A recent phase II trial examining nivolumab (Opdivo) in patients with anal cancer seeks to explore the biological makeup, and uncover potential biomarkers in anal cancer.
In an interview withTargeted Oncology, Van Morris, MD, Assistant Professor, GI Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses the phase II trial, which is the first-ever for patients with anal cancer who had prior therapy. Morris also discusses the future of treatment for anal cancer, as well as the major challenges facing oncologists currently, which includes a lack of information on the malignancy.
TARGETED ONCOLOGY:What was the motivation for this trial?
We see a lot of patients at MD Anderson, but also across the United States, with anal cancer at major academic centers. This is a disease where the annual incidence continues to rise year after year, and this is even despite the recent introduction of vaccines against HPV, since we know this is a cancer that's very much associated with infection with HPV. The issue is that there's no consensus for the standard of care for these patients.
If community oncologists go to the NCCN, which is often seen as the kind of standard for treatment guidance, there really aren't good recommendation for how to treat these patients. Given that we know that this is a virally-associated disease, our hypothesis is that these new immune checkpoint blockade agents may have activity in the treatment of this disease.
We worked with 11 other institutions in the United States in the ETCTN network, to conduct the first phase II trial ever for this disease for patients who had had prior therapy. Currently there is an ongoing international study called the EA1233 INTERACT trial. This the first prospective trial ever for patients with untreated metastatic anal cancer, but our trial was the first for patients who had had prior treatment for their metastatic disease.
TARGETED ONCOLOGY:What were the most significant findings from this trial?
What we're reporting is that we saw responses in 5 of 18 patients. The response rate was around 28% with nivolumab, which is the anti-PD1 agent. For the 18 patients who enrolled at MD Anderson, we offered them the option to participate in an optional correlative to this study. Here what we did before they went on the study; they got 1 pre-treatment tissue biopsy, and then after 2 additional doses, they got an on-treatment biopsy.
Of the 18 patients, 16 offered to participate in the study and we were able to get 12 baseline samples that were adequate for analysis. Of those patients, 9 were able to give us paired biopsies where we had tissue from the pre-treatment and on-treatment studies. What we saw was that in the patients who responded, at baseline they had higher levels of CD8-positive cells, and they also had higher levels of Granzyme B as well. What that suggested to us is that, although the numbers are small for these patients with metastatic anal cancer, they have higher levels of activated T-cells at baseline, and this may be associated with a positive response to nivolumab.
We also looked at the PD-1 and PD-L1 axis as well, and we found by immunohistochemistry that patients who responded had higher levels of PD-1 and higher levels of PD-L1 on the tumor cells as well. Then we looked at flow cytometry and again what we found was higher levels of PD-1 when we looked at the CD8-positive T-cells. We also found the higher levels of PD-L1 on the CD45-positive leukocytes in the responders at baseline before they received any treatment.
The final thing we were interested in was looking at other immune biomarkers, specifically some of the inhibitory biomarkers. We found by flow cytometry was that when you looked at the CD8-positive cells that were expressing PD-1, these cells and the responders also co-expressed LAG3 and TIM3 at baseline when you compared those to the patients that didn't respond. This really suggests to us that having more activated T-cells that are dependent on this kind of PD-1/PD-L1 axis at baseline may be associated with an improved response in patients with metastatic anal cancer who are treated with nivolumab.
TARGETED ONCOLOGY: What are the next steps following this study?
Keep in mind that what I'm talking about now is just from a single institution at MD Anderson, but there were 10 other sites in the United States that enrolled patients as well. Later in 2016 we plan to present the full clinical results summarizing all 37 patients that were treated on this study; the clinical outcomes but also the side effect toxicities as well. So the full analysis will come out later this year.
The next steps will be to think about combining the full amount possibly with other antibody immune checkpoint agents, which target the T-cell system in patients with metastatic anal cancer.
This is exciting though because anal cancer has been a traditionally orphaned disease, which has been understudied, and there's no standard of care. It’s very exciting for us to see activity in patients, but also to understand the biology that may be associated with an improved response to nivolumab so we can build on that for the trials that have these patients. Also, given this is a disease that's increasing in incidence globally every year, this isn't a disease that's going to go away in the decades to come. Also given the fact that it's an HPV-associated tumor, it's very possible that the results we find here can be extended to the treatment of advanced HPV-associated malignancies as well.
TARGETED ONCOLOGY:What have been some of the major challenges in anal cancer?
With this being a very rare malignancy, nobody understands the biology of this disease. Nobody understands the mutations that are the primary drivers of this disease, and everything is really extrapolated from cervical or head and neck cancers, which are better studied HPV-associated malignancies. Just the fact that we don't, at this point in time, have a good understanding of the underlying biology that's driving this disease, it's hard to match that with rationally designed, scientifically merited trials.
So I think this is the first step in designing trials for patients with this rare disease.