KIT Inhibition Promising for Select Few

ORLANDO – Patients who express a KIT genetic abnormality represent a small minority of those with melanoma, but there is a lot of interest in the development of specific inhibitors, said Dr. Richard D. Carvajal at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Studies from Dr. Carvajal and other researchers indicate that inhibitors could significantly prolong median progression-free survival for patients who have amplification, overexpression, or a mutation of this genetic driver of melanoma.

In his phase II study of Novartis’ imatinib (Gleevec) for patients with melanoma and KIT alterations, 4 of 25 evaluable patients responded, for an overall durable response rate of 16%. Median progression-free survival was "pretty modest at 3 to 3.5 months," Dr. Carvajal said. Two patients had a complete response to therapy, and another two achieved a partial response (JAMA 2011;305:2327-34).

"So the question is: Can we better select patients likely to respond?" Dr. Carvajal asked at the meeting. "Certainly this is not vemurafenib [Zelboraf], where we get a response in 50% of patients. It could be due to variability in KIT mutations," said Dr. Carvajal, a medical oncologist specializing in melanoma and sarcomas at Memorial Sloan-Kettering Cancer Center in New York.

Only 3% of patients with melanoma harbor a KIT mutation. "You have to have a mutation in KIT; otherwise, the patient is not going to respond to imatinib," he said. The study was preceded by three negative clinical trials in unselected patients (before the mutation was identified).

In another phase II study enrolling only patients with KIT alterations, investigators reported that 10 of 43 patients responded to treatment with imatinib, for a 23% overall response rate (J. Clin. Oncol. 2011;29:2904-9).

Studies are underway with potential KIT inhibitors other than imatinib, including Pfizer’s sunitinib (Sutent), Novartis’ nilotinib (Tasigna), and Bristol-Myers Squibb’s dasatinib (Sprycel).

Sunitinib

Sunitinib is "reasonably promising" for melanoma patients with KIT mutations, said Dr. David Minor, of the California Pacific Center for Melanoma Research and Treatment at the University of California, San Francisco.

He and his colleagues conducted gene sequencing of tumors from 90 patients with advanced melanoma. The findings revealed that 11% featured a KIT mutation (Clin. Cancer Res. 2012:18:1457-63).

Ten of 12 patients treated with sunitinib were evaluable – 4 with KIT mutations and 6 with KIT amplification or overexpression. Although the mutation was a significant predictor of shortened survival time, treatment with sunitinib was associated with complete remission in 1 patient for 15 months and 2 partial responses for 1 and 7 months, he noted. A KIT mutation might be more clinically relevant because there were no complete responses and only one partial response in patients with KIT amplification or overexpression. Dr. Minor is director of inpatient oncology at the California Pacific Medical Center.

Nilotinib

Because only a small percentage of melanoma patients harbor a KIT mutation, conducting large efficacy studies remains a challenge, Dr. Carvajal said. "Indeed, a randomized, phase III trial of nilotinib versus DTIC [dacarbazine] in KIT-mutant melanoma was designed to be the definitive study demonstrating improved outcomes with nilotinib versus DTIC," he said. However, after patient accrual began for the TEAM (Tasigna Efficacy in Advanced Melanoma) trial in 2010, researchers reported difficulty enrolling a sufficient number of patients with metastatic or inoperable melanoma and a KIT mutation. Therefore, they redesigned the study into a single-arm phase II trial of nilotinib alone.

Researchers at the University of Pittsburgh also termed nilotinib a promising agent for melanoma patients with relevant KIT mutations in a review article (Expert Opin. Investig. Drugs 2012;21:861-9).

Dasatinib

Dr. Harriet Kluger and her colleagues at Yale University in New Haven, Conn., reported mixed efficacy for dasatinib in a phase II study (Cancer 2011;117:2202-8).

"At this point I would say that other than in the setting of patients with c-KIT mutations in their tumors, which is still being studied, dasatinib is not a promising agent for this disease," Dr. Kluger said in an interview. She is on the medical oncology faculty at Yale.

She and her colleagues studied 36 evaluable patients with stage 3 or 4 unresectable melanoma. Dasatinib was associated with two partial responses (24 weeks and 64 weeks) and three minor responses. Another patient who initially responded discontinued because of noncompliance. The median progression-free survival was 8 weeks, and the 6-month progression-free survival was 13%. Some activity of dasatinib was observed in a small subset of patients without KIT mutations, suggesting that more research is needed to identify predictive biomarkers for response to this inhibitor.

The KIT gene is located on chromosome 4 and codes for a family of proteins, the receptor tyrosine kinases. KIT function is essential for normal melanocyte genesis and migration. KIT protein signaling also is important for the development of reproductive germ cells, early hematopoietic stem cells, immune mast cells, and interstitial cells of Cajal located in the gastrointestinal tract.

Available data suggest that patients with mutations affecting exons 11 or 13 of KIT may be more likely to achieve clinical benefit with KIT inhibition, Dr. Carvajal said. He added that greater expression of the mutant KIT allele, compared with the wild type, may be a marker of tumors more "addicted" to KIT activation and that may be more susceptible to inhibition.

"This work is still fairly new," he said.

Dr. Carvajal is a consultant to Novartis. Dr. Minor and Dr. Kluger said that they had no relevant disclosures.

ORLANDO – Patients who express a KIT genetic abnormality represent a small minority of those with melanoma, but there is a lot of interest in the development of specific inhibitors, said Dr. Richard D. Carvajal at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Studies from Dr. Carvajal and other researchers indicate that inhibitors could significantly prolong median progression-free survival for patients who have amplification, overexpression, or a mutation of this genetic driver of melanoma.

In his phase II study of Novartis’ imatinib (Gleevec) for patients with melanoma and KIT alterations, 4 of 25 evaluable patients responded, for an overall durable response rate of 16%. Median progression-free survival was "pretty modest at 3 to 3.5 months," Dr. Carvajal said. Two patients had a complete response to therapy, and another two achieved a partial response (JAMA 2011;305:2327-34).

"So the question is: Can we better select patients likely to respond?" Dr. Carvajal asked at the meeting. "Certainly this is not vemurafenib [Zelboraf], where we get a response in 50% of patients. It could be due to variability in KIT mutations," said Dr. Carvajal, a medical oncologist specializing in melanoma and sarcomas at Memorial Sloan-Kettering Cancer Center in New York.

Only 3% of patients with melanoma harbor a KIT mutation. "You have to have a mutation in KIT; otherwise, the patient is not going to respond to imatinib," he said. The study was preceded by three negative clinical trials in unselected patients (before the mutation was identified).

In another phase II study enrolling only patients with KIT alterations, investigators reported that 10 of 43 patients responded to treatment with imatinib, for a 23% overall response rate (J. Clin. Oncol. 2011;29:2904-9).

Studies are underway with potential KIT inhibitors other than imatinib, including Pfizer’s sunitinib (Sutent), Novartis’ nilotinib (Tasigna), and Bristol-Myers Squibb’s dasatinib (Sprycel).

Sunitinib

Sunitinib is "reasonably promising" for melanoma patients with KIT mutations, said Dr. David Minor, of the California Pacific Center for Melanoma Research and Treatment at the University of California, San Francisco.

He and his colleagues conducted gene sequencing of tumors from 90 patients with advanced melanoma. The findings revealed that 11% featured a KIT mutation (Clin. Cancer Res. 2012:18:1457-63).

Ten of 12 patients treated with sunitinib were evaluable – 4 with KIT mutations and 6 with KIT amplification or overexpression. Although the mutation was a significant predictor of shortened survival time, treatment with sunitinib was associated with complete remission in 1 patient for 15 months and 2 partial responses for 1 and 7 months, he noted. A KIT mutation might be more clinically relevant because there were no complete responses and only one partial response in patients with KIT amplification or overexpression. Dr. Minor is director of inpatient oncology at the California Pacific Medical Center.

Nilotinib

Because only a small percentage of melanoma patients harbor a KIT mutation, conducting large efficacy studies remains a challenge, Dr. Carvajal said. "Indeed, a randomized, phase III trial of nilotinib versus DTIC [dacarbazine] in KIT-mutant melanoma was designed to be the definitive study demonstrating improved outcomes with nilotinib versus DTIC," he said. However, after patient accrual began for the TEAM (Tasigna Efficacy in Advanced Melanoma) trial in 2010, researchers reported difficulty enrolling a sufficient number of patients with metastatic or inoperable melanoma and a KIT mutation. Therefore, they redesigned the study into a single-arm phase II trial of nilotinib alone.

Researchers at the University of Pittsburgh also termed nilotinib a promising agent for melanoma patients with relevant KIT mutations in a review article (Expert Opin. Investig. Drugs 2012;21:861-9).

Dasatinib

Dr. Harriet Kluger and her colleagues at Yale University in New Haven, Conn., reported mixed efficacy for dasatinib in a phase II study (Cancer 2011;117:2202-8).

"At this point I would say that other than in the setting of patients with c-KIT mutations in their tumors, which is still being studied, dasatinib is not a promising agent for this disease," Dr. Kluger said in an interview. She is on the medical oncology faculty at Yale.

She and her colleagues studied 36 evaluable patients with stage 3 or 4 unresectable melanoma. Dasatinib was associated with two partial responses (24 weeks and 64 weeks) and three minor responses. Another patient who initially responded discontinued because of noncompliance. The median progression-free survival was 8 weeks, and the 6-month progression-free survival was 13%. Some activity of dasatinib was observed in a small subset of patients without KIT mutations, suggesting that more research is needed to identify predictive biomarkers for response to this inhibitor.

The KIT gene is located on chromosome 4 and codes for a family of proteins, the receptor tyrosine kinases. KIT function is essential for normal melanocyte genesis and migration. KIT protein signaling also is important for the development of reproductive germ cells, early hematopoietic stem cells, immune mast cells, and interstitial cells of Cajal located in the gastrointestinal tract.

Available data suggest that patients with mutations affecting exons 11 or 13 of KIT may be more likely to achieve clinical benefit with KIT inhibition, Dr. Carvajal said. He added that greater expression of the mutant KIT allele, compared with the wild type, may be a marker of tumors more "addicted" to KIT activation and that may be more susceptible to inhibition.

"This work is still fairly new," he said.

Dr. Carvajal is a consultant to Novartis. Dr. Minor and Dr. Kluger said that they had no relevant disclosures.

ORLANDO – Patients who express a KIT genetic abnormality represent a small minority of those with melanoma, but there is a lot of interest in the development of specific inhibitors, said Dr. Richard D. Carvajal at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Studies from Dr. Carvajal and other researchers indicate that inhibitors could significantly prolong median progression-free survival for patients who have amplification, overexpression, or a mutation of this genetic driver of melanoma.

In his phase II study of Novartis’ imatinib (Gleevec) for patients with melanoma and KIT alterations, 4 of 25 evaluable patients responded, for an overall durable response rate of 16%. Median progression-free survival was "pretty modest at 3 to 3.5 months," Dr. Carvajal said. Two patients had a complete response to therapy, and another two achieved a partial response (JAMA 2011;305:2327-34).

"So the question is: Can we better select patients likely to respond?" Dr. Carvajal asked at the meeting. "Certainly this is not vemurafenib [Zelboraf], where we get a response in 50% of patients. It could be due to variability in KIT mutations," said Dr. Carvajal, a medical oncologist specializing in melanoma and sarcomas at Memorial Sloan-Kettering Cancer Center in New York.

Only 3% of patients with melanoma harbor a KIT mutation. "You have to have a mutation in KIT; otherwise, the patient is not going to respond to imatinib," he said. The study was preceded by three negative clinical trials in unselected patients (before the mutation was identified).

In another phase II study enrolling only patients with KIT alterations, investigators reported that 10 of 43 patients responded to treatment with imatinib, for a 23% overall response rate (J. Clin. Oncol. 2011;29:2904-9).

Studies are underway with potential KIT inhibitors other than imatinib, including Pfizer’s sunitinib (Sutent), Novartis’ nilotinib (Tasigna), and Bristol-Myers Squibb’s dasatinib (Sprycel).

Sunitinib

Sunitinib is "reasonably promising" for melanoma patients with KIT mutations, said Dr. David Minor, of the California Pacific Center for Melanoma Research and Treatment at the University of California, San Francisco.

He and his colleagues conducted gene sequencing of tumors from 90 patients with advanced melanoma. The findings revealed that 11% featured a KIT mutation (Clin. Cancer Res. 2012:18:1457-63).

Ten of 12 patients treated with sunitinib were evaluable – 4 with KIT mutations and 6 with KIT amplification or overexpression. Although the mutation was a significant predictor of shortened survival time, treatment with sunitinib was associated with complete remission in 1 patient for 15 months and 2 partial responses for 1 and 7 months, he noted. A KIT mutation might be more clinically relevant because there were no complete responses and only one partial response in patients with KIT amplification or overexpression. Dr. Minor is director of inpatient oncology at the California Pacific Medical Center.

Nilotinib

Because only a small percentage of melanoma patients harbor a KIT mutation, conducting large efficacy studies remains a challenge, Dr. Carvajal said. "Indeed, a randomized, phase III trial of nilotinib versus DTIC [dacarbazine] in KIT-mutant melanoma was designed to be the definitive study demonstrating improved outcomes with nilotinib versus DTIC," he said. However, after patient accrual began for the TEAM (Tasigna Efficacy in Advanced Melanoma) trial in 2010, researchers reported difficulty enrolling a sufficient number of patients with metastatic or inoperable melanoma and a KIT mutation. Therefore, they redesigned the study into a single-arm phase II trial of nilotinib alone.

Researchers at the University of Pittsburgh also termed nilotinib a promising agent for melanoma patients with relevant KIT mutations in a review article (Expert Opin. Investig. Drugs 2012;21:861-9).

Dasatinib

Dr. Harriet Kluger and her colleagues at Yale University in New Haven, Conn., reported mixed efficacy for dasatinib in a phase II study (Cancer 2011;117:2202-8).

"At this point I would say that other than in the setting of patients with c-KIT mutations in their tumors, which is still being studied, dasatinib is not a promising agent for this disease," Dr. Kluger said in an interview. She is on the medical oncology faculty at Yale.

She and her colleagues studied 36 evaluable patients with stage 3 or 4 unresectable melanoma. Dasatinib was associated with two partial responses (24 weeks and 64 weeks) and three minor responses. Another patient who initially responded discontinued because of noncompliance. The median progression-free survival was 8 weeks, and the 6-month progression-free survival was 13%. Some activity of dasatinib was observed in a small subset of patients without KIT mutations, suggesting that more research is needed to identify predictive biomarkers for response to this inhibitor.

The KIT gene is located on chromosome 4 and codes for a family of proteins, the receptor tyrosine kinases. KIT function is essential for normal melanocyte genesis and migration. KIT protein signaling also is important for the development of reproductive germ cells, early hematopoietic stem cells, immune mast cells, and interstitial cells of Cajal located in the gastrointestinal tract.

Available data suggest that patients with mutations affecting exons 11 or 13 of KIT may be more likely to achieve clinical benefit with KIT inhibition, Dr. Carvajal said. He added that greater expression of the mutant KIT allele, compared with the wild type, may be a marker of tumors more "addicted" to KIT activation and that may be more susceptible to inhibition.

"This work is still fairly new," he said.

Dr. Carvajal is a consultant to Novartis. Dr. Minor and Dr. Kluger said that they had no relevant disclosures.