Vismodegib study confirms safety, efficacy for BCC

The largest vismodegib trial to date reinforces the drug's safety and efficacy in locally advanced and metastatic basal cell carcinoma (LABCC, MBCC), according to a poster presented at the 2016 American Society of Clinical Oncology Meeting. For many patients worldwide, however, the treatment's affordability remains in question.

STEVIE study

Dr. HauschildIn the Study of Vismodegib in Patients with Locally Advanced or Metastatic Basal Cell Carcinoma (STEVIE study; NCT01367665), vismodegib 150 mg QD provided benefit for more than 90% of patients, including 68% who responded to treatment and 26.6% who had stable disease after treatment,¹ says study co-author Axel Hauschild, M.D. He is professor of dermatology at the University of Kiel in Kiel, Germany.

The massive number of patients treated-1,215-confirms findings of the drug's phase 1 and 3 trials, which included 30 and 100 patients, respectively, he says.

Dallas-based dermatologist and dermatopathologist Clay J. Cockerell, M.D., who performed a small study (unpublished) of vismodegib plus Mohs surgery in large BCCs, says, "The STEVIE paper's findings are very similar to those we saw in our pilot study-vismodegib appears to work. It's a major addition to our therapeutic armamentarium."

Dr. Hauschild says, "The most important finding is the complete response rate of 33% in LABCC in a real-world setting, including multiple institutions in multiple countries." Nearly all new drugs approved for metastatic melanoma and BCC undergo early studies in highly selected patient populations-those with no comorbidities or other underlying malignancies, he explained. "That's not the patient we are typically seeing with advanced BCC."

As a post-approval study, the STEVIE study could include a broad variety of patients, says Dr. Hauschild. The fact that only four patients with MBCC (or 4.8% of the 84 patients with this disease) achieved complete response suggests that "We are most likely curing patients with LABCC, but not with MBCC. Here, the issue is prolonging life." Median progression-free survival in MBCC was 13.1 months, versus 23.2 months for LABCC.

Dr. RossiAnthony M. Rossi, M.D., finds it encouraging to have one-year follow-up data from 1,215 patients showing that vismodegib's side effects were mostly low-grade, and expected. He is an assistant attending physician in dermatologic, Mohs and laser surgery at Memorial Sloan-Kettering Cancer Center and an assistant professor of dermatology at Weil Cornell Medical College.

Adverse events (AEs) that impacted more than 50% of study patients included muscle spasms, alopecia and dysgeusia. Such symptoms impact quality of life, says Dr. Hauschild. "But a large BCC, most of which occur on the face or head, also affects quality of life. If you have a benefit, you will certainly tolerate these toxicities." Furthermore, he says, study data reflect that AE frequency and severity decline over time. "If patients can make it through the first three months, they very likely can make it through long-term use."

Dr. Rossi counters that not all patients' side effects diminish. Strategies being explored to reduce side effects include drug holidays and pulsed treatment regimens, says Dr. Cockerell. In the study, average treatment interruption was 22 days.

Although serious AEs were rare, Dr. Rossi adds, dermatologists should be aware that seven treatment-related deaths occurred in the study (though these patients had confounding factors). Additionally, the fact that 40% of patients lost weight, and 25% experienced diminished appetite, indicates that dermatologists should monitor the nutritional status of patients on vismodegib, he says.

The phase 2 ERIVANCE trial of vismodegib

Next: Vismedegib as first-line therapy?

New gold standard?

Already, says Dr. Hauschild, German guidelines state that for any BCC that cannot be excised or irradiated, vismodegib is first-line therapy,² completely replacing chemotherapy. "That's for all patients." Because vismodegib is the only effective systemic treatment modality for LABCC and MBCC, he predicts that BCC guidelines worldwide will take a similar stance.

"The dilemma is that in many countries, the drug is not affordable." In the European Union, he says, drug approval automatically means that government-run healthcare systems will cover it for all patients indicated. He says that due to vismodegib's cost-approximately $100,000 per year in Germany and the United States-private insurers elsewhere often won't cover vismodegib, which most patients can't afford out-of-pocket.

Dr. Rossi says that in the rapidly changing U.S. insurance environment, affordability is "something to consider, especially if a patient is going to be on the drug for a long time."

Dr. CockerellGenentech offers a hotline and other help for coding properly, battling insurers and meeting copayments.⁴ Thanks to the manufacturer's advocacy efforts, Dr. Cockerell says that in most cases he's seen, "We were able to get some kind of compassionate coverage, in some cases totaling 75% or more of the drug's cost, for patients in need. Unfortunately, that's an issue with a lot of these new drugs. They're very expensive, and patients have a hard time paying for them-not only vismodegib, but also the biologics for psoriasis, for example. That will probably limit use of vismodegib."

One fact that might help sway insurers, says Dr. Hauschild, is that the vast majority of patients only need the treatment for three to six months. In the study, median treatment duration was 8.6 months.

Dr. Rossi says that with vismodegib, "Unfortunately there is no preset duration of use. It all depends on how patients are responding" based on clinical or radiological findings. The bottom line, he says, is that "We have to see how long patients can tolerate the drug. We know that many patients will stop treatment because of the adverse effects, which can be very debilitating. So we pre-counsel patients thoroughly before starting them on vismodegib."

Henceforth, says Dr. Rossi, "We need further studies to determine how long vismodegib should be given, and how patients fare with treatment breaks. We do know that poor responders may progress" while off therapy, so these patients need close clinical follow-up.

Dr. Hauschild adds, "My only advice is that patients with non-resectable, so-called advanced BCC should be treated with vismodegib. There's a very high likelihood they will respond: two-thirds have some response, including complete response in one-third. It's the treatment of choice for nonresectable BCC."

Dr. Cockerell says that targeting the hedgehog pathway, as vismodegib does, represents a major advance that several pharmaceutical companies are using to develop additional treatments for advanced BCC. Researchers also have begun exploring a topical hedgehog inhibitor that in select cases could replace surgery, he says.

From a scope-of-practice viewpoint, says Dr. Cockerell, the STEVIE study places vismodegib among a handful of novel therapies that is helping dermatologists provide full-service skin cancer treatments. "Most dermatologists think of themselves as diagnosticians and perform relatively limited surgery," explains Dr. Cockerell. If they treat skin cancer, they likely will perform basic in-office excision or curettage, or refer the patient for Mohs surgery.

With the introduction of vismodegib and new melanoma treatments-plus the reintroduction of radiation therapy-to dermatology, Dr. Cockerell says, "Dermatologists, especially Mohs surgeons, can market themselves as cutaneous oncologists. If someone refers them a BCC, they can look at the entire palette of therapeutic options. We're in an exciting time in medical and surgical dermatology."

A decade ago, he says, dermatologists had nothing for advanced melanoma or large BCCs. "I'm hoping that next, we'll see a similar breakthrough for squamous cell carcinoma," a disease in which the lung-cancer drug nivolumab has shown success in Phase 3 research (NCT02105636).³

Disclosures: Drs. Hauschild and Rossi report no relevant financial interests. Dr. Cockerell has served as an investigator and attended medical advisory board meetings on behalf of Genentech.

References:

1. Hansson J, Hauschild A, Kunstfeld R, et al. Vismodegib, a hedgehog pathway inhibitor in advanced basal cell carcinoma: STEVIE study analysis in 1,215 patients. Poster presented at: American Society of Clinical Oncology Annual Meeting. June 3-7, 2016. Chicago.

2. Hauschild A, Breuninger H, Kaufmann R, Kortmann RD, Klein M, Werner J, Reifenberger J, Dirschka T, Garbe C. Brief S2k guidelines – basal cell carcinoma of the skin.J Dtsch Dermatol Ges. 2013;11 Suppl 3:10-5, 11-6. 

3. Gillison ML, Blumenschein G Jr., Fayette J, et al. Nivolumab versus investigator's choice for recurrent or metastatic head and neck squamous cell carcinoma: CheckMate-141. American Society for Cancer Research Annual Meeting. Abstract CT099. Presented April 19, 2016.

4. https://www.genentech-access.com/hcp/brands/erivedge/learn-about-our-services/reimbursement.html