Melanoma

SAN ANTONIO – Patients with thin melanomas and positive deep margins on initial biopsy had the same incidence of sentinel lymph node metastasis as those with thicker melanomas, according to the results of a retrospective analysis of 260 patients with melanoma.

At least one positive sentinel lymph node was detected in 6 of 73 patients (8%) with a melanoma Breslow thickness of less than 0.8 mm and positive deep margins vs. 17 of 187 patients (9%) with a melanoma Breslow thickness of 0.8-2.0 mm, regardless of margin status (P = .82).

Immunohistochemistry was the most common method of identifying positive sentinel nodes in both the thin and thick melanoma groups (5 cases vs. 10 cases, respectively), Dr. Victor Koshenkov said at a symposium sponsored by the Society of Surgical Oncology.

The decision to perform sentinel node biopsy is largely driven by tumor thickness. When the initial biopsy of a thin melanoma shows positive deep margins, many clinicians will treat these cases as potentially thicker melanomas and perform sentinel lymph node (SLN) biopsy. There are few data on the impact of positive deep margins on surgical decision making, prognosis, and outcome, even though positive deep margins are the most common cause of incompletely measured or indeterminate tumor thickness, said Dr. Koshenkov of the department of surgery at Atlantic Health Memorial Hospital in Morristown, N.J.

He presented data from a retrospective analysis of 260 adult patients who underwent wide excision plus SLN biopsy for cutaneous melanoma from January 2004 to May 2010.

Demographics were not statistically different between the two groups, except for tumor site and Clark’s level, he said. In 53% of patients in the thicker melanoma group, the extremities were the primary tumor site vs. 38% in the thin melanoma group (P = .042), while 40% had Clark’s level IV-V vs. 22% in the thin melanoma group (P less than .001).

Multivariate regression analysis revealed that only female gender (P = .046; odds ratio, 2.68) and Clark’s level IV-V (P = .024; OR, 3.54) were significantly associated with an increased risk of positive SLNs. Belonging to the thin melanoma group versus the thicker melanoma group was not significant (P = .66; OR, 1.29) Dr. Koshenkov said.

The presence of residual disease approached, but did not reach, statistical significance (P = .062; OR, 2.60). Residual disease was found in about 20% of both groups. Only 4 of the 73 patients (5.5%) with positive SLNs in the thin melanoma group required further reexcision with wide margins.

Only 1 of the 23 sentinel node–positive patients went on to have additional positive nodes on completion of lymph node dissection, he said.

"Patients with thin melanomas and positive deep margins on initial biopsy have an incidence of SLN metastasis statistically no different than patients with thicker melanomas," Dr. Koshenkov concluded. "Thus, we believe that thin melanomas with positive deep margins should be treated with wide excision and a sentinel lymph node biopsy. Of course, these findings should be tested and verified in larger, multi-institutional databases."

During a discussion of the study, the audience questioned the ability to make almost a practice-changing conclusion based on the small number of patients and the low incidence of positive SLNs in the thicker melanoma group. Dr. Koshenkov replied that the reason the rate of sentinel node positivity was lower than predicted in this group was that a larger proportion of patients had melanomas 0.8-1 mm in depth, rather than 1-2 mm in depth.

Another attendee remarked that before concluding that every patient with a positive deep margin on initial biopsy needs to undergo SLN biopsy, it is important to know how many patients with positive sentinel nodes had a positive deep margin as their only indication or whether factors such as mitotic rate or ulceration played a role. Dr. Koshenkov said mitotic rate was not analyzed because it was not regularly included in the pathology report at the time of the review, and that ulceration and Clark's level IV were factored into the multivariate analysis.

The authors said they had no relevant financial disclosures.

SAN ANTONIO – Patients with thin melanomas and positive deep margins on initial biopsy had the same incidence of sentinel lymph node metastasis as those with thicker melanomas, according to the results of a retrospective analysis of 260 patients with melanoma.

At least one positive sentinel lymph node was detected in 6 of 73 patients (8%) with a melanoma Breslow thickness of less than 0.8 mm and positive deep margins vs. 17 of 187 patients (9%) with a melanoma Breslow thickness of 0.8-2.0 mm, regardless of margin status (P = .82).

Immunohistochemistry was the most common method of identifying positive sentinel nodes in both the thin and thick melanoma groups (5 cases vs. 10 cases, respectively), Dr. Victor Koshenkov said at a symposium sponsored by the Society of Surgical Oncology.

The decision to perform sentinel node biopsy is largely driven by tumor thickness. When the initial biopsy of a thin melanoma shows positive deep margins, many clinicians will treat these cases as potentially thicker melanomas and perform sentinel lymph node (SLN) biopsy. There are few data on the impact of positive deep margins on surgical decision making, prognosis, and outcome, even though positive deep margins are the most common cause of incompletely measured or indeterminate tumor thickness, said Dr. Koshenkov of the department of surgery at Atlantic Health Memorial Hospital in Morristown, N.J.

He presented data from a retrospective analysis of 260 adult patients who underwent wide excision plus SLN biopsy for cutaneous melanoma from January 2004 to May 2010.

Demographics were not statistically different between the two groups, except for tumor site and Clark’s level, he said. In 53% of patients in the thicker melanoma group, the extremities were the primary tumor site vs. 38% in the thin melanoma group (P = .042), while 40% had Clark’s level IV-V vs. 22% in the thin melanoma group (P less than .001).

Multivariate regression analysis revealed that only female gender (P = .046; odds ratio, 2.68) and Clark’s level IV-V (P = .024; OR, 3.54) were significantly associated with an increased risk of positive SLNs. Belonging to the thin melanoma group versus the thicker melanoma group was not significant (P = .66; OR, 1.29) Dr. Koshenkov said.

The presence of residual disease approached, but did not reach, statistical significance (P = .062; OR, 2.60). Residual disease was found in about 20% of both groups. Only 4 of the 73 patients (5.5%) with positive SLNs in the thin melanoma group required further reexcision with wide margins.

Only 1 of the 23 sentinel node–positive patients went on to have additional positive nodes on completion of lymph node dissection, he said.

"Patients with thin melanomas and positive deep margins on initial biopsy have an incidence of SLN metastasis statistically no different than patients with thicker melanomas," Dr. Koshenkov concluded. "Thus, we believe that thin melanomas with positive deep margins should be treated with wide excision and a sentinel lymph node biopsy. Of course, these findings should be tested and verified in larger, multi-institutional databases."

During a discussion of the study, the audience questioned the ability to make almost a practice-changing conclusion based on the small number of patients and the low incidence of positive SLNs in the thicker melanoma group. Dr. Koshenkov replied that the reason the rate of sentinel node positivity was lower than predicted in this group was that a larger proportion of patients had melanomas 0.8-1 mm in depth, rather than 1-2 mm in depth.

Another attendee remarked that before concluding that every patient with a positive deep margin on initial biopsy needs to undergo SLN biopsy, it is important to know how many patients with positive sentinel nodes had a positive deep margin as their only indication or whether factors such as mitotic rate or ulceration played a role. Dr. Koshenkov said mitotic rate was not analyzed because it was not regularly included in the pathology report at the time of the review, and that ulceration and Clark's level IV were factored into the multivariate analysis.

The authors said they had no relevant financial disclosures.

SAN ANTONIO – Patients with thin melanomas and positive deep margins on initial biopsy had the same incidence of sentinel lymph node metastasis as those with thicker melanomas, according to the results of a retrospective analysis of 260 patients with melanoma.

At least one positive sentinel lymph node was detected in 6 of 73 patients (8%) with a melanoma Breslow thickness of less than 0.8 mm and positive deep margins vs. 17 of 187 patients (9%) with a melanoma Breslow thickness of 0.8-2.0 mm, regardless of margin status (P = .82).

Immunohistochemistry was the most common method of identifying positive sentinel nodes in both the thin and thick melanoma groups (5 cases vs. 10 cases, respectively), Dr. Victor Koshenkov said at a symposium sponsored by the Society of Surgical Oncology.

The decision to perform sentinel node biopsy is largely driven by tumor thickness. When the initial biopsy of a thin melanoma shows positive deep margins, many clinicians will treat these cases as potentially thicker melanomas and perform sentinel lymph node (SLN) biopsy. There are few data on the impact of positive deep margins on surgical decision making, prognosis, and outcome, even though positive deep margins are the most common cause of incompletely measured or indeterminate tumor thickness, said Dr. Koshenkov of the department of surgery at Atlantic Health Memorial Hospital in Morristown, N.J.

He presented data from a retrospective analysis of 260 adult patients who underwent wide excision plus SLN biopsy for cutaneous melanoma from January 2004 to May 2010.

Demographics were not statistically different between the two groups, except for tumor site and Clark’s level, he said. In 53% of patients in the thicker melanoma group, the extremities were the primary tumor site vs. 38% in the thin melanoma group (P = .042), while 40% had Clark’s level IV-V vs. 22% in the thin melanoma group (P less than .001).

Multivariate regression analysis revealed that only female gender (P = .046; odds ratio, 2.68) and Clark’s level IV-V (P = .024; OR, 3.54) were significantly associated with an increased risk of positive SLNs. Belonging to the thin melanoma group versus the thicker melanoma group was not significant (P = .66; OR, 1.29) Dr. Koshenkov said.

The presence of residual disease approached, but did not reach, statistical significance (P = .062; OR, 2.60). Residual disease was found in about 20% of both groups. Only 4 of the 73 patients (5.5%) with positive SLNs in the thin melanoma group required further reexcision with wide margins.

Only 1 of the 23 sentinel node–positive patients went on to have additional positive nodes on completion of lymph node dissection, he said.

"Patients with thin melanomas and positive deep margins on initial biopsy have an incidence of SLN metastasis statistically no different than patients with thicker melanomas," Dr. Koshenkov concluded. "Thus, we believe that thin melanomas with positive deep margins should be treated with wide excision and a sentinel lymph node biopsy. Of course, these findings should be tested and verified in larger, multi-institutional databases."

During a discussion of the study, the audience questioned the ability to make almost a practice-changing conclusion based on the small number of patients and the low incidence of positive SLNs in the thicker melanoma group. Dr. Koshenkov replied that the reason the rate of sentinel node positivity was lower than predicted in this group was that a larger proportion of patients had melanomas 0.8-1 mm in depth, rather than 1-2 mm in depth.

Another attendee remarked that before concluding that every patient with a positive deep margin on initial biopsy needs to undergo SLN biopsy, it is important to know how many patients with positive sentinel nodes had a positive deep margin as their only indication or whether factors such as mitotic rate or ulceration played a role. Dr. Koshenkov said mitotic rate was not analyzed because it was not regularly included in the pathology report at the time of the review, and that ulceration and Clark's level IV were factored into the multivariate analysis.

The authors said they had no relevant financial disclosures.

WAILEA, HAWAII – Physicians will likely gain a novel short-course field therapy for multiple actinic keratoses next year.

Ingenol mebutate (Leo Pharmaceuticals) hit all of its end points in two phase III clinical trials. One trial was conducted in patients treated for fields of multiple actinic keratoses (AKs) on the head and neck, the other in patients with clusters of AKs anywhere else, Dr. Theodore Rosen said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Median reductions in AKs in these pivotal trials were comparable to results reported with other field therapies, such as imiquimod and 5-fluorouracil. What is remarkable about ingenol mebutate, however, is these outcomes were achieved with only 2 days of once-daily therapy for non–head and neck AKs and 3 days of therapy at a lower concentration for AKs on the head and neck, noted Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

In contrast, the original regimen for the 5% imiquimod dermatologists have been using since its 2004 marketing approval for AKs entails a full 16 weeks of twice-weekly therapy. That being said, last year, the FDA approved a new, shorter-duration formulation of imiquimod which Dr. Rosen said was a better product than the traditional 5% version.

Ingenol mebutate is a diterpene ester derived from the sap of a plant, Euphorbia peplus, traditionally used by Australian aborigines for topical treatment of various skin ailments. Ingenol mebutate's mechanism of action is not fully understood, but involves initial cell necrosis because of mitochondrial disruption followed by granulocyte-dependent cytotoxicity. Immune upregulation also appears to be involved, Dr. Rosen explained.

Non–Head and Neck AK Study

The phase III non–head and neck AK study involved 256 patients randomized to 2 consecutive days of once-daily ingenol mebutate 0.05% gel or placebo applied to up to a 25-cm² area of skin with four to eight visible AKs. The ingenol mebutate group showed a complete clearance rate at day 57 of 27.8%, compared with 4.7% for placebo, and a median 67% reduction in AKs.

The 27.8% complete clearance rate is nothing to write home about, but the 67% reduction in AKs is quite impressive, particularly for a 2-day therapy, according to Dr. Rosen, who was an investigator in these and other AK clinical trials.

"That 67% median reduction is very nice, and it’s really the most accurate measurement because it tells you how many of these things are going to go away by treating the field," Dr. Rosen said.

The complete clearance rate was highest on the chest, followed by the arms, legs, back of hand, and back.

Side effect rates were low at 1%-2%, and consisted of burning, irritation, pain, and other symptoms that are associated with most field therapies for AKs. Interestingly, the peak incidence of the skin side effects was not until day 8.

"You'll have to prepare patients for the fact that almost a week after they’re done with therapy, they may suddenly look worse," he noted.

The product labeling will limit treatment to areas of 25 cm² or less because that is how the pivotal trials were done. "If you want to treat more than 25 cm², you’ll probably be off-label, but we do that all the time," he said.

In an exploratory trial in which investigators treated AK fields of 25, 50, 75, and 100 cm² on the dorsal arms using 0.05% ingenol mebutate applied once daily for 2 days, cumulative local skin reaction scores correlated with the size of the area treated. Even in patients who underwent treatment of 100 cm² of involved skin, side-effect scores returned to baseline by 2 months. Most patients tolerated even the most severe reactions, he noted.

Head and Neck AK Study

The phase III head and neck AK trial involved treatment of areas up to 25 cm² in 264 patients. This trial featured several drug concentrations and durations; the one that produced the best outcomes and will move forward to the marketplace is 0.015% once daily for 3 days. It yielded a complete clearance rate of 50% on day 57, and an 85% median reduction in AKs, according to Dr. Rosen.

With two different concentrations of ingenol mebutate likely to be approved for application at different sites, physicians will need to remain vigilant regarding possible dispensing errors or patient misuse, he said.

Imiquimod

While ingenol mebutate's duration of efficacy remains unknown, that is not the case with imiquimod.

The new imiquimod 3.75% cream (Zyclara), approved last year for treatment of AKs, provides clear benefits over the older 5% formulation in terms of convenience, and with comparable efficacy.

Instead of the traditional 16 weeks of therapy, the 3.75% cream is used daily for 2 weeks, followed by a 2-week rest, then another 2 weeks of therapy, for a total 6-week treatment course. And the imiquimod 3.75% cream is approved for treatment of the full face or balding scalp, unlike imiquimod 5%, whose approved indication is limited to a much smaller area of 25 cm², Dr. Rosen said.

In the pivotal trial for imiquimod 3.75%, 160 treated patients showed a complete clearance rate of 35.6% and a median 81.8% reduction in AKs 8 weeks after the final treatment. That is near-identical to the 83.3% reduction noted in an earlier trial of 215 patients treated with imiquimod 5%.

Dr. Rosen said field therapy makes sound sense in patients with multiple AKs in the same area of the skin.

"When you have a patient with [a lot of] AKs, then all the skin in between those AKs is no more normal than the AK skin; it just hasn’t manifest yet. That’s where field therapy comes in," he explained.

As much as he likes field therapy, though, Dr. Rosen stressed that the emerging new paradigm for treatment of patients with multiple AKs is combination therapy. This can take the form of either a field therapy followed by individual lesion-directed therapy such as cryotherapy, or lesion-directed therapy followed by a field therapy. There are numerous possible combinations. Insurance reimbursement can be a problem for now, but payers will eventually have to come around to the new paradigm.

"The bottom line is for every study where field therapy is combined with lesion-directed therapy or with another field therapy, the combination proved superior to monotherapy," Dr. Rosen said. "It's a little more work, but in the end I think it's probably the best thing for your patient."

Other Agents in the AK Pipeline

AK remains an active target for new drug development. Among the wide range of drugs in the developmental pipeline, albeit still years away from the marketplace, are:

Resiquimod and sotirimod. These are the most promising of the more than 1,000 known analogues of imiquimod. Like the parent compound, they work via immune upregulation, said Dr. Rosen.

Betulin. A triterpene isolated from the extract of birch bark. It eliminates actinic keratoses through cytotoxicity.

Perillyl alcohol. A monoterpene isolated from essential oils of peppermint, spearmint, lavender, and other plants. Its mechanism of action involves induction of apoptosis in rapidly dividing cells without affecting normal cells.

Difluoromethylornithine. Irreversibly inhibits ornithine decarboxylase, which regulates cell division. DFMO is already marketed in a topical formulation for the treatment of facial hirsutism, and as an injectable drug for treatment of African trypanosomiasis.

Afamelanotide. This synthetic analogue of melanocyte-stimulating hormone is under development as a treatment for a diverse collection of skin diseases, including polymorphous light eruption, solar urticaria, and squamous cell carcinoma, as well as AKs.

T4 endonuclease V. This drug enhances repair of UV-induced DNA damage. "It might help prevent future AKs, but not existing ones," Dr. Rosen said.

Why does AK therapy remain such a busy area of new drug development? Simple: A substantial portion of the public continues to be casual about sun protection or disregards it altogether, and with the graying of the baby boomer generation, AKs are more common than ever, he said.

"Everybody in Texas has AKs, including me. I just found one on my hand, and now I need to go treat it," he said.

Dr. Rosen is on the speaker's bureau for Graceway and is a consultant to Graceway and Leo Pharmaceuticals. SDEF and this news organization are owned by Elsevier.

WAILEA, HAWAII – Physicians will likely gain a novel short-course field therapy for multiple actinic keratoses next year.

Ingenol mebutate (Leo Pharmaceuticals) hit all of its end points in two phase III clinical trials. One trial was conducted in patients treated for fields of multiple actinic keratoses (AKs) on the head and neck, the other in patients with clusters of AKs anywhere else, Dr. Theodore Rosen said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Median reductions in AKs in these pivotal trials were comparable to results reported with other field therapies, such as imiquimod and 5-fluorouracil. What is remarkable about ingenol mebutate, however, is these outcomes were achieved with only 2 days of once-daily therapy for non–head and neck AKs and 3 days of therapy at a lower concentration for AKs on the head and neck, noted Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

In contrast, the original regimen for the 5% imiquimod dermatologists have been using since its 2004 marketing approval for AKs entails a full 16 weeks of twice-weekly therapy. That being said, last year, the FDA approved a new, shorter-duration formulation of imiquimod which Dr. Rosen said was a better product than the traditional 5% version.

Ingenol mebutate is a diterpene ester derived from the sap of a plant, Euphorbia peplus, traditionally used by Australian aborigines for topical treatment of various skin ailments. Ingenol mebutate's mechanism of action is not fully understood, but involves initial cell necrosis because of mitochondrial disruption followed by granulocyte-dependent cytotoxicity. Immune upregulation also appears to be involved, Dr. Rosen explained.

Non–Head and Neck AK Study

The phase III non–head and neck AK study involved 256 patients randomized to 2 consecutive days of once-daily ingenol mebutate 0.05% gel or placebo applied to up to a 25-cm² area of skin with four to eight visible AKs. The ingenol mebutate group showed a complete clearance rate at day 57 of 27.8%, compared with 4.7% for placebo, and a median 67% reduction in AKs.

The 27.8% complete clearance rate is nothing to write home about, but the 67% reduction in AKs is quite impressive, particularly for a 2-day therapy, according to Dr. Rosen, who was an investigator in these and other AK clinical trials.

"That 67% median reduction is very nice, and it’s really the most accurate measurement because it tells you how many of these things are going to go away by treating the field," Dr. Rosen said.

The complete clearance rate was highest on the chest, followed by the arms, legs, back of hand, and back.

Side effect rates were low at 1%-2%, and consisted of burning, irritation, pain, and other symptoms that are associated with most field therapies for AKs. Interestingly, the peak incidence of the skin side effects was not until day 8.

"You'll have to prepare patients for the fact that almost a week after they’re done with therapy, they may suddenly look worse," he noted.

The product labeling will limit treatment to areas of 25 cm² or less because that is how the pivotal trials were done. "If you want to treat more than 25 cm², you’ll probably be off-label, but we do that all the time," he said.

In an exploratory trial in which investigators treated AK fields of 25, 50, 75, and 100 cm² on the dorsal arms using 0.05% ingenol mebutate applied once daily for 2 days, cumulative local skin reaction scores correlated with the size of the area treated. Even in patients who underwent treatment of 100 cm² of involved skin, side-effect scores returned to baseline by 2 months. Most patients tolerated even the most severe reactions, he noted.

Head and Neck AK Study

The phase III head and neck AK trial involved treatment of areas up to 25 cm² in 264 patients. This trial featured several drug concentrations and durations; the one that produced the best outcomes and will move forward to the marketplace is 0.015% once daily for 3 days. It yielded a complete clearance rate of 50% on day 57, and an 85% median reduction in AKs, according to Dr. Rosen.

With two different concentrations of ingenol mebutate likely to be approved for application at different sites, physicians will need to remain vigilant regarding possible dispensing errors or patient misuse, he said.

Imiquimod

While ingenol mebutate's duration of efficacy remains unknown, that is not the case with imiquimod.

The new imiquimod 3.75% cream (Zyclara), approved last year for treatment of AKs, provides clear benefits over the older 5% formulation in terms of convenience, and with comparable efficacy.

Instead of the traditional 16 weeks of therapy, the 3.75% cream is used daily for 2 weeks, followed by a 2-week rest, then another 2 weeks of therapy, for a total 6-week treatment course. And the imiquimod 3.75% cream is approved for treatment of the full face or balding scalp, unlike imiquimod 5%, whose approved indication is limited to a much smaller area of 25 cm², Dr. Rosen said.

In the pivotal trial for imiquimod 3.75%, 160 treated patients showed a complete clearance rate of 35.6% and a median 81.8% reduction in AKs 8 weeks after the final treatment. That is near-identical to the 83.3% reduction noted in an earlier trial of 215 patients treated with imiquimod 5%.

Dr. Rosen said field therapy makes sound sense in patients with multiple AKs in the same area of the skin.

"When you have a patient with [a lot of] AKs, then all the skin in between those AKs is no more normal than the AK skin; it just hasn’t manifest yet. That’s where field therapy comes in," he explained.

As much as he likes field therapy, though, Dr. Rosen stressed that the emerging new paradigm for treatment of patients with multiple AKs is combination therapy. This can take the form of either a field therapy followed by individual lesion-directed therapy such as cryotherapy, or lesion-directed therapy followed by a field therapy. There are numerous possible combinations. Insurance reimbursement can be a problem for now, but payers will eventually have to come around to the new paradigm.

"The bottom line is for every study where field therapy is combined with lesion-directed therapy or with another field therapy, the combination proved superior to monotherapy," Dr. Rosen said. "It's a little more work, but in the end I think it's probably the best thing for your patient."

Other Agents in the AK Pipeline

AK remains an active target for new drug development. Among the wide range of drugs in the developmental pipeline, albeit still years away from the marketplace, are:

Resiquimod and sotirimod. These are the most promising of the more than 1,000 known analogues of imiquimod. Like the parent compound, they work via immune upregulation, said Dr. Rosen.

Betulin. A triterpene isolated from the extract of birch bark. It eliminates actinic keratoses through cytotoxicity.

Perillyl alcohol. A monoterpene isolated from essential oils of peppermint, spearmint, lavender, and other plants. Its mechanism of action involves induction of apoptosis in rapidly dividing cells without affecting normal cells.

Difluoromethylornithine. Irreversibly inhibits ornithine decarboxylase, which regulates cell division. DFMO is already marketed in a topical formulation for the treatment of facial hirsutism, and as an injectable drug for treatment of African trypanosomiasis.

Afamelanotide. This synthetic analogue of melanocyte-stimulating hormone is under development as a treatment for a diverse collection of skin diseases, including polymorphous light eruption, solar urticaria, and squamous cell carcinoma, as well as AKs.

T4 endonuclease V. This drug enhances repair of UV-induced DNA damage. "It might help prevent future AKs, but not existing ones," Dr. Rosen said.

Why does AK therapy remain such a busy area of new drug development? Simple: A substantial portion of the public continues to be casual about sun protection or disregards it altogether, and with the graying of the baby boomer generation, AKs are more common than ever, he said.

"Everybody in Texas has AKs, including me. I just found one on my hand, and now I need to go treat it," he said.

Dr. Rosen is on the speaker's bureau for Graceway and is a consultant to Graceway and Leo Pharmaceuticals. SDEF and this news organization are owned by Elsevier.

WAILEA, HAWAII – Physicians will likely gain a novel short-course field therapy for multiple actinic keratoses next year.

Ingenol mebutate (Leo Pharmaceuticals) hit all of its end points in two phase III clinical trials. One trial was conducted in patients treated for fields of multiple actinic keratoses (AKs) on the head and neck, the other in patients with clusters of AKs anywhere else, Dr. Theodore Rosen said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Median reductions in AKs in these pivotal trials were comparable to results reported with other field therapies, such as imiquimod and 5-fluorouracil. What is remarkable about ingenol mebutate, however, is these outcomes were achieved with only 2 days of once-daily therapy for non–head and neck AKs and 3 days of therapy at a lower concentration for AKs on the head and neck, noted Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

In contrast, the original regimen for the 5% imiquimod dermatologists have been using since its 2004 marketing approval for AKs entails a full 16 weeks of twice-weekly therapy. That being said, last year, the FDA approved a new, shorter-duration formulation of imiquimod which Dr. Rosen said was a better product than the traditional 5% version.

Ingenol mebutate is a diterpene ester derived from the sap of a plant, Euphorbia peplus, traditionally used by Australian aborigines for topical treatment of various skin ailments. Ingenol mebutate's mechanism of action is not fully understood, but involves initial cell necrosis because of mitochondrial disruption followed by granulocyte-dependent cytotoxicity. Immune upregulation also appears to be involved, Dr. Rosen explained.

Non–Head and Neck AK Study

The phase III non–head and neck AK study involved 256 patients randomized to 2 consecutive days of once-daily ingenol mebutate 0.05% gel or placebo applied to up to a 25-cm² area of skin with four to eight visible AKs. The ingenol mebutate group showed a complete clearance rate at day 57 of 27.8%, compared with 4.7% for placebo, and a median 67% reduction in AKs.

The 27.8% complete clearance rate is nothing to write home about, but the 67% reduction in AKs is quite impressive, particularly for a 2-day therapy, according to Dr. Rosen, who was an investigator in these and other AK clinical trials.

"That 67% median reduction is very nice, and it’s really the most accurate measurement because it tells you how many of these things are going to go away by treating the field," Dr. Rosen said.

The complete clearance rate was highest on the chest, followed by the arms, legs, back of hand, and back.

Side effect rates were low at 1%-2%, and consisted of burning, irritation, pain, and other symptoms that are associated with most field therapies for AKs. Interestingly, the peak incidence of the skin side effects was not until day 8.

"You'll have to prepare patients for the fact that almost a week after they’re done with therapy, they may suddenly look worse," he noted.

The product labeling will limit treatment to areas of 25 cm² or less because that is how the pivotal trials were done. "If you want to treat more than 25 cm², you’ll probably be off-label, but we do that all the time," he said.

In an exploratory trial in which investigators treated AK fields of 25, 50, 75, and 100 cm² on the dorsal arms using 0.05% ingenol mebutate applied once daily for 2 days, cumulative local skin reaction scores correlated with the size of the area treated. Even in patients who underwent treatment of 100 cm² of involved skin, side-effect scores returned to baseline by 2 months. Most patients tolerated even the most severe reactions, he noted.

Head and Neck AK Study

The phase III head and neck AK trial involved treatment of areas up to 25 cm² in 264 patients. This trial featured several drug concentrations and durations; the one that produced the best outcomes and will move forward to the marketplace is 0.015% once daily for 3 days. It yielded a complete clearance rate of 50% on day 57, and an 85% median reduction in AKs, according to Dr. Rosen.

With two different concentrations of ingenol mebutate likely to be approved for application at different sites, physicians will need to remain vigilant regarding possible dispensing errors or patient misuse, he said.

Imiquimod

While ingenol mebutate's duration of efficacy remains unknown, that is not the case with imiquimod.

The new imiquimod 3.75% cream (Zyclara), approved last year for treatment of AKs, provides clear benefits over the older 5% formulation in terms of convenience, and with comparable efficacy.

Instead of the traditional 16 weeks of therapy, the 3.75% cream is used daily for 2 weeks, followed by a 2-week rest, then another 2 weeks of therapy, for a total 6-week treatment course. And the imiquimod 3.75% cream is approved for treatment of the full face or balding scalp, unlike imiquimod 5%, whose approved indication is limited to a much smaller area of 25 cm², Dr. Rosen said.

In the pivotal trial for imiquimod 3.75%, 160 treated patients showed a complete clearance rate of 35.6% and a median 81.8% reduction in AKs 8 weeks after the final treatment. That is near-identical to the 83.3% reduction noted in an earlier trial of 215 patients treated with imiquimod 5%.

Dr. Rosen said field therapy makes sound sense in patients with multiple AKs in the same area of the skin.

"When you have a patient with [a lot of] AKs, then all the skin in between those AKs is no more normal than the AK skin; it just hasn’t manifest yet. That’s where field therapy comes in," he explained.

As much as he likes field therapy, though, Dr. Rosen stressed that the emerging new paradigm for treatment of patients with multiple AKs is combination therapy. This can take the form of either a field therapy followed by individual lesion-directed therapy such as cryotherapy, or lesion-directed therapy followed by a field therapy. There are numerous possible combinations. Insurance reimbursement can be a problem for now, but payers will eventually have to come around to the new paradigm.

"The bottom line is for every study where field therapy is combined with lesion-directed therapy or with another field therapy, the combination proved superior to monotherapy," Dr. Rosen said. "It's a little more work, but in the end I think it's probably the best thing for your patient."

Other Agents in the AK Pipeline

AK remains an active target for new drug development. Among the wide range of drugs in the developmental pipeline, albeit still years away from the marketplace, are:

Resiquimod and sotirimod. These are the most promising of the more than 1,000 known analogues of imiquimod. Like the parent compound, they work via immune upregulation, said Dr. Rosen.

Betulin. A triterpene isolated from the extract of birch bark. It eliminates actinic keratoses through cytotoxicity.

Perillyl alcohol. A monoterpene isolated from essential oils of peppermint, spearmint, lavender, and other plants. Its mechanism of action involves induction of apoptosis in rapidly dividing cells without affecting normal cells.

Difluoromethylornithine. Irreversibly inhibits ornithine decarboxylase, which regulates cell division. DFMO is already marketed in a topical formulation for the treatment of facial hirsutism, and as an injectable drug for treatment of African trypanosomiasis.

Afamelanotide. This synthetic analogue of melanocyte-stimulating hormone is under development as a treatment for a diverse collection of skin diseases, including polymorphous light eruption, solar urticaria, and squamous cell carcinoma, as well as AKs.

T4 endonuclease V. This drug enhances repair of UV-induced DNA damage. "It might help prevent future AKs, but not existing ones," Dr. Rosen said.

Why does AK therapy remain such a busy area of new drug development? Simple: A substantial portion of the public continues to be casual about sun protection or disregards it altogether, and with the graying of the baby boomer generation, AKs are more common than ever, he said.

"Everybody in Texas has AKs, including me. I just found one on my hand, and now I need to go treat it," he said.

Dr. Rosen is on the speaker's bureau for Graceway and is a consultant to Graceway and Leo Pharmaceuticals. SDEF and this news organization are owned by Elsevier.

The Food and Drug Administration has approved peginterferon alfa-2b for adjuvant treatment of melanoma in patients with "microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy."

The drug, to be marketed as Sylatron by Schering Corp., a Merck & Co. subsidiary, is the second melanoma drug to receive FDA approval this year. The first, ipilimumab (Yervoy), was the first drug ever to improve survival of metastatic melanoma in a clinical trial.

Dr. Eric Rubin, Merck's vice president of clinical oncology, said in a statement that the company was "pleased to offer patients with node-positive melanoma this new option [Sylatron] to treat the disease." He pointed out that Sylatron "is the first such therapy approved for the adjuvant treatment of melanoma by the FDA in more than 15 years."

The FDA based its approval on a single study, EORTC (European Organisation for the Research and Treatment of Cancer) trial 18991, "Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation Alone in Resected Stage III Melanoma," the final results of which were published in 2008 in the Lancet (2008:372;117-26).

Peginterferon alfa-2b was shown to prolong relapse-free survival in this study, which enrolled 1,256 patients with resected stage III melanoma, but investigators saw no difference in overall survival. The median relapse-free survival was 34.8 months with peginterferon alfa-2b vs. 25.5 months with observation.

Peginterferon alfa-2b is given subcutaneously, and can be self-injected by melanoma patients. The recommended dose starts at 6 mcg/kg per week for eight doses, and then tapers to 3 mcg/kg per week for up to 5 years. Premedication with acetaminophen is advised when patients start treatment.

A safety analysis in 608 patients who were treated with peginterferon alfa-2b found the most serious adverse events to be fatigue, increased ALT, increased AST, and pyrexia.

Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, and also in those with autoimmune hepatitis or with hepatic decompensation, according to Merck. There is also a boxed warning on the increased risk of depression, suicidal ideation, suicide, and other neuropsychiatric disorders, which is consistent with all interferons.

Prescribing information can be found on the FDA Web site.

The Food and Drug Administration has approved peginterferon alfa-2b for adjuvant treatment of melanoma in patients with "microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy."

The drug, to be marketed as Sylatron by Schering Corp., a Merck & Co. subsidiary, is the second melanoma drug to receive FDA approval this year. The first, ipilimumab (Yervoy), was the first drug ever to improve survival of metastatic melanoma in a clinical trial.

Dr. Eric Rubin, Merck's vice president of clinical oncology, said in a statement that the company was "pleased to offer patients with node-positive melanoma this new option [Sylatron] to treat the disease." He pointed out that Sylatron "is the first such therapy approved for the adjuvant treatment of melanoma by the FDA in more than 15 years."

The FDA based its approval on a single study, EORTC (European Organisation for the Research and Treatment of Cancer) trial 18991, "Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation Alone in Resected Stage III Melanoma," the final results of which were published in 2008 in the Lancet (2008:372;117-26).

Peginterferon alfa-2b was shown to prolong relapse-free survival in this study, which enrolled 1,256 patients with resected stage III melanoma, but investigators saw no difference in overall survival. The median relapse-free survival was 34.8 months with peginterferon alfa-2b vs. 25.5 months with observation.

Peginterferon alfa-2b is given subcutaneously, and can be self-injected by melanoma patients. The recommended dose starts at 6 mcg/kg per week for eight doses, and then tapers to 3 mcg/kg per week for up to 5 years. Premedication with acetaminophen is advised when patients start treatment.

A safety analysis in 608 patients who were treated with peginterferon alfa-2b found the most serious adverse events to be fatigue, increased ALT, increased AST, and pyrexia.

Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, and also in those with autoimmune hepatitis or with hepatic decompensation, according to Merck. There is also a boxed warning on the increased risk of depression, suicidal ideation, suicide, and other neuropsychiatric disorders, which is consistent with all interferons.

Prescribing information can be found on the FDA Web site.

The Food and Drug Administration has approved peginterferon alfa-2b for adjuvant treatment of melanoma in patients with "microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy."

The drug, to be marketed as Sylatron by Schering Corp., a Merck & Co. subsidiary, is the second melanoma drug to receive FDA approval this year. The first, ipilimumab (Yervoy), was the first drug ever to improve survival of metastatic melanoma in a clinical trial.

Dr. Eric Rubin, Merck's vice president of clinical oncology, said in a statement that the company was "pleased to offer patients with node-positive melanoma this new option [Sylatron] to treat the disease." He pointed out that Sylatron "is the first such therapy approved for the adjuvant treatment of melanoma by the FDA in more than 15 years."

The FDA based its approval on a single study, EORTC (European Organisation for the Research and Treatment of Cancer) trial 18991, "Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation Alone in Resected Stage III Melanoma," the final results of which were published in 2008 in the Lancet (2008:372;117-26).

Peginterferon alfa-2b was shown to prolong relapse-free survival in this study, which enrolled 1,256 patients with resected stage III melanoma, but investigators saw no difference in overall survival. The median relapse-free survival was 34.8 months with peginterferon alfa-2b vs. 25.5 months with observation.

Peginterferon alfa-2b is given subcutaneously, and can be self-injected by melanoma patients. The recommended dose starts at 6 mcg/kg per week for eight doses, and then tapers to 3 mcg/kg per week for up to 5 years. Premedication with acetaminophen is advised when patients start treatment.

A safety analysis in 608 patients who were treated with peginterferon alfa-2b found the most serious adverse events to be fatigue, increased ALT, increased AST, and pyrexia.

Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, and also in those with autoimmune hepatitis or with hepatic decompensation, according to Merck. There is also a boxed warning on the increased risk of depression, suicidal ideation, suicide, and other neuropsychiatric disorders, which is consistent with all interferons.

Prescribing information can be found on the FDA Web site.

The Food and Drug Administration has approved peginterferon alfa-2b for adjuvant treatment of melanoma in patients with "microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy."

The drug, to be marketed as Sylatron by Schering Corp., a Merck & Co. subsidiary, is the second melanoma drug to receive FDA approval this year. The first, ipilimumab (Yervoy), was the first drug ever to improve survival of metastatic melanoma in a clinical trial.

Dr. Eric Rubin, Merck's vice president of clinical oncology, said in a statement that the company was "pleased to offer patients with node-positive melanoma this new option [Sylatron] to treat the disease." He pointed out that Sylatron "is the first such therapy approved for the adjuvant treatment of melanoma by the FDA in more than 15 years."

The FDA based its approval on a single study, EORTC (European Organisation for the Research and Treatment of Cancer) trial 18991, "Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation Alone in Resected Stage III Melanoma," the final results of which were published in 2008 in the Lancet (2008:372;117-26).

Peginterferon alfa-2b was shown to prolong relapse-free survival in this study, which enrolled 1,256 patients with resected stage III melanoma, but investigators saw no difference in overall survival. The median relapse-free survival was 34.8 months with peginterferon alfa-2b vs. 25.5 months with observation.

Peginterferon alfa-2b is given subcutaneously, and can be self-injected by melanoma patients. The recommended dose starts at 6 mcg/kg per week for eight doses, and then tapers to 3 mcg/kg per week for up to 5 years. Premedication with acetaminophen is advised when patients start treatment.

A safety analysis in 608 patients who were treated with peginterferon alfa-2b found the most serious adverse events to be fatigue, increased ALT, increased AST, and pyrexia.

Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, and also in those with autoimmune hepatitis or with hepatic decompensation, according to Merck. There is also a boxed warning on the increased risk of depression, suicidal ideation, suicide, and other neuropsychiatric disorders, which is consistent with all interferons.

Prescribing information can be found on the FDA Web site.

The Food and Drug Administration has approved peginterferon alfa-2b for adjuvant treatment of melanoma in patients with "microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy."

The drug, to be marketed as Sylatron by Schering Corp., a Merck & Co. subsidiary, is the second melanoma drug to receive FDA approval this year. The first, ipilimumab (Yervoy), was the first drug ever to improve survival of metastatic melanoma in a clinical trial.

Dr. Eric Rubin, Merck's vice president of clinical oncology, said in a statement that the company was "pleased to offer patients with node-positive melanoma this new option [Sylatron] to treat the disease." He pointed out that Sylatron "is the first such therapy approved for the adjuvant treatment of melanoma by the FDA in more than 15 years."

The FDA based its approval on a single study, EORTC (European Organisation for the Research and Treatment of Cancer) trial 18991, "Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation Alone in Resected Stage III Melanoma," the final results of which were published in 2008 in the Lancet (2008:372;117-26).

Peginterferon alfa-2b was shown to prolong relapse-free survival in this study, which enrolled 1,256 patients with resected stage III melanoma, but investigators saw no difference in overall survival. The median relapse-free survival was 34.8 months with peginterferon alfa-2b vs. 25.5 months with observation.

Peginterferon alfa-2b is given subcutaneously, and can be self-injected by melanoma patients. The recommended dose starts at 6 mcg/kg per week for eight doses, and then tapers to 3 mcg/kg per week for up to 5 years. Premedication with acetaminophen is advised when patients start treatment.

A safety analysis in 608 patients who were treated with peginterferon alfa-2b found the most serious adverse events to be fatigue, increased ALT, increased AST, and pyrexia.

Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, and also in those with autoimmune hepatitis or with hepatic decompensation, according to Merck. There is also a boxed warning on the increased risk of depression, suicidal ideation, suicide, and other neuropsychiatric disorders, which is consistent with all interferons.

Prescribing information can be found on the FDA Web site.

The Food and Drug Administration has approved peginterferon alfa-2b for adjuvant treatment of melanoma in patients with "microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy."

The drug, to be marketed as Sylatron by Schering Corp., a Merck & Co. subsidiary, is the second melanoma drug to receive FDA approval this year. The first, ipilimumab (Yervoy), was the first drug ever to improve survival of metastatic melanoma in a clinical trial.

Dr. Eric Rubin, Merck's vice president of clinical oncology, said in a statement that the company was "pleased to offer patients with node-positive melanoma this new option [Sylatron] to treat the disease." He pointed out that Sylatron "is the first such therapy approved for the adjuvant treatment of melanoma by the FDA in more than 15 years."

The FDA based its approval on a single study, EORTC (European Organisation for the Research and Treatment of Cancer) trial 18991, "Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation Alone in Resected Stage III Melanoma," the final results of which were published in 2008 in the Lancet (2008:372;117-26).

Peginterferon alfa-2b was shown to prolong relapse-free survival in this study, which enrolled 1,256 patients with resected stage III melanoma, but investigators saw no difference in overall survival. The median relapse-free survival was 34.8 months with peginterferon alfa-2b vs. 25.5 months with observation.

Peginterferon alfa-2b is given subcutaneously, and can be self-injected by melanoma patients. The recommended dose starts at 6 mcg/kg per week for eight doses, and then tapers to 3 mcg/kg per week for up to 5 years. Premedication with acetaminophen is advised when patients start treatment.

A safety analysis in 608 patients who were treated with peginterferon alfa-2b found the most serious adverse events to be fatigue, increased ALT, increased AST, and pyrexia.

Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, and also in those with autoimmune hepatitis or with hepatic decompensation, according to Merck. There is also a boxed warning on the increased risk of depression, suicidal ideation, suicide, and other neuropsychiatric disorders, which is consistent with all interferons.

Prescribing information can be found on the FDA Web site.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

ORLANDO – Combined treatment using compounds that block two interacting and frequently mutated cancer pathways was safe and well tolerated, and demonstrated antitumor activity in a phase Ib dose-escalation study of patients with advanced solid tumors.

Such combined approaches to cancer treatment are "likely the future of targeted therapy in cancer medicine," Dr. Johanna C. Bendell said at the annual meeting of the American Association for Cancer Research, where she presented early data from the ongoing study.

The two drugs tested by Dr. Bendell and her colleagues were:

• GDC-0973, a novel, potent selective MEK 1/2 inhibitor that targets the RAS/RAF/MEK/ERK signaling pathway.

• GDC-0941, a novel, potent, highly specific class I PI3K inhibitor that targets the PI3K/PTEN/AKT signaling pathway.

Both pathways are deregulated in multiple tumor types, and both agents have been shown in phase I trials to have suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration of these agents showed improved efficacy, compared with the efficacy of either agent when administered alone, said Dr. Bendell, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tenn.

In the current study, the combination was generally well tolerated in 30 patients who were treated on a once-daily 21-days-on/7-days-off schedule. The most common side effects were diarrhea (occurring in 90% of patients), fatigue (in 61%), nausea (in 61%), rash (in 50%), vomiting (in 33%), decreased appetite (in 17%), and taste changes (in 17%), but the vast majority were mild and did not differ from the adverse events seen in single-agent trials.

Furthermore, the pharmacokinetics of each agent did not appear to be altered by combined administration.

Six of 15 patients who underwent serial positron emission tomography at drug peak and trough concentrations showed a partial metabolic response to treatment, with at least a 20% decrease in the mean percent change from the baseline maximal standardized uptake value (SUVmax) at one or more time points.

Decreases in target lesions measurable by Response Evaluation Criteria in Solid Tumors (RECIST) occurred in five patients, including one melanoma patient with a wild-type BRAF(75% decrease), one melanoma patient with a BRAF mutation (27% decrease), one prostate cancer patient (21% decrease), and two non–small-cell lung cancer (NSCLC) patients with KRAS mutations (18% and 13% decreases). Four patients (two with NSCLC and two with melanoma) had stable disease for at least 6 months, Dr. Bendell said.

Dose escalation in this study was achieved using a unique 3+3 schema that allowed for increased dosing of each agent individually. Dosing began at two dose levels down from the maximum tolerated dose of each agent (20 mg and 80 mg daily of GDC-0973 and GDC-0941, respectively, in the first cohort), with dose increases in one drug at a time in consecutive cohorts. At the time of Dr. Bendell's presentation, dosing had reached the level at which drug activity had previously been seen in the individual drug studies, and dose escalation was ongoing to determine the maximum tolerable doses.

"Combining these agents is a very exciting thing for us in treating patients with cancer with targeted therapies," Dr. Bendell said, explaining that blocking two of the most commonly abnormal pathways in cancer cells has the potential to block each pathway individually as well as to prevent the "cross talk" between the pathways, which can lead to primary or acquired resistance to single-agent single-pathway therapy.

Seen within these pathways are mutations that cause upregulation leading to cancer cell proliferation, survival, invasiveness, and enhanced metabolism. Additionally, these pathways are downstream of many validated oncology drug targets including HER2, endothelial growth factor receptor, and KIT, she explained.

A particularly promising finding is the tolerability of therapy; there was concern that blocking two pathways instead of one would make treatment too toxic for patients, but that doesn't appear to be the case. "We're very pleased to find that we could do it safely – and with antitumor activity," she said.

As for whether this combined treatment approach represents the "elusive anti-RAS therapy" that researchers have been seeking for 3 decades, Channing J. Der, Ph.D., of Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., the discussant for Dr. Bendell's presentation, expressed skepticism.

Although this is a very promising study that adds to the available evidence supporting a combined MEK-PI3K inhibition approach for RAS-mutant cancers, a great deal more work needs to be done, he said.

"We've been here many times before with promising and exciting preclinical studies only to be disappointed when we get to clinic ... so I believe the search for the elusive RAS inhibitor will probably continue.

"I hope I am wrong," he said.

Genentech sponsored the study. Dr. Bendell said she had no relevant financial disclosures. Dr. Der disclosed relationships with GlaxoSmithKline, Millipore, Bristol-Myers Squibb, and Sanofi-Aventis.

SAN ANTONIO – Patients with thin melanomas and positive deep margins on initial biopsy had the same incidence of sentinel lymph node metastasis as those with thicker melanomas, according to the results of a retrospective analysis of 260 patients with melanoma.

At least one positive sentinel lymph node was detected in 6 of 73 patients (8%) with a melanoma Breslow thickness of less than 0.8 mm and positive deep margins vs. 17 of 187 patients (9%) with a melanoma Breslow thickness of 0.8-2.0 mm, regardless of margin status (P = .82).

Immunohistochemistry was the most common method of identifying positive sentinel nodes in both the thin and thick melanoma groups (5 cases vs. 10 cases, respectively), Dr. Victor Koshenkov said at a symposium sponsored by the Society of Surgical Oncology.

The decision to perform sentinel node biopsy is largely driven by tumor thickness. When the initial biopsy of a thin melanoma shows positive deep margins, many clinicians will treat these cases as potentially thicker melanomas and perform sentinel lymph node (SLN) biopsy. There are few data on the impact of positive deep margins on surgical decision making, prognosis, and outcome, even though positive deep margins are the most common cause of incompletely measured or indeterminate tumor thickness, said Dr. Koshenkov of the department of surgery at Atlantic Health Memorial Hospital in Morristown, N.J.

He presented data from a retrospective analysis of 260 adult patients who underwent wide excision plus SLN biopsy for cutaneous melanoma from January 2004 to May 2010.

Demographics were not statistically different between the two groups, except for tumor site and Clark’s level, he said. In 53% of patients in the thicker melanoma group, the extremities were the primary tumor site vs. 38% in the thin melanoma group (P = .042), while 40% had Clark’s level IV-V vs. 22% in the thin melanoma group (P less than .001).

Multivariate regression analysis revealed that only female gender (P = .046; odds ratio, 2.68) and Clark’s level IV-V (P = .024; OR, 3.54) were significantly associated with an increased risk of positive SLNs. Belonging to the thin melanoma group versus the thicker melanoma group was not significant (P = .66; OR, 1.29) Dr. Koshenkov said.

The presence of residual disease approached, but did not reach, statistical significance (P = .062; OR, 2.60). Residual disease was found in about 20% of both groups. Only 4 of the 73 patients (5.5%) with positive SLNs in the thin melanoma group required further reexcision with wide margins.

Only 1 of the 23 sentinel node–positive patients went on to have additional positive nodes on completion of lymph node dissection, he said.

"Patients with thin melanomas and positive deep margins on initial biopsy have an incidence of SLN metastasis statistically no different than patients with thicker melanomas," Dr. Koshenkov concluded. "Thus, we believe that thin melanomas with positive deep margins should be treated with wide excision and a sentinel lymph node biopsy. Of course, these findings should be tested and verified in larger, multi-institutional databases."

During a discussion of the study, the audience questioned the ability to make almost a practice-changing conclusion based on the small number of patients and the low incidence of positive SLNs in the thicker melanoma group. Dr. Koshenkov replied that the reason the rate of sentinel node positivity was lower than predicted in this group was that a larger proportion of patients had melanomas 0.8-1 mm in depth, rather than 1-2 mm in depth.

Another attendee remarked that before concluding that every patient with a positive deep margin on initial biopsy needs to undergo SLN biopsy, it is important to know how many patients with positive sentinel nodes had a positive deep margin as their only indication or whether factors such as mitotic rate or ulceration played a role. Dr. Koshenkov said mitotic rate was not analyzed because it was not regularly included in the pathology report at the time of the review, and that ulceration and Clark’s level IV were factored into the multivariate analysis.

The authors said they had no relevant financial disclosures.

SAN ANTONIO – Patients with thin melanomas and positive deep margins on initial biopsy had the same incidence of sentinel lymph node metastasis as those with thicker melanomas, according to the results of a retrospective analysis of 260 patients with melanoma.

At least one positive sentinel lymph node was detected in 6 of 73 patients (8%) with a melanoma Breslow thickness of less than 0.8 mm and positive deep margins vs. 17 of 187 patients (9%) with a melanoma Breslow thickness of 0.8-2.0 mm, regardless of margin status (P = .82).

Immunohistochemistry was the most common method of identifying positive sentinel nodes in both the thin and thick melanoma groups (5 cases vs. 10 cases, respectively), Dr. Victor Koshenkov said at a symposium sponsored by the Society of Surgical Oncology.

The decision to perform sentinel node biopsy is largely driven by tumor thickness. When the initial biopsy of a thin melanoma shows positive deep margins, many clinicians will treat these cases as potentially thicker melanomas and perform sentinel lymph node (SLN) biopsy. There are few data on the impact of positive deep margins on surgical decision making, prognosis, and outcome, even though positive deep margins are the most common cause of incompletely measured or indeterminate tumor thickness, said Dr. Koshenkov of the department of surgery at Atlantic Health Memorial Hospital in Morristown, N.J.

He presented data from a retrospective analysis of 260 adult patients who underwent wide excision plus SLN biopsy for cutaneous melanoma from January 2004 to May 2010.

Demographics were not statistically different between the two groups, except for tumor site and Clark’s level, he said. In 53% of patients in the thicker melanoma group, the extremities were the primary tumor site vs. 38% in the thin melanoma group (P = .042), while 40% had Clark’s level IV-V vs. 22% in the thin melanoma group (P less than .001).

Multivariate regression analysis revealed that only female gender (P = .046; odds ratio, 2.68) and Clark’s level IV-V (P = .024; OR, 3.54) were significantly associated with an increased risk of positive SLNs. Belonging to the thin melanoma group versus the thicker melanoma group was not significant (P = .66; OR, 1.29) Dr. Koshenkov said.

The presence of residual disease approached, but did not reach, statistical significance (P = .062; OR, 2.60). Residual disease was found in about 20% of both groups. Only 4 of the 73 patients (5.5%) with positive SLNs in the thin melanoma group required further reexcision with wide margins.

Only 1 of the 23 sentinel node–positive patients went on to have additional positive nodes on completion of lymph node dissection, he said.

"Patients with thin melanomas and positive deep margins on initial biopsy have an incidence of SLN metastasis statistically no different than patients with thicker melanomas," Dr. Koshenkov concluded. "Thus, we believe that thin melanomas with positive deep margins should be treated with wide excision and a sentinel lymph node biopsy. Of course, these findings should be tested and verified in larger, multi-institutional databases."

During a discussion of the study, the audience questioned the ability to make almost a practice-changing conclusion based on the small number of patients and the low incidence of positive SLNs in the thicker melanoma group. Dr. Koshenkov replied that the reason the rate of sentinel node positivity was lower than predicted in this group was that a larger proportion of patients had melanomas 0.8-1 mm in depth, rather than 1-2 mm in depth.

Another attendee remarked that before concluding that every patient with a positive deep margin on initial biopsy needs to undergo SLN biopsy, it is important to know how many patients with positive sentinel nodes had a positive deep margin as their only indication or whether factors such as mitotic rate or ulceration played a role. Dr. Koshenkov said mitotic rate was not analyzed because it was not regularly included in the pathology report at the time of the review, and that ulceration and Clark’s level IV were factored into the multivariate analysis.

The authors said they had no relevant financial disclosures.

SAN ANTONIO – Patients with thin melanomas and positive deep margins on initial biopsy had the same incidence of sentinel lymph node metastasis as those with thicker melanomas, according to the results of a retrospective analysis of 260 patients with melanoma.

At least one positive sentinel lymph node was detected in 6 of 73 patients (8%) with a melanoma Breslow thickness of less than 0.8 mm and positive deep margins vs. 17 of 187 patients (9%) with a melanoma Breslow thickness of 0.8-2.0 mm, regardless of margin status (P = .82).

Immunohistochemistry was the most common method of identifying positive sentinel nodes in both the thin and thick melanoma groups (5 cases vs. 10 cases, respectively), Dr. Victor Koshenkov said at a symposium sponsored by the Society of Surgical Oncology.

The decision to perform sentinel node biopsy is largely driven by tumor thickness. When the initial biopsy of a thin melanoma shows positive deep margins, many clinicians will treat these cases as potentially thicker melanomas and perform sentinel lymph node (SLN) biopsy. There are few data on the impact of positive deep margins on surgical decision making, prognosis, and outcome, even though positive deep margins are the most common cause of incompletely measured or indeterminate tumor thickness, said Dr. Koshenkov of the department of surgery at Atlantic Health Memorial Hospital in Morristown, N.J.

He presented data from a retrospective analysis of 260 adult patients who underwent wide excision plus SLN biopsy for cutaneous melanoma from January 2004 to May 2010.

Demographics were not statistically different between the two groups, except for tumor site and Clark’s level, he said. In 53% of patients in the thicker melanoma group, the extremities were the primary tumor site vs. 38% in the thin melanoma group (P = .042), while 40% had Clark’s level IV-V vs. 22% in the thin melanoma group (P less than .001).

Multivariate regression analysis revealed that only female gender (P = .046; odds ratio, 2.68) and Clark’s level IV-V (P = .024; OR, 3.54) were significantly associated with an increased risk of positive SLNs. Belonging to the thin melanoma group versus the thicker melanoma group was not significant (P = .66; OR, 1.29) Dr. Koshenkov said.

The presence of residual disease approached, but did not reach, statistical significance (P = .062; OR, 2.60). Residual disease was found in about 20% of both groups. Only 4 of the 73 patients (5.5%) with positive SLNs in the thin melanoma group required further reexcision with wide margins.

Only 1 of the 23 sentinel node–positive patients went on to have additional positive nodes on completion of lymph node dissection, he said.

"Patients with thin melanomas and positive deep margins on initial biopsy have an incidence of SLN metastasis statistically no different than patients with thicker melanomas," Dr. Koshenkov concluded. "Thus, we believe that thin melanomas with positive deep margins should be treated with wide excision and a sentinel lymph node biopsy. Of course, these findings should be tested and verified in larger, multi-institutional databases."

During a discussion of the study, the audience questioned the ability to make almost a practice-changing conclusion based on the small number of patients and the low incidence of positive SLNs in the thicker melanoma group. Dr. Koshenkov replied that the reason the rate of sentinel node positivity was lower than predicted in this group was that a larger proportion of patients had melanomas 0.8-1 mm in depth, rather than 1-2 mm in depth.

Another attendee remarked that before concluding that every patient with a positive deep margin on initial biopsy needs to undergo SLN biopsy, it is important to know how many patients with positive sentinel nodes had a positive deep margin as their only indication or whether factors such as mitotic rate or ulceration played a role. Dr. Koshenkov said mitotic rate was not analyzed because it was not regularly included in the pathology report at the time of the review, and that ulceration and Clark’s level IV were factored into the multivariate analysis.

The authors said they had no relevant financial disclosures.

SAN ANTONIO – In a large but nonrandomized group of patients with primary melanoma, sentinel node biopsy significantly prolonged disease-free survival, but offered no prolongation of distant metastases free- or melanoma-specific survival.

Researchers at the Melanoma Institute Australia in North Sydney evaluated survival among 5,567 patients who from 1992 to 2008 underwent wide local excision with or without sentinel node biopsy (SNB) for a primary melanoma that was at least 1 mm thick, Clark level IV or V, or had ulceration. Median follow-up was 3.5 years.

Among the 2,803 patients who underwent SNB, 390 had a positive sentinel node (14%), followed by early complete lymph node dissection. Of the 2,413 patients with a negative sentinel node, 88 experienced regional lymph node recurrence (3.6%) and underwent delayed total lymph node dissection. This resulted in a false-negative rate for SNB of 18.4%, Mr. Stijn van der Ploeg, M.Sc., reported.

Among the 2,765 patients who underwent wide local excision with nodal observation using ultrasound, 378 experienced regional lymph node recurrence (13.7%) and underwent delayed total lymph node dissection.

In univariate analysis, patients who underwent SNB had significantly improved disease-free survival and regional lymph node metastases-free survival (both P value less than .001), but no prolongation in distant metastases-free survival (P = .85) or melanoma-specific survival (P = .49), said Mr. van der Ploeg, now a doctoral student at Erasmus Medical Center in Rotterdam, The Netherlands.

When patients were stratified by tumor thickness, melanoma-specific survival significantly improved in SNB patients with tumors 1.2 mm to 3.5 mm thick (P = .01).

Mr. van der Ploeg pointed out that there were significant differences between the two groups. The SNB group had younger patients, more nodular melanomas, and more distant recurrence as the first site of recurrence, while the observation group had thinner primary tumors, more tumors located in the head and neck, and more nodal recurrences as the first site of recurrence.

After adjusting for these and other differences – including gender, age, histological subtype, mitotic rate, Clark level, and ulceration – the researchers observed no significant benefit for SNB vs. observation for melanoma-specific survival among patients in all thickness subgroups analyzed, he said.

Finally, in univariate analysis, early complete lymph node dissection failed to significantly improve distant metastases-free survival or melanoma-specific survival among SNB-positive patients of all thickness subgroups. There was a trend toward improved distant metastases free-survival favoring early vs. late dissection among patients with intermediate-thickness melanoma (P = .060).

"Our study suggests that patients with intermediate-thickness melanomas 1.2 [mm] to 3.5 [mm] are most likely to have therapeutic benefit from undergoing sentinel node biopsy," Mr. van der Ploeg concluded.

He added that the final results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) are awaited with great interest, to better define melanoma patient subgroups most likely to obtain a survival benefit from SNB.

Interim analyses from MSLT-1 have confirmed that disease-free and distant disease-free survival are improved with SNB among patients with intermediate-thickness melanomas, but the long-running trial has failed to show a definitive overall survival advantage for the procedure.

During a discussion of the Australian study, audience members asked what techniques were used for SNB, remarking that the false-negative rate of 18% is well above the 4% rate reached by many groups today. Mr. van der Ploeg said the false-negative rate has fallen over time with more experience to 15%, and that surgeons use blue dye, but not the 10% rule during lymph node mapping.

The authors reported no disclosures.

SAN ANTONIO – In a large but nonrandomized group of patients with primary melanoma, sentinel node biopsy significantly prolonged disease-free survival, but offered no prolongation of distant metastases free- or melanoma-specific survival.

Researchers at the Melanoma Institute Australia in North Sydney evaluated survival among 5,567 patients who from 1992 to 2008 underwent wide local excision with or without sentinel node biopsy (SNB) for a primary melanoma that was at least 1 mm thick, Clark level IV or V, or had ulceration. Median follow-up was 3.5 years.

Among the 2,803 patients who underwent SNB, 390 had a positive sentinel node (14%), followed by early complete lymph node dissection. Of the 2,413 patients with a negative sentinel node, 88 experienced regional lymph node recurrence (3.6%) and underwent delayed total lymph node dissection. This resulted in a false-negative rate for SNB of 18.4%, Mr. Stijn van der Ploeg, M.Sc., reported.

Among the 2,765 patients who underwent wide local excision with nodal observation using ultrasound, 378 experienced regional lymph node recurrence (13.7%) and underwent delayed total lymph node dissection.

In univariate analysis, patients who underwent SNB had significantly improved disease-free survival and regional lymph node metastases-free survival (both P value less than .001), but no prolongation in distant metastases-free survival (P = .85) or melanoma-specific survival (P = .49), said Mr. van der Ploeg, now a doctoral student at Erasmus Medical Center in Rotterdam, The Netherlands.

When patients were stratified by tumor thickness, melanoma-specific survival significantly improved in SNB patients with tumors 1.2 mm to 3.5 mm thick (P = .01).

Mr. van der Ploeg pointed out that there were significant differences between the two groups. The SNB group had younger patients, more nodular melanomas, and more distant recurrence as the first site of recurrence, while the observation group had thinner primary tumors, more tumors located in the head and neck, and more nodal recurrences as the first site of recurrence.

After adjusting for these and other differences – including gender, age, histological subtype, mitotic rate, Clark level, and ulceration – the researchers observed no significant benefit for SNB vs. observation for melanoma-specific survival among patients in all thickness subgroups analyzed, he said.

Finally, in univariate analysis, early complete lymph node dissection failed to significantly improve distant metastases-free survival or melanoma-specific survival among SNB-positive patients of all thickness subgroups. There was a trend toward improved distant metastases free-survival favoring early vs. late dissection among patients with intermediate-thickness melanoma (P = .060).

"Our study suggests that patients with intermediate-thickness melanomas 1.2 [mm] to 3.5 [mm] are most likely to have therapeutic benefit from undergoing sentinel node biopsy," Mr. van der Ploeg concluded.

He added that the final results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) are awaited with great interest, to better define melanoma patient subgroups most likely to obtain a survival benefit from SNB.

Interim analyses from MSLT-1 have confirmed that disease-free and distant disease-free survival are improved with SNB among patients with intermediate-thickness melanomas, but the long-running trial has failed to show a definitive overall survival advantage for the procedure.

During a discussion of the Australian study, audience members asked what techniques were used for SNB, remarking that the false-negative rate of 18% is well above the 4% rate reached by many groups today. Mr. van der Ploeg said the false-negative rate has fallen over time with more experience to 15%, and that surgeons use blue dye, but not the 10% rule during lymph node mapping.

The authors reported no disclosures.

SAN ANTONIO – In a large but nonrandomized group of patients with primary melanoma, sentinel node biopsy significantly prolonged disease-free survival, but offered no prolongation of distant metastases free- or melanoma-specific survival.

Researchers at the Melanoma Institute Australia in North Sydney evaluated survival among 5,567 patients who from 1992 to 2008 underwent wide local excision with or without sentinel node biopsy (SNB) for a primary melanoma that was at least 1 mm thick, Clark level IV or V, or had ulceration. Median follow-up was 3.5 years.

Among the 2,803 patients who underwent SNB, 390 had a positive sentinel node (14%), followed by early complete lymph node dissection. Of the 2,413 patients with a negative sentinel node, 88 experienced regional lymph node recurrence (3.6%) and underwent delayed total lymph node dissection. This resulted in a false-negative rate for SNB of 18.4%, Mr. Stijn van der Ploeg, M.Sc., reported.

Among the 2,765 patients who underwent wide local excision with nodal observation using ultrasound, 378 experienced regional lymph node recurrence (13.7%) and underwent delayed total lymph node dissection.

In univariate analysis, patients who underwent SNB had significantly improved disease-free survival and regional lymph node metastases-free survival (both P value less than .001), but no prolongation in distant metastases-free survival (P = .85) or melanoma-specific survival (P = .49), said Mr. van der Ploeg, now a doctoral student at Erasmus Medical Center in Rotterdam, The Netherlands.

When patients were stratified by tumor thickness, melanoma-specific survival significantly improved in SNB patients with tumors 1.2 mm to 3.5 mm thick (P = .01).

Mr. van der Ploeg pointed out that there were significant differences between the two groups. The SNB group had younger patients, more nodular melanomas, and more distant recurrence as the first site of recurrence, while the observation group had thinner primary tumors, more tumors located in the head and neck, and more nodal recurrences as the first site of recurrence.

After adjusting for these and other differences – including gender, age, histological subtype, mitotic rate, Clark level, and ulceration – the researchers observed no significant benefit for SNB vs. observation for melanoma-specific survival among patients in all thickness subgroups analyzed, he said.

Finally, in univariate analysis, early complete lymph node dissection failed to significantly improve distant metastases-free survival or melanoma-specific survival among SNB-positive patients of all thickness subgroups. There was a trend toward improved distant metastases free-survival favoring early vs. late dissection among patients with intermediate-thickness melanoma (P = .060).

"Our study suggests that patients with intermediate-thickness melanomas 1.2 [mm] to 3.5 [mm] are most likely to have therapeutic benefit from undergoing sentinel node biopsy," Mr. van der Ploeg concluded.

He added that the final results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) are awaited with great interest, to better define melanoma patient subgroups most likely to obtain a survival benefit from SNB.

Interim analyses from MSLT-1 have confirmed that disease-free and distant disease-free survival are improved with SNB among patients with intermediate-thickness melanomas, but the long-running trial has failed to show a definitive overall survival advantage for the procedure.

During a discussion of the Australian study, audience members asked what techniques were used for SNB, remarking that the false-negative rate of 18% is well above the 4% rate reached by many groups today. Mr. van der Ploeg said the false-negative rate has fallen over time with more experience to 15%, and that surgeons use blue dye, but not the 10% rule during lymph node mapping.

The authors reported no disclosures.

SAN ANTONIO – In a large but nonrandomized group of patients with primary melanoma, sentinel node biopsy significantly prolonged disease-free survival, but offered no prolongation of distant metastases free- or melanoma-specific survival.

Researchers at the Melanoma Institute Australia in North Sydney evaluated survival among 5,567 patients who from 1992 to 2008 underwent wide local excision with or without sentinel node biopsy (SNB) for a primary melanoma that was at least 1 mm thick, Clark level IV or V, or had ulceration. Median follow-up was 3.5 years.

Among the 2,803 patients who underwent SNB, 390 had a positive sentinel node (14%), followed by early complete lymph node dissection. Of the 2,413 patients with a negative sentinel node, 88 experienced regional lymph node recurrence (3.6%) and underwent delayed total lymph node dissection. This resulted in a false-negative rate for SNB of 18.4%, Mr. Stijn van der Ploeg, M.Sc., reported.

Among the 2,765 patients who underwent wide local excision with nodal observation using ultrasound, 378 experienced regional lymph node recurrence (13.7%) and underwent delayed total lymph node dissection.

In univariate analysis, patients who underwent SNB had significantly improved disease-free survival and regional lymph node metastases-free survival (both P value less than .001), but no prolongation in distant metastases-free survival (P = .85) or melanoma-specific survival (P = .49), said Mr. van der Ploeg, now a doctoral student at Erasmus Medical Center in Rotterdam, The Netherlands.

When patients were stratified by tumor thickness, melanoma-specific survival significantly improved in SNB patients with tumors 1.2 mm to 3.5 mm thick (P = .01).

Mr. van der Ploeg pointed out that there were significant differences between the two groups. The SNB group had younger patients, more nodular melanomas, and more distant recurrence as the first site of recurrence, while the observation group had thinner primary tumors, more tumors located in the head and neck, and more nodal recurrences as the first site of recurrence.

After adjusting for these and other differences – including gender, age, histological subtype, mitotic rate, Clark level, and ulceration – the researchers observed no significant benefit for SNB vs. observation for melanoma-specific survival among patients in all thickness subgroups analyzed, he said.

Finally, in univariate analysis, early complete lymph node dissection failed to significantly improve distant metastases-free survival or melanoma-specific survival among SNB-positive patients of all thickness subgroups. There was a trend toward improved distant metastases free-survival favoring early vs. late dissection among patients with intermediate-thickness melanoma (P = .060).

"Our study suggests that patients with intermediate-thickness melanomas 1.2 [mm] to 3.5 [mm] are most likely to have therapeutic benefit from undergoing sentinel node biopsy," Mr. van der Ploeg concluded.

He added that the final results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) are awaited with great interest, to better define melanoma patient subgroups most likely to obtain a survival benefit from SNB.

Interim analyses from MSLT-1 have confirmed that disease-free and distant disease-free survival are improved with SNB among patients with intermediate-thickness melanomas, but the long-running trial has failed to show a definitive overall survival advantage for the procedure.

During a discussion of the Australian study, audience members asked what techniques were used for SNB, remarking that the false-negative rate of 18% is well above the 4% rate reached by many groups today. Mr. van der Ploeg said the false-negative rate has fallen over time with more experience to 15%, and that surgeons use blue dye, but not the 10% rule during lymph node mapping.

The authors reported no disclosures.

SAN ANTONIO – In a large but nonrandomized group of patients with primary melanoma, sentinel node biopsy significantly prolonged disease-free survival, but offered no prolongation of distant metastases free- or melanoma-specific survival.

Researchers at the Melanoma Institute Australia in North Sydney evaluated survival among 5,567 patients who from 1992 to 2008 underwent wide local excision with or without sentinel node biopsy (SNB) for a primary melanoma that was at least 1 mm thick, Clark level IV or V, or had ulceration. Median follow-up was 3.5 years.

Among the 2,803 patients who underwent SNB, 390 had a positive sentinel node (14%), followed by early complete lymph node dissection. Of the 2,413 patients with a negative sentinel node, 88 experienced regional lymph node recurrence (3.6%) and underwent delayed total lymph node dissection. This resulted in a false-negative rate for SNB of 18.4%, Mr. Stijn van der Ploeg, M.Sc., reported.

Among the 2,765 patients who underwent wide local excision with nodal observation using ultrasound, 378 experienced regional lymph node recurrence (13.7%) and underwent delayed total lymph node dissection.

In univariate analysis, patients who underwent SNB had significantly improved disease-free survival and regional lymph node metastases-free survival (both P value less than .001), but no prolongation in distant metastases-free survival (P = .85) or melanoma-specific survival (P = .49), said Mr. van der Ploeg, now a doctoral student at Erasmus Medical Center in Rotterdam, The Netherlands.

When patients were stratified by tumor thickness, melanoma-specific survival significantly improved in SNB patients with tumors 1.2 mm to 3.5 mm thick (P = .01).

Mr. van der Ploeg pointed out that there were significant differences between the two groups. The SNB group had younger patients, more nodular melanomas, and more distant recurrence as the first site of recurrence, while the observation group had thinner primary tumors, more tumors located in the head and neck, and more nodal recurrences as the first site of recurrence.

After adjusting for these and other differences – including gender, age, histological subtype, mitotic rate, Clark level, and ulceration – the researchers observed no significant benefit for SNB vs. observation for melanoma-specific survival among patients in all thickness subgroups analyzed, he said.

Finally, in univariate analysis, early complete lymph node dissection failed to significantly improve distant metastases-free survival or melanoma-specific survival among SNB-positive patients of all thickness subgroups. There was a trend toward improved distant metastases free-survival favoring early vs. late dissection among patients with intermediate-thickness melanoma (P = .060).

"Our study suggests that patients with intermediate-thickness melanomas 1.2 [mm] to 3.5 [mm] are most likely to have therapeutic benefit from undergoing sentinel node biopsy," Mr. van der Ploeg concluded.

He added that the final results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) are awaited with great interest, to better define melanoma patient subgroups most likely to obtain a survival benefit from SNB.

Interim analyses from MSLT-1 have confirmed that disease-free and distant disease-free survival are improved with SNB among patients with intermediate-thickness melanomas, but the long-running trial has failed to show a definitive overall survival advantage for the procedure.

During a discussion of the Australian study, audience members asked what techniques were used for SNB, remarking that the false-negative rate of 18% is well above the 4% rate reached by many groups today. Mr. van der Ploeg said the false-negative rate has fallen over time with more experience to 15%, and that surgeons use blue dye, but not the 10% rule during lymph node mapping.

The authors reported no disclosures.

SAN ANTONIO – In a large but nonrandomized group of patients with primary melanoma, sentinel node biopsy significantly prolonged disease-free survival, but offered no prolongation of distant metastases free- or melanoma-specific survival.

Researchers at the Melanoma Institute Australia in North Sydney evaluated survival among 5,567 patients who from 1992 to 2008 underwent wide local excision with or without sentinel node biopsy (SNB) for a primary melanoma that was at least 1 mm thick, Clark level IV or V, or had ulceration. Median follow-up was 3.5 years.

Among the 2,803 patients who underwent SNB, 390 had a positive sentinel node (14%), followed by early complete lymph node dissection. Of the 2,413 patients with a negative sentinel node, 88 experienced regional lymph node recurrence (3.6%) and underwent delayed total lymph node dissection. This resulted in a false-negative rate for SNB of 18.4%, Mr. Stijn van der Ploeg, M.Sc., reported.

Among the 2,765 patients who underwent wide local excision with nodal observation using ultrasound, 378 experienced regional lymph node recurrence (13.7%) and underwent delayed total lymph node dissection.

In univariate analysis, patients who underwent SNB had significantly improved disease-free survival and regional lymph node metastases-free survival (both P value less than .001), but no prolongation in distant metastases-free survival (P = .85) or melanoma-specific survival (P = .49), said Mr. van der Ploeg, now a doctoral student at Erasmus Medical Center in Rotterdam, The Netherlands.

When patients were stratified by tumor thickness, melanoma-specific survival significantly improved in SNB patients with tumors 1.2 mm to 3.5 mm thick (P = .01).

Mr. van der Ploeg pointed out that there were significant differences between the two groups. The SNB group had younger patients, more nodular melanomas, and more distant recurrence as the first site of recurrence, while the observation group had thinner primary tumors, more tumors located in the head and neck, and more nodal recurrences as the first site of recurrence.

After adjusting for these and other differences – including gender, age, histological subtype, mitotic rate, Clark level, and ulceration – the researchers observed no significant benefit for SNB vs. observation for melanoma-specific survival among patients in all thickness subgroups analyzed, he said.

Finally, in univariate analysis, early complete lymph node dissection failed to significantly improve distant metastases-free survival or melanoma-specific survival among SNB-positive patients of all thickness subgroups. There was a trend toward improved distant metastases free-survival favoring early vs. late dissection among patients with intermediate-thickness melanoma (P = .060).

"Our study suggests that patients with intermediate-thickness melanomas 1.2 [mm] to 3.5 [mm] are most likely to have therapeutic benefit from undergoing sentinel node biopsy," Mr. van der Ploeg concluded.

He added that the final results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) are awaited with great interest, to better define melanoma patient subgroups most likely to obtain a survival benefit from SNB.

Interim analyses from MSLT-1 have confirmed that disease-free and distant disease-free survival are improved with SNB among patients with intermediate-thickness melanomas, but the long-running trial has failed to show a definitive overall survival advantage for the procedure.

During a discussion of the Australian study, audience members asked what techniques were used for SNB, remarking that the false-negative rate of 18% is well above the 4% rate reached by many groups today. Mr. van der Ploeg said the false-negative rate has fallen over time with more experience to 15%, and that surgeons use blue dye, but not the 10% rule during lymph node mapping.

The authors reported no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.