Biomarkers in Anal Cancer Remain Exploratory, PD-L1 Shows Promise


In an interview with Targeted Oncology™, Cathy Eng, MD, FACP, FASCO, discussed existing and novel biomarkers in anal cancer and ongoing research in the space.

Cathy Eng, MD, FACP, FASCO

Cathy Eng, MD, FACP, FASCO

Anal cancer is a rare cancer and the role of biomarkers in the space remains largely exploratory, according to Cathy Eng, MD, FACP, FASCO, who spoke on the issue during the World Congress on Gastrointestinal Cancers 2021.

PD-L1 is the most heavily explored biomarker in this space, Eng, the David H. Johnson Chair in Surgical and Medical Oncology and co-leader of the Gastrointestinal Cancer Research Program, at the Vanderbilt-Ingram Cancer Center noted. This means that treatment with checkpoint inhibitors such as nivolumab (Opdivo) may be efficacious for a large percentage of patients.

Further research is also currently being done in the area of human papillomavirus (HPV) circulating tumor DNA (ctDNA). HPV has a high rate of prevalence in anal cancer. According to Eng, it can be up to 90%. Understanding how HPV ctDNA plays a role in anal cancer may help treatment in the future. 

In an interview with Targeted Oncology™, Eng discussed existing and novel biomarkers in anal cancer and ongoing research in the space.

TARGTED ONCOLOGY™: What role do biomarkers play in the anal cancer space?

ENG: Currently, the role of biomarkers is largely exploratory. The one biomarker that's been most heavily explored is obviously PD-L1 expression, which has been explored in multiple other malignancies where immune checkpoint inhibitors are being considered. For anal carcinoma, keeping in mind this is a rare cancer, the original data regarding pembrolizumab (Keytruda) noted that there was still benefit in patients that were PD-L1 over expressive versus those that were not. In our EA2165 original trial (NCT03233711), looking at nivolumab in the refractory setting, it was a smaller study, but also, we were not selective and did not require PD-L1 expression to participate in the trial, and we still had patients that were also responders. Once again, the numbers are much smaller because we're a rare patient population. We hope to derive more data in the future moving forward with looking at immune checkpoint inhibition.

Are biomarkers being used to their full potential in this space? Why or why not?

That's a great question. I do not believe biomarkers are being utilized fully potentially in the space. think, in large part, funding has been an issue. As you are aware, there has been data that was created, or attempted to be created, from the InterAACT trial (NCT02051868), which I also participated in. And that was basically limited to select sites because of limited funding. When we wrote up our EA2165 trial, we had limited funding as well. We were only able to basically evaluate samples from patients that we treated at MD Anderson. And ironically enough, currently in our phase 2 randomized study, NCI9673 Part B (NCT02314169), although we actually have funding this time around, I think a lot of patients are more interested in circulating tumor DNA, just because of the convenience, rather than providing a tissue sample, even though we actually were able to obtain funding this time. So, I'm a little concerned, although we don't have the final numbers. I'm a little concerned about the number of tissue specimens we were hoping to achieve from our randomized phase 2 study. So, I think, moving forward, based upon all the phase 1 /phase 3 trials have been created, I hope we will be able to derive more information. And I'm hoping that similar information will be derived from all these individual studies so that we can learn something cumulatively.

Which patients should be tested for biomarkers?

I would say for our locally advanced patients, there's definitely a lot of interest in looking at the role of HPV circulating tumor DNA, keeping in mind that 90% of all anal carcinoma patients are HPV positive. So, there has been some data looking at both earlier stage disease as well as metastatic disease where HPV circulating tumor DNA can actually correlate with response to radiation therapy as well as correlate with response to chemotherapy. So, the data that's been published thus far are in smaller studies. I am the principle investigator for basically our EA2176 trial (NCT04444921), which is a phase 3 trial of carboplatin plus paclitaxel plus or minus nivolumab in treatment-naive metastatic patients. I'm hoping that we can derive more information from that. So, once again, I'm hoping that HPV circulating tumor DNA can be become a potential standardized biomarker moving forward.

What can be done to integrate biomarker testing into clinical practice?

What can be done at this point to integrate biomarkers, I think, increased recognition of immune checkpoint inhibition. I know there's a lot of interest in it currently, obviously, in multiple cancers, but we've seen some benefit in this rare cancer as well. And we're also looking at it in the adjuvant setting, in EA2165 for high risk recurrent patients. I think what we can learn from this is that for immune checkpoint inhibitors, we don't have the best answers in regard to biomarkers for our patient populations, we need to think about other aspects. And because HPV has such a large role in the development of anal carcinoma, I think consideration for HPV circulating tumor DNA really should be considered in all clinical trials moving forward, as well as trying our best to identify other biomarkers as well although. Once again, for all metastatic patients next generation sequencing should be completed when thinking about steps moving forward, should they need alternative treatment options. So, I always encourage in the metastatic setting, next generation sequencing. And then I think in current studies, both early stage and late stage, I'm hoping that they will also incorporate HPV circulating tumor DNA. I think that's very promising right now.

What is the biggest takeaway from recent research in this space? 

I think the biggest takeaway is that there appears to be a potential promising role for HPV circulating tumor DNA. And I think what a lot of people were surprised to see me present is that I showed a lot of data regarding correlate works and head neck. And that is because I think we have as a rare cancer; we have to learn from more common cancers that are attributed to very similar etiology. So, as many people are aware, HPV also is present in head neck cancer, not to the same extent, to a lesser extent, but still, very important data can be derived from a more common cancer. Same can be held true for cervical cancer, for instance. Once again, I tried to see where the field was going. And that's where extrapolate a lot of my data. And that's actually where a lot of my research came from, is based on my actual background in treating head neck patients for my fellowship.

Once again, want to encourage providers, caregivers, and patients to please enroll patients to clinical trials, especially in this setting of relatively rare cancer, because developments that we identify in either locally advanced or metastatic anal carcinoma have bearing potentially in other HPV related cancers. And that's how I think we make a greater impact.

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