NCCN Annual Conference 2014

HOLLYWOOD, FLA. – Patients with stage T1b gallbladder cancer who can tolerate surgery should undergo radical cholecystectomy, Dr. Chandrakanth Are said at the annual conference of the National Comprehensive Cancer Network.

Although there is little controversy about the need for simple cholecystectomy in patients with carcinoma in situ and those with T1a disease, or about the need for radical cholecystectomy in those with T2 disease or in those with T3 disease in whom the procedure will be curative, there has been less certainty about the treatment for T1b disease, said Dr. Are.

"Ten to 15 years ago we weren’t doing [radical cholecystectomy] in these patients, but we found out that is probably what we should be doing," he said. Multiple studies suggest that about 15% of patients with T1b disease have positive lymph nodes, compared with less than 3% of those with T1a disease, and that more than 10% of T1a and T1b patients have residual disease after simple cholecystectomy, with most of those cases attributable to T1b disease, he noted.

The problem is that patients with T1b disease, as well as patients with T2 disease, remain undertreated, said Dr. Are of the Fred & Pamela Buffett Cancer Center at the Nebraska Medical Center, Omaha.

At least two studies have demonstrated that few eligible patients undergo radical cholecystectomy. Both studies used data from the Surveillance, Epidemiology, and End Results (SEER) registry.

One showed that of 2,385 resected patients with T1-T3 M0 gallbladder cancer, only 8.6% underwent en bloc resection, and 5.3% had a lymphadenectomy (J. Am. Coll Surg. 2008;207:371-82).

Another showed that of 382 patients with T2 disease, only 14 underwent radical cholecystectomy (Am. J. Surg. 2007;194:820-5).

"If this is the fate of patients with T2, imagine where patients with T1b stand," he said, adding that more education is needed about the appropriate management of patients with Stage T1b disease, and more emphasis should be placed on referring these patients to centers of excellence.

Dr. Are cited other controversies in the treatment of gallbladder cancer as follows:

• Bile duct resection. Historically, bile duct resection has been performed at the time of cholecystectomy, but this practice has been found to increase morbidity without providing any survival benefit, Dr. Are said.

Current thinking is that bile duct resection should be performed only in patients with a positive cystic duct margin (because studies suggest that more than 40% of such cases will have common bile duct involvement), and in cases in which extensive lymph node dissection is necessary and might cause ischemia of the duct, he said.

• Extent of lymph node excision. There has been uncertainty regarding the appropriate number of lymph nodes to excise, but data suggest that survival improves with excision of five or more. In one study in which lymph node data were available for more than 2,500 patients, 68% had no lymph nodes excised, 28% had one to four excised, and 4% had more than five excised. The hazard ratios for survival were 0.55 (P less than .001) for one to four vs. no nodes, and 0.63 (P = .03) for more than five nodes vs. one to four nodes (Arch. Surg. 2011;146:734-8).

Another study of 122 patients showed improved survival among those with greater than six vs. less than six nodes excised, although the median total lymph node count was three (Ann. Surg. 2011;254:320-5).

The matter of setting a standard for the number of lymph nodes to dissect was discussed at a consensus conference in January, and guidelines are forthcoming.

Dr. Are predicted the consensus will be that three to six lymph nodes should be excised.

• Port sites metastases. Studies suggest that up to 19% of patients who undergo laparoscopic cholecystectomy will develop port site metastases, and it was thought that these sites should be resected. However, recent findings from a series of 113 patients, of whom 19% developed port site metastases, showed that while survival was significantly worse in those patients (42 months vs. 17 months in those without port site metastases), resection did not change the outcome (Ann. Surg. Oncol. 2012;19:409-17).

The current thinking is that port site metastases is a marker of underlying aggressive disease, and that resection is not warranted, Dr. Are said.

• Jaundice. A number of patients with gallbladder cancer present with jaundice, and data from countries in the West where the disease incidence is relatively low have suggested that jaundice is associated with poor prognosis and is thus a contraindication to resection. One U.S. study showed a 6-month survival among resected patients with jaundice, compared with 16 months for those with no jaundice. None of the patients with jaundice survived 2 years, compared with 21% of those without jaundice (Ann. Surg. Oncol. 2004;11:310-15).

Subsequent studies, including studies from India where the incidence is much higher, showed better survival. One, for example, demonstrated 50% survival among resected patients with jaundice; another demonstrated 23% 5-year survival.

"So the current recommendation is that the presence of jaundice is still a contraindication [to resection], but not an absolute contraindication," Dr. Are said.

It is a relative contraindication in selected patients; those with appropriate T stage who are fit enough for surgery and anesthesia should proceed to surgery, he added, noting that in those who are unresectable, it is important to think of biliary drainage.

"Unless you do that, it will be hard for them to get chemotherapy," he said.

• Extent of hepatic resection. The standard of care with respect to hepatic resection at the time of radical cholecystectomy is to resect only segments 4b and 5 of the liver. The controversy is whether more should be resected.

Data as to whether more extensive resection confers a survival benefit have been conflicting, with some studies showing a benefit with right lobectomy or extended right lobectomy, and others showing no such benefit, Dr. Are said.

The current standard of resecting 4b and 5 is adequate, except in selected cases where the intent of resecting more is to obtain negative margins, he said.

Dr. Are reported having no relevant disclosures.

HOLLYWOOD, FLA. – Patients with stage T1b gallbladder cancer who can tolerate surgery should undergo radical cholecystectomy, Dr. Chandrakanth Are said at the annual conference of the National Comprehensive Cancer Network.

Although there is little controversy about the need for simple cholecystectomy in patients with carcinoma in situ and those with T1a disease, or about the need for radical cholecystectomy in those with T2 disease or in those with T3 disease in whom the procedure will be curative, there has been less certainty about the treatment for T1b disease, said Dr. Are.

"Ten to 15 years ago we weren’t doing [radical cholecystectomy] in these patients, but we found out that is probably what we should be doing," he said. Multiple studies suggest that about 15% of patients with T1b disease have positive lymph nodes, compared with less than 3% of those with T1a disease, and that more than 10% of T1a and T1b patients have residual disease after simple cholecystectomy, with most of those cases attributable to T1b disease, he noted.

The problem is that patients with T1b disease, as well as patients with T2 disease, remain undertreated, said Dr. Are of the Fred & Pamela Buffett Cancer Center at the Nebraska Medical Center, Omaha.

At least two studies have demonstrated that few eligible patients undergo radical cholecystectomy. Both studies used data from the Surveillance, Epidemiology, and End Results (SEER) registry.

One showed that of 2,385 resected patients with T1-T3 M0 gallbladder cancer, only 8.6% underwent en bloc resection, and 5.3% had a lymphadenectomy (J. Am. Coll Surg. 2008;207:371-82).

Another showed that of 382 patients with T2 disease, only 14 underwent radical cholecystectomy (Am. J. Surg. 2007;194:820-5).

"If this is the fate of patients with T2, imagine where patients with T1b stand," he said, adding that more education is needed about the appropriate management of patients with Stage T1b disease, and more emphasis should be placed on referring these patients to centers of excellence.

Dr. Are cited other controversies in the treatment of gallbladder cancer as follows:

• Bile duct resection. Historically, bile duct resection has been performed at the time of cholecystectomy, but this practice has been found to increase morbidity without providing any survival benefit, Dr. Are said.

Current thinking is that bile duct resection should be performed only in patients with a positive cystic duct margin (because studies suggest that more than 40% of such cases will have common bile duct involvement), and in cases in which extensive lymph node dissection is necessary and might cause ischemia of the duct, he said.

• Extent of lymph node excision. There has been uncertainty regarding the appropriate number of lymph nodes to excise, but data suggest that survival improves with excision of five or more. In one study in which lymph node data were available for more than 2,500 patients, 68% had no lymph nodes excised, 28% had one to four excised, and 4% had more than five excised. The hazard ratios for survival were 0.55 (P less than .001) for one to four vs. no nodes, and 0.63 (P = .03) for more than five nodes vs. one to four nodes (Arch. Surg. 2011;146:734-8).

Another study of 122 patients showed improved survival among those with greater than six vs. less than six nodes excised, although the median total lymph node count was three (Ann. Surg. 2011;254:320-5).

The matter of setting a standard for the number of lymph nodes to dissect was discussed at a consensus conference in January, and guidelines are forthcoming.

Dr. Are predicted the consensus will be that three to six lymph nodes should be excised.

• Port sites metastases. Studies suggest that up to 19% of patients who undergo laparoscopic cholecystectomy will develop port site metastases, and it was thought that these sites should be resected. However, recent findings from a series of 113 patients, of whom 19% developed port site metastases, showed that while survival was significantly worse in those patients (42 months vs. 17 months in those without port site metastases), resection did not change the outcome (Ann. Surg. Oncol. 2012;19:409-17).

The current thinking is that port site metastases is a marker of underlying aggressive disease, and that resection is not warranted, Dr. Are said.

• Jaundice. A number of patients with gallbladder cancer present with jaundice, and data from countries in the West where the disease incidence is relatively low have suggested that jaundice is associated with poor prognosis and is thus a contraindication to resection. One U.S. study showed a 6-month survival among resected patients with jaundice, compared with 16 months for those with no jaundice. None of the patients with jaundice survived 2 years, compared with 21% of those without jaundice (Ann. Surg. Oncol. 2004;11:310-15).

Subsequent studies, including studies from India where the incidence is much higher, showed better survival. One, for example, demonstrated 50% survival among resected patients with jaundice; another demonstrated 23% 5-year survival.

"So the current recommendation is that the presence of jaundice is still a contraindication [to resection], but not an absolute contraindication," Dr. Are said.

It is a relative contraindication in selected patients; those with appropriate T stage who are fit enough for surgery and anesthesia should proceed to surgery, he added, noting that in those who are unresectable, it is important to think of biliary drainage.

"Unless you do that, it will be hard for them to get chemotherapy," he said.

• Extent of hepatic resection. The standard of care with respect to hepatic resection at the time of radical cholecystectomy is to resect only segments 4b and 5 of the liver. The controversy is whether more should be resected.

Data as to whether more extensive resection confers a survival benefit have been conflicting, with some studies showing a benefit with right lobectomy or extended right lobectomy, and others showing no such benefit, Dr. Are said.

The current standard of resecting 4b and 5 is adequate, except in selected cases where the intent of resecting more is to obtain negative margins, he said.

Dr. Are reported having no relevant disclosures.

HOLLYWOOD, FLA. – Patients with stage T1b gallbladder cancer who can tolerate surgery should undergo radical cholecystectomy, Dr. Chandrakanth Are said at the annual conference of the National Comprehensive Cancer Network.

Although there is little controversy about the need for simple cholecystectomy in patients with carcinoma in situ and those with T1a disease, or about the need for radical cholecystectomy in those with T2 disease or in those with T3 disease in whom the procedure will be curative, there has been less certainty about the treatment for T1b disease, said Dr. Are.

"Ten to 15 years ago we weren’t doing [radical cholecystectomy] in these patients, but we found out that is probably what we should be doing," he said. Multiple studies suggest that about 15% of patients with T1b disease have positive lymph nodes, compared with less than 3% of those with T1a disease, and that more than 10% of T1a and T1b patients have residual disease after simple cholecystectomy, with most of those cases attributable to T1b disease, he noted.

The problem is that patients with T1b disease, as well as patients with T2 disease, remain undertreated, said Dr. Are of the Fred & Pamela Buffett Cancer Center at the Nebraska Medical Center, Omaha.

At least two studies have demonstrated that few eligible patients undergo radical cholecystectomy. Both studies used data from the Surveillance, Epidemiology, and End Results (SEER) registry.

One showed that of 2,385 resected patients with T1-T3 M0 gallbladder cancer, only 8.6% underwent en bloc resection, and 5.3% had a lymphadenectomy (J. Am. Coll Surg. 2008;207:371-82).

Another showed that of 382 patients with T2 disease, only 14 underwent radical cholecystectomy (Am. J. Surg. 2007;194:820-5).

"If this is the fate of patients with T2, imagine where patients with T1b stand," he said, adding that more education is needed about the appropriate management of patients with Stage T1b disease, and more emphasis should be placed on referring these patients to centers of excellence.

Dr. Are cited other controversies in the treatment of gallbladder cancer as follows:

• Bile duct resection. Historically, bile duct resection has been performed at the time of cholecystectomy, but this practice has been found to increase morbidity without providing any survival benefit, Dr. Are said.

Current thinking is that bile duct resection should be performed only in patients with a positive cystic duct margin (because studies suggest that more than 40% of such cases will have common bile duct involvement), and in cases in which extensive lymph node dissection is necessary and might cause ischemia of the duct, he said.

• Extent of lymph node excision. There has been uncertainty regarding the appropriate number of lymph nodes to excise, but data suggest that survival improves with excision of five or more. In one study in which lymph node data were available for more than 2,500 patients, 68% had no lymph nodes excised, 28% had one to four excised, and 4% had more than five excised. The hazard ratios for survival were 0.55 (P less than .001) for one to four vs. no nodes, and 0.63 (P = .03) for more than five nodes vs. one to four nodes (Arch. Surg. 2011;146:734-8).

Another study of 122 patients showed improved survival among those with greater than six vs. less than six nodes excised, although the median total lymph node count was three (Ann. Surg. 2011;254:320-5).

The matter of setting a standard for the number of lymph nodes to dissect was discussed at a consensus conference in January, and guidelines are forthcoming.

Dr. Are predicted the consensus will be that three to six lymph nodes should be excised.

• Port sites metastases. Studies suggest that up to 19% of patients who undergo laparoscopic cholecystectomy will develop port site metastases, and it was thought that these sites should be resected. However, recent findings from a series of 113 patients, of whom 19% developed port site metastases, showed that while survival was significantly worse in those patients (42 months vs. 17 months in those without port site metastases), resection did not change the outcome (Ann. Surg. Oncol. 2012;19:409-17).

The current thinking is that port site metastases is a marker of underlying aggressive disease, and that resection is not warranted, Dr. Are said.

• Jaundice. A number of patients with gallbladder cancer present with jaundice, and data from countries in the West where the disease incidence is relatively low have suggested that jaundice is associated with poor prognosis and is thus a contraindication to resection. One U.S. study showed a 6-month survival among resected patients with jaundice, compared with 16 months for those with no jaundice. None of the patients with jaundice survived 2 years, compared with 21% of those without jaundice (Ann. Surg. Oncol. 2004;11:310-15).

Subsequent studies, including studies from India where the incidence is much higher, showed better survival. One, for example, demonstrated 50% survival among resected patients with jaundice; another demonstrated 23% 5-year survival.

"So the current recommendation is that the presence of jaundice is still a contraindication [to resection], but not an absolute contraindication," Dr. Are said.

It is a relative contraindication in selected patients; those with appropriate T stage who are fit enough for surgery and anesthesia should proceed to surgery, he added, noting that in those who are unresectable, it is important to think of biliary drainage.

"Unless you do that, it will be hard for them to get chemotherapy," he said.

• Extent of hepatic resection. The standard of care with respect to hepatic resection at the time of radical cholecystectomy is to resect only segments 4b and 5 of the liver. The controversy is whether more should be resected.

Data as to whether more extensive resection confers a survival benefit have been conflicting, with some studies showing a benefit with right lobectomy or extended right lobectomy, and others showing no such benefit, Dr. Are said.

The current standard of resecting 4b and 5 is adequate, except in selected cases where the intent of resecting more is to obtain negative margins, he said.

Dr. Are reported having no relevant disclosures.

HOLLYWOOD, FLA. – The ongoing exploration of immune therapy options for non–small cell lung cancer is a particularly exciting area of lung cancer research, because "traditionally, immune therapy hasn’t worked in lung cancer," according to Dr. Leora Horn.

The results of the exploration thus far suggest that is no longer the case.

A programmed death-1 (PD-1) inhibitor and a PD-1 ligand (PD-L1) inhibitor, for example, were shown in recent phase I studies to prolong progression-free and overall survival in NSCLC patients, and other similar agents are currently in development, Dr. Horn of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said at the annual conference of the National Comprehensive Cancer Network.

In one study, median progression-free and overall survival among 129 heavily pretreated NSCLC patients who received the PD-1 inhibitor nivolumab – an IgG4 monoclonal antibody - were 2.3 and 9.6 months, respectively (N. Engl. J. Med. 2012;366:2455-65), Dr. Horn said.

The patients received intravenous nivolumab monotherapy at doses of 1, 3, or 10 mg/kg every 2 weeks for up to 12 cycles.

"These data presented a couple of years ago showed us a really impressive response rate of 17% for all patients treated with nivolumab. What we also saw was a slightly higher response rate in the patients treated with the 3-mg/kg dose of 24.3%," she said.

Stable disease was also seen in a significant number of patients (8.1% at 24 weeks and 5.4% at 48 weeks), and the median overall survival among those in the 3-g/kg group was 14.9 months, which is "very impressive for this heavily pretreated population," she noted.

The median overall survival among those with squamous cell lung cancer was 9.2 months, and the overall stable disease rate was 14.8%; among those with nonsquamous disease, the overall survival was 10.1 months, and the stable disease rate was 6.8%, Dr. Horn noted.

In this study, nivolumab was fairly well tolerated; the rate of grade 3-4 drug-related adverse events was 14%, the most common being fatigue in 24% of patients, decreased appetite in 12%, and diarrhea in 10%.

"Importantly for this group of patients, a new toxicity that we’re dealing with is pneumonitis, and drug-related pneumonitis occurred in eight NSCLC patients. Three patients had grade 3-4 pneumonitis, of which two cases were fatal," Dr. Horn said, noting that the deaths occurred early in the study, "before we were aware of this particular toxicity in this patient population."

The anti–PD-L1 agent MPDL3280A is also showing promise in an ongoing phase Ia expansion study. Patients in that study received 10, 15, or 20 mg/kg by IV every 3 weeks for up to 16 cycles for 1 year.

"Again, what we saw in this trial was rapid durable responses in both squamous and nonsquamous non–small cell lung cancer patients," she said.

Most responded by 12 or 21 weeks of therapy, and durable responses were seen even after discontinuation of therapy.

The response rate was best (83%) in patients in whom at least 10% of their tumor was positive for expression of PD-L1. The response rates were 46% and 31% in patients in whom at least 5% and 1% of their tumor was positive for expression of PD-L1, respectively.

"The overall response rate was 23% for the patient population, indicating that there were tumors that were PD-L1 negative that responded to therapy," Dr. Horn said.

Response rates were higher among former/current smokers than in never smokers (26% vs. 10%), but they did not differ significantly by EGFR or KRAS mutational status.

This agent was extremely well tolerated; the majority of adverse events were grade 1-2 and did not require intervention, and there was no maximum tolerated dose or dose-limiting toxicity.

"And importantly for patients on this trial, no grade 3-5 pneumonitis was observed, and this may have to do with differential expression of PD-1 vs. PD-2 within the lung."

A number of phase II and III studies involving these and other immune therapy agents for NSCLC are now underway, including studies of MPDL3180A in patients with PD-L1-positive NSCLC, in combination with bevacizumab and/or chemotherapy, and compared with docetaxel as second-line therapy in PD-L1-positive NSCLC.

Nivolumab is being compared with chemotherapy as first-line therapy in PD-L1-positive NSCLC, and is being evaluated with vs. without ipilimumab in SCLC.

Other immune therapy agents in development include the PD-1 inhibitor MK3475 and the PD-L1 inhibitors MEDI-4736 and MSB0010718C. MK3475 is being evaluated in PD-L1-positive NSCLC, is being compared with docetaxel as second-line therapy in PD-L1-positive NSCLC, and is being studied in combination with chemotherapy and targeted therapy. MEDI-4736 is currently being evaluated in a phase I dose-escalation study in expanded cohorts.

Dr. Horn reported receiving grant or research support from Astellas Pharma, and consulting fees or honoraria from Boehringer Ingelheim. She has served as a scientific adviser for Bristol-Myers Squibb, Helix BioPharma, and Puma Biotechnology.

HOLLYWOOD, FLA. – The ongoing exploration of immune therapy options for non–small cell lung cancer is a particularly exciting area of lung cancer research, because "traditionally, immune therapy hasn’t worked in lung cancer," according to Dr. Leora Horn.

The results of the exploration thus far suggest that is no longer the case.

A programmed death-1 (PD-1) inhibitor and a PD-1 ligand (PD-L1) inhibitor, for example, were shown in recent phase I studies to prolong progression-free and overall survival in NSCLC patients, and other similar agents are currently in development, Dr. Horn of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said at the annual conference of the National Comprehensive Cancer Network.

In one study, median progression-free and overall survival among 129 heavily pretreated NSCLC patients who received the PD-1 inhibitor nivolumab – an IgG4 monoclonal antibody - were 2.3 and 9.6 months, respectively (N. Engl. J. Med. 2012;366:2455-65), Dr. Horn said.

The patients received intravenous nivolumab monotherapy at doses of 1, 3, or 10 mg/kg every 2 weeks for up to 12 cycles.

"These data presented a couple of years ago showed us a really impressive response rate of 17% for all patients treated with nivolumab. What we also saw was a slightly higher response rate in the patients treated with the 3-mg/kg dose of 24.3%," she said.

Stable disease was also seen in a significant number of patients (8.1% at 24 weeks and 5.4% at 48 weeks), and the median overall survival among those in the 3-g/kg group was 14.9 months, which is "very impressive for this heavily pretreated population," she noted.

The median overall survival among those with squamous cell lung cancer was 9.2 months, and the overall stable disease rate was 14.8%; among those with nonsquamous disease, the overall survival was 10.1 months, and the stable disease rate was 6.8%, Dr. Horn noted.

In this study, nivolumab was fairly well tolerated; the rate of grade 3-4 drug-related adverse events was 14%, the most common being fatigue in 24% of patients, decreased appetite in 12%, and diarrhea in 10%.

"Importantly for this group of patients, a new toxicity that we’re dealing with is pneumonitis, and drug-related pneumonitis occurred in eight NSCLC patients. Three patients had grade 3-4 pneumonitis, of which two cases were fatal," Dr. Horn said, noting that the deaths occurred early in the study, "before we were aware of this particular toxicity in this patient population."

The anti–PD-L1 agent MPDL3280A is also showing promise in an ongoing phase Ia expansion study. Patients in that study received 10, 15, or 20 mg/kg by IV every 3 weeks for up to 16 cycles for 1 year.

"Again, what we saw in this trial was rapid durable responses in both squamous and nonsquamous non–small cell lung cancer patients," she said.

Most responded by 12 or 21 weeks of therapy, and durable responses were seen even after discontinuation of therapy.

The response rate was best (83%) in patients in whom at least 10% of their tumor was positive for expression of PD-L1. The response rates were 46% and 31% in patients in whom at least 5% and 1% of their tumor was positive for expression of PD-L1, respectively.

"The overall response rate was 23% for the patient population, indicating that there were tumors that were PD-L1 negative that responded to therapy," Dr. Horn said.

Response rates were higher among former/current smokers than in never smokers (26% vs. 10%), but they did not differ significantly by EGFR or KRAS mutational status.

This agent was extremely well tolerated; the majority of adverse events were grade 1-2 and did not require intervention, and there was no maximum tolerated dose or dose-limiting toxicity.

"And importantly for patients on this trial, no grade 3-5 pneumonitis was observed, and this may have to do with differential expression of PD-1 vs. PD-2 within the lung."

A number of phase II and III studies involving these and other immune therapy agents for NSCLC are now underway, including studies of MPDL3180A in patients with PD-L1-positive NSCLC, in combination with bevacizumab and/or chemotherapy, and compared with docetaxel as second-line therapy in PD-L1-positive NSCLC.

Nivolumab is being compared with chemotherapy as first-line therapy in PD-L1-positive NSCLC, and is being evaluated with vs. without ipilimumab in SCLC.

Other immune therapy agents in development include the PD-1 inhibitor MK3475 and the PD-L1 inhibitors MEDI-4736 and MSB0010718C. MK3475 is being evaluated in PD-L1-positive NSCLC, is being compared with docetaxel as second-line therapy in PD-L1-positive NSCLC, and is being studied in combination with chemotherapy and targeted therapy. MEDI-4736 is currently being evaluated in a phase I dose-escalation study in expanded cohorts.

Dr. Horn reported receiving grant or research support from Astellas Pharma, and consulting fees or honoraria from Boehringer Ingelheim. She has served as a scientific adviser for Bristol-Myers Squibb, Helix BioPharma, and Puma Biotechnology.

HOLLYWOOD, FLA. – The ongoing exploration of immune therapy options for non–small cell lung cancer is a particularly exciting area of lung cancer research, because "traditionally, immune therapy hasn’t worked in lung cancer," according to Dr. Leora Horn.

The results of the exploration thus far suggest that is no longer the case.

A programmed death-1 (PD-1) inhibitor and a PD-1 ligand (PD-L1) inhibitor, for example, were shown in recent phase I studies to prolong progression-free and overall survival in NSCLC patients, and other similar agents are currently in development, Dr. Horn of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said at the annual conference of the National Comprehensive Cancer Network.

In one study, median progression-free and overall survival among 129 heavily pretreated NSCLC patients who received the PD-1 inhibitor nivolumab – an IgG4 monoclonal antibody - were 2.3 and 9.6 months, respectively (N. Engl. J. Med. 2012;366:2455-65), Dr. Horn said.

The patients received intravenous nivolumab monotherapy at doses of 1, 3, or 10 mg/kg every 2 weeks for up to 12 cycles.

"These data presented a couple of years ago showed us a really impressive response rate of 17% for all patients treated with nivolumab. What we also saw was a slightly higher response rate in the patients treated with the 3-mg/kg dose of 24.3%," she said.

Stable disease was also seen in a significant number of patients (8.1% at 24 weeks and 5.4% at 48 weeks), and the median overall survival among those in the 3-g/kg group was 14.9 months, which is "very impressive for this heavily pretreated population," she noted.

The median overall survival among those with squamous cell lung cancer was 9.2 months, and the overall stable disease rate was 14.8%; among those with nonsquamous disease, the overall survival was 10.1 months, and the stable disease rate was 6.8%, Dr. Horn noted.

In this study, nivolumab was fairly well tolerated; the rate of grade 3-4 drug-related adverse events was 14%, the most common being fatigue in 24% of patients, decreased appetite in 12%, and diarrhea in 10%.

"Importantly for this group of patients, a new toxicity that we’re dealing with is pneumonitis, and drug-related pneumonitis occurred in eight NSCLC patients. Three patients had grade 3-4 pneumonitis, of which two cases were fatal," Dr. Horn said, noting that the deaths occurred early in the study, "before we were aware of this particular toxicity in this patient population."

The anti–PD-L1 agent MPDL3280A is also showing promise in an ongoing phase Ia expansion study. Patients in that study received 10, 15, or 20 mg/kg by IV every 3 weeks for up to 16 cycles for 1 year.

"Again, what we saw in this trial was rapid durable responses in both squamous and nonsquamous non–small cell lung cancer patients," she said.

Most responded by 12 or 21 weeks of therapy, and durable responses were seen even after discontinuation of therapy.

The response rate was best (83%) in patients in whom at least 10% of their tumor was positive for expression of PD-L1. The response rates were 46% and 31% in patients in whom at least 5% and 1% of their tumor was positive for expression of PD-L1, respectively.

"The overall response rate was 23% for the patient population, indicating that there were tumors that were PD-L1 negative that responded to therapy," Dr. Horn said.

Response rates were higher among former/current smokers than in never smokers (26% vs. 10%), but they did not differ significantly by EGFR or KRAS mutational status.

This agent was extremely well tolerated; the majority of adverse events were grade 1-2 and did not require intervention, and there was no maximum tolerated dose or dose-limiting toxicity.

"And importantly for patients on this trial, no grade 3-5 pneumonitis was observed, and this may have to do with differential expression of PD-1 vs. PD-2 within the lung."

A number of phase II and III studies involving these and other immune therapy agents for NSCLC are now underway, including studies of MPDL3180A in patients with PD-L1-positive NSCLC, in combination with bevacizumab and/or chemotherapy, and compared with docetaxel as second-line therapy in PD-L1-positive NSCLC.

Nivolumab is being compared with chemotherapy as first-line therapy in PD-L1-positive NSCLC, and is being evaluated with vs. without ipilimumab in SCLC.

Other immune therapy agents in development include the PD-1 inhibitor MK3475 and the PD-L1 inhibitors MEDI-4736 and MSB0010718C. MK3475 is being evaluated in PD-L1-positive NSCLC, is being compared with docetaxel as second-line therapy in PD-L1-positive NSCLC, and is being studied in combination with chemotherapy and targeted therapy. MEDI-4736 is currently being evaluated in a phase I dose-escalation study in expanded cohorts.

Dr. Horn reported receiving grant or research support from Astellas Pharma, and consulting fees or honoraria from Boehringer Ingelheim. She has served as a scientific adviser for Bristol-Myers Squibb, Helix BioPharma, and Puma Biotechnology.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

HOLLYWOOD, FLA. – Compliance with tamoxifen treatment regimens among hormone receptor–positive breast cancer patients is suboptimal, but use of an oral liquid formulation could help change that, findings from a large CAPTURE (Compliance and Preference for Tamoxifen Registry) Internet-based survey suggest.

Of 626 women with breast cancer who were using tamoxifen and who participated in the health care provider–administered survey, 88 (14%) reported missing between 2 and 10 doses each month, and 75 (12%) said they had stopped taking tamoxifen for periods of more than 2 weeks; 13% said they would prefer an oral liquid formulation over the tablet formulation, 22% said they would be willing to try an oral liquid formulation, and 7% said they believed an oral liquid formulation would help them improve long-term adherence, Dr. Stefan Gluck reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Of those who reported missing two or more doses per month, 22% said they would prefer an oral liquid formulation, 30% said they would try a liquid formulation, and 16% said they thought an oral liquid formulation would help improve their compliance, said Dr. Gluck of the University of Miami Health System’s Sylvester Comprehensive Cancer Center, Miami.

Responses on the validated Eating Assessment Tool (EAT-10), which was administered along with the 36-item survey, suggested that swallowing difficulties contributed to the lack of compliance in 48 (8%) of respondents, Dr. Gluck said.

Those with swallowing difficulties did not differ significantly from the overall study population with respect to age, race, or education, although a higher percentage of those with swallowing difficulties had undergone a mastectomy (65% vs. 46%), and had experienced or been diagnosed with persistent or frequent symptoms of heartburn, acid reflux, or gastroesophageal reflux disease (44% vs. 26%). Of those with swallowing difficulties, 35% said they would prefer an oral liquid form, 50% said they were willing to try a liquid formulation, and 25% said a liquid formulation would help improve their compliance with long-term tamoxifen therapy.

Reasons given for stopping tamoxifen for more than 2 weeks included side effects in 27% of cases, physician recommendation in 17% of cases, "felt better" in 4% of cases, expense in 3% of cases, and "other" reasons in 49% of cases.

Respondents were women with a mean age of 55 years at a mean of 3 years since breast cancer diagnosis. Most (66%) had invasive disease, 29% had noninvasive disease, and 5% had metastatic disease. The vast majority (97%) had undergone surgery, 58% received radiation therapy, and 47% received chemotherapy. The women had been taking tamoxifen for a median of 2 years, with the vast majority (98%) taking a 20-mg dose.

The importance of adherence to 5 full years of tamoxifen for long-term positive outcomes in women with hormone receptor–positive breast cancer has been well documented, and breast cancer treatment guidelines updated by the National Comprehensive Cancer Network in March 2013 recommend consideration of up to 10 years of tamoxifen therapy, Dr. Gluck noted.

Though limited by factors inherent in survey methodology, including self-reported data, the findings of this study "provide an avenue for improving the adherence of patients to long-term tamoxifen treatment by providing them a choice between a tablet and an oral liquid," he concluded.

CAPTURE is a project of DARA BioSciences, which markets the only Food and Drug Administration–approved liquid tamoxifen formulation (Soltamox).

HOLLYWOOD, FLA. – Compliance with tamoxifen treatment regimens among hormone receptor–positive breast cancer patients is suboptimal, but use of an oral liquid formulation could help change that, findings from a large CAPTURE (Compliance and Preference for Tamoxifen Registry) Internet-based survey suggest.

Of 626 women with breast cancer who were using tamoxifen and who participated in the health care provider–administered survey, 88 (14%) reported missing between 2 and 10 doses each month, and 75 (12%) said they had stopped taking tamoxifen for periods of more than 2 weeks; 13% said they would prefer an oral liquid formulation over the tablet formulation, 22% said they would be willing to try an oral liquid formulation, and 7% said they believed an oral liquid formulation would help them improve long-term adherence, Dr. Stefan Gluck reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Of those who reported missing two or more doses per month, 22% said they would prefer an oral liquid formulation, 30% said they would try a liquid formulation, and 16% said they thought an oral liquid formulation would help improve their compliance, said Dr. Gluck of the University of Miami Health System’s Sylvester Comprehensive Cancer Center, Miami.

Responses on the validated Eating Assessment Tool (EAT-10), which was administered along with the 36-item survey, suggested that swallowing difficulties contributed to the lack of compliance in 48 (8%) of respondents, Dr. Gluck said.

Those with swallowing difficulties did not differ significantly from the overall study population with respect to age, race, or education, although a higher percentage of those with swallowing difficulties had undergone a mastectomy (65% vs. 46%), and had experienced or been diagnosed with persistent or frequent symptoms of heartburn, acid reflux, or gastroesophageal reflux disease (44% vs. 26%). Of those with swallowing difficulties, 35% said they would prefer an oral liquid form, 50% said they were willing to try a liquid formulation, and 25% said a liquid formulation would help improve their compliance with long-term tamoxifen therapy.

Reasons given for stopping tamoxifen for more than 2 weeks included side effects in 27% of cases, physician recommendation in 17% of cases, "felt better" in 4% of cases, expense in 3% of cases, and "other" reasons in 49% of cases.

Respondents were women with a mean age of 55 years at a mean of 3 years since breast cancer diagnosis. Most (66%) had invasive disease, 29% had noninvasive disease, and 5% had metastatic disease. The vast majority (97%) had undergone surgery, 58% received radiation therapy, and 47% received chemotherapy. The women had been taking tamoxifen for a median of 2 years, with the vast majority (98%) taking a 20-mg dose.

The importance of adherence to 5 full years of tamoxifen for long-term positive outcomes in women with hormone receptor–positive breast cancer has been well documented, and breast cancer treatment guidelines updated by the National Comprehensive Cancer Network in March 2013 recommend consideration of up to 10 years of tamoxifen therapy, Dr. Gluck noted.

Though limited by factors inherent in survey methodology, including self-reported data, the findings of this study "provide an avenue for improving the adherence of patients to long-term tamoxifen treatment by providing them a choice between a tablet and an oral liquid," he concluded.

CAPTURE is a project of DARA BioSciences, which markets the only Food and Drug Administration–approved liquid tamoxifen formulation (Soltamox).

HOLLYWOOD, FLA. – Compliance with tamoxifen treatment regimens among hormone receptor–positive breast cancer patients is suboptimal, but use of an oral liquid formulation could help change that, findings from a large CAPTURE (Compliance and Preference for Tamoxifen Registry) Internet-based survey suggest.

Of 626 women with breast cancer who were using tamoxifen and who participated in the health care provider–administered survey, 88 (14%) reported missing between 2 and 10 doses each month, and 75 (12%) said they had stopped taking tamoxifen for periods of more than 2 weeks; 13% said they would prefer an oral liquid formulation over the tablet formulation, 22% said they would be willing to try an oral liquid formulation, and 7% said they believed an oral liquid formulation would help them improve long-term adherence, Dr. Stefan Gluck reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Of those who reported missing two or more doses per month, 22% said they would prefer an oral liquid formulation, 30% said they would try a liquid formulation, and 16% said they thought an oral liquid formulation would help improve their compliance, said Dr. Gluck of the University of Miami Health System’s Sylvester Comprehensive Cancer Center, Miami.

Responses on the validated Eating Assessment Tool (EAT-10), which was administered along with the 36-item survey, suggested that swallowing difficulties contributed to the lack of compliance in 48 (8%) of respondents, Dr. Gluck said.

Those with swallowing difficulties did not differ significantly from the overall study population with respect to age, race, or education, although a higher percentage of those with swallowing difficulties had undergone a mastectomy (65% vs. 46%), and had experienced or been diagnosed with persistent or frequent symptoms of heartburn, acid reflux, or gastroesophageal reflux disease (44% vs. 26%). Of those with swallowing difficulties, 35% said they would prefer an oral liquid form, 50% said they were willing to try a liquid formulation, and 25% said a liquid formulation would help improve their compliance with long-term tamoxifen therapy.

Reasons given for stopping tamoxifen for more than 2 weeks included side effects in 27% of cases, physician recommendation in 17% of cases, "felt better" in 4% of cases, expense in 3% of cases, and "other" reasons in 49% of cases.

Respondents were women with a mean age of 55 years at a mean of 3 years since breast cancer diagnosis. Most (66%) had invasive disease, 29% had noninvasive disease, and 5% had metastatic disease. The vast majority (97%) had undergone surgery, 58% received radiation therapy, and 47% received chemotherapy. The women had been taking tamoxifen for a median of 2 years, with the vast majority (98%) taking a 20-mg dose.

The importance of adherence to 5 full years of tamoxifen for long-term positive outcomes in women with hormone receptor–positive breast cancer has been well documented, and breast cancer treatment guidelines updated by the National Comprehensive Cancer Network in March 2013 recommend consideration of up to 10 years of tamoxifen therapy, Dr. Gluck noted.

Though limited by factors inherent in survey methodology, including self-reported data, the findings of this study "provide an avenue for improving the adherence of patients to long-term tamoxifen treatment by providing them a choice between a tablet and an oral liquid," he concluded.

CAPTURE is a project of DARA BioSciences, which markets the only Food and Drug Administration–approved liquid tamoxifen formulation (Soltamox).