Archive for September, 2011
Genentech Submits New Drug Application to FDA for Vismodegib for Rare Form of Advanced Skin Cancer
Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the company has submitted a New Drug Application for vismodegib to the U.S. Food and Drug Administration (FDA) for the treatment of people with advanced basal cell carcinoma (BCC) for whom surgery is considered inappropriate. Vismodegib is an investigational, oral, targeted medicine designed to selectively inhibit signaling in the Hedgehog pathway, which is implicated in more than 90 percent of BCC cases. BCC is the most common type of skin cancer, which is generally considered curable by surgery. However, when it advances, BCC can cause disfiguring and debilitating effects and can ultimately be life-threatening.
“We are excited by the pivotal study results that showed vismodegib substantially reduced tumor size or healed lesions for people with this rare skin cancer, which has no approved treatments,” said Hal Barron, M.D., chief medical officer and head, Global Product Development.“We look forward to continuing our discussions with the FDA about these data.”
This submission to the FDA is based on results from the pivotal ERIVANCE BCC study that evaluated vismodegib in people with advanced BCC. The trial showed vismodegib substantially shrank tumors or healed visible lesions (overall response rate, or ORR) in 43 percent of patients with locally advanced BCC (laBCC) and 30 percent of patients with metastatic BCC (mBCC), as assessed by independent review, the primary endpoint of the study.
The ORR as assessed by study investigators, a secondary endpoint, was 60 percent for laBCC and 46 percent for mBCC. The median duration of progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.
The most common drug-related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. Serious adverse events (SAEs) were observed in 26 patients (25 percent). Four patients (4 percent) had SAEs that were considered to be related to vismodegib, including one case each of: blocked bile flow from the liver (cholestasis), dehydration with loss of consciousness (syncope), pneumonia accompanied by an inability of the heart to pump enough blood (cardiac failure) and a sudden arterial blockage in the lung (pulmonary embolism). Fatal events were reported in seven patients (7 percent); none were considered by investigators to be related to vismodegib. In all cases, patients had other pre-existing diseases or symptoms that were related to their presumed cause of death.
In order to provide people with advanced BCC who are appropriate candidates access to vismodegib while Genentech discusses next steps with the FDA, the company is conducting an expanded patient access study in the United States. For more information, patients and doctors can contact the Genentech clinical trial call center at 888-662-6728 or visit http://www.clinicaltrials.gov.
About Basal Cell Carcinoma and the Hedgehog Pathway
According to the American Cancer Society, BCC accounts for approximately 80 percent of all diagnosed skin cancers. In the majority of cases, the disease is generally considered curable if the cancer is restricted to a small area of the skin. However, in a very small group of people, if the disease is left untreated or recurs after surgery, it becomes locally advanced, and the cancer may invade further into surrounding tissues such as sensory organs (ears, nose and eyes), bones or other tissues. In a small proportion of patients (estimated at less than one percent of those affected), BCC can metastasize, spreading to other parts of the body. Currently, there are limited treatment options for advanced BCC with no standard of care.
The Hedgehog signaling pathway plays an important role in regulating proper growth and development in the early stages of life and becomes less active in adults. In addition to BCC, mutations in the pathway that reactivate Hedgehog signaling are seen in several types of cancer.
About the Phase II Trial (ERIVANCE BCC/SHH4476g)
ERIVANCE BCC is an international, single-arm, multicenter, two-cohort, open-label Phase II study that enrolled 104 patients with advanced BCC, including laBCC (71) and mBCC (33). laBCC patients had lesions that were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for which radiotherapy was unsuccessful or contraindicated. mBCC was defined as BCC that had spread to other parts of the body, including the lymph nodes, lungs, bones and/or internal organs. Study participants received 150mg vismodegib orally, once daily until disease progression or intolerable toxicity.
About Vismodegib (RG3616/GDC-0449)
Vismodegib is an investigational medicine designed to selectively inhibit abnormal signaling in the Hedgehog pathway, which is the underlying molecular driver of BCC. Roche and Genentech are also evaluating vismodegib in a Phase II trial in people with operable forms of BCC.
Genentech is developing vismodegib under a collaboration agreement with Curis, Inc. Vismodegib was discovered by Genentech and jointly validated by Genentech and Curis through a series of preclinical studies. Through this collaboration, Genentech (United States), Roche (ex-United States excluding Japan) and Chugai Pharmaceuticals (Japan) are responsible for the clinical development and commercialization of vismodegib. Curis is eligible to receive cash payments upon the successful achievement of specified clinical development and regulatory approval milestones, as well as royalties upon commercialization of vismodegib.
Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com
This is an interesting review of some newer non-surgical techniques.
Let me know what you think.
There are innovations in nonsurgical modalities for the treatment of actinic keratoses (AKs) and nonmelanoma skin cancers (NMSCs) and a basis for broadening the use of preventive strategies, says Leonard H. Goldberg, M.D. “Surgical excision remains the gold standard for treating basal cell and squamous cell carcinomas, but we now have alternatives offering cure rates approaching those achieved with surgery,” says Dr. Goldberg, who is in private practice, DermSurgery Associates, Houston, and clinical professor of dermatology, The Methodist Hospital, Weill Medical College, Houston.
“Oral compounds in clinical development are producing exciting results, and we recognize that our nonsurgical modalities represent a valuable approach to providing field-directed prophylaxis,” he says.
Oral acitretin (Soriatane, Roche) has a long history of use as NMSC chemoprophylaxis in organ transplant recipients and other immunosuppressed patients. However, Dr. Goldberg also believes all immunocompetent patients who have had a NMSC or multiple AKs on the face or scalp should be offered the option of routine, field-directed prophylaxis using topical chemoprevention with 5-fluorouracil (Efudex, Valeant; Carac, Sanofi-Aventis) or diclofenac (Solaraze, PharmaDerm), topical immunotherapy (Aldara, Zyclara; Graceway) or photodynamic therapy (PDT).
In his practice, patients who have been treated for AKs are asked to return for follow-up after six months and are retreated as needed. Patients who develop recurrent lesions are scheduled for prophylactic treatment every six months while others are treated on an annual schedule. Chemoprevention agents may be rotated at successive treatment intervals, particularly in patients who develop new lesions, in order to take advantage of the different mechanisms of action.
For primary treatment of AKs, the efficacy and safety of cryotherapy are improved with the use of a newer liquid nitrogen dispenser (Cry-Ac Tracker, Brymill) featuring an integrated infrared sensor that enables temperature-controlled treatment, Dr. Goldberg says.
The sensor measures skin surface temperature and, using a three-color-coded light system, provides a visual indication to the operator when the desired skin temperature is reached. The system is able to guide freezing of the epidermis and upper dermis to -5 degrees Celsius, which is adequate for AK clearance. This will avoid destruction of deeper tissue and therefore the development of scarring and hypopigmentation, Dr. Goldberg says.
“Cryosurgery remains the treatment of choice for individual AKs because it achieves high rates of clearance. However, the response can be unpredictable due to variability in treatment delivery. As reported in several published studies, average clearance rates for AKs are only about 75 percent,” he says.
A recently published study by Dr. Goldberg and colleagues demonstrated the efficacy and safety of the new cryotherapy unit (Dermatol Surg. 2010;36(12):1956-1961). It included 36 patients with Fitzpatrick skin types I-III who had a total of 180 thin AKs treated using a circular, painting method with a wide freeze. All lesions were marked at baseline and photographed. At follow-up at six weeks, 100 percent clearance was achieved, and patients were satisfied with the results.
At one week post-treatment, erythema (42 percent) and crusting (21 percent) were the most common complications seen; oozing and ulceration each occurred at rates of 3 percent. All skin-related adverse events had resolved completely by six weeks and there were no cases of AK recurrence, scarring or hypopigmentation, Dr. Goldberg says.
The oral Hedgehog signaling pathway inhibitor GDC-0449 (Vismodegib, (Genentech/Curis) is currently being evaluated in phase 2 clinical trials for the treatment of basal cell nevus syndrome (BCNS) and sporadic basal cell carcinomas (BCCs). Based on his experience as an investigator in a clinical study of GDC-0449, Dr. Goldberg says he considers it to be an absolute miracle drug for BCNS, and he believes it also has the potential to change the treatment paradigm for BCC in the future.
Dr. Goldberg has published on the efficacy of GDC-0449 for treating BCNS-associated BCCs and odontogenic keratocysts of the jaw (Arch Dermatol. 2010;146(1):17-19; Arch Dermatol. 2011;Mar 21 Epub ahead of print).
“GDC-0449 has shown itself to be well-tolerated and a life-altering drug for BCNS patients, and I believe it is the long-sought after silver bullet for this condition because it frees patients from frequent, mutilating surgery,” he says.
Capecitabine (Xeloda, Hoffman-LaRoche), an oral nucleoside metabolic inhibitor with antineoplastic activity approved for use in treatment of colon, colorectal and breast cancer, is also being investigated for the treatment of advanced squamous cell carcinoma.
Capecitabine is a prodrug that is enzymatically converted to 5-fluorouracil selectively within tumor cells and has shown promise alone and when combined with subcutaneous interferon alpha in patients with advanced cutaneous squamous cell carcinoma (Wollina U, Hansel G, Koch A, et al. J Cancer Res Clin Oncol. 2005;131(5):300-304). It is useful for reducing new lesion development in organ transplant recipients with a history of recurrent NMSCs (J Clin Oncol. 29;27:1519).
As a downside, its side effect profile in these early studies included relatively high rates of grade 3/4 fatigue, hand-foot-syndrome and diarrhea.
Although nonablative fractional laser resurfacing with a 1,550 nm proprietary device (Fraxel re:store, Solta Medical) has been approved for treatment of AKs, it was found to be ineffective in a histologically controlled study conducted by Dr. Goldberg and colleagues (J Am Acad Dermatol. in press). The study included 14 patients who underwent five laser treatments at two- to four-week intervals using a fluence of 20 mJ to 7 mJ, treatment level of 11, 32 to 40 percent surface area coverage, and eight to 10 passes. Lesions were counted and photographed at baseline, before each treatment and at one, three and six months after the last treatment, and biopsies were obtained at baseline and at the three-month follow-up.
The clinical efficacy assessment showed the lesion clearance rate decreased as follow-up lengthened. At one month, there was an almost 75 percent reduction from baseline lesion count, but by six months only half of the AKs remained cleared, and the post-treatment biopsies documented lesion persistence.
“The fractional laser treatment coagulates epidermal and dermal tissue up to a depth of 140 microns. However, it only ablates small microzones, and clearance of AKs requires total ablation of the involved skin. Clearance of this device for treatment of AKs was based on demonstration of its clinical efficacy and safety, but there was no requirement of proof based on pathological evaluation,” Dr. Goldberg says.