Meeting News CoveragePerspective

Greater understanding of resistance mechanisms needed in basal cell carcinoma

NEW YORK — Hedgehog inhibitors have demonstrated high activity and durability in patients with advanced basal cell carcinoma, and they also possess a predictable toxicity profile, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.

However, the impact of these agents on the natural history of metastatic disease remains unclear, and a greater understanding of resistance mechanisms is needed, Karl D. Lewis, MD, associate professor of medicine at the University of Colorado Denver’s cutaneous oncology program, said during a presentation.

Basal cell carcinoma (BCC) is the most common skin cancer in the United States. Although exact incidence is imprecise due to lack of a registry, more than 1 million cases occur each year.

The cell of origin likely is a pluripotent stem cell or progenitor cell in the interfollicular epidermis and hair follicles. Patients can develop hundreds of BCCs in their lifetimes. They usually start at a young age, typically by age 35 but as early as teenage years, Lewis said.

BCCs develop secondary to activation of target genes in the hedgehog pathway, a series of proteins that is highly active during embryogenesis but widely considered to be dormant after birth.

“These tumors generally have a low metastatic potential, but they can be very difficult sometimes because they can be locally advanced with destruction of the skin and surrounding structures,” Lewis said.

Traditional treatments for low-risk lesions include cryosurgery, electrodessication and topical therapy, whereas high-risk lesions often are treated with surgical excision, Mohs’ micrographic surgery and radiation therapy.

“Since the hedgehog pathway seems to be ubiquitously expressed in this disease, the question arose whether there was a potential for targeted therapy, and certainly that has come to fruition,” Lewis said. 

ERIVANCE BCC

ERIVANCE BCC — a multicenter, international phase 2 study — evaluated the hedgehog pathway inhibitor vismodegib (Erivedge, Genentech) in 99 patients with BCC. The cohort included 33 patients with metastatic disease, and 63 patients with locally advanced BCC who had inoperable disease or for whom surgery was inappropriate due to multiple recurrences, the potential for disfigurement or low likelihood of surgical cure.

All patients received 150 mg vismodegib daily. Treatment continued until progression, inoperable toxicity or study withdrawal.

The results, published in 2012 in The New England Journal of Medicine, showed the trial met its primary endpoint of objective response rate by independent review. Researchers reported response rates of 42.9% (95% CI, 31-56) in patients with locally advanced disease and 30.3% (95% CI, 16-48) in patients with metastatic disease.

The primary analysis — performed after data cutoff on Nov. 26, 2010 — showed a median duration of response of 7.6 months in both groups. A 30-month analysis — performed after data cutoff on May 30, 2013 — showed the median duration of response among patients with locally advanced disease increased to 26.2 months.

“This indicates there is a group of patients who can benefit from treatment with this drug for a very long time,” Lewis said. “The vast majority of patients who received this targeted agent experienced a decrease in tumor burden. A few patients had primary resistance, but it’s not quite clear what led to that resistance.”

The most common adverse events included muscle spasms (68%), alopecia (64%), dysgeusia (51%), weight loss (46%) and fatigue (36%).

“Even though most of these were grade 1 or grade 2, they can wear on patients,” Lewis said. “If you treat them for a long time, they begin to have a significant effect on quality of life.”

BOLT study

The phase 2 BOLT study evaluated two doses of sonidegib (LDE225), a hedgehog signaling pathway inhibitor, in 194 patients with locally advanced or metastatic BCC.

Researchers assigned 128 patients to 800 mg daily, and the other 66 patients received 200 mg daily. Treatment continued until disease progression, unacceptable toxicity, death or study discontinuation. Objective response rate of 30% or greater served as the primary endpoint.

The results, presented at the European Society for Medical Oncology Congress last year, showed overall response rates at 12 months of 58% (95% CI, 45-70) in the 200-mg cohort and 44% (95% CI, 35-53) in the 800-mg cohort. The 200-dose of sonidegib was better tolerated, so that was chosen as the dose for future investigations.

Aside from observed increases of creatine kinase (CK) elevation — which occurred in 30% of patients — adverse events associated with sonidegib generally mirrored those observed with vismodegib. The majority of these events were grade 1 or grade 2.

The ERIVANCE study did not measure CK elevation. Consequently, the true instance of CK elevation with vismodegib is not known, nor is it clear whether CK elevation is a class effect of these agents or due more to sonidegib, Lewis said.

Survival and resistance

Although both vismodegib and sonidegib are clearly active in locally advanced and metastatic disease, whether they have an impact on survival is unknown, Lewis said.

“We really don’t have a lot of knowledge about the natural history of metastatic basal cell carcinoma,” Lewis said. “We don’t know what median survival is because it has been poorly studied … and it likely will never be known because there are unlikely to be prospective trials done.”

Additional questions remain, Lewis said.

“It will be important to determine the resistance mechanisms, both for primary and acquired resistance,” he said. “Some patients have primary resistance to these agents and it’s not clear why.

“I think it’s analogous to the BRAF inhibitor story in melanoma,” Lewis added. “A number of studies have demonstrated that smoothened variants explain the majority of drug resistance in basal cell carcinoma. … Overcoming this resistance will be very important. That is all work yet to be done, and hopefully those trials can get underway soon.” – by Mark Leiser

References:

Lewis KD. Current management of advanced basal cell carcinoma. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 10-11, 2015; New York.

Dummer R, et al. Abstract LBA33. Presented at: European Society for Medical Oncology Congress; Sept. 26-30, 2014; Madrid.

Sekulic A, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1113713.

Disclosure: Lewis reports consultant fees from Genentech and Roche, as well as contracted research with Novartis.

NEW YORK — Hedgehog inhibitors have demonstrated high activity and durability in patients with advanced basal cell carcinoma, and they also possess a predictable toxicity profile, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.

However, the impact of these agents on the natural history of metastatic disease remains unclear, and a greater understanding of resistance mechanisms is needed, Karl D. Lewis, MD, associate professor of medicine at the University of Colorado Denver’s cutaneous oncology program, said during a presentation.

Basal cell carcinoma (BCC) is the most common skin cancer in the United States. Although exact incidence is imprecise due to lack of a registry, more than 1 million cases occur each year.

The cell of origin likely is a pluripotent stem cell or progenitor cell in the interfollicular epidermis and hair follicles. Patients can develop hundreds of BCCs in their lifetimes. They usually start at a young age, typically by age 35 but as early as teenage years, Lewis said.

BCCs develop secondary to activation of target genes in the hedgehog pathway, a series of proteins that is highly active during embryogenesis but widely considered to be dormant after birth.

“These tumors generally have a low metastatic potential, but they can be very difficult sometimes because they can be locally advanced with destruction of the skin and surrounding structures,” Lewis said.

Traditional treatments for low-risk lesions include cryosurgery, electrodessication and topical therapy, whereas high-risk lesions often are treated with surgical excision, Mohs’ micrographic surgery and radiation therapy.

“Since the hedgehog pathway seems to be ubiquitously expressed in this disease, the question arose whether there was a potential for targeted therapy, and certainly that has come to fruition,” Lewis said. 

ERIVANCE BCC

ERIVANCE BCC — a multicenter, international phase 2 study — evaluated the hedgehog pathway inhibitor vismodegib (Erivedge, Genentech) in 99 patients with BCC. The cohort included 33 patients with metastatic disease, and 63 patients with locally advanced BCC who had inoperable disease or for whom surgery was inappropriate due to multiple recurrences, the potential for disfigurement or low likelihood of surgical cure.

All patients received 150 mg vismodegib daily. Treatment continued until progression, inoperable toxicity or study withdrawal.

The results, published in 2012 in The New England Journal of Medicine, showed the trial met its primary endpoint of objective response rate by independent review. Researchers reported response rates of 42.9% (95% CI, 31-56) in patients with locally advanced disease and 30.3% (95% CI, 16-48) in patients with metastatic disease.

The primary analysis — performed after data cutoff on Nov. 26, 2010 — showed a median duration of response of 7.6 months in both groups. A 30-month analysis — performed after data cutoff on May 30, 2013 — showed the median duration of response among patients with locally advanced disease increased to 26.2 months.

“This indicates there is a group of patients who can benefit from treatment with this drug for a very long time,” Lewis said. “The vast majority of patients who received this targeted agent experienced a decrease in tumor burden. A few patients had primary resistance, but it’s not quite clear what led to that resistance.”

The most common adverse events included muscle spasms (68%), alopecia (64%), dysgeusia (51%), weight loss (46%) and fatigue (36%).

“Even though most of these were grade 1 or grade 2, they can wear on patients,” Lewis said. “If you treat them for a long time, they begin to have a significant effect on quality of life.”

BOLT study

The phase 2 BOLT study evaluated two doses of sonidegib (LDE225), a hedgehog signaling pathway inhibitor, in 194 patients with locally advanced or metastatic BCC.

Researchers assigned 128 patients to 800 mg daily, and the other 66 patients received 200 mg daily. Treatment continued until disease progression, unacceptable toxicity, death or study discontinuation. Objective response rate of 30% or greater served as the primary endpoint.

The results, presented at the European Society for Medical Oncology Congress last year, showed overall response rates at 12 months of 58% (95% CI, 45-70) in the 200-mg cohort and 44% (95% CI, 35-53) in the 800-mg cohort. The 200-dose of sonidegib was better tolerated, so that was chosen as the dose for future investigations.

Aside from observed increases of creatine kinase (CK) elevation — which occurred in 30% of patients — adverse events associated with sonidegib generally mirrored those observed with vismodegib. The majority of these events were grade 1 or grade 2.

The ERIVANCE study did not measure CK elevation. Consequently, the true instance of CK elevation with vismodegib is not known, nor is it clear whether CK elevation is a class effect of these agents or due more to sonidegib, Lewis said.

Survival and resistance

Although both vismodegib and sonidegib are clearly active in locally advanced and metastatic disease, whether they have an impact on survival is unknown, Lewis said.

“We really don’t have a lot of knowledge about the natural history of metastatic basal cell carcinoma,” Lewis said. “We don’t know what median survival is because it has been poorly studied … and it likely will never be known because there are unlikely to be prospective trials done.”

Additional questions remain, Lewis said.

“It will be important to determine the resistance mechanisms, both for primary and acquired resistance,” he said. “Some patients have primary resistance to these agents and it’s not clear why.

“I think it’s analogous to the BRAF inhibitor story in melanoma,” Lewis added. “A number of studies have demonstrated that smoothened variants explain the majority of drug resistance in basal cell carcinoma. … Overcoming this resistance will be very important. That is all work yet to be done, and hopefully those trials can get underway soon.” – by Mark Leiser

References:

Lewis KD. Current management of advanced basal cell carcinoma. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 10-11, 2015; New York.

Dummer R, et al. Abstract LBA33. Presented at: European Society for Medical Oncology Congress; Sept. 26-30, 2014; Madrid.

Sekulic A, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1113713.

Disclosure: Lewis reports consultant fees from Genentech and Roche, as well as contracted research with Novartis.

    Perspective
    Sanjiv S. Agarwala

    Sanjiv S. Agarwala

    Metastatic and advanced basal cell carcinoma is not a common diagnosis. The average oncologist never sees such a patient, and if you have a cutaneous oncology program, you may see one every few months, if that. But when it occurs, it’s a tough problem. These are not resectable patients and — in the past — when we gave chemotherapy to patients with metastatic disease, it was useless.
    We now have an established pathway, the hedgehog pathway, that can be targeted. We have good results with vismodegib, an oral agent that has good science behind it but has some significant toxicities. Sonidegib, which is not yet approved, has shown similar results. It is very gratifying to know there is drug development in a rare disease like this.
    It is important to note there were no randomized trials here. Everything in this setting is phase 2 because there are no other drugs that work. The FDA approved [vismodegib] based on a phase 2 trial, and I think that is exactly what needs to happen. We are going to need to move away from doing randomized studies for everybody for everything and instead look at the science. If the science is good and we have good results, we are going to have to be able to approve drugs based on that.

    • Sanjiv S. Agarwala, MD
    • Program director, HemOnc Today Melanoma and Cutaneous Malignancies HemOnc Today Editorial Board member St. Luke’s Cancer Center Temple University School of Medicine

    Disclosures: Agarwala reports no relevant financial disclosures.

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