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New treatment options emerge for intermediate, advanced HCC
SAN FRANCISCO – Two new therapies that target vascular endothelial growth factor signaling are efficacious and may expand the treatment armamentarium for intermediate and advanced hepatocellular carcinoma, data from a pair of randomized trials suggest.
In the phase 2 TACTICS (Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib) trial, median progression-free survival, using a new, more narrow definition of progression, was almost a year longer when the oral tyrosine kinase inhibitor sorafenib (Nexavar) was added to transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), translating to a 41% reduction in risk of events. This benefit came at the price of higher rates of certain grade 3 adverse events, but the combination was overall feasible and safe.
Results of both trials were reported at the 2018 GI Cancers Symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
As welcome as such new therapeutic options are, they will likely increase the complexity of the treatment landscape for HCC and could muddy the ability of future trials to establish survival benefit, Jordi Bruix, MD, PhD, cautioned in an invited discussion. In addition, patients who cannot receive anti–vascular endothelial growth factor (VEGF) therapy because of comorbidities still represent an unmet need, underscoring the importance of continued research on other fronts.
TACTICS trial
“Because TACE has been shown to lead to a spike in the intratumoral concentration of VEGF, blockade of VEGF receptors may prevent the effects of a surge in proangiogenic factors,” said TACTICS lead investigator Masatoshi Kudo, MD, professor and chairman of the department of gastroenterology and hepatology at Kindai University, Osaka, Japan. “Since TACE and sorafenib have been shown to prolong survival in patients with unresectable HCC, their combination may improve clinical outcomes.”
The 156 patients enrolled in the TACTICS trial, sponsored by the Japan Liver Oncology Group, had unresectable HCC, a Child-Pugh score of 7 or lower, and no vascular invasion or extrahepatic spread.
They were randomly assigned to as-needed TACE alone or TACE plus sorafenib, which inhibits VEGF receptors, platelet-derived growth factor receptors, and Raf kinases, reducing growth signaling and angiogenesis. Sorafenib therapy was interrupted only for several days before and after each TACE session.
With a median follow-up of 2.4 years, median progression-free survival using a new definition of progression – either untreatable “unTACEable” disease or TACE failure/refractoriness (by Japanese Society of Hepatology criteria) – was 25.2 months with TACE plus sorafenib compared with 13.5 months with TACE alone (hazard ratio, 0.59; P = .006). Benefit was similar across patient subgroups.
Overall survival results are not yet mature, according to Dr. Kudo. Overall response rate and disease control rate did not differ significantly between groups.
Adding sorafenib to TACE led to higher rates of certain grade 3 adverse events, including thrombocytopenia (12.8% vs. 2.8%), hand-foot skin reaction (5.1% vs. 0%), and hypertension (10.3% vs. 4.2%). But there were no unexpected events.
The trial’s positive results contrast with those of the earlier randomized Post-TACE trial, SPACE trial, and TACE 2 trial, noted Dr. Kudo. This may be due to both the new, narrower definition of progression and the longer duration of sorafenib therapy in TACTICS (median 38.7 weeks) as compared with those trials (17.0-21.0 weeks).
“The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage HCC,” he concluded.
CELESTIAL trial
The 707 patients in the phase 3 CELESTIAL trial, sponsored by Exelixis, had advanced HCC with Child-Pugh class A and had previously received sorafenib. About 70% had received only one prior systemic regimen for their advanced disease, according to lead investigator Ghassan K. Abou-Alfa, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center, New York.
Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (HR, 0.76; P = .0049). Median progression-free survival was 5.2 months and 1.9 months, respectively (HR, 0.44; P less than .0001). For both outcomes, benefit was similar across most patient subgroups and among patients whose only prior therapy was sorafenib.
The objective response rate was 4% with cabozantinib (all partial responses) and 0.4% with placebo. Median time to subsequent systemic anticancer therapy – most commonly cytotoxic chemotherapy – was 6.6 months with the drug and 3.3 months with placebo.
Median duration of treatment was 3.8 months and 2.0 months, respectively. The rate of discontinuation from treatment-related adverse events was 16% and 3%.
Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group (mainly hand-foot syndrome, hypertension, and gastrointestinal events) and 36% in the placebo group. Six patients in the former group and one in the latter group had grade 5 treatment-related adverse events, most due to worsening of hepatic function.
“Cabozantinib represents a new treatment option for advanced HCC patients after prior systemic anticancer therapy,” concluded Dr. Abou-Alfa.
New treatments increase options, complexity
The new endpoint of unTACEable progression used in TACTICS “is an interesting potential surrogate endpoint for survival. It probably needs to be refined. I would not follow exactly the Japanese methodology,” said Dr. Bruix, the invited discussant.
“More importantly, it needs to be validated,” he added. “The survival data need to be there to see what is the value of the surrogate intermediate endpoint.”
The pattern of overall survival thus far suggests that an early advantage from adding sorafenib to TACE is lost over time. “Potentially, what we have here is the treatment maintained a bit beyond what would be recommended in the Western guidelines,” proposed Dr. Bruix, professor of medicine at the University of Barcelona and director of the Barcelona Clinic Liver Cancer Group. “The longer duration of sorafenib obviously may be related to the specific management in Japan, but also to the fact that progression recognition is delayed. If you delay recognition, you delay the definition of treatment interruption.”
Results of TACTICS probably will not lead to incorporation of sorafenib in clinical practice at this time, he concluded. “This will take a while. There is lots of noise in the chemoembolization trials, there are lots of discussions about what should be done.” In addition, “this should be studied in the West and in a large sample size.”
In the CELESTIAL trial, it would have been helpful to see biomarker data (given that tumor MET status may influence benefit from cabozantinib) and patient stratification according to reason for stopping prior sorafenib (intolerance versus progression), according to Dr. Bruix.
Furthermore, pattern of progression was not reported. “What drives a poorer outcome [in HCC] is the extrahepatic dissemination, meaning vascular invasion or extrahepatic spread. The trials, at least as a post hoc analysis, should have nowadays this kind of analysis that I think is not going to be available in the cabozantinib trial,” he said.
The fact that time to progression with cabozantinib was longer than time on the drug hints at possible safety and tolerability issues, according to Dr. Bruix. “This makes me suspect that some patients had something prior to progression that primed treatment interruption. This is something that I would like to see better explored … to understand to what extent the drug is safe, can be managed, or whether there are too many treatment interruptions that can lead to this discrepancy.”
All of the emerging systemic therapies for first- and second-line therapy in HCC, now also including immune checkpoint inhibitors, are likely to complicate the treatment landscape in the next few years, he cautioned. “The positioning of agents and the sequencing of treatments is different across the world. So there may be confusion in the field and that will affect all the trials that are going to be run by different companies, because if we do not maintain the discipline, patients will jump from one trial to the other and the follow-up after progression will be contaminated.” Ultimately, this could lead to noninformative trials.
Finally, “something that needs to be stated is that all the agents that are positive act on the VEGF pathway. This leaves a proportion of patients that cannot benefit from these agents because of comorbidity that are still in need of something that improves survival,” Dr. Bruix concluded. “We all should focus beyond VEGF and try to develop new strategies.”
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 206. Abou-Alfa GK et al. GI Cancers Symposium, Abstract 207.
SAN FRANCISCO – Two new therapies that target vascular endothelial growth factor signaling are efficacious and may expand the treatment armamentarium for intermediate and advanced hepatocellular carcinoma, data from a pair of randomized trials suggest.
In the phase 2 TACTICS (Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib) trial, median progression-free survival, using a new, more narrow definition of progression, was almost a year longer when the oral tyrosine kinase inhibitor sorafenib (Nexavar) was added to transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), translating to a 41% reduction in risk of events. This benefit came at the price of higher rates of certain grade 3 adverse events, but the combination was overall feasible and safe.
Results of both trials were reported at the 2018 GI Cancers Symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
As welcome as such new therapeutic options are, they will likely increase the complexity of the treatment landscape for HCC and could muddy the ability of future trials to establish survival benefit, Jordi Bruix, MD, PhD, cautioned in an invited discussion. In addition, patients who cannot receive anti–vascular endothelial growth factor (VEGF) therapy because of comorbidities still represent an unmet need, underscoring the importance of continued research on other fronts.
TACTICS trial
“Because TACE has been shown to lead to a spike in the intratumoral concentration of VEGF, blockade of VEGF receptors may prevent the effects of a surge in proangiogenic factors,” said TACTICS lead investigator Masatoshi Kudo, MD, professor and chairman of the department of gastroenterology and hepatology at Kindai University, Osaka, Japan. “Since TACE and sorafenib have been shown to prolong survival in patients with unresectable HCC, their combination may improve clinical outcomes.”
The 156 patients enrolled in the TACTICS trial, sponsored by the Japan Liver Oncology Group, had unresectable HCC, a Child-Pugh score of 7 or lower, and no vascular invasion or extrahepatic spread.
They were randomly assigned to as-needed TACE alone or TACE plus sorafenib, which inhibits VEGF receptors, platelet-derived growth factor receptors, and Raf kinases, reducing growth signaling and angiogenesis. Sorafenib therapy was interrupted only for several days before and after each TACE session.
With a median follow-up of 2.4 years, median progression-free survival using a new definition of progression – either untreatable “unTACEable” disease or TACE failure/refractoriness (by Japanese Society of Hepatology criteria) – was 25.2 months with TACE plus sorafenib compared with 13.5 months with TACE alone (hazard ratio, 0.59; P = .006). Benefit was similar across patient subgroups.
Overall survival results are not yet mature, according to Dr. Kudo. Overall response rate and disease control rate did not differ significantly between groups.
Adding sorafenib to TACE led to higher rates of certain grade 3 adverse events, including thrombocytopenia (12.8% vs. 2.8%), hand-foot skin reaction (5.1% vs. 0%), and hypertension (10.3% vs. 4.2%). But there were no unexpected events.
The trial’s positive results contrast with those of the earlier randomized Post-TACE trial, SPACE trial, and TACE 2 trial, noted Dr. Kudo. This may be due to both the new, narrower definition of progression and the longer duration of sorafenib therapy in TACTICS (median 38.7 weeks) as compared with those trials (17.0-21.0 weeks).
“The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage HCC,” he concluded.
CELESTIAL trial
The 707 patients in the phase 3 CELESTIAL trial, sponsored by Exelixis, had advanced HCC with Child-Pugh class A and had previously received sorafenib. About 70% had received only one prior systemic regimen for their advanced disease, according to lead investigator Ghassan K. Abou-Alfa, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center, New York.
Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (HR, 0.76; P = .0049). Median progression-free survival was 5.2 months and 1.9 months, respectively (HR, 0.44; P less than .0001). For both outcomes, benefit was similar across most patient subgroups and among patients whose only prior therapy was sorafenib.
The objective response rate was 4% with cabozantinib (all partial responses) and 0.4% with placebo. Median time to subsequent systemic anticancer therapy – most commonly cytotoxic chemotherapy – was 6.6 months with the drug and 3.3 months with placebo.
Median duration of treatment was 3.8 months and 2.0 months, respectively. The rate of discontinuation from treatment-related adverse events was 16% and 3%.
Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group (mainly hand-foot syndrome, hypertension, and gastrointestinal events) and 36% in the placebo group. Six patients in the former group and one in the latter group had grade 5 treatment-related adverse events, most due to worsening of hepatic function.
“Cabozantinib represents a new treatment option for advanced HCC patients after prior systemic anticancer therapy,” concluded Dr. Abou-Alfa.
New treatments increase options, complexity
The new endpoint of unTACEable progression used in TACTICS “is an interesting potential surrogate endpoint for survival. It probably needs to be refined. I would not follow exactly the Japanese methodology,” said Dr. Bruix, the invited discussant.
“More importantly, it needs to be validated,” he added. “The survival data need to be there to see what is the value of the surrogate intermediate endpoint.”
The pattern of overall survival thus far suggests that an early advantage from adding sorafenib to TACE is lost over time. “Potentially, what we have here is the treatment maintained a bit beyond what would be recommended in the Western guidelines,” proposed Dr. Bruix, professor of medicine at the University of Barcelona and director of the Barcelona Clinic Liver Cancer Group. “The longer duration of sorafenib obviously may be related to the specific management in Japan, but also to the fact that progression recognition is delayed. If you delay recognition, you delay the definition of treatment interruption.”
Results of TACTICS probably will not lead to incorporation of sorafenib in clinical practice at this time, he concluded. “This will take a while. There is lots of noise in the chemoembolization trials, there are lots of discussions about what should be done.” In addition, “this should be studied in the West and in a large sample size.”
In the CELESTIAL trial, it would have been helpful to see biomarker data (given that tumor MET status may influence benefit from cabozantinib) and patient stratification according to reason for stopping prior sorafenib (intolerance versus progression), according to Dr. Bruix.
Furthermore, pattern of progression was not reported. “What drives a poorer outcome [in HCC] is the extrahepatic dissemination, meaning vascular invasion or extrahepatic spread. The trials, at least as a post hoc analysis, should have nowadays this kind of analysis that I think is not going to be available in the cabozantinib trial,” he said.
The fact that time to progression with cabozantinib was longer than time on the drug hints at possible safety and tolerability issues, according to Dr. Bruix. “This makes me suspect that some patients had something prior to progression that primed treatment interruption. This is something that I would like to see better explored … to understand to what extent the drug is safe, can be managed, or whether there are too many treatment interruptions that can lead to this discrepancy.”
All of the emerging systemic therapies for first- and second-line therapy in HCC, now also including immune checkpoint inhibitors, are likely to complicate the treatment landscape in the next few years, he cautioned. “The positioning of agents and the sequencing of treatments is different across the world. So there may be confusion in the field and that will affect all the trials that are going to be run by different companies, because if we do not maintain the discipline, patients will jump from one trial to the other and the follow-up after progression will be contaminated.” Ultimately, this could lead to noninformative trials.
Finally, “something that needs to be stated is that all the agents that are positive act on the VEGF pathway. This leaves a proportion of patients that cannot benefit from these agents because of comorbidity that are still in need of something that improves survival,” Dr. Bruix concluded. “We all should focus beyond VEGF and try to develop new strategies.”
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 206. Abou-Alfa GK et al. GI Cancers Symposium, Abstract 207.
SAN FRANCISCO – Two new therapies that target vascular endothelial growth factor signaling are efficacious and may expand the treatment armamentarium for intermediate and advanced hepatocellular carcinoma, data from a pair of randomized trials suggest.
In the phase 2 TACTICS (Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib) trial, median progression-free survival, using a new, more narrow definition of progression, was almost a year longer when the oral tyrosine kinase inhibitor sorafenib (Nexavar) was added to transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), translating to a 41% reduction in risk of events. This benefit came at the price of higher rates of certain grade 3 adverse events, but the combination was overall feasible and safe.
Results of both trials were reported at the 2018 GI Cancers Symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
As welcome as such new therapeutic options are, they will likely increase the complexity of the treatment landscape for HCC and could muddy the ability of future trials to establish survival benefit, Jordi Bruix, MD, PhD, cautioned in an invited discussion. In addition, patients who cannot receive anti–vascular endothelial growth factor (VEGF) therapy because of comorbidities still represent an unmet need, underscoring the importance of continued research on other fronts.
TACTICS trial
“Because TACE has been shown to lead to a spike in the intratumoral concentration of VEGF, blockade of VEGF receptors may prevent the effects of a surge in proangiogenic factors,” said TACTICS lead investigator Masatoshi Kudo, MD, professor and chairman of the department of gastroenterology and hepatology at Kindai University, Osaka, Japan. “Since TACE and sorafenib have been shown to prolong survival in patients with unresectable HCC, their combination may improve clinical outcomes.”
The 156 patients enrolled in the TACTICS trial, sponsored by the Japan Liver Oncology Group, had unresectable HCC, a Child-Pugh score of 7 or lower, and no vascular invasion or extrahepatic spread.
They were randomly assigned to as-needed TACE alone or TACE plus sorafenib, which inhibits VEGF receptors, platelet-derived growth factor receptors, and Raf kinases, reducing growth signaling and angiogenesis. Sorafenib therapy was interrupted only for several days before and after each TACE session.
With a median follow-up of 2.4 years, median progression-free survival using a new definition of progression – either untreatable “unTACEable” disease or TACE failure/refractoriness (by Japanese Society of Hepatology criteria) – was 25.2 months with TACE plus sorafenib compared with 13.5 months with TACE alone (hazard ratio, 0.59; P = .006). Benefit was similar across patient subgroups.
Overall survival results are not yet mature, according to Dr. Kudo. Overall response rate and disease control rate did not differ significantly between groups.
Adding sorafenib to TACE led to higher rates of certain grade 3 adverse events, including thrombocytopenia (12.8% vs. 2.8%), hand-foot skin reaction (5.1% vs. 0%), and hypertension (10.3% vs. 4.2%). But there were no unexpected events.
The trial’s positive results contrast with those of the earlier randomized Post-TACE trial, SPACE trial, and TACE 2 trial, noted Dr. Kudo. This may be due to both the new, narrower definition of progression and the longer duration of sorafenib therapy in TACTICS (median 38.7 weeks) as compared with those trials (17.0-21.0 weeks).
“The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage HCC,” he concluded.
CELESTIAL trial
The 707 patients in the phase 3 CELESTIAL trial, sponsored by Exelixis, had advanced HCC with Child-Pugh class A and had previously received sorafenib. About 70% had received only one prior systemic regimen for their advanced disease, according to lead investigator Ghassan K. Abou-Alfa, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center, New York.
Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (HR, 0.76; P = .0049). Median progression-free survival was 5.2 months and 1.9 months, respectively (HR, 0.44; P less than .0001). For both outcomes, benefit was similar across most patient subgroups and among patients whose only prior therapy was sorafenib.
The objective response rate was 4% with cabozantinib (all partial responses) and 0.4% with placebo. Median time to subsequent systemic anticancer therapy – most commonly cytotoxic chemotherapy – was 6.6 months with the drug and 3.3 months with placebo.
Median duration of treatment was 3.8 months and 2.0 months, respectively. The rate of discontinuation from treatment-related adverse events was 16% and 3%.
Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group (mainly hand-foot syndrome, hypertension, and gastrointestinal events) and 36% in the placebo group. Six patients in the former group and one in the latter group had grade 5 treatment-related adverse events, most due to worsening of hepatic function.
“Cabozantinib represents a new treatment option for advanced HCC patients after prior systemic anticancer therapy,” concluded Dr. Abou-Alfa.
New treatments increase options, complexity
The new endpoint of unTACEable progression used in TACTICS “is an interesting potential surrogate endpoint for survival. It probably needs to be refined. I would not follow exactly the Japanese methodology,” said Dr. Bruix, the invited discussant.
“More importantly, it needs to be validated,” he added. “The survival data need to be there to see what is the value of the surrogate intermediate endpoint.”
The pattern of overall survival thus far suggests that an early advantage from adding sorafenib to TACE is lost over time. “Potentially, what we have here is the treatment maintained a bit beyond what would be recommended in the Western guidelines,” proposed Dr. Bruix, professor of medicine at the University of Barcelona and director of the Barcelona Clinic Liver Cancer Group. “The longer duration of sorafenib obviously may be related to the specific management in Japan, but also to the fact that progression recognition is delayed. If you delay recognition, you delay the definition of treatment interruption.”
Results of TACTICS probably will not lead to incorporation of sorafenib in clinical practice at this time, he concluded. “This will take a while. There is lots of noise in the chemoembolization trials, there are lots of discussions about what should be done.” In addition, “this should be studied in the West and in a large sample size.”
In the CELESTIAL trial, it would have been helpful to see biomarker data (given that tumor MET status may influence benefit from cabozantinib) and patient stratification according to reason for stopping prior sorafenib (intolerance versus progression), according to Dr. Bruix.
Furthermore, pattern of progression was not reported. “What drives a poorer outcome [in HCC] is the extrahepatic dissemination, meaning vascular invasion or extrahepatic spread. The trials, at least as a post hoc analysis, should have nowadays this kind of analysis that I think is not going to be available in the cabozantinib trial,” he said.
The fact that time to progression with cabozantinib was longer than time on the drug hints at possible safety and tolerability issues, according to Dr. Bruix. “This makes me suspect that some patients had something prior to progression that primed treatment interruption. This is something that I would like to see better explored … to understand to what extent the drug is safe, can be managed, or whether there are too many treatment interruptions that can lead to this discrepancy.”
All of the emerging systemic therapies for first- and second-line therapy in HCC, now also including immune checkpoint inhibitors, are likely to complicate the treatment landscape in the next few years, he cautioned. “The positioning of agents and the sequencing of treatments is different across the world. So there may be confusion in the field and that will affect all the trials that are going to be run by different companies, because if we do not maintain the discipline, patients will jump from one trial to the other and the follow-up after progression will be contaminated.” Ultimately, this could lead to noninformative trials.
Finally, “something that needs to be stated is that all the agents that are positive act on the VEGF pathway. This leaves a proportion of patients that cannot benefit from these agents because of comorbidity that are still in need of something that improves survival,” Dr. Bruix concluded. “We all should focus beyond VEGF and try to develop new strategies.”
SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 206. Abou-Alfa GK et al. GI Cancers Symposium, Abstract 207.
REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: Progression-free survival was longer with TACE plus sorafenib vs. TACE alone (25.2 vs. 13.5 months; P = .006). Overall survival was longer with cabozantinib vs. placebo (10.2 vs. 8.0 months; P = .0049).
Data source: A randomized phase 2 trial among 156 patients with unresectable HCC (TACTICS trial). A randomized phase 3 trial among 707 patients with advanced HCC previously treated with sorafenib (CELESTIAL trial).
Disclosures: Dr. Kudo disclosed that he receives honoraria and research funding from, and has a consulting or advisory role with Bayer, among other disclosures; TACTICS was sponsored by the Japan Liver Oncology Group. Dr. Abou-Alfa disclosed that his institution receives research funding from Exelixis, among other disclosures; CELESTIAL was sponsored by Exelixis.
Source: Kudo M et al. GI Cancers Symposium, Abstract 206. Abou-Alfa GK et al. GI Cancers Symposium, Abstract 207.
Pembrolizumab nets durable responses in sorafenib-treated advanced HCC
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab is active and well tolerated when used as second-line therapy for hepatocellular carcinoma, according to results of the KEYNOTE-224 trial.
The 104 patients treated on the single-arm, open-label phase 2 trial had advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar), the standard of care for first-line therapy. All received monotherapy with pembrolizumab (Keytruda), an anti–programmed death 1 antibody.
A quarter of patients experienced grade 3 or worse treatment–related adverse events, but only about 7% stopped treatment because of such events.
“Pembrolizumab treatment demonstrated efficacy in advanced HCC previously treated with sorafenib as evidenced by durable responses and promising progression-free and overall survival,” said Andrew X. Zhu, MD, PhD, director of liver cancer research at Massachusetts General Hospital, Boston, and a professor of medicine at Harvard Medical School, Boston. “The safety profile was generally comparable to what has been established for pembrolizumab monotherapy in other indications, and no viral flares were seen in this cohort.”
The investigators are analyzing data for biomarkers such as programmed death ligand 1, alpha-fetoprotein, and microsatellite instability, to identify predictors of benefit, he added. In addition, a phase 3 randomized trial evaluating pembrolizumab versus placebo as second-line therapy in this population (KEYNOTE-240) is under way.
Session cochair Shishir K. Maithel, MD, of Emory University, Atlanta wondered whether the findings are robust enough to justify use of immune checkpoint inhibitors earlier in the course of HCC today.
“Do we have to wait for the trials that look at immunotherapy in the first-line setting before we start using immunotherapy in the first-line setting?” he asked. “I’ve spoken with many people, and it seems like, based on these data in the second line, people have actually moved immunotherapy to the first line, given the relatively modest responses to sorafenib.”
“It’s fair to say the ongoing first-line trial is needed to definitively demonstrate whether there is an overall survival benefit,” Dr. Zhu replied. “As of now, nivolumab [Opdivo] is approved in the second-line setting. If you are really evidence based, we still have to follow the guideline. But having said that, in selected settings, it’s up to the treating physician’s consideration and mutual agreement and discussion with the patient. I think decisions will be made regardless of what you say or I say.”
Patients treated in the KEYNOTE-224 trial, sponsored by Merck, had stopped sorafenib because of progression (80%) or intolerance (20%). Some 21.2% were hepatitis B virus–positive and 26% were hepatitis C virus–positive.
Additional findings showed that median time to response with pembrolizumab was 2.1 months, corresponding to the timing of the first planned response assessment, Dr. Zhu said at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The disease control rate was 61.5%. Waterfall plots showed a similar pattern of responses regardless of whether patients had hepatitis B virus infection, hepatitis C virus infection, or no hepatitis virus infection.
The rate of grade 3 or worse adverse events was 25%; the rate of events leading to discontinuation was just 6.7%, and the rate of events leading to death was 1.0%, reported Dr. Zhu. The most common events of any grade were pruritus (21.2%) and fatigue (12.5%).
In terms of hepatic-related events, 2.9% of patients developed immune-mediated hepatitis on pembrolizumab, but none experienced a viral flare.
Dr. Zhu disclosed that he has a consulting or advisory role with Merck. The trial was sponsored by Merck.
SOURCE: Zhu AX et al. GI Cancers Symposium Abstract 209
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab is active and well tolerated when used as second-line therapy for hepatocellular carcinoma, according to results of the KEYNOTE-224 trial.
The 104 patients treated on the single-arm, open-label phase 2 trial had advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar), the standard of care for first-line therapy. All received monotherapy with pembrolizumab (Keytruda), an anti–programmed death 1 antibody.
A quarter of patients experienced grade 3 or worse treatment–related adverse events, but only about 7% stopped treatment because of such events.
“Pembrolizumab treatment demonstrated efficacy in advanced HCC previously treated with sorafenib as evidenced by durable responses and promising progression-free and overall survival,” said Andrew X. Zhu, MD, PhD, director of liver cancer research at Massachusetts General Hospital, Boston, and a professor of medicine at Harvard Medical School, Boston. “The safety profile was generally comparable to what has been established for pembrolizumab monotherapy in other indications, and no viral flares were seen in this cohort.”
The investigators are analyzing data for biomarkers such as programmed death ligand 1, alpha-fetoprotein, and microsatellite instability, to identify predictors of benefit, he added. In addition, a phase 3 randomized trial evaluating pembrolizumab versus placebo as second-line therapy in this population (KEYNOTE-240) is under way.
Session cochair Shishir K. Maithel, MD, of Emory University, Atlanta wondered whether the findings are robust enough to justify use of immune checkpoint inhibitors earlier in the course of HCC today.
“Do we have to wait for the trials that look at immunotherapy in the first-line setting before we start using immunotherapy in the first-line setting?” he asked. “I’ve spoken with many people, and it seems like, based on these data in the second line, people have actually moved immunotherapy to the first line, given the relatively modest responses to sorafenib.”
“It’s fair to say the ongoing first-line trial is needed to definitively demonstrate whether there is an overall survival benefit,” Dr. Zhu replied. “As of now, nivolumab [Opdivo] is approved in the second-line setting. If you are really evidence based, we still have to follow the guideline. But having said that, in selected settings, it’s up to the treating physician’s consideration and mutual agreement and discussion with the patient. I think decisions will be made regardless of what you say or I say.”
Patients treated in the KEYNOTE-224 trial, sponsored by Merck, had stopped sorafenib because of progression (80%) or intolerance (20%). Some 21.2% were hepatitis B virus–positive and 26% were hepatitis C virus–positive.
Additional findings showed that median time to response with pembrolizumab was 2.1 months, corresponding to the timing of the first planned response assessment, Dr. Zhu said at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The disease control rate was 61.5%. Waterfall plots showed a similar pattern of responses regardless of whether patients had hepatitis B virus infection, hepatitis C virus infection, or no hepatitis virus infection.
The rate of grade 3 or worse adverse events was 25%; the rate of events leading to discontinuation was just 6.7%, and the rate of events leading to death was 1.0%, reported Dr. Zhu. The most common events of any grade were pruritus (21.2%) and fatigue (12.5%).
In terms of hepatic-related events, 2.9% of patients developed immune-mediated hepatitis on pembrolizumab, but none experienced a viral flare.
Dr. Zhu disclosed that he has a consulting or advisory role with Merck. The trial was sponsored by Merck.
SOURCE: Zhu AX et al. GI Cancers Symposium Abstract 209
SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab is active and well tolerated when used as second-line therapy for hepatocellular carcinoma, according to results of the KEYNOTE-224 trial.
The 104 patients treated on the single-arm, open-label phase 2 trial had advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar), the standard of care for first-line therapy. All received monotherapy with pembrolizumab (Keytruda), an anti–programmed death 1 antibody.
A quarter of patients experienced grade 3 or worse treatment–related adverse events, but only about 7% stopped treatment because of such events.
“Pembrolizumab treatment demonstrated efficacy in advanced HCC previously treated with sorafenib as evidenced by durable responses and promising progression-free and overall survival,” said Andrew X. Zhu, MD, PhD, director of liver cancer research at Massachusetts General Hospital, Boston, and a professor of medicine at Harvard Medical School, Boston. “The safety profile was generally comparable to what has been established for pembrolizumab monotherapy in other indications, and no viral flares were seen in this cohort.”
The investigators are analyzing data for biomarkers such as programmed death ligand 1, alpha-fetoprotein, and microsatellite instability, to identify predictors of benefit, he added. In addition, a phase 3 randomized trial evaluating pembrolizumab versus placebo as second-line therapy in this population (KEYNOTE-240) is under way.
Session cochair Shishir K. Maithel, MD, of Emory University, Atlanta wondered whether the findings are robust enough to justify use of immune checkpoint inhibitors earlier in the course of HCC today.
“Do we have to wait for the trials that look at immunotherapy in the first-line setting before we start using immunotherapy in the first-line setting?” he asked. “I’ve spoken with many people, and it seems like, based on these data in the second line, people have actually moved immunotherapy to the first line, given the relatively modest responses to sorafenib.”
“It’s fair to say the ongoing first-line trial is needed to definitively demonstrate whether there is an overall survival benefit,” Dr. Zhu replied. “As of now, nivolumab [Opdivo] is approved in the second-line setting. If you are really evidence based, we still have to follow the guideline. But having said that, in selected settings, it’s up to the treating physician’s consideration and mutual agreement and discussion with the patient. I think decisions will be made regardless of what you say or I say.”
Patients treated in the KEYNOTE-224 trial, sponsored by Merck, had stopped sorafenib because of progression (80%) or intolerance (20%). Some 21.2% were hepatitis B virus–positive and 26% were hepatitis C virus–positive.
Additional findings showed that median time to response with pembrolizumab was 2.1 months, corresponding to the timing of the first planned response assessment, Dr. Zhu said at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The disease control rate was 61.5%. Waterfall plots showed a similar pattern of responses regardless of whether patients had hepatitis B virus infection, hepatitis C virus infection, or no hepatitis virus infection.
The rate of grade 3 or worse adverse events was 25%; the rate of events leading to discontinuation was just 6.7%, and the rate of events leading to death was 1.0%, reported Dr. Zhu. The most common events of any grade were pruritus (21.2%) and fatigue (12.5%).
In terms of hepatic-related events, 2.9% of patients developed immune-mediated hepatitis on pembrolizumab, but none experienced a viral flare.
Dr. Zhu disclosed that he has a consulting or advisory role with Merck. The trial was sponsored by Merck.
SOURCE: Zhu AX et al. GI Cancers Symposium Abstract 209
REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: The overall response rate with pembrolizumab was 16.3%, and median duration of response was 8.2 months.
Data source: A single-arm phase 2 trial among 104 patients with advanced HCC previously treated with sorafenib (KEYNOTE-224).
Disclosures: Dr. Zhu disclosed that he has a consulting or advisory role with Merck. The trial was sponsored by Merck.
Source: Zhu AX et al. GI Cancers Symposium, Abstract 209
Sequence of regorafenib, cetuximab matters in later-line CRC therapy
SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.
Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).
Main results at a median follow-up of 29.0 months showed that median overall survival was almost 6 months longer when regorafenib was given first as compared with when cetuximab was given first, a difference translating to a 39% reduction in risk of death with the former sequence.
“These results suggest that overall survival was longer with regorafenib as the first treatment followed by cetuximab than that of the current standard sequence,” Dr. Shitara said. “Efficacy was observed in almost all subgroups.”
Progression-free survival on the first treatment did not differ significantly by agent, but on the second treatment, it was almost 3.5 months longer with cetuximab. “This might contribute to the overall survival difference,” he proposed.
The specific biologic mechanisms driving the differing efficacy of the two sequences are still unclear, but one possibility is that regorafenib downregulates MAP kinase and certain other signaling molecules, sensitizing cells to subsequent anti-EGFR therapy, Dr. Shitara said. “Biomarker analyses are still ongoing. We hope that further biomarker analysis will clarify the reason for the survival difference.”
The data did not reveal any unexpected safety signals. Although quality of life scores were lower with regorafenib during each treatment period, scores for all time on treatment were similar for the two sequences.
Clinical implications
“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.
“This trial adds excitement to the idea that there is still a lot of work to be done in sequencing of therapies and also our understanding of how induction of molecular events by one therapy, for instance, the cetuximab leading to RAS mutations, then affects how the downstream therapies work,” Dr. Hall maintained. “So maybe we need to think more intelligently about that.”
Study details
The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.
About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.
Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).
The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).
Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.
Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).
Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.
SOURCE: Shitara et al. GI Cancers Symposium Abstract 557
SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.
Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).
Main results at a median follow-up of 29.0 months showed that median overall survival was almost 6 months longer when regorafenib was given first as compared with when cetuximab was given first, a difference translating to a 39% reduction in risk of death with the former sequence.
“These results suggest that overall survival was longer with regorafenib as the first treatment followed by cetuximab than that of the current standard sequence,” Dr. Shitara said. “Efficacy was observed in almost all subgroups.”
Progression-free survival on the first treatment did not differ significantly by agent, but on the second treatment, it was almost 3.5 months longer with cetuximab. “This might contribute to the overall survival difference,” he proposed.
The specific biologic mechanisms driving the differing efficacy of the two sequences are still unclear, but one possibility is that regorafenib downregulates MAP kinase and certain other signaling molecules, sensitizing cells to subsequent anti-EGFR therapy, Dr. Shitara said. “Biomarker analyses are still ongoing. We hope that further biomarker analysis will clarify the reason for the survival difference.”
The data did not reveal any unexpected safety signals. Although quality of life scores were lower with regorafenib during each treatment period, scores for all time on treatment were similar for the two sequences.
Clinical implications
“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.
“This trial adds excitement to the idea that there is still a lot of work to be done in sequencing of therapies and also our understanding of how induction of molecular events by one therapy, for instance, the cetuximab leading to RAS mutations, then affects how the downstream therapies work,” Dr. Hall maintained. “So maybe we need to think more intelligently about that.”
Study details
The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.
About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.
Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).
The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).
Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.
Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).
Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.
SOURCE: Shitara et al. GI Cancers Symposium Abstract 557
SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.
Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).
Main results at a median follow-up of 29.0 months showed that median overall survival was almost 6 months longer when regorafenib was given first as compared with when cetuximab was given first, a difference translating to a 39% reduction in risk of death with the former sequence.
“These results suggest that overall survival was longer with regorafenib as the first treatment followed by cetuximab than that of the current standard sequence,” Dr. Shitara said. “Efficacy was observed in almost all subgroups.”
Progression-free survival on the first treatment did not differ significantly by agent, but on the second treatment, it was almost 3.5 months longer with cetuximab. “This might contribute to the overall survival difference,” he proposed.
The specific biologic mechanisms driving the differing efficacy of the two sequences are still unclear, but one possibility is that regorafenib downregulates MAP kinase and certain other signaling molecules, sensitizing cells to subsequent anti-EGFR therapy, Dr. Shitara said. “Biomarker analyses are still ongoing. We hope that further biomarker analysis will clarify the reason for the survival difference.”
The data did not reveal any unexpected safety signals. Although quality of life scores were lower with regorafenib during each treatment period, scores for all time on treatment were similar for the two sequences.
Clinical implications
“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.
“This trial adds excitement to the idea that there is still a lot of work to be done in sequencing of therapies and also our understanding of how induction of molecular events by one therapy, for instance, the cetuximab leading to RAS mutations, then affects how the downstream therapies work,” Dr. Hall maintained. “So maybe we need to think more intelligently about that.”
Study details
The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.
About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.
Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).
The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).
Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.
Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).
Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.
SOURCE: Shitara et al. GI Cancers Symposium Abstract 557
REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was given first (HR, 0.61; P = .029).
Data source: A multicenter, randomized, phase 2 trial of regorafenib followed by cetuximab, versus the reverse sequence, among 101 patients with metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and irinotecan (REVERCE trial).
Disclosures: Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.
Source: Shitara et al. GI Cancers Symposium Abstract 557
ROBOT trial compares surgical approaches to esophagectomy
SAN FRANCISCO – Patients undergoing had less morbidity and pain and similarly good oncologic outcomes, when the surgery was performed by robot-assisted laparoscopy instead of by the open technique, a phase 3 clinical trial has found.
Investigators of the ROBOT (Robot-assisted Thoracolaparoscopic Esophagectomy vs. Open Transthoracic Esophagectomy) trial, led by Pieter C. van der Sluis, MD, a surgeon at the University Medical Center Utrecht, the Netherlands, randomized 112 patients with resectable esophageal cancer to open transthoracic esophagectomy – considered to be the gold standard – or robot-assisted minimally invasive thoracolaparoscopic esophagectomy.
“Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy improves postoperative outcome. There were no differences in oncologic outcomes, and our oncologic outcomes were in concordance with the highest standards nowadays,” Dr. van der Sluis summarized. “This trial provides evidence for the minimally invasive approach over the open approach, and especially the robot-assisted minimally invasive esophagectomy.”
The investigators will report a full cost comparison separately. “We see that costs are lower, though not significantly lower, with the robot,” he said, giving a preview. “We are going to show that the real costs of the operation are in the complications. When you have complications that involve the ICU and reoperations, some patients are in the hospital for months after the surgery. So by investing a little extra money in the surgical procedure, you might actually get it back by reducing the complications.”
When asked by an attendee why the trial did not compare robotic esophagectomy with thoracoscopic esophagectomy, Dr. van der Sluis noted that such comparison is complicated by many factors; for example, the challenge of finding surgeons skilled in both techniques, and the likelihood of small differences in outcomes, potentially requiring enrollment of thousands of patients to have adequate study power. “We concluded that such a trial might not be feasible,” he said.
Parsing the findings
“The complication rates [in this trial] are very high in the robotic and open groups, much higher than reported in some well-controlled prospective and retrospective studies,” commented session attendee Kenneth Meredith, MD, FACS, professor at Florida State University, Sarasota, and director of gastrointestinal oncology, Sarasota Memorial Institute for Cancer Care.
He wondered how extensive the investigators’ experience with robotics was and how many cases they had done on their learning curve. Data from his group suggest that surgeons must perform 29 cases of robotic esophagectomy before the complication rate drops (Dis Esophagus. 2017;30:1-7).
“That’s more then half of the patients in the robotic arm of their study,” he noted in an interview. “I find this needs to be explained. If the authors are past their learning curve, why were the complication rates so high?” Additionally, the 80% rate in the open group “is among the highest I’ve seen in many years.”
The lack of significant differences in complete resection rate and in lymph node harvest was also surprising, as he and other robotics users have found that this technique can improve these outcomes, Dr. Meredith added. This could likewise be a learning curve phenomenon.
Although ROBOT’s comparison of robotic with open esophagectomy is relevant, “it would have been more relevant to compare robotic to minimally invasive esophagectomy [MIE],” he maintained, as MIE has been shown to improve outcomes relative to open surgery (Lancet. 2012;379:1887-92).
“There are many high-volume centers in MIE but not necessarily robotics. The two are often mutually exclusive, and a multicenter trial in which each center performs high volumes of their respective technique, rather then mandating each center perform an operation they may not be facile in,” would be practical, Dr. Meredith concluded.
Study details
“The main objective in our trial was to reduce surgical trauma and reduce the percentage of complications,” Dr. van der Sluis told attendees of the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Results showed that compared with peers in the open surgery group, patients in the robotic-assisted surgery group specifically had a lower rate of pulmonary complications (32% vs. 58%, P = .005), largely due to a reduction in rate of pneumonia (28% vs. 55%, P = .005), and a lower rate of cardiac complications (22% vs. 47%, P = .006), almost entirely due to a reduction in rate of atrial fibrillation (22% vs. 46%, P = .01).
There was a trend toward fewer wound infections with robotics (4% vs. 14%, P = .09), with a large difference in thoracic wound infections (0% vs. 9%, P = .06).
The two groups were statistically indistinguishable on rates of anastomotic leakage (24% and 20%) and recurrent laryngeal nerve injury (9% and 11%). The fairly high rate of anastomotic leakage was likely due to the center’s use of cervical anastomosis at the time of the trial, according to Dr. van der Sluis; they have since started using thoracic anastomosis, and will report results with that technique soon.
There was also no significant difference between groups in the rate of in-hospital mortality (4% with robotic surgery and 2% with open surgery), median hospital length of stay (14 and 16 days), and ICU length of stay (1 day in each group).
Patients in the robotics group more commonly had functional recovery within 2 weeks (70% vs. 51%, P = .04). And on the Quality of Life Questionnaire Core 30, they had better scores for health-related quality of life at discharge (57.9 vs 44.6, P = .02) and at 6 weeks (68.7 vs. 57.6, P = .03), and for physical functioning at discharge (54.5 vs. 41.0, P = .03) and 6 weeks (69.3 vs. 58.6, P = .049).
The two groups were similar on rates of R0 resection (93% and 96%) and median number of lymph nodes retrieved (27 and 25), reported Dr. van der Sluis. Pain during the first 14 days after surgery was lower for the robotics group (P = .003).
With a median follow-up of 40 months, the robotics and open groups did not differ significantly on disease-free survival (median, 26 and 28 months) and overall survival (not reached in either group).
Dr. van der Sluis disclosed no relevant conflicts of interest.
SOURCE: van der Sluis PC et al. 2018 GI Cancer Symposium, Abstract 156148
SAN FRANCISCO – Patients undergoing had less morbidity and pain and similarly good oncologic outcomes, when the surgery was performed by robot-assisted laparoscopy instead of by the open technique, a phase 3 clinical trial has found.
Investigators of the ROBOT (Robot-assisted Thoracolaparoscopic Esophagectomy vs. Open Transthoracic Esophagectomy) trial, led by Pieter C. van der Sluis, MD, a surgeon at the University Medical Center Utrecht, the Netherlands, randomized 112 patients with resectable esophageal cancer to open transthoracic esophagectomy – considered to be the gold standard – or robot-assisted minimally invasive thoracolaparoscopic esophagectomy.
“Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy improves postoperative outcome. There were no differences in oncologic outcomes, and our oncologic outcomes were in concordance with the highest standards nowadays,” Dr. van der Sluis summarized. “This trial provides evidence for the minimally invasive approach over the open approach, and especially the robot-assisted minimally invasive esophagectomy.”
The investigators will report a full cost comparison separately. “We see that costs are lower, though not significantly lower, with the robot,” he said, giving a preview. “We are going to show that the real costs of the operation are in the complications. When you have complications that involve the ICU and reoperations, some patients are in the hospital for months after the surgery. So by investing a little extra money in the surgical procedure, you might actually get it back by reducing the complications.”
When asked by an attendee why the trial did not compare robotic esophagectomy with thoracoscopic esophagectomy, Dr. van der Sluis noted that such comparison is complicated by many factors; for example, the challenge of finding surgeons skilled in both techniques, and the likelihood of small differences in outcomes, potentially requiring enrollment of thousands of patients to have adequate study power. “We concluded that such a trial might not be feasible,” he said.
Parsing the findings
“The complication rates [in this trial] are very high in the robotic and open groups, much higher than reported in some well-controlled prospective and retrospective studies,” commented session attendee Kenneth Meredith, MD, FACS, professor at Florida State University, Sarasota, and director of gastrointestinal oncology, Sarasota Memorial Institute for Cancer Care.
He wondered how extensive the investigators’ experience with robotics was and how many cases they had done on their learning curve. Data from his group suggest that surgeons must perform 29 cases of robotic esophagectomy before the complication rate drops (Dis Esophagus. 2017;30:1-7).
“That’s more then half of the patients in the robotic arm of their study,” he noted in an interview. “I find this needs to be explained. If the authors are past their learning curve, why were the complication rates so high?” Additionally, the 80% rate in the open group “is among the highest I’ve seen in many years.”
The lack of significant differences in complete resection rate and in lymph node harvest was also surprising, as he and other robotics users have found that this technique can improve these outcomes, Dr. Meredith added. This could likewise be a learning curve phenomenon.
Although ROBOT’s comparison of robotic with open esophagectomy is relevant, “it would have been more relevant to compare robotic to minimally invasive esophagectomy [MIE],” he maintained, as MIE has been shown to improve outcomes relative to open surgery (Lancet. 2012;379:1887-92).
“There are many high-volume centers in MIE but not necessarily robotics. The two are often mutually exclusive, and a multicenter trial in which each center performs high volumes of their respective technique, rather then mandating each center perform an operation they may not be facile in,” would be practical, Dr. Meredith concluded.
Study details
“The main objective in our trial was to reduce surgical trauma and reduce the percentage of complications,” Dr. van der Sluis told attendees of the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Results showed that compared with peers in the open surgery group, patients in the robotic-assisted surgery group specifically had a lower rate of pulmonary complications (32% vs. 58%, P = .005), largely due to a reduction in rate of pneumonia (28% vs. 55%, P = .005), and a lower rate of cardiac complications (22% vs. 47%, P = .006), almost entirely due to a reduction in rate of atrial fibrillation (22% vs. 46%, P = .01).
There was a trend toward fewer wound infections with robotics (4% vs. 14%, P = .09), with a large difference in thoracic wound infections (0% vs. 9%, P = .06).
The two groups were statistically indistinguishable on rates of anastomotic leakage (24% and 20%) and recurrent laryngeal nerve injury (9% and 11%). The fairly high rate of anastomotic leakage was likely due to the center’s use of cervical anastomosis at the time of the trial, according to Dr. van der Sluis; they have since started using thoracic anastomosis, and will report results with that technique soon.
There was also no significant difference between groups in the rate of in-hospital mortality (4% with robotic surgery and 2% with open surgery), median hospital length of stay (14 and 16 days), and ICU length of stay (1 day in each group).
Patients in the robotics group more commonly had functional recovery within 2 weeks (70% vs. 51%, P = .04). And on the Quality of Life Questionnaire Core 30, they had better scores for health-related quality of life at discharge (57.9 vs 44.6, P = .02) and at 6 weeks (68.7 vs. 57.6, P = .03), and for physical functioning at discharge (54.5 vs. 41.0, P = .03) and 6 weeks (69.3 vs. 58.6, P = .049).
The two groups were similar on rates of R0 resection (93% and 96%) and median number of lymph nodes retrieved (27 and 25), reported Dr. van der Sluis. Pain during the first 14 days after surgery was lower for the robotics group (P = .003).
With a median follow-up of 40 months, the robotics and open groups did not differ significantly on disease-free survival (median, 26 and 28 months) and overall survival (not reached in either group).
Dr. van der Sluis disclosed no relevant conflicts of interest.
SOURCE: van der Sluis PC et al. 2018 GI Cancer Symposium, Abstract 156148
SAN FRANCISCO – Patients undergoing had less morbidity and pain and similarly good oncologic outcomes, when the surgery was performed by robot-assisted laparoscopy instead of by the open technique, a phase 3 clinical trial has found.
Investigators of the ROBOT (Robot-assisted Thoracolaparoscopic Esophagectomy vs. Open Transthoracic Esophagectomy) trial, led by Pieter C. van der Sluis, MD, a surgeon at the University Medical Center Utrecht, the Netherlands, randomized 112 patients with resectable esophageal cancer to open transthoracic esophagectomy – considered to be the gold standard – or robot-assisted minimally invasive thoracolaparoscopic esophagectomy.
“Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open transthoracic esophagectomy improves postoperative outcome. There were no differences in oncologic outcomes, and our oncologic outcomes were in concordance with the highest standards nowadays,” Dr. van der Sluis summarized. “This trial provides evidence for the minimally invasive approach over the open approach, and especially the robot-assisted minimally invasive esophagectomy.”
The investigators will report a full cost comparison separately. “We see that costs are lower, though not significantly lower, with the robot,” he said, giving a preview. “We are going to show that the real costs of the operation are in the complications. When you have complications that involve the ICU and reoperations, some patients are in the hospital for months after the surgery. So by investing a little extra money in the surgical procedure, you might actually get it back by reducing the complications.”
When asked by an attendee why the trial did not compare robotic esophagectomy with thoracoscopic esophagectomy, Dr. van der Sluis noted that such comparison is complicated by many factors; for example, the challenge of finding surgeons skilled in both techniques, and the likelihood of small differences in outcomes, potentially requiring enrollment of thousands of patients to have adequate study power. “We concluded that such a trial might not be feasible,” he said.
Parsing the findings
“The complication rates [in this trial] are very high in the robotic and open groups, much higher than reported in some well-controlled prospective and retrospective studies,” commented session attendee Kenneth Meredith, MD, FACS, professor at Florida State University, Sarasota, and director of gastrointestinal oncology, Sarasota Memorial Institute for Cancer Care.
He wondered how extensive the investigators’ experience with robotics was and how many cases they had done on their learning curve. Data from his group suggest that surgeons must perform 29 cases of robotic esophagectomy before the complication rate drops (Dis Esophagus. 2017;30:1-7).
“That’s more then half of the patients in the robotic arm of their study,” he noted in an interview. “I find this needs to be explained. If the authors are past their learning curve, why were the complication rates so high?” Additionally, the 80% rate in the open group “is among the highest I’ve seen in many years.”
The lack of significant differences in complete resection rate and in lymph node harvest was also surprising, as he and other robotics users have found that this technique can improve these outcomes, Dr. Meredith added. This could likewise be a learning curve phenomenon.
Although ROBOT’s comparison of robotic with open esophagectomy is relevant, “it would have been more relevant to compare robotic to minimally invasive esophagectomy [MIE],” he maintained, as MIE has been shown to improve outcomes relative to open surgery (Lancet. 2012;379:1887-92).
“There are many high-volume centers in MIE but not necessarily robotics. The two are often mutually exclusive, and a multicenter trial in which each center performs high volumes of their respective technique, rather then mandating each center perform an operation they may not be facile in,” would be practical, Dr. Meredith concluded.
Study details
“The main objective in our trial was to reduce surgical trauma and reduce the percentage of complications,” Dr. van der Sluis told attendees of the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Results showed that compared with peers in the open surgery group, patients in the robotic-assisted surgery group specifically had a lower rate of pulmonary complications (32% vs. 58%, P = .005), largely due to a reduction in rate of pneumonia (28% vs. 55%, P = .005), and a lower rate of cardiac complications (22% vs. 47%, P = .006), almost entirely due to a reduction in rate of atrial fibrillation (22% vs. 46%, P = .01).
There was a trend toward fewer wound infections with robotics (4% vs. 14%, P = .09), with a large difference in thoracic wound infections (0% vs. 9%, P = .06).
The two groups were statistically indistinguishable on rates of anastomotic leakage (24% and 20%) and recurrent laryngeal nerve injury (9% and 11%). The fairly high rate of anastomotic leakage was likely due to the center’s use of cervical anastomosis at the time of the trial, according to Dr. van der Sluis; they have since started using thoracic anastomosis, and will report results with that technique soon.
There was also no significant difference between groups in the rate of in-hospital mortality (4% with robotic surgery and 2% with open surgery), median hospital length of stay (14 and 16 days), and ICU length of stay (1 day in each group).
Patients in the robotics group more commonly had functional recovery within 2 weeks (70% vs. 51%, P = .04). And on the Quality of Life Questionnaire Core 30, they had better scores for health-related quality of life at discharge (57.9 vs 44.6, P = .02) and at 6 weeks (68.7 vs. 57.6, P = .03), and for physical functioning at discharge (54.5 vs. 41.0, P = .03) and 6 weeks (69.3 vs. 58.6, P = .049).
The two groups were similar on rates of R0 resection (93% and 96%) and median number of lymph nodes retrieved (27 and 25), reported Dr. van der Sluis. Pain during the first 14 days after surgery was lower for the robotics group (P = .003).
With a median follow-up of 40 months, the robotics and open groups did not differ significantly on disease-free survival (median, 26 and 28 months) and overall survival (not reached in either group).
Dr. van der Sluis disclosed no relevant conflicts of interest.
SOURCE: van der Sluis PC et al. 2018 GI Cancer Symposium, Abstract 156148
REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
Key clinical point: Patients with esophageal cancer undergoing esophagectomy are less likely to experience complications when the surgery is performed robotically.
Major finding: Compared with open transthoracic esophagectomy, robot-assisted minimally invasive thoracolaparoscopic esophagectomy had a lower rate of MCDC grade 2 or higher surgery-related postoperative complications (59% vs. 80%).
Data source: A single-center phase 3 randomized controlled trial among 112 patients with resectable esophageal cancer.
Disclosures: Dr. van der Sluis disclosed no relevant conflicts of interest.
Source: van der Sluis PC et al. 2018 GI Cancer Symposium, Abstract 156148
First-line ramucirumab nets small PFS benefit in gastric cancer
SAN FRANCISCO – Adding ramucirumab to first-line chemotherapy for gastric and gastroesophageal junction cancer prolongs progression-free survival, but not by much, according to results of the phase 3 international RAINFALL trial.
A total of 645 patients were randomized to receive chemotherapy (cisplatin with capecitabine or 5FU) plus either placebo or ramucirumab (Cyramza), an antibody that targets human vascular endothelial growth factor receptor 2. The antiangiogenic antibody has been found to prolong overall survival in the second-line setting, as shown in the REGARD monotherapy and RAINBOW combination therapy trials.
“In patients with treatment-naive gastric and gastroesophageal junction adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant improvement in the primary endpoint of investigator-assessed progression-free survival, but did not confer any improvement in overall survival,” said lead investigator Charles S. Fuchs, MD, director of the Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital, New Haven, Connecticut. “Ramucirumab in combination with first-line chemotherapy did appear to be well tolerated.”
A session attendee asked, “Given the high cost and limited benefit in progression-free survival, what do you think of the statistical significance versus the clinical significance of the findings of this study?”
“We did have a statistically significant benefit in progression-free survival but did not see a survival benefit by any measure, so I wouldn’t purport that ramucirumab should be a first-line therapy,” Dr. Fuchs replied. “Should it supplant existing therapy in the first line? I don’t think the data support that.”
Clinical implications
“RAINFALL did meet its primary endpoint of progression-free survival. However, it was disappointing not to see some survival benefit,” commented invited discussant Stephen Leong, MD, of the University of Colorado Comprehensive Cancer Center, Denver. “Ramucirumab’s role in the first-line setting is debatable.”
The gain in median progression-free survival of 0.3 months, or 9 days, comes at an approximate drug cost of $67,112, he noted. And that does not include port or infusion costs.
The trial still leaves some important questions to be answered, he said. In particular, the secondary endpoint of quality of life and biomarker analyses have not yet been reported.
“Will ramucirumab get FDA approval for a first-line indication? No. The answer is quite simple. [The manufacturer] has already indicated that they are not going to pursue a first-line indication,” Dr. Leong said.
“Will this replace our current standard of care? Right now the standard of care is the doublet or triplet with a 5FU or platinum backbone. This is not going to replace that,” he said. Finally, “will the NCCN add ramucirumab to the first-line setting? This will be debated shortly.”
Study details
In RAINFALL, median investigator-assessed progression-free survival in the final intention-to-treat analysis was 5.85 months with ramucirumab and 5.55 months with placebo (hazard ratio, 0.75; P = .0024), Dr. Fuchs reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Median overall survival was 11.17 months with ramucirumab and 10.74 months with placebo, a nonsignificant difference. Findings for both endpoints were consistent across subgroups stratified by patient, disease, and treatment characteristics.
The overall response rate was 41% and 36%, respectively (P = .17), and the disease control rate was 82% and 77%, respectively (P = .10).
Treatment-emergent adverse events of grade 3 or worse were generally similar for the two groups, Dr. Fuchs reported. Patients in the ramucirumab group had higher rates of certain grade 3 or worse adverse events known to be related to the antibody’s mechanism of action (26% vs. 15%), such as hypertension (9.9% vs 1.5%) and gastrointestinal perforation (4.0% vs. 0.3%).
After the study, about half of patients in each group went on to receive additional (second-line) systemic therapy, mainly paclitaxel and (more) ramucirumab.
In an exploratory analysis, patients who received poststudy ramucirumab versus some other systemic therapy tended to have better overall survival, whether originally in the ramucirumab group (16.2 vs. 13.2 months) or the placebo group (14.9 vs. 13.0 months). Findings were similar when overall survival was assessed from initiation of the poststudy therapy.
Dr. Fuchs disclosed that he is a consultant to Agios, Bayer, Eli Lilly, Entrinsic Health, Five Prime Therapeutics, Genentech, Merck, Sanofi, and Taiho Pharmaceutical, and that he is on the board of directors of CytomX. The trial was sponsored by Eli Lilly.
SOURCE: Fuchs CS et al. GI CANCERS SYMPOSIUM Abstract 5
SAN FRANCISCO – Adding ramucirumab to first-line chemotherapy for gastric and gastroesophageal junction cancer prolongs progression-free survival, but not by much, according to results of the phase 3 international RAINFALL trial.
A total of 645 patients were randomized to receive chemotherapy (cisplatin with capecitabine or 5FU) plus either placebo or ramucirumab (Cyramza), an antibody that targets human vascular endothelial growth factor receptor 2. The antiangiogenic antibody has been found to prolong overall survival in the second-line setting, as shown in the REGARD monotherapy and RAINBOW combination therapy trials.
“In patients with treatment-naive gastric and gastroesophageal junction adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant improvement in the primary endpoint of investigator-assessed progression-free survival, but did not confer any improvement in overall survival,” said lead investigator Charles S. Fuchs, MD, director of the Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital, New Haven, Connecticut. “Ramucirumab in combination with first-line chemotherapy did appear to be well tolerated.”
A session attendee asked, “Given the high cost and limited benefit in progression-free survival, what do you think of the statistical significance versus the clinical significance of the findings of this study?”
“We did have a statistically significant benefit in progression-free survival but did not see a survival benefit by any measure, so I wouldn’t purport that ramucirumab should be a first-line therapy,” Dr. Fuchs replied. “Should it supplant existing therapy in the first line? I don’t think the data support that.”
Clinical implications
“RAINFALL did meet its primary endpoint of progression-free survival. However, it was disappointing not to see some survival benefit,” commented invited discussant Stephen Leong, MD, of the University of Colorado Comprehensive Cancer Center, Denver. “Ramucirumab’s role in the first-line setting is debatable.”
The gain in median progression-free survival of 0.3 months, or 9 days, comes at an approximate drug cost of $67,112, he noted. And that does not include port or infusion costs.
The trial still leaves some important questions to be answered, he said. In particular, the secondary endpoint of quality of life and biomarker analyses have not yet been reported.
“Will ramucirumab get FDA approval for a first-line indication? No. The answer is quite simple. [The manufacturer] has already indicated that they are not going to pursue a first-line indication,” Dr. Leong said.
“Will this replace our current standard of care? Right now the standard of care is the doublet or triplet with a 5FU or platinum backbone. This is not going to replace that,” he said. Finally, “will the NCCN add ramucirumab to the first-line setting? This will be debated shortly.”
Study details
In RAINFALL, median investigator-assessed progression-free survival in the final intention-to-treat analysis was 5.85 months with ramucirumab and 5.55 months with placebo (hazard ratio, 0.75; P = .0024), Dr. Fuchs reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Median overall survival was 11.17 months with ramucirumab and 10.74 months with placebo, a nonsignificant difference. Findings for both endpoints were consistent across subgroups stratified by patient, disease, and treatment characteristics.
The overall response rate was 41% and 36%, respectively (P = .17), and the disease control rate was 82% and 77%, respectively (P = .10).
Treatment-emergent adverse events of grade 3 or worse were generally similar for the two groups, Dr. Fuchs reported. Patients in the ramucirumab group had higher rates of certain grade 3 or worse adverse events known to be related to the antibody’s mechanism of action (26% vs. 15%), such as hypertension (9.9% vs 1.5%) and gastrointestinal perforation (4.0% vs. 0.3%).
After the study, about half of patients in each group went on to receive additional (second-line) systemic therapy, mainly paclitaxel and (more) ramucirumab.
In an exploratory analysis, patients who received poststudy ramucirumab versus some other systemic therapy tended to have better overall survival, whether originally in the ramucirumab group (16.2 vs. 13.2 months) or the placebo group (14.9 vs. 13.0 months). Findings were similar when overall survival was assessed from initiation of the poststudy therapy.
Dr. Fuchs disclosed that he is a consultant to Agios, Bayer, Eli Lilly, Entrinsic Health, Five Prime Therapeutics, Genentech, Merck, Sanofi, and Taiho Pharmaceutical, and that he is on the board of directors of CytomX. The trial was sponsored by Eli Lilly.
SOURCE: Fuchs CS et al. GI CANCERS SYMPOSIUM Abstract 5
SAN FRANCISCO – Adding ramucirumab to first-line chemotherapy for gastric and gastroesophageal junction cancer prolongs progression-free survival, but not by much, according to results of the phase 3 international RAINFALL trial.
A total of 645 patients were randomized to receive chemotherapy (cisplatin with capecitabine or 5FU) plus either placebo or ramucirumab (Cyramza), an antibody that targets human vascular endothelial growth factor receptor 2. The antiangiogenic antibody has been found to prolong overall survival in the second-line setting, as shown in the REGARD monotherapy and RAINBOW combination therapy trials.
“In patients with treatment-naive gastric and gastroesophageal junction adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant improvement in the primary endpoint of investigator-assessed progression-free survival, but did not confer any improvement in overall survival,” said lead investigator Charles S. Fuchs, MD, director of the Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital, New Haven, Connecticut. “Ramucirumab in combination with first-line chemotherapy did appear to be well tolerated.”
A session attendee asked, “Given the high cost and limited benefit in progression-free survival, what do you think of the statistical significance versus the clinical significance of the findings of this study?”
“We did have a statistically significant benefit in progression-free survival but did not see a survival benefit by any measure, so I wouldn’t purport that ramucirumab should be a first-line therapy,” Dr. Fuchs replied. “Should it supplant existing therapy in the first line? I don’t think the data support that.”
Clinical implications
“RAINFALL did meet its primary endpoint of progression-free survival. However, it was disappointing not to see some survival benefit,” commented invited discussant Stephen Leong, MD, of the University of Colorado Comprehensive Cancer Center, Denver. “Ramucirumab’s role in the first-line setting is debatable.”
The gain in median progression-free survival of 0.3 months, or 9 days, comes at an approximate drug cost of $67,112, he noted. And that does not include port or infusion costs.
The trial still leaves some important questions to be answered, he said. In particular, the secondary endpoint of quality of life and biomarker analyses have not yet been reported.
“Will ramucirumab get FDA approval for a first-line indication? No. The answer is quite simple. [The manufacturer] has already indicated that they are not going to pursue a first-line indication,” Dr. Leong said.
“Will this replace our current standard of care? Right now the standard of care is the doublet or triplet with a 5FU or platinum backbone. This is not going to replace that,” he said. Finally, “will the NCCN add ramucirumab to the first-line setting? This will be debated shortly.”
Study details
In RAINFALL, median investigator-assessed progression-free survival in the final intention-to-treat analysis was 5.85 months with ramucirumab and 5.55 months with placebo (hazard ratio, 0.75; P = .0024), Dr. Fuchs reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Median overall survival was 11.17 months with ramucirumab and 10.74 months with placebo, a nonsignificant difference. Findings for both endpoints were consistent across subgroups stratified by patient, disease, and treatment characteristics.
The overall response rate was 41% and 36%, respectively (P = .17), and the disease control rate was 82% and 77%, respectively (P = .10).
Treatment-emergent adverse events of grade 3 or worse were generally similar for the two groups, Dr. Fuchs reported. Patients in the ramucirumab group had higher rates of certain grade 3 or worse adverse events known to be related to the antibody’s mechanism of action (26% vs. 15%), such as hypertension (9.9% vs 1.5%) and gastrointestinal perforation (4.0% vs. 0.3%).
After the study, about half of patients in each group went on to receive additional (second-line) systemic therapy, mainly paclitaxel and (more) ramucirumab.
In an exploratory analysis, patients who received poststudy ramucirumab versus some other systemic therapy tended to have better overall survival, whether originally in the ramucirumab group (16.2 vs. 13.2 months) or the placebo group (14.9 vs. 13.0 months). Findings were similar when overall survival was assessed from initiation of the poststudy therapy.
Dr. Fuchs disclosed that he is a consultant to Agios, Bayer, Eli Lilly, Entrinsic Health, Five Prime Therapeutics, Genentech, Merck, Sanofi, and Taiho Pharmaceutical, and that he is on the board of directors of CytomX. The trial was sponsored by Eli Lilly.
SOURCE: Fuchs CS et al. GI CANCERS SYMPOSIUM Abstract 5
REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: Median progression-free survival was 5.85 months with ramucirumab and 5.55 months with placebo (hazard ratio, 0.75; P = .0024).
Data source: A phase 3 randomized, controlled trial among 645 patients with metastatic gastric or gastroesophageal junction adenocarcinoma given first-line chemotherapy plus ramucirumab or placebo (RAINFALL trial).
Disclosures: Dr. Fuchs disclosed that he is a consultant to Agios, Bayer, Eli Lilly, Entrinsic Health, Five Prime Therapeutics, Genentech, Merck, Sanofi, and Taiho Pharmaceutical, and that he is on the board of directors of CytomX. Eli Lilly sponsored the trial.
Source: Fuchs CS et al. GI CANCERS SYMPOSIUM Abstract 5.
Combination immunotherapy is active in dMMR/MSI-H metastatic colorectal cancer
SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.
“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.
Initial results for the latter cohort established a durable clinical benefit of nivolumab monotherapy, according to Dr. André. “It’s clear that there is a rationale to combine nivolumab and ipilimumab because they act synergistically to promote T-cell antitumor activity. Therefore, combination could further improve results,” he said.
With median follow-up of 13.4 months, 55% of patients had a response to the combination of nivolumab and ipilimumab, according to results reported at the symposium and simultaneously published (J Clin Oncol. 2018 Jan 20:JCO2017769901). Median progression-free and overall survival were not reached.
In addition, comparison with the nivolumab monotherapy cohort, albeit in nonrandomized fashion, suggested that addition of ipilimumab netted better outcomes.
“Nivolumab plus ipilimumab represents a promising new treatment option for patients with previously treated dMMR/MSI-H metastatic colorectal cancer,” Dr. André summarized. The results “are really very unusual in metastatic colorectal cancer, and we have a test, MSI, to select this population. It’s really a new hope for patients with metastatic colorectal cancer.”
Findings in context
“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.
“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”
“Further studies are clearly needed to identify those particular subgroups of patients who may benefit from combination therapies, so can we predict which MSI-H patients may progress on monotherapy, and whether we can salvage patients on monotherapy who are not responding and are having progression of disease,” she concluded. “Those are important questions that need to be addressed.”
Study details
In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).
The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.
The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)
Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.
“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
Long-term outcomes with monotherapy
In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.
Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).
“Deepening of response was shown with further follow-up,” he noted; in particular, the rate of complete response increased from 3% to 9%. “This is primarily related to partial responses that have converted to complete responses with additional time.” Median duration of response was not reached.
The overall response rate was 26% in the more heavily pretreated group and 52% in the less heavily pretreated group, although confidence intervals overlapped. The disease control rate was 55% and 81%, respectively.
Both progression-free and overall survival curves for the entire monotherapy cohort showed a plateau. The 12-month rates were 44% (also 44% at 18 months) and 72% (67% at 18 months), respectively.
The rate of grade 3 or 4 treatment-related adverse events was 20%. “No new signals were seen with this longer follow-up,” Dr. Overman noted.
“Nivolumab continued to provide durable clinical benefit with long-term follow-up in previously treated patients with dMMR/MSI-H metastatic colorectal cancer. “Durable clinical benefit with deepening of response was observed regardless of prior chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan,” he summarized. “These results support ongoing evaluation of nivolumab-based therapy in the first-line setting in patients with deficient–mismatch repair colorectal cancer.”
Findings in context
“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”
The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”
“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”
Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.
SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.
SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.
“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.
Initial results for the latter cohort established a durable clinical benefit of nivolumab monotherapy, according to Dr. André. “It’s clear that there is a rationale to combine nivolumab and ipilimumab because they act synergistically to promote T-cell antitumor activity. Therefore, combination could further improve results,” he said.
With median follow-up of 13.4 months, 55% of patients had a response to the combination of nivolumab and ipilimumab, according to results reported at the symposium and simultaneously published (J Clin Oncol. 2018 Jan 20:JCO2017769901). Median progression-free and overall survival were not reached.
In addition, comparison with the nivolumab monotherapy cohort, albeit in nonrandomized fashion, suggested that addition of ipilimumab netted better outcomes.
“Nivolumab plus ipilimumab represents a promising new treatment option for patients with previously treated dMMR/MSI-H metastatic colorectal cancer,” Dr. André summarized. The results “are really very unusual in metastatic colorectal cancer, and we have a test, MSI, to select this population. It’s really a new hope for patients with metastatic colorectal cancer.”
Findings in context
“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.
“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”
“Further studies are clearly needed to identify those particular subgroups of patients who may benefit from combination therapies, so can we predict which MSI-H patients may progress on monotherapy, and whether we can salvage patients on monotherapy who are not responding and are having progression of disease,” she concluded. “Those are important questions that need to be addressed.”
Study details
In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).
The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.
The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)
Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.
“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
Long-term outcomes with monotherapy
In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.
Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).
“Deepening of response was shown with further follow-up,” he noted; in particular, the rate of complete response increased from 3% to 9%. “This is primarily related to partial responses that have converted to complete responses with additional time.” Median duration of response was not reached.
The overall response rate was 26% in the more heavily pretreated group and 52% in the less heavily pretreated group, although confidence intervals overlapped. The disease control rate was 55% and 81%, respectively.
Both progression-free and overall survival curves for the entire monotherapy cohort showed a plateau. The 12-month rates were 44% (also 44% at 18 months) and 72% (67% at 18 months), respectively.
The rate of grade 3 or 4 treatment-related adverse events was 20%. “No new signals were seen with this longer follow-up,” Dr. Overman noted.
“Nivolumab continued to provide durable clinical benefit with long-term follow-up in previously treated patients with dMMR/MSI-H metastatic colorectal cancer. “Durable clinical benefit with deepening of response was observed regardless of prior chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan,” he summarized. “These results support ongoing evaluation of nivolumab-based therapy in the first-line setting in patients with deficient–mismatch repair colorectal cancer.”
Findings in context
“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”
The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”
“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”
Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.
SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.
SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.
“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.
Initial results for the latter cohort established a durable clinical benefit of nivolumab monotherapy, according to Dr. André. “It’s clear that there is a rationale to combine nivolumab and ipilimumab because they act synergistically to promote T-cell antitumor activity. Therefore, combination could further improve results,” he said.
With median follow-up of 13.4 months, 55% of patients had a response to the combination of nivolumab and ipilimumab, according to results reported at the symposium and simultaneously published (J Clin Oncol. 2018 Jan 20:JCO2017769901). Median progression-free and overall survival were not reached.
In addition, comparison with the nivolumab monotherapy cohort, albeit in nonrandomized fashion, suggested that addition of ipilimumab netted better outcomes.
“Nivolumab plus ipilimumab represents a promising new treatment option for patients with previously treated dMMR/MSI-H metastatic colorectal cancer,” Dr. André summarized. The results “are really very unusual in metastatic colorectal cancer, and we have a test, MSI, to select this population. It’s really a new hope for patients with metastatic colorectal cancer.”
Findings in context
“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.
“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”
“Further studies are clearly needed to identify those particular subgroups of patients who may benefit from combination therapies, so can we predict which MSI-H patients may progress on monotherapy, and whether we can salvage patients on monotherapy who are not responding and are having progression of disease,” she concluded. “Those are important questions that need to be addressed.”
Study details
In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).
The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.
The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)
Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.
“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
Long-term outcomes with monotherapy
In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.
Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).
“Deepening of response was shown with further follow-up,” he noted; in particular, the rate of complete response increased from 3% to 9%. “This is primarily related to partial responses that have converted to complete responses with additional time.” Median duration of response was not reached.
The overall response rate was 26% in the more heavily pretreated group and 52% in the less heavily pretreated group, although confidence intervals overlapped. The disease control rate was 55% and 81%, respectively.
Both progression-free and overall survival curves for the entire monotherapy cohort showed a plateau. The 12-month rates were 44% (also 44% at 18 months) and 72% (67% at 18 months), respectively.
The rate of grade 3 or 4 treatment-related adverse events was 20%. “No new signals were seen with this longer follow-up,” Dr. Overman noted.
“Nivolumab continued to provide durable clinical benefit with long-term follow-up in previously treated patients with dMMR/MSI-H metastatic colorectal cancer. “Durable clinical benefit with deepening of response was observed regardless of prior chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan,” he summarized. “These results support ongoing evaluation of nivolumab-based therapy in the first-line setting in patients with deficient–mismatch repair colorectal cancer.”
Findings in context
“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”
The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”
“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”
Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.
SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.
REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: The combination of nivolumab and ipilimumab yielded an overall response rate of 55% and a disease control rate of 80%. Nivolumab monotherapy yielded similar benefit regardless of prior lines of treatment.
Data source: A nonrandomized phase 2 trial among patients with dMMR/MSI-H metastatic colorectal cancer: 119 received both nivolumab and ipilimumab and 74 received nivolumab alone (CheckMate-142).
Disclosures: Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding from Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.
Source: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.
Circulating tumor cell assay shows promise for colorectal cancer screening
SAN FRANCISCO – A new blood-based assay that measures circulating tumor cells (CTCs) shows good performance in detecting colorectal cancer and precancer, investigators reported at the 2018 GI Cancers Symposium.
Although colorectal cancer screening is a grade A recommendation of the U.S. Preventive Services Task Force, poor uptake remains problematic and contributes to more advanced disease at diagnosis, noted lead investigator Wen-Sy Tsai, MD, assistant professor at Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
“Currently, one-third of Americans have never been screened for colorectal cancer,” he said, due in part to reluctance to undergo colonoscopy and poor compliance with stool tests. Further complicating matters, the fecal immunochemical test (FIT) has a high false-positive rate.
He and his coinvestigators tested the new assay, called CMx (CTCs in Maximum), among 620 individuals in Taiwan who underwent colonoscopy – some with colorectal cancer, some with precancerous lesions, and some healthy. Results showed the assay’s sensitivity was nearly 87% for cancer and 77% for precancerous lesions. Specificity exceeded 97%.
“The CMx assay is capable of detecting … early-stage cancer with a low false-positive rate. As it is a blood test, higher compliance will lead to better outcomes,” Dr. Tsai proposed. “Because the mechanism of CTC dissemination is similar, the CTC assay can be applied in other cancer types such as prostate, breast, and lung cancer.”
The investigators are also identifying collaborators for testing the new assay among U.S. populations, he noted.
“Screening tests offer some of the greatest potential for getting to zero colorectal cancer deaths,” said invited discussant Douglas A. Corley, MD, PhD, clinical professor and gastroenterologist at the University of California, San Francisco, and a research scientist at Kaiser Permanente, San Francisco.
CTCs are especially attractive for screening because they could be both sensitive and specific, he said. “Unlike something such as fecal immunotesting, which is not testing specifically for cancer, or colonoscopy, which is quite invasive and detects a lot of things that may never progress to cancer, CTCs offer this potential,” said Dr. Corley.
Challenges of interpreting new screening tests include their heavy dependence on the population being tested and the need for replication, according to Dr. Corley. For example, initial results for the septin 9 methylated DNA blood test looked very good, with sensitivity of about 90% (BMC Med. 2011;9:133), but after its testing in 14 populations, a meta-analysis showed that pooled sensitivity was just 67% (Biomed Rep. 2017;7[4]:353-60).
“Circulating tumor markers are an incredibly interesting target for screening, particularly because of their potential for being very specific for what you are looking for, and potentially markedly decreasing the subsequent follow-up that would need to be done for invasive tests such as colonoscopy,” Dr. Corley said. “However, this [CTC assay] really requires confirmation in screening populations, especially given some of the information we have from prior tests.”
Study details
Dr. Tsai’s team studied 327 patients with colorectal cancer of all stages, 111 patients with precancerous lesions (adenomas, advanced adenomas, carcinoma in situ/stage 0), and 182 healthy controls. All had blood drawn for the CTC assay before undergoing colonoscopy. Results of each test were ascertained with blinding to the results of the other.
CTCs are rarely shed into the circulation from precancerous lesions, with approximate density of only 1 per billion blood cells, Dr. Tsai said. The CMx assay (manufactured by CellMax Life) is able to detect these cells with high sensitivity through use of advanced technologies such as affinity-based microfluidics and a biomimetic surface coating.
The assay is performed with just 2 mL of whole blood. CTCs are defined as intact nucleated cells staining positive for CD20 and negative for CD45; they were combined with patient age in an algorithm, ultimately producing a risk score.
Study results showed that the CTC assay had an accuracy of 87.9% in the entire cohort, reported Dr. Tsai. The false-positive rate was just 3.3%, and the false-negative rate was 15.8%.
Sensitivity was 84.0% overall (76.6% for precancer and 86.9% for cancer), specificity was 97.3% overall (97.3% and 97.3%), and area under the receiver operating characteristic curve was 0.87 overall (0.84 and 0.88).
Dr. Tsai noted that the CTC assay’s sensitivity of nearly 77% for precancer compares favorably with that of a variety of other screening tests, such as the stool guaiac test for fecal occult blood (2%-10%), FIT alone (23.8%), and a stool DNA test combined with FIT (42%), and, in fact, falls within the range reported for colonoscopy (76%-94%).
The symposium was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
SOURCE: Tsai W et al., ASCO GI Abstract 556
SAN FRANCISCO – A new blood-based assay that measures circulating tumor cells (CTCs) shows good performance in detecting colorectal cancer and precancer, investigators reported at the 2018 GI Cancers Symposium.
Although colorectal cancer screening is a grade A recommendation of the U.S. Preventive Services Task Force, poor uptake remains problematic and contributes to more advanced disease at diagnosis, noted lead investigator Wen-Sy Tsai, MD, assistant professor at Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
“Currently, one-third of Americans have never been screened for colorectal cancer,” he said, due in part to reluctance to undergo colonoscopy and poor compliance with stool tests. Further complicating matters, the fecal immunochemical test (FIT) has a high false-positive rate.
He and his coinvestigators tested the new assay, called CMx (CTCs in Maximum), among 620 individuals in Taiwan who underwent colonoscopy – some with colorectal cancer, some with precancerous lesions, and some healthy. Results showed the assay’s sensitivity was nearly 87% for cancer and 77% for precancerous lesions. Specificity exceeded 97%.
“The CMx assay is capable of detecting … early-stage cancer with a low false-positive rate. As it is a blood test, higher compliance will lead to better outcomes,” Dr. Tsai proposed. “Because the mechanism of CTC dissemination is similar, the CTC assay can be applied in other cancer types such as prostate, breast, and lung cancer.”
The investigators are also identifying collaborators for testing the new assay among U.S. populations, he noted.
“Screening tests offer some of the greatest potential for getting to zero colorectal cancer deaths,” said invited discussant Douglas A. Corley, MD, PhD, clinical professor and gastroenterologist at the University of California, San Francisco, and a research scientist at Kaiser Permanente, San Francisco.
CTCs are especially attractive for screening because they could be both sensitive and specific, he said. “Unlike something such as fecal immunotesting, which is not testing specifically for cancer, or colonoscopy, which is quite invasive and detects a lot of things that may never progress to cancer, CTCs offer this potential,” said Dr. Corley.
Challenges of interpreting new screening tests include their heavy dependence on the population being tested and the need for replication, according to Dr. Corley. For example, initial results for the septin 9 methylated DNA blood test looked very good, with sensitivity of about 90% (BMC Med. 2011;9:133), but after its testing in 14 populations, a meta-analysis showed that pooled sensitivity was just 67% (Biomed Rep. 2017;7[4]:353-60).
“Circulating tumor markers are an incredibly interesting target for screening, particularly because of their potential for being very specific for what you are looking for, and potentially markedly decreasing the subsequent follow-up that would need to be done for invasive tests such as colonoscopy,” Dr. Corley said. “However, this [CTC assay] really requires confirmation in screening populations, especially given some of the information we have from prior tests.”
Study details
Dr. Tsai’s team studied 327 patients with colorectal cancer of all stages, 111 patients with precancerous lesions (adenomas, advanced adenomas, carcinoma in situ/stage 0), and 182 healthy controls. All had blood drawn for the CTC assay before undergoing colonoscopy. Results of each test were ascertained with blinding to the results of the other.
CTCs are rarely shed into the circulation from precancerous lesions, with approximate density of only 1 per billion blood cells, Dr. Tsai said. The CMx assay (manufactured by CellMax Life) is able to detect these cells with high sensitivity through use of advanced technologies such as affinity-based microfluidics and a biomimetic surface coating.
The assay is performed with just 2 mL of whole blood. CTCs are defined as intact nucleated cells staining positive for CD20 and negative for CD45; they were combined with patient age in an algorithm, ultimately producing a risk score.
Study results showed that the CTC assay had an accuracy of 87.9% in the entire cohort, reported Dr. Tsai. The false-positive rate was just 3.3%, and the false-negative rate was 15.8%.
Sensitivity was 84.0% overall (76.6% for precancer and 86.9% for cancer), specificity was 97.3% overall (97.3% and 97.3%), and area under the receiver operating characteristic curve was 0.87 overall (0.84 and 0.88).
Dr. Tsai noted that the CTC assay’s sensitivity of nearly 77% for precancer compares favorably with that of a variety of other screening tests, such as the stool guaiac test for fecal occult blood (2%-10%), FIT alone (23.8%), and a stool DNA test combined with FIT (42%), and, in fact, falls within the range reported for colonoscopy (76%-94%).
The symposium was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
SOURCE: Tsai W et al., ASCO GI Abstract 556
SAN FRANCISCO – A new blood-based assay that measures circulating tumor cells (CTCs) shows good performance in detecting colorectal cancer and precancer, investigators reported at the 2018 GI Cancers Symposium.
Although colorectal cancer screening is a grade A recommendation of the U.S. Preventive Services Task Force, poor uptake remains problematic and contributes to more advanced disease at diagnosis, noted lead investigator Wen-Sy Tsai, MD, assistant professor at Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
“Currently, one-third of Americans have never been screened for colorectal cancer,” he said, due in part to reluctance to undergo colonoscopy and poor compliance with stool tests. Further complicating matters, the fecal immunochemical test (FIT) has a high false-positive rate.
He and his coinvestigators tested the new assay, called CMx (CTCs in Maximum), among 620 individuals in Taiwan who underwent colonoscopy – some with colorectal cancer, some with precancerous lesions, and some healthy. Results showed the assay’s sensitivity was nearly 87% for cancer and 77% for precancerous lesions. Specificity exceeded 97%.
“The CMx assay is capable of detecting … early-stage cancer with a low false-positive rate. As it is a blood test, higher compliance will lead to better outcomes,” Dr. Tsai proposed. “Because the mechanism of CTC dissemination is similar, the CTC assay can be applied in other cancer types such as prostate, breast, and lung cancer.”
The investigators are also identifying collaborators for testing the new assay among U.S. populations, he noted.
“Screening tests offer some of the greatest potential for getting to zero colorectal cancer deaths,” said invited discussant Douglas A. Corley, MD, PhD, clinical professor and gastroenterologist at the University of California, San Francisco, and a research scientist at Kaiser Permanente, San Francisco.
CTCs are especially attractive for screening because they could be both sensitive and specific, he said. “Unlike something such as fecal immunotesting, which is not testing specifically for cancer, or colonoscopy, which is quite invasive and detects a lot of things that may never progress to cancer, CTCs offer this potential,” said Dr. Corley.
Challenges of interpreting new screening tests include their heavy dependence on the population being tested and the need for replication, according to Dr. Corley. For example, initial results for the septin 9 methylated DNA blood test looked very good, with sensitivity of about 90% (BMC Med. 2011;9:133), but after its testing in 14 populations, a meta-analysis showed that pooled sensitivity was just 67% (Biomed Rep. 2017;7[4]:353-60).
“Circulating tumor markers are an incredibly interesting target for screening, particularly because of their potential for being very specific for what you are looking for, and potentially markedly decreasing the subsequent follow-up that would need to be done for invasive tests such as colonoscopy,” Dr. Corley said. “However, this [CTC assay] really requires confirmation in screening populations, especially given some of the information we have from prior tests.”
Study details
Dr. Tsai’s team studied 327 patients with colorectal cancer of all stages, 111 patients with precancerous lesions (adenomas, advanced adenomas, carcinoma in situ/stage 0), and 182 healthy controls. All had blood drawn for the CTC assay before undergoing colonoscopy. Results of each test were ascertained with blinding to the results of the other.
CTCs are rarely shed into the circulation from precancerous lesions, with approximate density of only 1 per billion blood cells, Dr. Tsai said. The CMx assay (manufactured by CellMax Life) is able to detect these cells with high sensitivity through use of advanced technologies such as affinity-based microfluidics and a biomimetic surface coating.
The assay is performed with just 2 mL of whole blood. CTCs are defined as intact nucleated cells staining positive for CD20 and negative for CD45; they were combined with patient age in an algorithm, ultimately producing a risk score.
Study results showed that the CTC assay had an accuracy of 87.9% in the entire cohort, reported Dr. Tsai. The false-positive rate was just 3.3%, and the false-negative rate was 15.8%.
Sensitivity was 84.0% overall (76.6% for precancer and 86.9% for cancer), specificity was 97.3% overall (97.3% and 97.3%), and area under the receiver operating characteristic curve was 0.87 overall (0.84 and 0.88).
Dr. Tsai noted that the CTC assay’s sensitivity of nearly 77% for precancer compares favorably with that of a variety of other screening tests, such as the stool guaiac test for fecal occult blood (2%-10%), FIT alone (23.8%), and a stool DNA test combined with FIT (42%), and, in fact, falls within the range reported for colonoscopy (76%-94%).
The symposium was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
SOURCE: Tsai W et al., ASCO GI Abstract 556
REPORTING FROM 2018 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: The CMx assay had a sensitivity of nearly 87% for colorectal cancer and nearly 77% for precancerous lesions.
Data source: A single-center, blinded, prospective cohort study among 327 patients with colorectal cancer of various stages, 111 patients with precancerous lesions, and 182 healthy individuals.
Disclosures: Dr. Tsai disclosed that he had no relevant relationships.
Source: Tsai W et al. ASCO GI Abstract 556.
Right-sided CRC has poorer disease-free survival after adjuvant chemo
SAN FRANCISCO – Colorectal cancer originating on the right side carries a higher risk of recurrence or death after adjuvant oxaliplatin-based chemotherapy, suggests a new analysis of data from the SCOT (Short Course Oncology Therapy) trial. But patients with right-sided disease fare about the same whether given the usual 6 months of chemotherapy or half that.
“It’s becoming clear that right-sided tumors are different from left-sided tumors,” commented first author Mark P. Saunders, MD, PhD, a consultant oncologist at the Christie NHS Foundation Trust, Manchester, England. A large meta-analysis showed that early right-sided tumors were associated with poorer overall survival (JAMA Oncol. 2016 Oct 27. doi: 10.1001/jamaoncol.2016.4227), but it remains unclear at what point(s) in the course of disease and its treatment sidedness is exerting its influence.
In the new analysis, the investigators assessed the impact of tumor sidedness among 3,219 patients having that information. Results reported at the 2018 GI Cancers Symposium showed that those with right-sided tumors (up to but not including the splenic flexure) had a 40% higher risk of disease-free survival events. However, there was no significant difference by side according to duration of chemotherapy.
“This is the first trial to show that unselected patients with right-sided tumors have worse disease-free survival, compared to those with left-sided tumors,” Dr. Saunders summarized. This finding suggests that greater recurrence risk is driving the poorer overall survival of the former.
“Tumor sidedness did not impact on the 3 months versus 6 months comparison in SCOT,” he further noted. “I suppose it would have fitted a very nice story that the rights did worse, and therefore, 6 months was better [for this group]. We didn’t show that in this trial here, so I don’t think we can say that at all. We still have to say that the outcome of the SCOT trial was that 3 months is noninferior to 6 months.”
Findings in context
“This study was interesting, but I feel that we still need more data coming from the main study,” session chair Michael J. Hall, MD, MS, a medical oncologist at the Fox Chase Cancer Center, Philadelphia, said in an interview. “It’s important to let us know that adjuvant chemotherapy appears to be beneficial, regardless of side, but there are still some other important questions.”
More detail on the difference by side according to chemotherapy duration and according to regimen (because recent data suggest CAPOX may have an edge over FOLFOX) could help tailor treatment, he proposed. For example, it is possible that patients with right-sided tumors will fare better if given 6 months of the CAPOX regimen.
Study details
The majority of the 3,219 patients studied, 63%, had tumors originating on the left side (splenic flexure or distally), according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Compared with patients who had left-sided tumors, those with right-sided tumors (including any in the transverse colon) were older (median, 66 vs. 64 years; P less than .001), less often male (53% vs. 66%; P less than .001), more often had T4 stage (41% vs. 24%; P less than .001), and less often had stage II disease (17% vs. 21%; P =.001).
Patients with right-sided tumors had poorer 3-year disease-free survival (73% vs. 80%; hazard ratio, 1.401; P less than .0001), reported Dr. Saunders. This association weakened slightly after adjustment for T stage and N stage (HR, 1.215; P = .009).
However, benefit of 3 months versus 6 months of chemotherapy was similar whether patients had right-sided tumors (HR, 1.049) or left-sided tumors (HR, 0.910), with no statistically significant heterogeneity between these groups (P =.327).
A large translational substudy, Trans SCOT, is looking at various biomarkers such as microsatellite instability and mutations, and may shed more light on the mechanisms driving the different outcomes for right- and left-sided colorectal cancer, according to Dr. Saunders.
However, even when starting with more than 3,000 patients, drilling down by tumor sidedness and then further by characteristics such as molecular features (or regimen, overall stage, or T and N components) may result in underpowered analyses, he cautioned.
Dr. Saunders disclosed that he received honoraria from and has a consulting or advisory role with Amgen, Merck, Roche, and Servier.
SOURCE: Saunders MP et al. 2018 Gastrointestinal Cancers Symposium, Abstract 558.
SAN FRANCISCO – Colorectal cancer originating on the right side carries a higher risk of recurrence or death after adjuvant oxaliplatin-based chemotherapy, suggests a new analysis of data from the SCOT (Short Course Oncology Therapy) trial. But patients with right-sided disease fare about the same whether given the usual 6 months of chemotherapy or half that.
“It’s becoming clear that right-sided tumors are different from left-sided tumors,” commented first author Mark P. Saunders, MD, PhD, a consultant oncologist at the Christie NHS Foundation Trust, Manchester, England. A large meta-analysis showed that early right-sided tumors were associated with poorer overall survival (JAMA Oncol. 2016 Oct 27. doi: 10.1001/jamaoncol.2016.4227), but it remains unclear at what point(s) in the course of disease and its treatment sidedness is exerting its influence.
In the new analysis, the investigators assessed the impact of tumor sidedness among 3,219 patients having that information. Results reported at the 2018 GI Cancers Symposium showed that those with right-sided tumors (up to but not including the splenic flexure) had a 40% higher risk of disease-free survival events. However, there was no significant difference by side according to duration of chemotherapy.
“This is the first trial to show that unselected patients with right-sided tumors have worse disease-free survival, compared to those with left-sided tumors,” Dr. Saunders summarized. This finding suggests that greater recurrence risk is driving the poorer overall survival of the former.
“Tumor sidedness did not impact on the 3 months versus 6 months comparison in SCOT,” he further noted. “I suppose it would have fitted a very nice story that the rights did worse, and therefore, 6 months was better [for this group]. We didn’t show that in this trial here, so I don’t think we can say that at all. We still have to say that the outcome of the SCOT trial was that 3 months is noninferior to 6 months.”
Findings in context
“This study was interesting, but I feel that we still need more data coming from the main study,” session chair Michael J. Hall, MD, MS, a medical oncologist at the Fox Chase Cancer Center, Philadelphia, said in an interview. “It’s important to let us know that adjuvant chemotherapy appears to be beneficial, regardless of side, but there are still some other important questions.”
More detail on the difference by side according to chemotherapy duration and according to regimen (because recent data suggest CAPOX may have an edge over FOLFOX) could help tailor treatment, he proposed. For example, it is possible that patients with right-sided tumors will fare better if given 6 months of the CAPOX regimen.
Study details
The majority of the 3,219 patients studied, 63%, had tumors originating on the left side (splenic flexure or distally), according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Compared with patients who had left-sided tumors, those with right-sided tumors (including any in the transverse colon) were older (median, 66 vs. 64 years; P less than .001), less often male (53% vs. 66%; P less than .001), more often had T4 stage (41% vs. 24%; P less than .001), and less often had stage II disease (17% vs. 21%; P =.001).
Patients with right-sided tumors had poorer 3-year disease-free survival (73% vs. 80%; hazard ratio, 1.401; P less than .0001), reported Dr. Saunders. This association weakened slightly after adjustment for T stage and N stage (HR, 1.215; P = .009).
However, benefit of 3 months versus 6 months of chemotherapy was similar whether patients had right-sided tumors (HR, 1.049) or left-sided tumors (HR, 0.910), with no statistically significant heterogeneity between these groups (P =.327).
A large translational substudy, Trans SCOT, is looking at various biomarkers such as microsatellite instability and mutations, and may shed more light on the mechanisms driving the different outcomes for right- and left-sided colorectal cancer, according to Dr. Saunders.
However, even when starting with more than 3,000 patients, drilling down by tumor sidedness and then further by characteristics such as molecular features (or regimen, overall stage, or T and N components) may result in underpowered analyses, he cautioned.
Dr. Saunders disclosed that he received honoraria from and has a consulting or advisory role with Amgen, Merck, Roche, and Servier.
SOURCE: Saunders MP et al. 2018 Gastrointestinal Cancers Symposium, Abstract 558.
SAN FRANCISCO – Colorectal cancer originating on the right side carries a higher risk of recurrence or death after adjuvant oxaliplatin-based chemotherapy, suggests a new analysis of data from the SCOT (Short Course Oncology Therapy) trial. But patients with right-sided disease fare about the same whether given the usual 6 months of chemotherapy or half that.
“It’s becoming clear that right-sided tumors are different from left-sided tumors,” commented first author Mark P. Saunders, MD, PhD, a consultant oncologist at the Christie NHS Foundation Trust, Manchester, England. A large meta-analysis showed that early right-sided tumors were associated with poorer overall survival (JAMA Oncol. 2016 Oct 27. doi: 10.1001/jamaoncol.2016.4227), but it remains unclear at what point(s) in the course of disease and its treatment sidedness is exerting its influence.
In the new analysis, the investigators assessed the impact of tumor sidedness among 3,219 patients having that information. Results reported at the 2018 GI Cancers Symposium showed that those with right-sided tumors (up to but not including the splenic flexure) had a 40% higher risk of disease-free survival events. However, there was no significant difference by side according to duration of chemotherapy.
“This is the first trial to show that unselected patients with right-sided tumors have worse disease-free survival, compared to those with left-sided tumors,” Dr. Saunders summarized. This finding suggests that greater recurrence risk is driving the poorer overall survival of the former.
“Tumor sidedness did not impact on the 3 months versus 6 months comparison in SCOT,” he further noted. “I suppose it would have fitted a very nice story that the rights did worse, and therefore, 6 months was better [for this group]. We didn’t show that in this trial here, so I don’t think we can say that at all. We still have to say that the outcome of the SCOT trial was that 3 months is noninferior to 6 months.”
Findings in context
“This study was interesting, but I feel that we still need more data coming from the main study,” session chair Michael J. Hall, MD, MS, a medical oncologist at the Fox Chase Cancer Center, Philadelphia, said in an interview. “It’s important to let us know that adjuvant chemotherapy appears to be beneficial, regardless of side, but there are still some other important questions.”
More detail on the difference by side according to chemotherapy duration and according to regimen (because recent data suggest CAPOX may have an edge over FOLFOX) could help tailor treatment, he proposed. For example, it is possible that patients with right-sided tumors will fare better if given 6 months of the CAPOX regimen.
Study details
The majority of the 3,219 patients studied, 63%, had tumors originating on the left side (splenic flexure or distally), according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Compared with patients who had left-sided tumors, those with right-sided tumors (including any in the transverse colon) were older (median, 66 vs. 64 years; P less than .001), less often male (53% vs. 66%; P less than .001), more often had T4 stage (41% vs. 24%; P less than .001), and less often had stage II disease (17% vs. 21%; P =.001).
Patients with right-sided tumors had poorer 3-year disease-free survival (73% vs. 80%; hazard ratio, 1.401; P less than .0001), reported Dr. Saunders. This association weakened slightly after adjustment for T stage and N stage (HR, 1.215; P = .009).
However, benefit of 3 months versus 6 months of chemotherapy was similar whether patients had right-sided tumors (HR, 1.049) or left-sided tumors (HR, 0.910), with no statistically significant heterogeneity between these groups (P =.327).
A large translational substudy, Trans SCOT, is looking at various biomarkers such as microsatellite instability and mutations, and may shed more light on the mechanisms driving the different outcomes for right- and left-sided colorectal cancer, according to Dr. Saunders.
However, even when starting with more than 3,000 patients, drilling down by tumor sidedness and then further by characteristics such as molecular features (or regimen, overall stage, or T and N components) may result in underpowered analyses, he cautioned.
Dr. Saunders disclosed that he received honoraria from and has a consulting or advisory role with Amgen, Merck, Roche, and Servier.
SOURCE: Saunders MP et al. 2018 Gastrointestinal Cancers Symposium, Abstract 558.
REPORTING FROM THE 2018 GI CANCERS SYMPOSIUM
Key clinical point:
Major finding: The 3-year rate of disease-free survival was 73% for right-sided tumors and 80% for left-sided tumors (HR, 1.401; P less than .0001).
Data source: An analysis of data from 3,219 patients with high-risk stage II or stage III colorectal cancer given adjuvant chemotherapy in a randomized controlled trial.
Disclosures: Dr. Saunders disclosed that he received honoraria from and has a consulting or advisory role with Amgen, Merck, Roche, and Servier.
Source: Saunders MP et al. 2018 Gastrointestinal Cancers Symposium, Abstract 558.