There is consistent effort nationally to educate people about melanoma, which accounts for only 1 percent of all skin cancers yet is the cause of most skin cancer deaths. But many of us would be hard-pressed to name another form of skin cancer.
We tend not to hear as much about basal cell and squamous cell carcinomas, cancers that arise from a host of potential risk factors — the main one being exposure to ultraviolet light from the sun or tanning lamps — mainly because they are limited to the skin and thus are usually treatable with surgery or radiation, rarely progressing to an advanced stage. Still, these cancers, like melanoma, can become metastatic, and once they reach stage 4, the treatment options are less clear.
Just 0.5 percent of basal cell carcinomas spread beyond the skin, often in patients who have compromised immune systems (such as those who have HIV/AIDS or have undergone organ transplants). Among patients with squamous cell skin cancers, 5 percent eventually develop metastatic disease; similar to the demographic in basal cell carcinoma, patients who have undergone solid organ or bone marrow transplants are most at risk for squamous cell disease.
For a long time, the rarity of these two conditions meant that treatment options were severely limited. Now, however, there are targeted drugs capable of treating basal cell and squamous cell cancers that have metastasized — with immunotherapies waiting in the wings.
Morganna Freeman, D.O., associate director of the Melanoma and Cutaneous Oncology Program at The Angeles Clinic, in California, discussed the latest strategies in an interview with CURE®.
Let's start by discussing treatments for basal cell carcinoma. Please give us the basics about a ket recent strategy, the use of targeted drugs called hedgehog inhibitors.
Dr. Freeman: About 20 years ago, it was discovered that there were abnormal genes in basal cell cancers that controlled a “hedgehog cell signaling pathway” which is essential to basal cell growth. This pathway is activated by a protein called “smoothened,” which can be blocked with targeted therapy to prevent cancer growth. Currently, we have two hedgehog inhibitors — Erivedge (vismodegib), approved by the FDA in 2012, and Odomzo (sonidegib), approved in 2015 — which target this protein and can kill basal cells successfully. These drugs are not like chemotherapy because, instead of interfering with DNA replication, they block a growth pathway the tumors are addicted to. Based on the data we have seen with both drugs, patients with advanced, unresectable and metastatic basal cell cancers can get a long-lasting clinical benefit with a fairly tolerable side-effect profile.
In the trial that led to its approval, patients with locally advanced basal cell carcinoma who took Odomzo had an overall response rate of 47 percent; at the time of the analysis, data was not mature enough to determine the median length of progression-free survival (PFS) or overall survival (OS). Patients with metastatic disease in that trial demonstrated an overall response rate of 15.4 percent and a median PFS of 13.1 months, but overall survival data were not yet mature. In the ERIVANCE BCC study that led to the FDA’s approval of Erivedge, those with locally advanced disease demonstrated an overall response rate of 60.3 percent, PFS of 12.9 months and OS of 33.4 months. Their counterparts with metastatic disease experienced an ORR of 48.5 percent and a PFS of 9.3 months; OS had not yet been reached at the time of the analysis.
The most common side effects seen with hedgehog inhibitors are muscle spasms, hair loss, loss of taste perception, nausea, diarrhea and weight loss. At times, it can be challenging for patients to remain on therapy; however there are ways to modify the dose, including reducing the number or frequency of pills taken and offering patients “drug holidays,” or temporary breaks in therapy.
Who are the optimal patients to receive hedgehog inhibitors?
If I am seeing a patient who either has a large number of basal cell growths or a single large tumor the surgeon thinks is too extensive to remove, then this is where systemic treatment with hedgehog inhibitors has a role. Oftentimes, we may try to use these drugs to shrink a single large tumor, making that patient a better candidate for surgery.
If the patient has metastatic basal cell carcinoma, the decision to start treatment depends mainly on the burden of disease. Some patients have a few spots in the bone that are asymptomatic and, if they are slowly growing, then we may just decide to watch them with scans every few months. However, if they have metastases that are large, symptomatic or growing quickly, then we would definitely think about systemic treatment to control that growth.
As with many other cancers, we know that, once the patient stops therapy, the basal cell will regrow. Therefore, patients should expect a long-term treatment plan to keep their disease in remission. A lot of discussions I have with patients are on the risks and benefits regarding when we should initiate therapy and for how long, and what we would do if the cancer should end up recurring or relapsing in a different place.
Does basal cell carcinoma tend to develop a resistance against hedgehog inhibitors?
According to data from clinical trials, it usually becomes resistant within eight to 12 months, although every patient is different. The trials for both drugs approved did show that patients with metastatic disease had a remission rate that was lower and shorter than for patients who had locally advanced disease. That points to the biologic aggressiveness of basal cell once it does become metastatic.
What might work for a patient after his basal cell carcinoma becomes resistant to treatment with a hegehog inhibitor?
Once it progresses on a hedgehog itor, basal cell can be notoriously difficult to treat. Chemotherapy is often not welltolerated or not very effective. But when we use genomic precision medicine to try to find a targeted drug for the patient that matches the mutations that drive his or her cancer, we can often get very dramatic results.
Precision medicine has taught us that basal cell, in addition to relying on the hedgehog pathway, is dependent on VEGF, another important protein in cancer. VEGF is essentially what enables cancer to grow blood vessels toward itself, and allows it to continue to grow and metastasize. We recently published a case in JAMA Dermatology about a patient with metastatic basal cell who had progressed on standard therapy, and through precision medicine testing was found to have a VEGF mutation. We put him on the VEGF-targeting drug Votrient (pazopanib, indicated for renal cell and soft tissue carcinomas) off-label, and he had a complete response for nine months.
Precision genomic medicine is gaining a lot of use for rare and advanced cancers, but it may not occur to all oncologists that it should be performed. Most of the time, when we encounter a patient with metastatic basal cell, we’ll appropriately think to use Erivedge or Odomzo. Where genomic medicine should enter the picture is either the first time the patient is being seen for metastatic disease, which is usually my practice, or after the patient’s cancer has progressed on a standard firstline therapy. This allows us to learn what the genetic escape mechanisms might be, and if they can be targeted with a second therapy.
Getting the patient’s insurance to cover a drug for off-label use often requires a little work on the oncologist’s part to convince the insurer the therapy is needed, but we’re usually pretty successful with the appeals process. With basal cell, in particular, treatment options are so limited that they’ll often grant coverage based on compassionate use.
What other novel strategies are being explored for the treatment of basal cell carcinoma?
There are clinical trials combining hedgehog inhibitors with immunotherapies — one that is currently recruiting patients is using Erivedge and the PD-1-inhibiting immunotherapy Keytruda (pembrolizumab). It will be interesting to see how that pans out in terms of basal cell cancer, and whether we can use immune therapy in this disease just as successfully as we have in other cancers.
There’s also a clinical trial of the antifungal drug itraconazole given with an oral anticancer agent, arsenic trioxide, for patients with advanced basal cell. Other therapies are mostly topical; there’s a trial looking at topical itraconazole and another looking at a topical hedgehog inhibitor, patidegib. The immune-stimulating drug imiquimod has some activity in basal cell, with about a 50 to 60 percent control rate, and we’re looking at whether topical imiquimod plus limited surgery could help treat some of these larger tumors.
Researchers are also looking at different treatments combined with radiation therapy, because we know that basal cell is very sensitive to this modality. In cancer care, we’re constantly asking whether we can improve on our current therapies by combining them to make them more effective.
The toolbox is different for squamous cell skin cancers. What is being explored by researchers?
There are over 700,000 cases of squamous cancer diagnosed each year, so if you consider the statistics, 35,000 patients will have metastatic disease at some point. Therefore, we recognize a great need for better treatment options and clinical trials for this cancer. Squamous cell skin cancers do seem to respond really well to immunotherapy; I’ve successfully used PD-1- targeting agents in patients with advanced squamous skin cancer and have seen some very dramatic results, and there is one new trial of an anti-PD-1 agent being conducted in advanced squamous skin cancer. In addition, just like in other cancers, we are looking to determine whether we can combine immune therapy with other treatments.
There is some overlap between the two skin cancer types when it comes to topical therapies. As an example, imiquimod is just as effective for squamous cell as it is for basal cell if the disease is locally advanced, and we also use the topical chemotherapy 5-fluorouracil for both. Once squamous skin cancers become metastatic, however, it’s a different story, because they often metastasize to the lungs and can grow rather quickly. The chemotherapies we use in stage 4 disease are borrowed from squamous head and neck cancer, and because PD-1 agents work in that disease, a lot of oncologists are looking to use them in squamous skin cancer. Compared to immunotherapy, standard chemotherapy can be toxic and lack the durability and effectiveness seen with PD-1 agents.
We can also use Erbitux (cetuximab), a targeted drug that works against EGFR, since a lot of cutaneous squamous cell cancers overexpress this protein, and small trials have shown that anti-EGFR drugs can induce about a 30 percent reduction in tumor size, with fairly durable remissions of eight to 10 months.
Where the field will be advanced further is by looking at whether we can combine an EGFR agent with another drug to get an even better response, as we’ve seen with chemotherapy in head and neck cancer. Combining EGFR drugs with immune therapy is being explored in lung cancer, and early data suggest this combination might be safe and effective.
When patients are diagnosed with metastatic basal cell or squamous cell skin cancers, how can they help direct their own treatment?
If a patient has an advanced or metastatic nonmelanoma skin cancer and has access to an academic center, he or she should seek a specialist and ask about clinical trial options. In a community cancer center, it is worthwhile for patients to ask about referrals to oncologists who manage these rare cancers on a regular basis. They should seek information about any clinical trials to consider and ask whether their doctor recommends chemotherapy, immunotherapy or possibly targeted treatments.
Asking those three questions in either setting should help set the stage for how that cancer should be approached. There may not be a straightforward answer, though, especially in cutaneous squamous cell, because no singular FDA-approved therapy currently exists; as I mentioned, most of our treatment plans are derived from head and neck squamous cancer.
That’s one reason clinical trials should be explored, if available. In addition to furthering our understanding of these cancers, clinical trials enable patients to access new and promising treatments in high-quality, medically supervised settings. Trials may also allow patients to sidestep the lengthy, often stressful appeals process involved in getting an off-label drug through a health insurance company, and this represents an additional benefit.