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EGFR Vaccine Early Results Published

April 16, 2008 - 3:49 pm email to a friend printer friendly view / write comments

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Dr. West

The epidermal growth factor receptor (EGFR) is a central component of a cell pathway for growth and cell division that is thought to be affected in many cancers, including NSCLC. EGFR inhibitors have been the focus of clinical trials for several years and are now used for many types of cancer. Nearly all of this work has focused on either oral tyrosine kinase inhibitors that inhibit the back end activity of the receptor inside the cell or monoclonal antibodies that block the extracellular front end of the receptor that binds to the ligand (the matching protein that attaches to the receptor) that is supposed to trigger the receptor. But a new study was just published in the Journal of Clinical Oncology that describes the early experience of studying a new vaccine against EGFR in the treatment of advanced NSCLC (abstract here).

This study came out of Cuba (investigators not known to me) and used a vaccine made of one of the proteins that serves as a ligand for EGFR, attached to a carrier protein. This vaccine is given with an adjuvant, which in this case doesn’t mean post-operative treatment, but rather refers to a treatment that is given with a vaccine to help stimulate the immune system to generate a robust immune response.

A total of 80 patients with advanced NSCLC who had completed first line platinum-based chemo (4-6 cycles) at least 28 days earlier were then randomized (1:1, so evenly divided) between the active vaccine approach and “supportive care”, or general follow-up and treatment of any specific symptoms a patient developed. The patients who received the actual treatment received a low dose of cyclophosphamide, a chemotherapy that in this setting was used as an immunostimulant/adjuvant, 3 days before the vaccine, and then the vaccine injection on days 1, 7, 14, 28, and then monthly after that.

The groups of 40 patients each were pretty well balanced, but as luck would have it, more patients on the supportive care arm had shown progression and not stable disease or a response as their best response to first line chemo (34.% vs. 26.7%). In contrast, 36.7% of the patients on the active vaccine arm had achieved a complete or partial response, compared with just 24.1% on the supportive care arm.

As many other vaccine trials have shown, treatment was well tolerated, with a modest increase in fevers, chills, muscle aches, headache, and local pain at the injection site compared with the people who didn’t receive the vaccine, but no serious side effects.

One of the endpoints the investigators evaluated was a “good antibody response” or GAR. This is a blood-based test of whether the immune system responded to the vaccine, and it was developed by these same investigators as they have worked on this vaccine over the past several years. Importantly, this result isn’t a standardized, universally used endpoint.

Among the 80 patients enrolled, 69 had blood sent for testing of immune response, and 51.4% of the patients on the vaccine arm achieved the desired immune response, compared with none who did not receive the vaccine (not surprising). Immune response was not particularly correlated with response or progression on prior chemo, nor with age of patients. Interestingly, survival was much higher in the patients who had a robust immune response/GAR than in the patients who did not, among the vaccinated group (median overall survival 11.7 vs. 3.6 months). And the serum levels of EGF in vaccinated patients was also correlated with survival: those patients with lower EGF levels had a longer median overall survival than the vaccinated patients who had higher EGF levels (13 vs. 5.6 months).

There was no overall improvement in survival among the vaccine recipients compared with the patients who received supportive care alone, but when the investigators looked at the patients under 60 (younger patients tend to develop stronger immune responses), the vaccinated patients did show a better survival:

(Click on image to enlarge)

Taken together, these results are definitely encouraging, but at this point the story is far from definitive. When you see results that show that the patients who developed a good immune response did better than those who didn’t, it raises the question of whether something about a patient’s immune response could be a surrogate for their overall health, their constitution. Perhaps the patients who didn’t achieve a robust immune response had a shorter survival because they were generally sicker and didn’t consume as much protein. We’ve been speculating about these issues in other settings, such as related to the question of why patients on EGFR inhibitors like tarceva and erbitux who don’t develop a rash do poorly compared with those who develop significant skin toxicities. Perhaps rash on EGFR inhibitors is a marker of immunocompetence and general constitution. We don’t know. (By the way, rash was very rarely seen and mild on this trial, and it was apparently not seen in the earliest trials with this EGFR vaccine).

There is also reason to wonder whether the best results with vaccination approaches may not be in advanced disease, where patients have already received chemo and may be sicker, less immunocompetent, and less able to benefit, compared with earlier stage disease, such as after surgery or chemo and radiation as an attempt to eradicate microscopic residual disease. We don’t use vaccines for infections when someone is already very ill from it, but rather before they become sick, so the immune system can attack minimal disease before it becomes rampant. We’ve seen some evidence that the Stimuvax vaccine against another antigen (MUC-1) seems to work much better in stage III compared with advanced stage NSCLC (prior post here). Perhaps the EGFR vaccine would be particularly effective in other settings.

At this point, we certainly need more evidence with larger numbers of patients and studies by a broader group of investigators, but I’ll definitely be watching for more work with this strategy. After decades of disappointment with tumor vaccines, we’re seeing more and more examples of promising work that could perhaps translate to new and minimally toxic cancer treatments.

PS: you can add comments and questions for this post on the GRACE site, where this post appears in the lung cancer section.