
Researchers enrolled 13 patients (median age, 58 years; range, 46-69) with advanced disease. All patients had received prior treatment but were immunotherapy-naive.
Dy and colleagues investigated intramuscular CIMAvax at two dose levels (1.2 mg and 1.4 mg) given every 2 weeks for four doses in the induction phase, then monthly during the maintenance phase. Patients also received 240 mg IV nivolumab every 2 weeks.
Treatment continued until disease progression, serious toxicity or withdrawal of consent.
Safety and determination of a recommended phase 2 dose served as primary objectives. Secondary objectives included tumor response and correlative markers of immune response.
No patients experienced life-threatening side effects attributable to the combination. One patient experienced grade 3 myocarditis attributed to nivolumab.
Four of the 12 patients who received at least two doses of nivolumab and CIMAvax achieved partial response. Three of the four responders had PD-L1 tumor proportion score of less than 1%; a fourth had PD-L1 tumor proportion score of greater than 50%.
HemOnc Today spoke with Dy about the safety results observed in the phase 1 portion of the trial, the early indication of efficacy, and what investigators intend to assess in the phase 2 portion of the study.
Question: Why is CIMAvax so exciting?
Answer: If you track traditional therapeutic cancer vaccine development for many cancers, including lung cancer, the field has been beset with a lot of failures, in part because these vaccines were designed to stimulate T-cell responses against specific antigens found on cancer cells. But when the CIM group developed this particular immunotherapy — which is uniquely designed to stimulate an antibody response to neutralize and deplete an important cancer-related growth factor, EGF — they were able to demonstrate survival benefits that had eluded traditional therapeutic cancer vaccines.
Q: How is the Roswell Park study being conducted?
A: The first step was to make sure no unusual side effects would appear from combining these two drugs, which appear to be safe separately. The second goal will be to look at the effectiveness of the combination from two perspectives. First, we want to see if nivolumab enhances response to CIMAvax. The other question is whether these two therapies lead to better anti-cancer effects. That will be addressed in the phase 2 portion.
Q: Can you provide an overview of the safety results you observed with this combination?
A: The most common side effects were mild, grade 1 pain in the injection area. Some patients have chills, or fever and flu-like symptoms. One patient experienced myocarditis a week after receiving one dose of nivolumab and one dose of the vaccine. The patient was taken off the study and, sadly, died of cancer progression. A post-mortem examination showed cardiac metastases, and our conclusion is that this incident represented an on-target effect of nivolumab.
Going into this study, we knew there was a possibility that CIMAvax could cause increased frequency of skin rash or diarrhea based on the pathway involved, but so far, we haven’t seen that. We will gain more information about the safety profile from the phase 2 portion, when larger numbers of patients are included.
Q: Could you elaborate on the efficacy results?
A: We are always glad to see some good signals, but it might be too premature to say that we are seeing true, good results. The initial small sample size was not really large enough to tell us with confidence how robust or how true our observation is, but we were still happy to see some hint of activity. The true efficacy analysis will be in the phase 2 portion, which has just started. This will use nivolumab at the original FDA-approved schedule, followed by CIMAvax at 2.4 mg, divided into four injections for the induction phase, followed by once-monthly injections.
Q: What do you hope to find in the phase 2 portion of the study?
A: We will look at baseline epidermal growth factor levels and identify which group of patients derive the most benefit. We also hope to find if there are other markers of response. We are collecting blood and tumor specimens so we can analyze them for any relationships that might explain which patient groups derive the most benefit from the combination. The majority of patients who enroll in our study will have low PD-L1 levels, because those who have high levels will be treated with standard pembrolizumab (Keytruda, Merck). Patients on this trial will have lower rates of expected response, and we have built-in statistical methods to account for this.
Q: Looking ahead, can you describe the potential of CIMAvax, both as a component of treatment for lung cancer and as a cancer prevention strategy?
A: For individuals at a high risk for lung cancer, it certainly is interesting to explore the possibility that CIMAvax may work to prevent cancer occurrence or recurrence, and one of my Roswell Park colleagues is designing a study to do just that. We also will have to see how immune checkpoint inhibitors will be positioned in the adjuvant setting for patients with lung cancer. There are many ongoing trials in this adjuvant setting, so if there is a signal that immunotherapy may be beneficial, we’ll look at how we can incorporate CIMAvax in this setting.– by Joe Gramigna
For more information:
Grace Dy, MD, can be reached at grace.dy@roswellpark.org.
Reference:
Dy G, et al. Abstract P2.04-26. Presented at: International Association for the Study of Lung Cancer’s World Conference on Lung Cancer; Sept. 23-26, 2018; Toronto.
Disclosure: Dy reports no relevant financial disclosures.