Combining Vismodegib With Radiation May Benefit Patients With Basal Cell Carcinoma

Chris Barker, MD, PhD

For most patients with basal cell carcinoma, surgery and radiation have proven to be effective approaches. However, a small subset of patients develop locally advanced basal cell carcinoma, which presents a greater treatment challenge, explains Chris Barker, MD, PhD, a radiation oncologist at Memorial Sloan Kettering Cancer Center (MSKCC).

“The bigger challenge with basal cell carcinoma occurs when it has grown in a locally advanced fashion, meaning it has grown to such a size, or has invaded and caused such local destruction, that surgery is no longer a viable option,” he says.

As a potential treatment for some patients in this setting, a single-arm phase II study (NCT01835626), led by Barker at MSKCC and Sue Yom, MD, at the University of California San Francisco, is investigating radiation therapy plus the hedgehog pathway inhibitor vismodegib (Erivedge) in patients with locally advanced basal cell carcinoma of the head and neck.

The study, which is currently accruing, will include an estimated 24 patients who will receive vismodegib daily for 12 weeks followed by vismodegib and radiation for 7 weeks.

The primary endpoint is to determine the local-regional control rate at 12 months from protocol therapy completion, defined as complete or partial response, with absence of progressive disease within the irradiated planning tumor volumes. Secondary endpoints include safety and probability of progression-free survival.

This study will provide important insight in treating a patient population that currently does not have many options, says Barker.

“Thankfully, most patients don’t end up with a large, unresectable basal cell carcinoma,” he says. “But for the few patients who find themselves in that situation, I think this study is very valuable. It really provides a novel treatment option that does not currently exist.”

OncLive: What is the objective of this study?

In an interview with OncLive, Barker further explains the goals of the study, the possible synergy between vismodegib and radiation, and what oncologists should know about using hedgehog pathway inhibitors.Barker: The goal of the study is to see if we can improve upon regional and local control of the basal cell carcinoma. For the patients who are being studied in this trial, surgery would be a very radical, drastic, and potentially morbid undertaking. Patients in that situation can often be treated and cured with radiation therapy.

Why investigate this combination in head and neck basal cell carcinoma?

However, we know from previous studies, that although many patients do well with the approach of radiation alone, it is unsuccessful for many. The idea with this study is to combine vismodegib with radiation with the intent of creating a more effective therapeutic combination. We think this an interesting and rational combination of treatment, which is radiation and drugs, such as vismodegib.We are studying the head and neck—primary carcinomas because, with very locally advanced basal cell carcinomas, it is a harder area for surgeons to remove them. This is due to the important tissues that are near the basal cells. They are near the eyes, the mouth, and the ears.

Is there a potential synergy between radiation therapy and vismodegib?

In those cases, a surgical procedure that would require a removal of the entire basal cell carcinoma would require the removal of a very important body part—so that is why we focused on that population. The head and neck is full of essential body parts. Most basal cell cancers happen in the head and neck area, so it is an area where we tend to see this problem most often.Preclinical studies have shown that vismodegib may actually change the way that cancer cells respond to radiation. It may make them more sensitive to radiation.

Are there toxicities seen with vismodegib that may be a challenge in this trial?

There have been a lot of interesting advances in the biology of hedgehog pathway signaling and how that plays a part in cancer development and growth. Studies have been exploring the sensitivity of cancer cells to radiation therapy in the presence or absence of these types of drugs that block the hedgehog pathway. Those studies have shown that the sensitivity to radiation goes up in the presence of these medicines. The precise mechanisms aren’t entirely clear, but it probably has something to do with this complex interaction or pathway, and the development and growth of the cancers.There are number of side effects with the drug; however, they tend to be things such as upset stomach, cramps, and general hair loss. Because we are targeting cancers of the head and neck area, we don’t think that radiation will exasperate any of the side effects of the medicine, since the side effects of radiation to the head and neck area don’t overlap with those of vismodegib.

What should oncologists know about using hedgehog inhibitors for the treatment of advanced basal cell carcinomas?

We don’t anticipate that there will be many side effects that are worse than either treatment alone. However, the study will help truly define that, in a prospective way, to give us clear evidence that there are no safety concerns with this combination.It is important to recognize that these medications, by themselves, are not usually curative for locally advanced basal cell carcinomas.

From time to time, we see people who are treated with medicine when radiation therapy really hasn’t been considered. It actually does have a track record for being effective in locally advanced, unresectable basal cell carcinoma. We have seen a few patients who started on these agents probably before it was the right time to do so. Nevertheless, they have subsequently been ineligible for our trial.

As these agents are developed, it is important for doctors to recognize the right place that they fit into as a treatment option. The NCCN guidelines will likely help to clarify it.