ESMO Congress 2017

MADRID – Although pembrolizumab (Keytruda) was associated with a 19% reduction in the risk of death compared with the standard of care in patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE 040 trial, the immune checkpoint inhibitor just missed meeting its primary efficacy endpoint of an improvement in overall survival.

The fault may lie in the confounding of overall survival results when patients who were initially assigned to standard of care were crossed over to subsequent therapy with a checkpoint inhibitor after the study ended, said lead investigator Ezra Cohen, MD, of Moores Cancer Center at UC San Diego Health Sciences in La Jolla, Calif.

“This was a trial that clearly did not meet its primary endpoint, but was felt to confer some benefit – at least in the opinion of this investigator – to pembrolizumab vs. standard of care,” he said at the European Society for Medical Oncology Congress.

The byzantine statistical design of the trial, while it may warm a mathematician’s heart, imposed stringent restrictions on the data that may also have led to the ultimate failure of the programmed death-1 (PD-1) inhibitor to meet the efficacy endpoint, he said.

In July 2017, Merck, which markets pembrolizumab, announced the failure in a press release, promising to present the data in a future medical meeting. Dr. Cohen’s ESMO presentation was the fulfillment of that promise.

In the trial, patients with squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, or larynx with disease progression after a platinum-containing chemotherapy regimen, or recurrence/disease progress within 3-6 months of multimodal therapy using platinum, were randomly assigned to therapy with either pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or to standard of care at the investigator’s choice: either methotrexate 40 mg/m² weekly, docetaxel 75 mg/m² every 3 weeks, or cetuximab (Erbitux) 250 mg/m² weekly after a loading dose of 400 mg per m².

Some math required

Dr. Cohen explained that the statistical design of the trial involved a multiplicity strategy using a family-wise alpha strictly controlled at 0.025. The alpha was allocated in a stepwise fashion. The study hypothesis was that pembrolizumab would have an overall survival (OS) advantage with a one-side alpha, and if that was met, OS would then be looked at in specific cohorts according to expression of the PD ligand 1 (PD-L1) on cells, followed by evaluation of objective response rates and progression-free survival in each subgroup.

The final analysis was to be performed after 380 OS events had occurred among 495 randomized patients. The prespecified efficacy boundary for OS in the intention-to-treat (ITT) population was .0175, translating into a hazard ratio (HR) of 0.80.

Median OS in the ITT population was 8.4 months for the pembrolizumab arm, compared with 7.1 months for the standard-of-care arm. This translated into an HR of 0.81 (P = .0204), which do not reach the aforementioned efficacy boundary.

Rates of 1-year overall survival were 37% in the experimental arm, vs. 27% in the standard-of-care arm.

“When one looks at the biomarker-specific cohorts, we can see that these differences are further exaggerated in favor of pembrolizumab, Dr. Cohen said.

An analysis stratified by patients with PD-L1 expression on 1% or more of cells vs. less than 1% showed median overall OS of 8.7 months for those with higher levels of expression, vs. 7.1 months for expression levels below 1% (HR 0.75, P = .0078).

Similarly, an analysis comparing patients with a tumor proportion score (TPS; expression of PD-L1 in the membranes of 50% or more of tumor cells) with patients whose tumors had lower TPS levels showed a median OS of 11.6 months with pembrolizumab, vs. 7.9 months with standard of care (HR 0.54, P = .0017).

Objective response rates were also significantly higher with pembrolizumab in the patients with higher levels of both overall PD-L1 expression (17.3% vs. 9.9% with standard care), and in patients with 50% or more of tumor cells expressing membrane PD-L1 (26.6% vs. 65%, P = .0009).

In an exploratory analysis, the investigators also found that among patients in the standard of care arm who went on to receive a checkpoint inhibitor as subsequent therapy, the median OS was 20.1 months, compared with 9.8 months for patients who received other subsequent therapies, and 4.8 months for those who did not receive subsequent therapy, suggesting that crossover to a checkpoint inhibitor may have diluted overall survival differences between the trial arms, Dr. Cohen said.

Treatment-related adverse events of any grade were more frequent in the standard of care arm, except for hypothyroidism, which was substantially more frequent with pembrolizumab. The incidence of immune-mediated adverse events other than hypothyroidism was generally similar between the treatment arms.

“I think pembrolizumab, despite not meeting the primary endpoint of overall survival, showed evidence of activity and a [good] safety profile. So I think this study is borderline possible, since there is a 19% reduction in the risk of death, with a hazard ratio borderline to the statistical hypothesis that was initially planned,” said invited discussant Sandrine Faivre, MD, PhD, of Bichat-Beaujon University Hospitals in Paris.

Although pembrolizumab did not reach the primary efficacy endpoint in the ITT population, among patients with TPS of 50% or greater, the benefit with the PD-1 inhibitor was “exquisite” she said, adding that this subgroup of patients made up only 26% of the ITT population.

The study was funded by Merck. Dr. Cohen disclosed stock ownership in Human Longevity, Inc, and being an advisory board member for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, and Pfizer. Dr. Faivre disclosed unspecified relationships with Bayer Pharma, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck, Serono, and Novartis.

 

 

MADRID – Although pembrolizumab (Keytruda) was associated with a 19% reduction in the risk of death compared with the standard of care in patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE 040 trial, the immune checkpoint inhibitor just missed meeting its primary efficacy endpoint of an improvement in overall survival.

The fault may lie in the confounding of overall survival results when patients who were initially assigned to standard of care were crossed over to subsequent therapy with a checkpoint inhibitor after the study ended, said lead investigator Ezra Cohen, MD, of Moores Cancer Center at UC San Diego Health Sciences in La Jolla, Calif.

“This was a trial that clearly did not meet its primary endpoint, but was felt to confer some benefit – at least in the opinion of this investigator – to pembrolizumab vs. standard of care,” he said at the European Society for Medical Oncology Congress.

The byzantine statistical design of the trial, while it may warm a mathematician’s heart, imposed stringent restrictions on the data that may also have led to the ultimate failure of the programmed death-1 (PD-1) inhibitor to meet the efficacy endpoint, he said.

In July 2017, Merck, which markets pembrolizumab, announced the failure in a press release, promising to present the data in a future medical meeting. Dr. Cohen’s ESMO presentation was the fulfillment of that promise.

In the trial, patients with squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, or larynx with disease progression after a platinum-containing chemotherapy regimen, or recurrence/disease progress within 3-6 months of multimodal therapy using platinum, were randomly assigned to therapy with either pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or to standard of care at the investigator’s choice: either methotrexate 40 mg/m² weekly, docetaxel 75 mg/m² every 3 weeks, or cetuximab (Erbitux) 250 mg/m² weekly after a loading dose of 400 mg per m².

Some math required

Dr. Cohen explained that the statistical design of the trial involved a multiplicity strategy using a family-wise alpha strictly controlled at 0.025. The alpha was allocated in a stepwise fashion. The study hypothesis was that pembrolizumab would have an overall survival (OS) advantage with a one-side alpha, and if that was met, OS would then be looked at in specific cohorts according to expression of the PD ligand 1 (PD-L1) on cells, followed by evaluation of objective response rates and progression-free survival in each subgroup.

The final analysis was to be performed after 380 OS events had occurred among 495 randomized patients. The prespecified efficacy boundary for OS in the intention-to-treat (ITT) population was .0175, translating into a hazard ratio (HR) of 0.80.

Median OS in the ITT population was 8.4 months for the pembrolizumab arm, compared with 7.1 months for the standard-of-care arm. This translated into an HR of 0.81 (P = .0204), which do not reach the aforementioned efficacy boundary.

Rates of 1-year overall survival were 37% in the experimental arm, vs. 27% in the standard-of-care arm.

“When one looks at the biomarker-specific cohorts, we can see that these differences are further exaggerated in favor of pembrolizumab, Dr. Cohen said.

An analysis stratified by patients with PD-L1 expression on 1% or more of cells vs. less than 1% showed median overall OS of 8.7 months for those with higher levels of expression, vs. 7.1 months for expression levels below 1% (HR 0.75, P = .0078).

Similarly, an analysis comparing patients with a tumor proportion score (TPS; expression of PD-L1 in the membranes of 50% or more of tumor cells) with patients whose tumors had lower TPS levels showed a median OS of 11.6 months with pembrolizumab, vs. 7.9 months with standard of care (HR 0.54, P = .0017).

Objective response rates were also significantly higher with pembrolizumab in the patients with higher levels of both overall PD-L1 expression (17.3% vs. 9.9% with standard care), and in patients with 50% or more of tumor cells expressing membrane PD-L1 (26.6% vs. 65%, P = .0009).

In an exploratory analysis, the investigators also found that among patients in the standard of care arm who went on to receive a checkpoint inhibitor as subsequent therapy, the median OS was 20.1 months, compared with 9.8 months for patients who received other subsequent therapies, and 4.8 months for those who did not receive subsequent therapy, suggesting that crossover to a checkpoint inhibitor may have diluted overall survival differences between the trial arms, Dr. Cohen said.

Treatment-related adverse events of any grade were more frequent in the standard of care arm, except for hypothyroidism, which was substantially more frequent with pembrolizumab. The incidence of immune-mediated adverse events other than hypothyroidism was generally similar between the treatment arms.

“I think pembrolizumab, despite not meeting the primary endpoint of overall survival, showed evidence of activity and a [good] safety profile. So I think this study is borderline possible, since there is a 19% reduction in the risk of death, with a hazard ratio borderline to the statistical hypothesis that was initially planned,” said invited discussant Sandrine Faivre, MD, PhD, of Bichat-Beaujon University Hospitals in Paris.

Although pembrolizumab did not reach the primary efficacy endpoint in the ITT population, among patients with TPS of 50% or greater, the benefit with the PD-1 inhibitor was “exquisite” she said, adding that this subgroup of patients made up only 26% of the ITT population.

The study was funded by Merck. Dr. Cohen disclosed stock ownership in Human Longevity, Inc, and being an advisory board member for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, and Pfizer. Dr. Faivre disclosed unspecified relationships with Bayer Pharma, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck, Serono, and Novartis.

 

 

MADRID – Although pembrolizumab (Keytruda) was associated with a 19% reduction in the risk of death compared with the standard of care in patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE 040 trial, the immune checkpoint inhibitor just missed meeting its primary efficacy endpoint of an improvement in overall survival.

The fault may lie in the confounding of overall survival results when patients who were initially assigned to standard of care were crossed over to subsequent therapy with a checkpoint inhibitor after the study ended, said lead investigator Ezra Cohen, MD, of Moores Cancer Center at UC San Diego Health Sciences in La Jolla, Calif.

“This was a trial that clearly did not meet its primary endpoint, but was felt to confer some benefit – at least in the opinion of this investigator – to pembrolizumab vs. standard of care,” he said at the European Society for Medical Oncology Congress.

The byzantine statistical design of the trial, while it may warm a mathematician’s heart, imposed stringent restrictions on the data that may also have led to the ultimate failure of the programmed death-1 (PD-1) inhibitor to meet the efficacy endpoint, he said.

In July 2017, Merck, which markets pembrolizumab, announced the failure in a press release, promising to present the data in a future medical meeting. Dr. Cohen’s ESMO presentation was the fulfillment of that promise.

In the trial, patients with squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, or larynx with disease progression after a platinum-containing chemotherapy regimen, or recurrence/disease progress within 3-6 months of multimodal therapy using platinum, were randomly assigned to therapy with either pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or to standard of care at the investigator’s choice: either methotrexate 40 mg/m² weekly, docetaxel 75 mg/m² every 3 weeks, or cetuximab (Erbitux) 250 mg/m² weekly after a loading dose of 400 mg per m².

Some math required

Dr. Cohen explained that the statistical design of the trial involved a multiplicity strategy using a family-wise alpha strictly controlled at 0.025. The alpha was allocated in a stepwise fashion. The study hypothesis was that pembrolizumab would have an overall survival (OS) advantage with a one-side alpha, and if that was met, OS would then be looked at in specific cohorts according to expression of the PD ligand 1 (PD-L1) on cells, followed by evaluation of objective response rates and progression-free survival in each subgroup.

The final analysis was to be performed after 380 OS events had occurred among 495 randomized patients. The prespecified efficacy boundary for OS in the intention-to-treat (ITT) population was .0175, translating into a hazard ratio (HR) of 0.80.

Median OS in the ITT population was 8.4 months for the pembrolizumab arm, compared with 7.1 months for the standard-of-care arm. This translated into an HR of 0.81 (P = .0204), which do not reach the aforementioned efficacy boundary.

Rates of 1-year overall survival were 37% in the experimental arm, vs. 27% in the standard-of-care arm.

“When one looks at the biomarker-specific cohorts, we can see that these differences are further exaggerated in favor of pembrolizumab, Dr. Cohen said.

An analysis stratified by patients with PD-L1 expression on 1% or more of cells vs. less than 1% showed median overall OS of 8.7 months for those with higher levels of expression, vs. 7.1 months for expression levels below 1% (HR 0.75, P = .0078).

Similarly, an analysis comparing patients with a tumor proportion score (TPS; expression of PD-L1 in the membranes of 50% or more of tumor cells) with patients whose tumors had lower TPS levels showed a median OS of 11.6 months with pembrolizumab, vs. 7.9 months with standard of care (HR 0.54, P = .0017).

Objective response rates were also significantly higher with pembrolizumab in the patients with higher levels of both overall PD-L1 expression (17.3% vs. 9.9% with standard care), and in patients with 50% or more of tumor cells expressing membrane PD-L1 (26.6% vs. 65%, P = .0009).

In an exploratory analysis, the investigators also found that among patients in the standard of care arm who went on to receive a checkpoint inhibitor as subsequent therapy, the median OS was 20.1 months, compared with 9.8 months for patients who received other subsequent therapies, and 4.8 months for those who did not receive subsequent therapy, suggesting that crossover to a checkpoint inhibitor may have diluted overall survival differences between the trial arms, Dr. Cohen said.

Treatment-related adverse events of any grade were more frequent in the standard of care arm, except for hypothyroidism, which was substantially more frequent with pembrolizumab. The incidence of immune-mediated adverse events other than hypothyroidism was generally similar between the treatment arms.

“I think pembrolizumab, despite not meeting the primary endpoint of overall survival, showed evidence of activity and a [good] safety profile. So I think this study is borderline possible, since there is a 19% reduction in the risk of death, with a hazard ratio borderline to the statistical hypothesis that was initially planned,” said invited discussant Sandrine Faivre, MD, PhD, of Bichat-Beaujon University Hospitals in Paris.

Although pembrolizumab did not reach the primary efficacy endpoint in the ITT population, among patients with TPS of 50% or greater, the benefit with the PD-1 inhibitor was “exquisite” she said, adding that this subgroup of patients made up only 26% of the ITT population.

The study was funded by Merck. Dr. Cohen disclosed stock ownership in Human Longevity, Inc, and being an advisory board member for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, and Pfizer. Dr. Faivre disclosed unspecified relationships with Bayer Pharma, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck, Serono, and Novartis.

 

 

 

MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.

The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.

Neil Osterweil/Frontline Medical News

“The primary endpoint, total PFS demonstrating noninferiority for the sequence sorafenib followed by pazopanib vs. the sequence pazopanib followed by sorafenib was not met,” she said.

The trial design specified that to show noninferiority for the sorafenib-pazopanib combination, the upper limit of the one-sided 95% confidence interval of the hazard ratio would have to be less than 1.225, but the upper limit was instead 1.68.

However, two key secondary endpoints – progression-free survival during first line-therapy and disease-control rate – clearly favored the pazopanib-first sequence, although there were no significant differences in overall survival (OS), Dr. Retz said at the European Society for Medical Oncology Congress.

SWITCH-2 was a phase 3, randomized, open-label crossover trial designed to test the combination and sequencing of sorafenib and pazopanib, each of which is approved for the treatment of mRCC.

In the SWITCH-1 trial, investigators looked at sorafenib followed by sunitinib (Sutent) or vice-versa and found no significant differences in either total PFS or OS. Based on these results, they conducted a similar trial using sorafenib and pazopanib.

A total of 377 patients in Germany, Austria, and the Netherlands with mRCC who were not good candidates for cytokines and had no prior systemic therapies were enrolled and randomly assigned to sorafenib 400 mg twice daily or pazopanib 800 mg once daily until progression or intolerable toxicity. In each arm, patients were crossed over to the other drug at the time of first progression.

After 42 months of follow-up, the hazard ratio for the primary endpoint of total PFS was 1.36 trending in favor of pazopanib.

For the secondary endpoint of first-line PFS, pazopanib-first was clearly superior, with a median PFS of 9.3 months, compared with 5.6 months for sorafenib-first (HR, 1.56, P = .0017). There was no difference in second-line PFS, at 2.2 vs. 2.9 months, respectively.

Overall survival trended in favor of up-front pazopanib, with a median of 28 months vs. a median of 22.7 months for up-front sorafenib, but this difference, as noted before, was not significant.

An analysis of tumor response and disease-control rates showed that in the first line, the pazopanib-sorafenib sequence was associated with a disease-control rate (composite of complete and partial responses and stable disease) of 77.7%, compared with 67.7% for sorafenib-pazopanib (P = .0304).

In the second line, however, the disease control rate favored the sorafenib-followed-by-pazopanib arm, at 56.6% vs. 43.6% (P = .0112).

A subgroup analysis showed that, in terms of total PFS, the pazopanib-sorafenib sequence offered greater benefit to patients older than 65, those with favorable Memorial Sloan Kettering Cancer Center (MSKCC/Motzer) scores, patients with good Karnofsky Performance Status, and patients whose tumors had a non–clear cell histology.

In each study arm, adverse events were more commonly seen during first-line therapy. With sorafenib, the most frequent adverse events were hand-foot skin reaction, alopecia, and rash. For pazopanib, the most common adverse events were fatigue, hypertension, nausea, abdominal pain, and elevation of liver enzymes.

Neil Osterweil/Frontline Medical News

Invited discussant Michael Staehler, MD, of Ludwig-Maximilian University in Munich, noted that the overall survival detriment with sorafenib in the first lines was equivalent to half a year.

Although the investigators reported no differences in overall survival, “I question that: I think half a year of survival is a meaningful difference. Although it’s statistically insignificant, it might be important for the patients,” he said.

He suggested that ESMO guidelines regarding treatment of patients with mRCC should be revised to reflect data from this and other trials suggesting that sorafenib should be dropped as a treatment option in either first- or second-line therapy.

The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.

[email protected]

 

MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.

The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.

Neil Osterweil/Frontline Medical News

“The primary endpoint, total PFS demonstrating noninferiority for the sequence sorafenib followed by pazopanib vs. the sequence pazopanib followed by sorafenib was not met,” she said.

The trial design specified that to show noninferiority for the sorafenib-pazopanib combination, the upper limit of the one-sided 95% confidence interval of the hazard ratio would have to be less than 1.225, but the upper limit was instead 1.68.

However, two key secondary endpoints – progression-free survival during first line-therapy and disease-control rate – clearly favored the pazopanib-first sequence, although there were no significant differences in overall survival (OS), Dr. Retz said at the European Society for Medical Oncology Congress.

SWITCH-2 was a phase 3, randomized, open-label crossover trial designed to test the combination and sequencing of sorafenib and pazopanib, each of which is approved for the treatment of mRCC.

In the SWITCH-1 trial, investigators looked at sorafenib followed by sunitinib (Sutent) or vice-versa and found no significant differences in either total PFS or OS. Based on these results, they conducted a similar trial using sorafenib and pazopanib.

A total of 377 patients in Germany, Austria, and the Netherlands with mRCC who were not good candidates for cytokines and had no prior systemic therapies were enrolled and randomly assigned to sorafenib 400 mg twice daily or pazopanib 800 mg once daily until progression or intolerable toxicity. In each arm, patients were crossed over to the other drug at the time of first progression.

After 42 months of follow-up, the hazard ratio for the primary endpoint of total PFS was 1.36 trending in favor of pazopanib.

For the secondary endpoint of first-line PFS, pazopanib-first was clearly superior, with a median PFS of 9.3 months, compared with 5.6 months for sorafenib-first (HR, 1.56, P = .0017). There was no difference in second-line PFS, at 2.2 vs. 2.9 months, respectively.

Overall survival trended in favor of up-front pazopanib, with a median of 28 months vs. a median of 22.7 months for up-front sorafenib, but this difference, as noted before, was not significant.

An analysis of tumor response and disease-control rates showed that in the first line, the pazopanib-sorafenib sequence was associated with a disease-control rate (composite of complete and partial responses and stable disease) of 77.7%, compared with 67.7% for sorafenib-pazopanib (P = .0304).

In the second line, however, the disease control rate favored the sorafenib-followed-by-pazopanib arm, at 56.6% vs. 43.6% (P = .0112).

A subgroup analysis showed that, in terms of total PFS, the pazopanib-sorafenib sequence offered greater benefit to patients older than 65, those with favorable Memorial Sloan Kettering Cancer Center (MSKCC/Motzer) scores, patients with good Karnofsky Performance Status, and patients whose tumors had a non–clear cell histology.

In each study arm, adverse events were more commonly seen during first-line therapy. With sorafenib, the most frequent adverse events were hand-foot skin reaction, alopecia, and rash. For pazopanib, the most common adverse events were fatigue, hypertension, nausea, abdominal pain, and elevation of liver enzymes.

Neil Osterweil/Frontline Medical News

Invited discussant Michael Staehler, MD, of Ludwig-Maximilian University in Munich, noted that the overall survival detriment with sorafenib in the first lines was equivalent to half a year.

Although the investigators reported no differences in overall survival, “I question that: I think half a year of survival is a meaningful difference. Although it’s statistically insignificant, it might be important for the patients,” he said.

He suggested that ESMO guidelines regarding treatment of patients with mRCC should be revised to reflect data from this and other trials suggesting that sorafenib should be dropped as a treatment option in either first- or second-line therapy.

The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.

[email protected]

 

MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.

The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.

Neil Osterweil/Frontline Medical News

“The primary endpoint, total PFS demonstrating noninferiority for the sequence sorafenib followed by pazopanib vs. the sequence pazopanib followed by sorafenib was not met,” she said.

The trial design specified that to show noninferiority for the sorafenib-pazopanib combination, the upper limit of the one-sided 95% confidence interval of the hazard ratio would have to be less than 1.225, but the upper limit was instead 1.68.

However, two key secondary endpoints – progression-free survival during first line-therapy and disease-control rate – clearly favored the pazopanib-first sequence, although there were no significant differences in overall survival (OS), Dr. Retz said at the European Society for Medical Oncology Congress.

SWITCH-2 was a phase 3, randomized, open-label crossover trial designed to test the combination and sequencing of sorafenib and pazopanib, each of which is approved for the treatment of mRCC.

In the SWITCH-1 trial, investigators looked at sorafenib followed by sunitinib (Sutent) or vice-versa and found no significant differences in either total PFS or OS. Based on these results, they conducted a similar trial using sorafenib and pazopanib.

A total of 377 patients in Germany, Austria, and the Netherlands with mRCC who were not good candidates for cytokines and had no prior systemic therapies were enrolled and randomly assigned to sorafenib 400 mg twice daily or pazopanib 800 mg once daily until progression or intolerable toxicity. In each arm, patients were crossed over to the other drug at the time of first progression.

After 42 months of follow-up, the hazard ratio for the primary endpoint of total PFS was 1.36 trending in favor of pazopanib.

For the secondary endpoint of first-line PFS, pazopanib-first was clearly superior, with a median PFS of 9.3 months, compared with 5.6 months for sorafenib-first (HR, 1.56, P = .0017). There was no difference in second-line PFS, at 2.2 vs. 2.9 months, respectively.

Overall survival trended in favor of up-front pazopanib, with a median of 28 months vs. a median of 22.7 months for up-front sorafenib, but this difference, as noted before, was not significant.

An analysis of tumor response and disease-control rates showed that in the first line, the pazopanib-sorafenib sequence was associated with a disease-control rate (composite of complete and partial responses and stable disease) of 77.7%, compared with 67.7% for sorafenib-pazopanib (P = .0304).

In the second line, however, the disease control rate favored the sorafenib-followed-by-pazopanib arm, at 56.6% vs. 43.6% (P = .0112).

A subgroup analysis showed that, in terms of total PFS, the pazopanib-sorafenib sequence offered greater benefit to patients older than 65, those with favorable Memorial Sloan Kettering Cancer Center (MSKCC/Motzer) scores, patients with good Karnofsky Performance Status, and patients whose tumors had a non–clear cell histology.

In each study arm, adverse events were more commonly seen during first-line therapy. With sorafenib, the most frequent adverse events were hand-foot skin reaction, alopecia, and rash. For pazopanib, the most common adverse events were fatigue, hypertension, nausea, abdominal pain, and elevation of liver enzymes.

Neil Osterweil/Frontline Medical News

Invited discussant Michael Staehler, MD, of Ludwig-Maximilian University in Munich, noted that the overall survival detriment with sorafenib in the first lines was equivalent to half a year.

Although the investigators reported no differences in overall survival, “I question that: I think half a year of survival is a meaningful difference. Although it’s statistically insignificant, it might be important for the patients,” he said.

He suggested that ESMO guidelines regarding treatment of patients with mRCC should be revised to reflect data from this and other trials suggesting that sorafenib should be dropped as a treatment option in either first- or second-line therapy.

The trial was supported by grants from Bayer and Novartis. Dr. Retz disclosed honoraria from those companies and others, and advisory board participation for other drug makers. Dr. Staehler disclosed but did not specify relationships with Bayer, Novartis, and others.

[email protected]

 

MADRID – Five years on, extended adjuvant therapy with neratinib (Nerlynx) continues to show a significant clinical benefit in women with HER2-positive breast cancer who received postoperative trastuzumab (Herceptin) and chemotherapy, long-term follow-up results from the ExteNET trial show.

In a planned intention-to-treat analysis at 5 years of follow-up, extended adjuvant therapy with the tyrosine kinase inhibitor neratinib was associated with a small but significant improvement in invasive disease-free survival (iDFS), compared with placebo, with most of the benefit occurring in women with hormone receptor–positive disease, reported Miguel Martin, MD, of the Gregorio Marañón Health Research Institute in Madrid.

Neil Osterweil/Frontline Medical News

“The 5-year analysis of the ExteNET trial confirms the early results of sustained benefit with extended adjuvant neratinib after chemotherapy and trastuzumab,” he said at the European Society for Medical Oncology Congress.

Data from an earlier analysis of the trial supported the Food and Drug Administration’s decision to approve neratinib in the extended adjuvant setting in July 2017.

In the ExteNET trial, 2,840 women with early HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab and chemotherapy were stratified by nodal and hormone receptor status and by concurrent vs. sequential chemotherapy and trastuzumab, and were then randomly assigned to receive oral neratinib 240 mg/day for 1 year, or placebo. Analyses of iDFS were planned for 2 and 5 years, and an overall survival analysis was planned after 248 patient deaths had occurred. Overall survival data have not matured as yet, Dr. Martin noted.

Results of an unspecified 3-year analysis of the trial, presented at the San Antonio Breast Cancer Symposium in 2015, showed a continued benefit for the addition of neratinib, a finding that has now been extended out to 5 years.

At ESMO 2017, Dr. Martin presented data on all efficacy endpoints except overall survival in the intention-to-treat population.

By the cutoff date in March 2017, 2,117 of the original 2,840 patients (76%) gave consent for collection of additional data, including 1,028 who had been assigned to neratinib, and 1,089 assigned to placebo.

The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo, an absolute difference of 2.5%. This translated into a hazard ratio favoring neratinib of 0.73 (P = .008). Neratinib was also significantly better than placebo for DFS in patients with ductal carcinoma in situ (89.7% vs. 86.8, HR, 0.71, P = .004).

However, there were no significant differences at 5 years between trial arms in either distant DFS, time to distant recurrence, or central nervous system recurrences. Dr. Martin noted that the although there were fewer CNS recurrences with neratinib (1.30% vs. 1.82%), the total number of cases was too small to detect a possible difference.

In a subgroup analysis, neratinib trended toward better performance in all categories, but was significantly better than placebo only among patients from Asia, Eastern Europe, and South America, and among patients with four or more positive lymph nodes. ­

An analysis of iDFS by hormone receptor status showed that for HR-positive patients, the 5-year iDFS rate was 91.2% with neratinib vs. 86.8% with placebo, translating into a hazard ratio of 0.60, P = .002). In contrast, iDFS rates were nearly identical among HR-negative patients, at 88.9% vs. 88.8%, respectively.

Following treatment discontinuation, there was no evidence of increased symptomatic cardiotoxicity or second primary malignancies vs. placebo, and no late-term consequences of neratinib-associated diarrhea, Dr. Martin said.

A separate poster on health-related quality of life, also presented at ESMO 2017, showed that patients assigned to neratinib had a drop in quality-of-life measures during the first month of treatment, possibly because of diarrhea, but then had a steady improvement toward baseline. There is an ongoing study to evaluate whether loperamide-based regimens can reduce or prevent neratinib-associated diarrhea, the investigators noted.

“In ExteNET, we’ve seen continued demonstration of clinically significant benefit, particularly in higher-risk, hormone receptor–positive disease, despite many limitations, with change in sponsor and initial plan for only 2 years of follow-up,” said Hope S. Rugo, MD, from the University of California, San Francisco, the invited discussant.

“Survival data is pending, and we’re looking forward to seeing that in 2019, but the reduction in distant events, although small, is still encouraging,” she said.

The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board. 

 

MADRID – Five years on, extended adjuvant therapy with neratinib (Nerlynx) continues to show a significant clinical benefit in women with HER2-positive breast cancer who received postoperative trastuzumab (Herceptin) and chemotherapy, long-term follow-up results from the ExteNET trial show.

In a planned intention-to-treat analysis at 5 years of follow-up, extended adjuvant therapy with the tyrosine kinase inhibitor neratinib was associated with a small but significant improvement in invasive disease-free survival (iDFS), compared with placebo, with most of the benefit occurring in women with hormone receptor–positive disease, reported Miguel Martin, MD, of the Gregorio Marañón Health Research Institute in Madrid.

Neil Osterweil/Frontline Medical News

“The 5-year analysis of the ExteNET trial confirms the early results of sustained benefit with extended adjuvant neratinib after chemotherapy and trastuzumab,” he said at the European Society for Medical Oncology Congress.

Data from an earlier analysis of the trial supported the Food and Drug Administration’s decision to approve neratinib in the extended adjuvant setting in July 2017.

In the ExteNET trial, 2,840 women with early HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab and chemotherapy were stratified by nodal and hormone receptor status and by concurrent vs. sequential chemotherapy and trastuzumab, and were then randomly assigned to receive oral neratinib 240 mg/day for 1 year, or placebo. Analyses of iDFS were planned for 2 and 5 years, and an overall survival analysis was planned after 248 patient deaths had occurred. Overall survival data have not matured as yet, Dr. Martin noted.

Results of an unspecified 3-year analysis of the trial, presented at the San Antonio Breast Cancer Symposium in 2015, showed a continued benefit for the addition of neratinib, a finding that has now been extended out to 5 years.

At ESMO 2017, Dr. Martin presented data on all efficacy endpoints except overall survival in the intention-to-treat population.

By the cutoff date in March 2017, 2,117 of the original 2,840 patients (76%) gave consent for collection of additional data, including 1,028 who had been assigned to neratinib, and 1,089 assigned to placebo.

The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo, an absolute difference of 2.5%. This translated into a hazard ratio favoring neratinib of 0.73 (P = .008). Neratinib was also significantly better than placebo for DFS in patients with ductal carcinoma in situ (89.7% vs. 86.8, HR, 0.71, P = .004).

However, there were no significant differences at 5 years between trial arms in either distant DFS, time to distant recurrence, or central nervous system recurrences. Dr. Martin noted that the although there were fewer CNS recurrences with neratinib (1.30% vs. 1.82%), the total number of cases was too small to detect a possible difference.

In a subgroup analysis, neratinib trended toward better performance in all categories, but was significantly better than placebo only among patients from Asia, Eastern Europe, and South America, and among patients with four or more positive lymph nodes. ­

An analysis of iDFS by hormone receptor status showed that for HR-positive patients, the 5-year iDFS rate was 91.2% with neratinib vs. 86.8% with placebo, translating into a hazard ratio of 0.60, P = .002). In contrast, iDFS rates were nearly identical among HR-negative patients, at 88.9% vs. 88.8%, respectively.

Following treatment discontinuation, there was no evidence of increased symptomatic cardiotoxicity or second primary malignancies vs. placebo, and no late-term consequences of neratinib-associated diarrhea, Dr. Martin said.

A separate poster on health-related quality of life, also presented at ESMO 2017, showed that patients assigned to neratinib had a drop in quality-of-life measures during the first month of treatment, possibly because of diarrhea, but then had a steady improvement toward baseline. There is an ongoing study to evaluate whether loperamide-based regimens can reduce or prevent neratinib-associated diarrhea, the investigators noted.

“In ExteNET, we’ve seen continued demonstration of clinically significant benefit, particularly in higher-risk, hormone receptor–positive disease, despite many limitations, with change in sponsor and initial plan for only 2 years of follow-up,” said Hope S. Rugo, MD, from the University of California, San Francisco, the invited discussant.

“Survival data is pending, and we’re looking forward to seeing that in 2019, but the reduction in distant events, although small, is still encouraging,” she said.

The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board. 

 

MADRID – Five years on, extended adjuvant therapy with neratinib (Nerlynx) continues to show a significant clinical benefit in women with HER2-positive breast cancer who received postoperative trastuzumab (Herceptin) and chemotherapy, long-term follow-up results from the ExteNET trial show.

In a planned intention-to-treat analysis at 5 years of follow-up, extended adjuvant therapy with the tyrosine kinase inhibitor neratinib was associated with a small but significant improvement in invasive disease-free survival (iDFS), compared with placebo, with most of the benefit occurring in women with hormone receptor–positive disease, reported Miguel Martin, MD, of the Gregorio Marañón Health Research Institute in Madrid.

Neil Osterweil/Frontline Medical News

“The 5-year analysis of the ExteNET trial confirms the early results of sustained benefit with extended adjuvant neratinib after chemotherapy and trastuzumab,” he said at the European Society for Medical Oncology Congress.

Data from an earlier analysis of the trial supported the Food and Drug Administration’s decision to approve neratinib in the extended adjuvant setting in July 2017.

In the ExteNET trial, 2,840 women with early HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab and chemotherapy were stratified by nodal and hormone receptor status and by concurrent vs. sequential chemotherapy and trastuzumab, and were then randomly assigned to receive oral neratinib 240 mg/day for 1 year, or placebo. Analyses of iDFS were planned for 2 and 5 years, and an overall survival analysis was planned after 248 patient deaths had occurred. Overall survival data have not matured as yet, Dr. Martin noted.

Results of an unspecified 3-year analysis of the trial, presented at the San Antonio Breast Cancer Symposium in 2015, showed a continued benefit for the addition of neratinib, a finding that has now been extended out to 5 years.

At ESMO 2017, Dr. Martin presented data on all efficacy endpoints except overall survival in the intention-to-treat population.

By the cutoff date in March 2017, 2,117 of the original 2,840 patients (76%) gave consent for collection of additional data, including 1,028 who had been assigned to neratinib, and 1,089 assigned to placebo.

The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo, an absolute difference of 2.5%. This translated into a hazard ratio favoring neratinib of 0.73 (P = .008). Neratinib was also significantly better than placebo for DFS in patients with ductal carcinoma in situ (89.7% vs. 86.8, HR, 0.71, P = .004).

However, there were no significant differences at 5 years between trial arms in either distant DFS, time to distant recurrence, or central nervous system recurrences. Dr. Martin noted that the although there were fewer CNS recurrences with neratinib (1.30% vs. 1.82%), the total number of cases was too small to detect a possible difference.

In a subgroup analysis, neratinib trended toward better performance in all categories, but was significantly better than placebo only among patients from Asia, Eastern Europe, and South America, and among patients with four or more positive lymph nodes. ­

An analysis of iDFS by hormone receptor status showed that for HR-positive patients, the 5-year iDFS rate was 91.2% with neratinib vs. 86.8% with placebo, translating into a hazard ratio of 0.60, P = .002). In contrast, iDFS rates were nearly identical among HR-negative patients, at 88.9% vs. 88.8%, respectively.

Following treatment discontinuation, there was no evidence of increased symptomatic cardiotoxicity or second primary malignancies vs. placebo, and no late-term consequences of neratinib-associated diarrhea, Dr. Martin said.

A separate poster on health-related quality of life, also presented at ESMO 2017, showed that patients assigned to neratinib had a drop in quality-of-life measures during the first month of treatment, possibly because of diarrhea, but then had a steady improvement toward baseline. There is an ongoing study to evaluate whether loperamide-based regimens can reduce or prevent neratinib-associated diarrhea, the investigators noted.

“In ExteNET, we’ve seen continued demonstration of clinically significant benefit, particularly in higher-risk, hormone receptor–positive disease, despite many limitations, with change in sponsor and initial plan for only 2 years of follow-up,” said Hope S. Rugo, MD, from the University of California, San Francisco, the invited discussant.

“Survival data is pending, and we’re looking forward to seeing that in 2019, but the reduction in distant events, although small, is still encouraging,” she said.

The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board. 

 

MADRID – Adding cetuximab (Erbitux) to chemotherapy before or after surgery for resectable colorectal liver metastases resulted in significantly worse survival compared with perioperative chemotherapy alone, mature results of the randomized New EPOC trial confirmed.

Among 257 patients with KRAS exon 2 wild-type resectable colorectal liver metastases (CRLM) or suboptimally resectable CRLM, median overall survival (OS) was 81 months for patients assigned to neoadjuvant and adjuvant chemotherapy alone, compared with 55.4 months for patients who received perioperative chemotherapy plus cetuximab, reported John Bridgewater, MD, of University College London Cancer Institute.

Postprogression survival (PPS) was “particularly poor” for patients assigned to cetuximab, the investigators noted in a poster presented at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) was 22.2 months without cetuximab, vs. 15.5 months with chemotherapy plus cetuximab, a difference that was not statistically significant. However, when the primary analysis of the trial was reported in 2014 in The Lancet: Oncology, cetuximab was associated with significantly shorter PFS. The trial was halted in 2012 on the recommendation of the data monitoring committee.

“In the context of perioperative therapy for resectable CRLM, chemotherapy plus cetuximab confers a shorter OS and PPS,” Dr. Bridgewater and his associates wrote.”This is primarily in those with conventionally favorable prognostic features suggesting that cetuximab induces adverse biology in some patients, whose biomarker profile is ongoing.”

They also found that there were no differences in overall survival among patients with responses to chemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) and those who did not have responses, “suggesting that in this predominantly operable population, any conferred benefit of systemic treatment is through elimination of micro-metastatic disease rather than by downsizing of radiologically evaluable disease.

The randomized phase 3 Medical Research Council COIN trial, results of which were reported at the 2010 annual meeting of the American Society of Clinical Oncology and later published in The Lancet, failed to show a benefit for the addition of cetuximab to front-line oxaliplatin-based chemotherapy for metastatic CRC. Median OS in KRAS wild-type patients was 17 months when cetuximab was added to chemotherapy with oxaliplatin and an intravenous or oral fluoropyrimidine, compared with 17.9 months when chemotherapy was delivered without cetuximab. Median PFS held at 8.6 months in both arms of the trial.

The New EPOC investigators described their study as a “natural extension” of the COIN study as well as earlier trials and phase 2 studies of neoadjuvant and adjuvant therapy in this patient population.

From 2007 through 2012, 257 patients were randomly assigned to receive chemotherapy alone, or chemotherapy with rituximab. Chemotherapy consisted of one of two regimens: oxaliplatin 85 mg/m² intravenously over 2 hours and fluorouracil bolus 400 mg/m² intravenously over 5 minutes followed by a 46-hour infusion of fluorouracil 2,400 mg/m² repeated every 2 weeks; or oxaliplatin 130 mg/m² intravenously over 2 hours and oral capecitabine (Xeloda) 1,000 mg/m2 twice daily on days 1-14 repeated every 3 weeks.

After a median follow-up of 69 months, there were 130 deaths from any cause. As noted before, median OS was significantly shorter with cetuximab. The hazard ratio for death with cetuximab was 1.45 (P = .035). Median PFS did not differ in this most recent analysis, however.

Median PPS was 35.4 months for chemotherapy alone, compared with 23.5 months for chemotherapy plus cetuximab (P = .014).

The poor overall survival and PFS results indicate that “cetuximab cannot be recommended for perioperative treatment in patients with resectable disease,” said Thomas Gruenberger, MD, an oncologic surgeon at Rudolf Hospital in Vienna, who was invited to review the results in a poster discussion session.

Cancer Research UK supported the study. Dr. Bridgewater disclosed honoraria and speakers fees from Merck, Celgene, and Servier, and travel support from Amgen, Merck Sharpe Dohme, and Servier.

 

MADRID – Adding cetuximab (Erbitux) to chemotherapy before or after surgery for resectable colorectal liver metastases resulted in significantly worse survival compared with perioperative chemotherapy alone, mature results of the randomized New EPOC trial confirmed.

Among 257 patients with KRAS exon 2 wild-type resectable colorectal liver metastases (CRLM) or suboptimally resectable CRLM, median overall survival (OS) was 81 months for patients assigned to neoadjuvant and adjuvant chemotherapy alone, compared with 55.4 months for patients who received perioperative chemotherapy plus cetuximab, reported John Bridgewater, MD, of University College London Cancer Institute.

Postprogression survival (PPS) was “particularly poor” for patients assigned to cetuximab, the investigators noted in a poster presented at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) was 22.2 months without cetuximab, vs. 15.5 months with chemotherapy plus cetuximab, a difference that was not statistically significant. However, when the primary analysis of the trial was reported in 2014 in The Lancet: Oncology, cetuximab was associated with significantly shorter PFS. The trial was halted in 2012 on the recommendation of the data monitoring committee.

“In the context of perioperative therapy for resectable CRLM, chemotherapy plus cetuximab confers a shorter OS and PPS,” Dr. Bridgewater and his associates wrote.”This is primarily in those with conventionally favorable prognostic features suggesting that cetuximab induces adverse biology in some patients, whose biomarker profile is ongoing.”

They also found that there were no differences in overall survival among patients with responses to chemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) and those who did not have responses, “suggesting that in this predominantly operable population, any conferred benefit of systemic treatment is through elimination of micro-metastatic disease rather than by downsizing of radiologically evaluable disease.

The randomized phase 3 Medical Research Council COIN trial, results of which were reported at the 2010 annual meeting of the American Society of Clinical Oncology and later published in The Lancet, failed to show a benefit for the addition of cetuximab to front-line oxaliplatin-based chemotherapy for metastatic CRC. Median OS in KRAS wild-type patients was 17 months when cetuximab was added to chemotherapy with oxaliplatin and an intravenous or oral fluoropyrimidine, compared with 17.9 months when chemotherapy was delivered without cetuximab. Median PFS held at 8.6 months in both arms of the trial.

The New EPOC investigators described their study as a “natural extension” of the COIN study as well as earlier trials and phase 2 studies of neoadjuvant and adjuvant therapy in this patient population.

From 2007 through 2012, 257 patients were randomly assigned to receive chemotherapy alone, or chemotherapy with rituximab. Chemotherapy consisted of one of two regimens: oxaliplatin 85 mg/m² intravenously over 2 hours and fluorouracil bolus 400 mg/m² intravenously over 5 minutes followed by a 46-hour infusion of fluorouracil 2,400 mg/m² repeated every 2 weeks; or oxaliplatin 130 mg/m² intravenously over 2 hours and oral capecitabine (Xeloda) 1,000 mg/m2 twice daily on days 1-14 repeated every 3 weeks.

After a median follow-up of 69 months, there were 130 deaths from any cause. As noted before, median OS was significantly shorter with cetuximab. The hazard ratio for death with cetuximab was 1.45 (P = .035). Median PFS did not differ in this most recent analysis, however.

Median PPS was 35.4 months for chemotherapy alone, compared with 23.5 months for chemotherapy plus cetuximab (P = .014).

The poor overall survival and PFS results indicate that “cetuximab cannot be recommended for perioperative treatment in patients with resectable disease,” said Thomas Gruenberger, MD, an oncologic surgeon at Rudolf Hospital in Vienna, who was invited to review the results in a poster discussion session.

Cancer Research UK supported the study. Dr. Bridgewater disclosed honoraria and speakers fees from Merck, Celgene, and Servier, and travel support from Amgen, Merck Sharpe Dohme, and Servier.

 

MADRID – Adding cetuximab (Erbitux) to chemotherapy before or after surgery for resectable colorectal liver metastases resulted in significantly worse survival compared with perioperative chemotherapy alone, mature results of the randomized New EPOC trial confirmed.

Among 257 patients with KRAS exon 2 wild-type resectable colorectal liver metastases (CRLM) or suboptimally resectable CRLM, median overall survival (OS) was 81 months for patients assigned to neoadjuvant and adjuvant chemotherapy alone, compared with 55.4 months for patients who received perioperative chemotherapy plus cetuximab, reported John Bridgewater, MD, of University College London Cancer Institute.

Postprogression survival (PPS) was “particularly poor” for patients assigned to cetuximab, the investigators noted in a poster presented at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) was 22.2 months without cetuximab, vs. 15.5 months with chemotherapy plus cetuximab, a difference that was not statistically significant. However, when the primary analysis of the trial was reported in 2014 in The Lancet: Oncology, cetuximab was associated with significantly shorter PFS. The trial was halted in 2012 on the recommendation of the data monitoring committee.

“In the context of perioperative therapy for resectable CRLM, chemotherapy plus cetuximab confers a shorter OS and PPS,” Dr. Bridgewater and his associates wrote.”This is primarily in those with conventionally favorable prognostic features suggesting that cetuximab induces adverse biology in some patients, whose biomarker profile is ongoing.”

They also found that there were no differences in overall survival among patients with responses to chemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) and those who did not have responses, “suggesting that in this predominantly operable population, any conferred benefit of systemic treatment is through elimination of micro-metastatic disease rather than by downsizing of radiologically evaluable disease.

The randomized phase 3 Medical Research Council COIN trial, results of which were reported at the 2010 annual meeting of the American Society of Clinical Oncology and later published in The Lancet, failed to show a benefit for the addition of cetuximab to front-line oxaliplatin-based chemotherapy for metastatic CRC. Median OS in KRAS wild-type patients was 17 months when cetuximab was added to chemotherapy with oxaliplatin and an intravenous or oral fluoropyrimidine, compared with 17.9 months when chemotherapy was delivered without cetuximab. Median PFS held at 8.6 months in both arms of the trial.

The New EPOC investigators described their study as a “natural extension” of the COIN study as well as earlier trials and phase 2 studies of neoadjuvant and adjuvant therapy in this patient population.

From 2007 through 2012, 257 patients were randomly assigned to receive chemotherapy alone, or chemotherapy with rituximab. Chemotherapy consisted of one of two regimens: oxaliplatin 85 mg/m² intravenously over 2 hours and fluorouracil bolus 400 mg/m² intravenously over 5 minutes followed by a 46-hour infusion of fluorouracil 2,400 mg/m² repeated every 2 weeks; or oxaliplatin 130 mg/m² intravenously over 2 hours and oral capecitabine (Xeloda) 1,000 mg/m2 twice daily on days 1-14 repeated every 3 weeks.

After a median follow-up of 69 months, there were 130 deaths from any cause. As noted before, median OS was significantly shorter with cetuximab. The hazard ratio for death with cetuximab was 1.45 (P = .035). Median PFS did not differ in this most recent analysis, however.

Median PPS was 35.4 months for chemotherapy alone, compared with 23.5 months for chemotherapy plus cetuximab (P = .014).

The poor overall survival and PFS results indicate that “cetuximab cannot be recommended for perioperative treatment in patients with resectable disease,” said Thomas Gruenberger, MD, an oncologic surgeon at Rudolf Hospital in Vienna, who was invited to review the results in a poster discussion session.

Cancer Research UK supported the study. Dr. Bridgewater disclosed honoraria and speakers fees from Merck, Celgene, and Servier, and travel support from Amgen, Merck Sharpe Dohme, and Servier.

MADRID – The automaton uprising continues: Robot-assisted abdominoperineal resection (APR) can be safely performed in patients with rectal cancers within 5 cm of the anal verge, with surgical results equivalent to those seen with open or laparoscopic APR, investigators say.

Robot-assisted procedures were associated with a significantly lower rate of postoperative complications and with faster functional recovery than either laparoscopic or open surgery in a randomized trial, reported Jianmin Xu, MD, PhD., from Fudan University in Shanghai, China, and colleagues in a scientific poster presented at the European Society for Medical Oncology Congress.
 

“Retrospective studies have showed that robotic surgery was better than laparoscopic surgery in ensuring radical resection, reducing complications, and promoting recovery. However, there is no clinical trial reported for robotic surgery for rectal cancer. Thus, we conduct this randomized controlled trial to compare the safety and efficacy of robotic, laparoscopic, and open surgery for low rectal cancer,” they wrote.

Dr. Xu and colleagues enrolled 506 patients from 18 to 75 years of age with clinical stage T1 to T3 cancers within 5 cm of the anal verge and no distant metastases and randomly assigned them to resection with either a robot-assisted, laparoscopic, or open APR technique. Three of the 506 patients randomized did not undergo resection, leaving 503 for the per-protocol analysis presented here.

For the primary endpoint of complications rates within 30 days following surgery, the investigators found that patients assigned to robotic-assisted surgery (173 patients) had a total complication rate of 10.4%, compared with 18.8% for 176 patients assigned to laparoscopy (P = .027), and 26% for 154 assigned to open APR (P less than .001). The latter group included four patients assigned to laparoscopy whose procedures were converted to open surgery.

Among patients without complications, robot-assisted procedures were also associated with faster recovery, as measured by days to first flatus, at a median of 1 vs. 2 for laparoscopy and 3 for open procedures (P less than .001 for robots vs. each other surgery type). The robotic surgery was also significantly associated with fewer days to first automatic urination (median 2 vs. 4 for each of the other procedures; P less than .001), and with fewer days to discharge (median 5 vs. 7 for the other procedures; P less than .001).

There were no significant differences among the groups in resection margins achieved or numbers of lymph nodes harvested.

"These are excellent postoperative complication rates reported, especially for the robotic treatment group, commented Thomas Gruenberger, MD, an oncologic surgeon at Rudolf Hospital in Vienna, in a poster discussion session.

“We all are now favoring laparoscopic surgery for these kinds of patients. The robot is a nice thing to have; however, we cannot use it in every hospital because it’s still quite expensive,” he said.

“We require – and this is a secondary endpoint of the study – long-term follow-up for local and distant outcomes,” he added,

The investigators did not report a funding source. All authors declared having no conflicts of interest. Dr. Gruenberger disclosed research funding, speakers bureau participation, and/or advisory roles with several companies.

 

MADRID – The automaton uprising continues: Robot-assisted abdominoperineal resection (APR) can be safely performed in patients with rectal cancers within 5 cm of the anal verge, with surgical results equivalent to those seen with open or laparoscopic APR, investigators say.

Robot-assisted procedures were associated with a significantly lower rate of postoperative complications and with faster functional recovery than either laparoscopic or open surgery in a randomized trial, reported Jianmin Xu, MD, PhD., from Fudan University in Shanghai, China, and colleagues in a scientific poster presented at the European Society for Medical Oncology Congress.
 

“Retrospective studies have showed that robotic surgery was better than laparoscopic surgery in ensuring radical resection, reducing complications, and promoting recovery. However, there is no clinical trial reported for robotic surgery for rectal cancer. Thus, we conduct this randomized controlled trial to compare the safety and efficacy of robotic, laparoscopic, and open surgery for low rectal cancer,” they wrote.

Dr. Xu and colleagues enrolled 506 patients from 18 to 75 years of age with clinical stage T1 to T3 cancers within 5 cm of the anal verge and no distant metastases and randomly assigned them to resection with either a robot-assisted, laparoscopic, or open APR technique. Three of the 506 patients randomized did not undergo resection, leaving 503 for the per-protocol analysis presented here.

For the primary endpoint of complications rates within 30 days following surgery, the investigators found that patients assigned to robotic-assisted surgery (173 patients) had a total complication rate of 10.4%, compared with 18.8% for 176 patients assigned to laparoscopy (P = .027), and 26% for 154 assigned to open APR (P less than .001). The latter group included four patients assigned to laparoscopy whose procedures were converted to open surgery.

Among patients without complications, robot-assisted procedures were also associated with faster recovery, as measured by days to first flatus, at a median of 1 vs. 2 for laparoscopy and 3 for open procedures (P less than .001 for robots vs. each other surgery type). The robotic surgery was also significantly associated with fewer days to first automatic urination (median 2 vs. 4 for each of the other procedures; P less than .001), and with fewer days to discharge (median 5 vs. 7 for the other procedures; P less than .001).

There were no significant differences among the groups in resection margins achieved or numbers of lymph nodes harvested.

"These are excellent postoperative complication rates reported, especially for the robotic treatment group, commented Thomas Gruenberger, MD, an oncologic surgeon at Rudolf Hospital in Vienna, in a poster discussion session.

“We all are now favoring laparoscopic surgery for these kinds of patients. The robot is a nice thing to have; however, we cannot use it in every hospital because it’s still quite expensive,” he said.

“We require – and this is a secondary endpoint of the study – long-term follow-up for local and distant outcomes,” he added,

The investigators did not report a funding source. All authors declared having no conflicts of interest. Dr. Gruenberger disclosed research funding, speakers bureau participation, and/or advisory roles with several companies.

 

MADRID – The automaton uprising continues: Robot-assisted abdominoperineal resection (APR) can be safely performed in patients with rectal cancers within 5 cm of the anal verge, with surgical results equivalent to those seen with open or laparoscopic APR, investigators say.

Robot-assisted procedures were associated with a significantly lower rate of postoperative complications and with faster functional recovery than either laparoscopic or open surgery in a randomized trial, reported Jianmin Xu, MD, PhD., from Fudan University in Shanghai, China, and colleagues in a scientific poster presented at the European Society for Medical Oncology Congress.
 

“Retrospective studies have showed that robotic surgery was better than laparoscopic surgery in ensuring radical resection, reducing complications, and promoting recovery. However, there is no clinical trial reported for robotic surgery for rectal cancer. Thus, we conduct this randomized controlled trial to compare the safety and efficacy of robotic, laparoscopic, and open surgery for low rectal cancer,” they wrote.

Dr. Xu and colleagues enrolled 506 patients from 18 to 75 years of age with clinical stage T1 to T3 cancers within 5 cm of the anal verge and no distant metastases and randomly assigned them to resection with either a robot-assisted, laparoscopic, or open APR technique. Three of the 506 patients randomized did not undergo resection, leaving 503 for the per-protocol analysis presented here.

For the primary endpoint of complications rates within 30 days following surgery, the investigators found that patients assigned to robotic-assisted surgery (173 patients) had a total complication rate of 10.4%, compared with 18.8% for 176 patients assigned to laparoscopy (P = .027), and 26% for 154 assigned to open APR (P less than .001). The latter group included four patients assigned to laparoscopy whose procedures were converted to open surgery.

Among patients without complications, robot-assisted procedures were also associated with faster recovery, as measured by days to first flatus, at a median of 1 vs. 2 for laparoscopy and 3 for open procedures (P less than .001 for robots vs. each other surgery type). The robotic surgery was also significantly associated with fewer days to first automatic urination (median 2 vs. 4 for each of the other procedures; P less than .001), and with fewer days to discharge (median 5 vs. 7 for the other procedures; P less than .001).

There were no significant differences among the groups in resection margins achieved or numbers of lymph nodes harvested.

"These are excellent postoperative complication rates reported, especially for the robotic treatment group, commented Thomas Gruenberger, MD, an oncologic surgeon at Rudolf Hospital in Vienna, in a poster discussion session.

“We all are now favoring laparoscopic surgery for these kinds of patients. The robot is a nice thing to have; however, we cannot use it in every hospital because it’s still quite expensive,” he said.

“We require – and this is a secondary endpoint of the study – long-term follow-up for local and distant outcomes,” he added,

The investigators did not report a funding source. All authors declared having no conflicts of interest. Dr. Gruenberger disclosed research funding, speakers bureau participation, and/or advisory roles with several companies.

 

MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported

Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.

Investigators previously had reported that progression-free survival (PFS), which, together with overall response rate (ORR), constituted the other coprimary endpoint, also favored the checkpoint inhibitors, with a median of 11.6 months versus 8.4 months for sunitinib (P = .0331), he reported at the European Society of Medical Oncology Congress.

Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).

“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.

Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .

The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.

The results for the coprimary endpoints are noted above.

Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.

For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.

The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).

In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.

There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.

In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.

There were seven treatment-related deaths in the combination group and four in the sunitinib group.

“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.

“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.

The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
 

 

[email protected]

MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported

Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.

Investigators previously had reported that progression-free survival (PFS), which, together with overall response rate (ORR), constituted the other coprimary endpoint, also favored the checkpoint inhibitors, with a median of 11.6 months versus 8.4 months for sunitinib (P = .0331), he reported at the European Society of Medical Oncology Congress.

Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).

“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.

Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .

The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.

The results for the coprimary endpoints are noted above.

Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.

For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.

The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).

In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.

There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.

In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.

There were seven treatment-related deaths in the combination group and four in the sunitinib group.

“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.

“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.

The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
 

 

[email protected]

MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported

Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.

Investigators previously had reported that progression-free survival (PFS), which, together with overall response rate (ORR), constituted the other coprimary endpoint, also favored the checkpoint inhibitors, with a median of 11.6 months versus 8.4 months for sunitinib (P = .0331), he reported at the European Society of Medical Oncology Congress.

Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).

“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.

Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .

The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.

The results for the coprimary endpoints are noted above.

Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.

For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.

The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).

In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.

There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.

In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.

There were seven treatment-related deaths in the combination group and four in the sunitinib group.

“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.

“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.

The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
 

 

[email protected]

 

MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.

But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.

Thus, the woefully underpowered trial, in which the dose of the selective estrogen receptor degrader (SERD) fulvestrant tested was only half that of the current recommended dose, was unable to detect a potential treatment benefit, leaving unsettled the question of whether adding high-dose fulvestrant to anastrozole can improve adjuvant therapy in early-stage breast cancer, said Manuel Ruíz-Borrego, MD, PhD, from Hospital Universitario Virgen del Rocío, Seville, Spain, at the European Society of Medical Oncology congress.

“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.

Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.

“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.

Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.

The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.

The investigators enro­­­lled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.

As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).

After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).

Grade 2-3 hypertension and LDL cholesterol level increases were more common with anastrozole alone, while anastrozole/fulvestrant was associated with higher incidences of fatigue, osteoporosis, and musculoskeletal pain.

The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.

“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.

The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.

 

MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.

But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.

Thus, the woefully underpowered trial, in which the dose of the selective estrogen receptor degrader (SERD) fulvestrant tested was only half that of the current recommended dose, was unable to detect a potential treatment benefit, leaving unsettled the question of whether adding high-dose fulvestrant to anastrozole can improve adjuvant therapy in early-stage breast cancer, said Manuel Ruíz-Borrego, MD, PhD, from Hospital Universitario Virgen del Rocío, Seville, Spain, at the European Society of Medical Oncology congress.

“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.

Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.

“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.

Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.

The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.

The investigators enro­­­lled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.

As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).

After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).

Grade 2-3 hypertension and LDL cholesterol level increases were more common with anastrozole alone, while anastrozole/fulvestrant was associated with higher incidences of fatigue, osteoporosis, and musculoskeletal pain.

The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.

“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.

The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.

 

MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.

But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.

Thus, the woefully underpowered trial, in which the dose of the selective estrogen receptor degrader (SERD) fulvestrant tested was only half that of the current recommended dose, was unable to detect a potential treatment benefit, leaving unsettled the question of whether adding high-dose fulvestrant to anastrozole can improve adjuvant therapy in early-stage breast cancer, said Manuel Ruíz-Borrego, MD, PhD, from Hospital Universitario Virgen del Rocío, Seville, Spain, at the European Society of Medical Oncology congress.

“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.

Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.

“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.

Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.

The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.

The investigators enro­­­lled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.

As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).

After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).

Grade 2-3 hypertension and LDL cholesterol level increases were more common with anastrozole alone, while anastrozole/fulvestrant was associated with higher incidences of fatigue, osteoporosis, and musculoskeletal pain.

The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.

“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.

The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.

MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.

Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.

Despite the failure of the trial to achieve its primary endpoint of a 20% or better RCB 0 or I rate with letrozole/palbociclib, “the findings warrant larger studies to validate CDK inhibitor use as a replacement strategy in patients with high-risk luminal breast cancer in the neoadjuvant setting,” he said at the European Society of Medical Oncology Congress.

Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.

The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.

“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.

The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.

They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m² every 3 weeks, followed by surgery.

An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.

The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.

There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.

The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.

Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.

In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.

The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.

Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”

“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.

She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.

“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.

The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.

MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.

Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.

Despite the failure of the trial to achieve its primary endpoint of a 20% or better RCB 0 or I rate with letrozole/palbociclib, “the findings warrant larger studies to validate CDK inhibitor use as a replacement strategy in patients with high-risk luminal breast cancer in the neoadjuvant setting,” he said at the European Society of Medical Oncology Congress.

Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.

The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.

“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.

The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.

They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m² every 3 weeks, followed by surgery.

An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.

The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.

There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.

The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.

Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.

In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.

The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.

Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”

“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.

She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.

“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.

The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.

MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.

Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.

Despite the failure of the trial to achieve its primary endpoint of a 20% or better RCB 0 or I rate with letrozole/palbociclib, “the findings warrant larger studies to validate CDK inhibitor use as a replacement strategy in patients with high-risk luminal breast cancer in the neoadjuvant setting,” he said at the European Society of Medical Oncology Congress.

Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.

The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.

“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.

The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.

They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m² every 3 weeks, followed by surgery.

An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.

The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.

There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.

The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.

Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.

In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.

The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.

Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”

“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.

She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.

“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.

The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.

Madrid – Computed tomography scans do not appear to be superior to plain old chest x-rays for follow-up of patients with completely resected non–small cell lung cancer (NSCLC), results of a randomized clinical trial suggest.

Among 1,775 patients followed out to 10 years with either a “minimal” protocol – consisting of history, physical exam, and periodic chest x-rays – or a “maximal” protocol – including CT scans of the thorax and upper abdomen, as well as bronchoscopy for squamous-cell carcinomas – there were no significant differences in overall survival at either 3, 5, or 8 years of follow-up, reported Virginie Westeel, MD, from the Centre Hospitalier Régional Universitaire of the Hôpital Jean Minjoz in Besançon, France.

“Most clinical practice guidelines recommend follow-up after resection for non–small cell lung cancer, including clinic visits with history and physical examination with chest x-rays every 6 to 12 months for 2 years and then yearly. This recommendation relies on expert opinion and small prospective series, but there [were] until now no randomized controlled trials to answer this question,” she said at a briefing at the European Society of Medical Oncology Congress.

In hopes of finding that answer, Dr. Westeel and colleagues in the French Cooperative Thoracic Oncology Group conducted a clinical trial comparing the standard follow-up approach recommended in most clinical guidelines, as described by Dr. Westeel, with an experimental protocol consisting of history and exam plus chest x-ray, CT scans, and fiber-optic bronchoscopy (mandatory for squamous- and large-cell carcinomas, optional for adenocarcinomas).

Patients with completely resected stage I, II, and IIIA tumors, and T4 tumors with pulmonary nodules in the same lobe, were randomly assigned to follow-up with one of the two protocols.

In each trial arm, the assigned procedures were repeated every 6 months after randomization for the first 2 years, then yearly until 5 years.

After a median follow-up of 8.7 years, there was no significant difference in the primary endpoint of overall survival. Median OS was 123.6 months in the maximal protocol group, compared with 99.7 months in the minimal protocol group (P = .037)

The 3-, 5-, and 8-year survival rates for the maximal and minimal protocols, respectively, were 76.1% vs. 77.3%, 65.8% vs. 66.7%, and 54.6% vs. 51.7%.

Because there appeared to be a separation of the survival curve beginning around 8 years, the investigators performed an exploratory 2-year landmark analysis.

They found that, among patients who had a recurrence within 24 months of randomization, there was no difference in OS between each follow-up protocol. However, among those patients with no recurrence within 24 months of resection, the median OS was not reached among patients assigned to the maximal protocol versus 129.3 months for those assigned to the minimal protocol (P = .04).

Patients without early recurrence had higher rates of secondary primary cancers, and for these patients, early detection with CT-based surveillance could explain the differences in overall survival, Dr. Westeel said.

“Our suggestion for practice is that, because there is no survival difference, both follow-up protocols are acceptable. However, a CT scan every 6 months is probably of no value in the first 2 years,” but yearly chest CTs to detect second primary cancers early may be of interest, she said.

Enriqueta Felip, MD, from Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in the trial, commented that, while the study needed to be conducted, it was unlikely to change her clinical practice because of potential differences among patients with varying stages of NSCLC at the time of resection.

“I think it’s an important trial, [but] tomorrow I will follow my patients with a CT scan,” she said.

Dr. Felip was an invited expert at the briefing.

The study was supported by the French Ministry of Health, Fondation de France, and Laboratoire Lilly. Dr. Westeel and Dr. Felip reported no conflicts of interest relevant to the study.

[email protected]

Madrid – Computed tomography scans do not appear to be superior to plain old chest x-rays for follow-up of patients with completely resected non–small cell lung cancer (NSCLC), results of a randomized clinical trial suggest.

Among 1,775 patients followed out to 10 years with either a “minimal” protocol – consisting of history, physical exam, and periodic chest x-rays – or a “maximal” protocol – including CT scans of the thorax and upper abdomen, as well as bronchoscopy for squamous-cell carcinomas – there were no significant differences in overall survival at either 3, 5, or 8 years of follow-up, reported Virginie Westeel, MD, from the Centre Hospitalier Régional Universitaire of the Hôpital Jean Minjoz in Besançon, France.

“Most clinical practice guidelines recommend follow-up after resection for non–small cell lung cancer, including clinic visits with history and physical examination with chest x-rays every 6 to 12 months for 2 years and then yearly. This recommendation relies on expert opinion and small prospective series, but there [were] until now no randomized controlled trials to answer this question,” she said at a briefing at the European Society of Medical Oncology Congress.

In hopes of finding that answer, Dr. Westeel and colleagues in the French Cooperative Thoracic Oncology Group conducted a clinical trial comparing the standard follow-up approach recommended in most clinical guidelines, as described by Dr. Westeel, with an experimental protocol consisting of history and exam plus chest x-ray, CT scans, and fiber-optic bronchoscopy (mandatory for squamous- and large-cell carcinomas, optional for adenocarcinomas).

Patients with completely resected stage I, II, and IIIA tumors, and T4 tumors with pulmonary nodules in the same lobe, were randomly assigned to follow-up with one of the two protocols.

In each trial arm, the assigned procedures were repeated every 6 months after randomization for the first 2 years, then yearly until 5 years.

After a median follow-up of 8.7 years, there was no significant difference in the primary endpoint of overall survival. Median OS was 123.6 months in the maximal protocol group, compared with 99.7 months in the minimal protocol group (P = .037)

The 3-, 5-, and 8-year survival rates for the maximal and minimal protocols, respectively, were 76.1% vs. 77.3%, 65.8% vs. 66.7%, and 54.6% vs. 51.7%.

Because there appeared to be a separation of the survival curve beginning around 8 years, the investigators performed an exploratory 2-year landmark analysis.

They found that, among patients who had a recurrence within 24 months of randomization, there was no difference in OS between each follow-up protocol. However, among those patients with no recurrence within 24 months of resection, the median OS was not reached among patients assigned to the maximal protocol versus 129.3 months for those assigned to the minimal protocol (P = .04).

Patients without early recurrence had higher rates of secondary primary cancers, and for these patients, early detection with CT-based surveillance could explain the differences in overall survival, Dr. Westeel said.

“Our suggestion for practice is that, because there is no survival difference, both follow-up protocols are acceptable. However, a CT scan every 6 months is probably of no value in the first 2 years,” but yearly chest CTs to detect second primary cancers early may be of interest, she said.

Enriqueta Felip, MD, from Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in the trial, commented that, while the study needed to be conducted, it was unlikely to change her clinical practice because of potential differences among patients with varying stages of NSCLC at the time of resection.

“I think it’s an important trial, [but] tomorrow I will follow my patients with a CT scan,” she said.

Dr. Felip was an invited expert at the briefing.

The study was supported by the French Ministry of Health, Fondation de France, and Laboratoire Lilly. Dr. Westeel and Dr. Felip reported no conflicts of interest relevant to the study.

[email protected]

Madrid – Computed tomography scans do not appear to be superior to plain old chest x-rays for follow-up of patients with completely resected non–small cell lung cancer (NSCLC), results of a randomized clinical trial suggest.

Among 1,775 patients followed out to 10 years with either a “minimal” protocol – consisting of history, physical exam, and periodic chest x-rays – or a “maximal” protocol – including CT scans of the thorax and upper abdomen, as well as bronchoscopy for squamous-cell carcinomas – there were no significant differences in overall survival at either 3, 5, or 8 years of follow-up, reported Virginie Westeel, MD, from the Centre Hospitalier Régional Universitaire of the Hôpital Jean Minjoz in Besançon, France.

“Most clinical practice guidelines recommend follow-up after resection for non–small cell lung cancer, including clinic visits with history and physical examination with chest x-rays every 6 to 12 months for 2 years and then yearly. This recommendation relies on expert opinion and small prospective series, but there [were] until now no randomized controlled trials to answer this question,” she said at a briefing at the European Society of Medical Oncology Congress.

In hopes of finding that answer, Dr. Westeel and colleagues in the French Cooperative Thoracic Oncology Group conducted a clinical trial comparing the standard follow-up approach recommended in most clinical guidelines, as described by Dr. Westeel, with an experimental protocol consisting of history and exam plus chest x-ray, CT scans, and fiber-optic bronchoscopy (mandatory for squamous- and large-cell carcinomas, optional for adenocarcinomas).

Patients with completely resected stage I, II, and IIIA tumors, and T4 tumors with pulmonary nodules in the same lobe, were randomly assigned to follow-up with one of the two protocols.

In each trial arm, the assigned procedures were repeated every 6 months after randomization for the first 2 years, then yearly until 5 years.

After a median follow-up of 8.7 years, there was no significant difference in the primary endpoint of overall survival. Median OS was 123.6 months in the maximal protocol group, compared with 99.7 months in the minimal protocol group (P = .037)

The 3-, 5-, and 8-year survival rates for the maximal and minimal protocols, respectively, were 76.1% vs. 77.3%, 65.8% vs. 66.7%, and 54.6% vs. 51.7%.

Because there appeared to be a separation of the survival curve beginning around 8 years, the investigators performed an exploratory 2-year landmark analysis.

They found that, among patients who had a recurrence within 24 months of randomization, there was no difference in OS between each follow-up protocol. However, among those patients with no recurrence within 24 months of resection, the median OS was not reached among patients assigned to the maximal protocol versus 129.3 months for those assigned to the minimal protocol (P = .04).

Patients without early recurrence had higher rates of secondary primary cancers, and for these patients, early detection with CT-based surveillance could explain the differences in overall survival, Dr. Westeel said.

“Our suggestion for practice is that, because there is no survival difference, both follow-up protocols are acceptable. However, a CT scan every 6 months is probably of no value in the first 2 years,” but yearly chest CTs to detect second primary cancers early may be of interest, she said.

Enriqueta Felip, MD, from Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in the trial, commented that, while the study needed to be conducted, it was unlikely to change her clinical practice because of potential differences among patients with varying stages of NSCLC at the time of resection.

“I think it’s an important trial, [but] tomorrow I will follow my patients with a CT scan,” she said.

Dr. Felip was an invited expert at the briefing.

The study was supported by the French Ministry of Health, Fondation de France, and Laboratoire Lilly. Dr. Westeel and Dr. Felip reported no conflicts of interest relevant to the study.

[email protected]

MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.

Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).

“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.

But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”

He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”

He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.

In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.

Patients were randomly assigned to receive intravenous docetaxel 75 mg/m² plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.

As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).

Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.

Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.

In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.

There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.

Ultimately, the combination of ramucirumab and docetaxel may be best suited for use as a third-line treatment for patients with platinum-resistant metastatic urothelial cancer that has progressed after second-line therapy with an immune checkpoint inhibitor, said Yohann Loriot, MD, of Gustave-Roussy Cancer Institute in Villejuif, France, the invited discussant at the presidential symposium where the RANGE data were presented.

However, for patients who have a short response to first-line platinum-based chemotherapy, have no visceral metastases, or are ineligible to receive immunotherapy, ramucirumab plus docetaxel could be a suitable second-line option, he said.

The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.

[email protected]

MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.

Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).

“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.

But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”

He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”

He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.

In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.

Patients were randomly assigned to receive intravenous docetaxel 75 mg/m² plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.

As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).

Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.

Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.

In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.

There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.

Ultimately, the combination of ramucirumab and docetaxel may be best suited for use as a third-line treatment for patients with platinum-resistant metastatic urothelial cancer that has progressed after second-line therapy with an immune checkpoint inhibitor, said Yohann Loriot, MD, of Gustave-Roussy Cancer Institute in Villejuif, France, the invited discussant at the presidential symposium where the RANGE data were presented.

However, for patients who have a short response to first-line platinum-based chemotherapy, have no visceral metastases, or are ineligible to receive immunotherapy, ramucirumab plus docetaxel could be a suitable second-line option, he said.

The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.

[email protected]

MADRID – For patients with advanced or metastatic urothelial cancer that progressed on platinum-based chemotherapy, a combination of the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab and docetaxel offered a small but significant improvement in progression-free survival (PFS) compared with docetaxel alone.

Among 437 patients treated in the phase 3 RANGE trial, investigator-assessed PFS, the primary endpoint, was 4.07 months for patients randomized to ramucirumab and docetaxel, compared with 2.76 months for patients assigned to docetaxel and placebo, translating into a hazard ratio (HR) for ramucirumab of 0.757 (P = .0118).

“RANGE is the first phase 3 study to demonstrate a progression-free survival advantage over chemotherapy alone in platinum-refractory advanced or metastatic urothelial carcinoma,” lead author Daniel P. Petrylak, MD of Yale University, New Haven, Conn., said at a briefing at the European Society for Medical Oncology Congress.

But Richard Cathomas, Dr.med, of Kantonsspital Graubünden, in Chur, Switzerland, who was not involved in the study, said it “is too early for these results alone to change the standard of care second-line treatment, which is immune checkpoint inhibition.”

He noted that the magnitude of the benefit with ramucirumab was just 1.3 months, “and, while statistically significant, it raises the question of whether it is clinically relevant.”

He acknowledged that the improvement in response rates seen with ramucirumab in RANGE indicates a potential role for angiogenesis inhibitors in the treatment of urothelial cancers.

In the RANGE trial, results of which were published in The Lancet, investigators at 124 sites in 23 countries enrolled 530 patients with advanced or metastatic urothelial carcinoma who experienced progression during or after platinum-based chemotherapy.

Patients were randomly assigned to receive intravenous docetaxel 75 mg/m² plus intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of each repeating 21-day cycle until disease progression or discontinuation of treatment for other reasons. The primary endpoint was assessed in an intention-to-treat analysis in the first 437 patients randomized.

As noted, at a median follow-up in the ITT analysis of 5.0 months, investigator-assessed PFS favored the addition of ramucirumab, as did a blinded central review of outcomes, which determined a median PFS of 4.04 months with ramucirumab plus docetaxel compared with 2.46 months for docetaxel alone (HR 0.672, P = .0005).

Ramucirumab/docetaxel was also associated with an improvement in the objective response rate, at 24.5% compared with 14.0% for placebo/docetaxel.

Treatment toxicities were similar between the study arms, although patients in the ramucirumab arm experienced slightly less anemia compared with those in the placebo arm.

In all, 209 of 263 patients assigned to ramucirumab/docetaxel, and 229 of 267 patients assigned to placebo/docetaxel had their treatments discontinued, primarily because they experienced disease progression.

There were no significant changes in quality of life measures during the trial, and there were no differences in quality of life between the treatment arms, Dr. Petrylak reported.

Ultimately, the combination of ramucirumab and docetaxel may be best suited for use as a third-line treatment for patients with platinum-resistant metastatic urothelial cancer that has progressed after second-line therapy with an immune checkpoint inhibitor, said Yohann Loriot, MD, of Gustave-Roussy Cancer Institute in Villejuif, France, the invited discussant at the presidential symposium where the RANGE data were presented.

However, for patients who have a short response to first-line platinum-based chemotherapy, have no visceral metastases, or are ineligible to receive immunotherapy, ramucirumab plus docetaxel could be a suitable second-line option, he said.

The RANGE trial was funded by Eli Lilly. Dr. Petrylak disclosed research funding from the company. Dr. Cathomas and Dr. Loriot disclosed consulting or advisory roles with companies other than Lilly.

[email protected]