RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors

SAN FRANCISCO – Everolimus improves progression-free survival in all subgroups of patients with progressive advanced neuroendocrine tumors, and does so regardless of prior use of somatostatin analogs, according to updated results of the randomized RADIANT-2 and RADIANT-3 trials.

Both trials showed that the reduced risk of progression seen with everolimus in their study populations overall also was present to some extent in subgroups stratified by patient and disease characteristics, and by prior use of somatostatin analogs.

The updates were reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"There is a significant unmet medical need for patients with advanced NETs [neuroendocrine tumors]," asserted RADIANT-2 lead investigator Dr. James C. Yao of the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. In particular, "there are currently no drugs approved by the health authorities for the oncologic therapy of advanced carcinoid tumors."

RADIANT-2: Unselected NETs

The RADIANT-2 trial was conducted among 429 patients with progressive advanced NETs of diverse primary sites who had carcinoid syndrome. It compared everolimus (Afinitor) plus octreotide LAR (Sandostatin LAR, or long-acting release) with placebo plus octreotide LAR.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved by the Food and Drug Administration for the treatment of certain subependymal giant cell astrocytomas and advanced renal cell carcinoma.

Octreotide LAR is a somatostatin analog approved for symptom control in patients with metastatic carcinoid tumors, a subset of NETs that cause secretory symptoms.

The trial found a 23% reduction in the risk of progression, as assessed by independent central review, with everolimus vs. placebo (hazard ratio [HR] 0.77, P = .026), but it fell just short of its predefined statistical boundary for significance (P = .0246), according to Dr. Yao.

Updated analyses showed that the benefit seen in the entire study population was also evident in subgroups stratified by patient and disease factors, and by prior treatment, although most of the hazard ratios overlapped unity.

About 80% of patients in both treatment groups had previously used long-acting somatostatin analogs. In exploratory analyses, everolimus was associated a reduced risk of progression in previous users (HR 0.81, P = .077) and in previous nonusers (HR 0.63, P = .054). "However, the absolute and relative benefits were perhaps greater among patients who have not had prior somatostatin [analog] exposure," he observed.

Dr. Yao also reported new analyses of the trial’s main results, showing that, when progression was assessed by local investigators instead of central reviewers, everolimus was associated with a 22% reduction in risk and the study met its statistical boundary (P = .018). The difference was due to 51 more events tallied by the local investigators vs. the central reviewers.

Additionally, the progression-free survival estimates for both treatment groups were longer with central review than with local investigator assessment. "These findings are actually hallmarks of informative censoring," he said. "The main source of informative censoring lies in the fact that patient management is based on investigator review, while the end point assessment is based on central review."

Issues arise when the local investigator calls progression before the central reviewer does. "In these cases, because of the crossover and change in therapy, the cases are censored. In fact, the central radiologist is effectively prevented from seeing the progression event," Dr. Yao explained. "This results in an inflation of PFS [progression-free survival] and reduced power in the study."

When the trial’s main analysis was repeated with correction for informative censoring, reduced power, and imbalances in randomization, the median progression-free survival was 13.8 months with everolimus and 8.3 months with placebo. That difference corresponds to a 40% reduction in risk and far exceeds the predefined boundary for significance (HR 0.60, P = .0014).

Commenting on the discrepancy between local and central review, discussant Dr. Mary F. Mulcahy said, "I think what this tells us ... is that progression-free survival may not be the right end point to be looking at when evaluating these diseases with secretory symptoms," because the symptoms may prompt investigators to switch treatment before radiographic progression occurs.

"So I think more so than these fancy calculations to try and rectify this, we need to maybe consider what our end point is for these very clinical syndromes that we see," she commented.

She called attention to the fact that the rate of discontinuation for progressive disease or adverse events was similarly high in the everolimus and placebo groups (70% and 75%), and median duration of treatment exposure was the same.

"So I have some concerns about the benefit of everolimus," said Dr. Mulcahy of the Robert H. Lurie Comprehensive Cancer Center in Chicago. "For the population studied, I think the benefit of everolimus with octreotide LAR is undefined. The activity of everolimus is demonstrated, but it’s associated with significant adverse events."

RADIANT-3: Pancreatic NET

The RADIANT-3 trial was conducted among 410 patients with progressive advanced pancreatic NET (pNET). It found a 65% reduction in the risk of progression with everolimus plus best supportive care, compared with placebo plus best supportive care (HR 0.35, P less than .0001).

Updated analyses showed that the benefit seen in the whole study population was also evident in subgroups stratified by patient and disease factors, and prior treatment, reported lead investigator Dr. Manisha H. Shah of the Ohio State University Comprehensive Cancer Center in Columbus.

"No matter how we slice the data based on different characteristics, we saw the significant benefit of everolimus compared to placebo," she commented. Some 50% of the patients had previously used somatostatin analogs, and 40% of patients used these agents concomitantly while in the trial.

In exploratory analyses, the progression-free survival benefit of everolimus was similar in subgroups of patients who had and had not previously used somatostatin analogs, and who did and did not use them concomitantly during the trial.

"Everolimus showed a consistent benefit in all subgroups regardless of presence or absence of somatostatin analog," commented Dr. Shah.

"RADIANT-3 is the largest randomized controlled trial ever completed in patients with progressive advanced pNET," she noted. "These data support the use of everolimus as the standard of care for patients with progressive advanced pNET."

In her discussion, Dr. Mulcahy noted that, in this trial, results were similar for central and local review. "That’s probably because these patients did not necessarily have the secretory symptoms of the patients in the RADIANT-2 study," she speculated.

The results are "strikingly similar" to those seen previously with the tyrosine kinase inhibitor sunitinib (Sutent) in patients with pNET. "We are seeing consistent results. How we are going to sequence these is something that needs to be further evaluated."

Her overall assessment of RADIANT-3 was more positive than that of RADIANT-2. "There is a significant and durable benefit of everolimus in previously treated [pNET] patients," she commented.

A variety of markers are being assessed in NET, including some associated with response to mTOR inhibitors, according to Dr. Mulcahy.

"This is hopefully the direction where we are going to be going, looking at these different prognostic and predictive markers, and assigning therapy and doing rationally designed clinical trials to find the best sequence of drugs," she concluded.

Novartis sponsored both trials. Dr. Yao and Dr. Shah reported being advisors to and receiving honoraria and research support from Novartis. Dr. Mulcahy did not report any relevant conflicts of interest.

SAN FRANCISCO – Everolimus improves progression-free survival in all subgroups of patients with progressive advanced neuroendocrine tumors, and does so regardless of prior use of somatostatin analogs, according to updated results of the randomized RADIANT-2 and RADIANT-3 trials.

Both trials showed that the reduced risk of progression seen with everolimus in their study populations overall also was present to some extent in subgroups stratified by patient and disease characteristics, and by prior use of somatostatin analogs.

The updates were reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"There is a significant unmet medical need for patients with advanced NETs [neuroendocrine tumors]," asserted RADIANT-2 lead investigator Dr. James C. Yao of the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. In particular, "there are currently no drugs approved by the health authorities for the oncologic therapy of advanced carcinoid tumors."

RADIANT-2: Unselected NETs

The RADIANT-2 trial was conducted among 429 patients with progressive advanced NETs of diverse primary sites who had carcinoid syndrome. It compared everolimus (Afinitor) plus octreotide LAR (Sandostatin LAR, or long-acting release) with placebo plus octreotide LAR.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved by the Food and Drug Administration for the treatment of certain subependymal giant cell astrocytomas and advanced renal cell carcinoma.

Octreotide LAR is a somatostatin analog approved for symptom control in patients with metastatic carcinoid tumors, a subset of NETs that cause secretory symptoms.

The trial found a 23% reduction in the risk of progression, as assessed by independent central review, with everolimus vs. placebo (hazard ratio [HR] 0.77, P = .026), but it fell just short of its predefined statistical boundary for significance (P = .0246), according to Dr. Yao.

Updated analyses showed that the benefit seen in the entire study population was also evident in subgroups stratified by patient and disease factors, and by prior treatment, although most of the hazard ratios overlapped unity.

About 80% of patients in both treatment groups had previously used long-acting somatostatin analogs. In exploratory analyses, everolimus was associated a reduced risk of progression in previous users (HR 0.81, P = .077) and in previous nonusers (HR 0.63, P = .054). "However, the absolute and relative benefits were perhaps greater among patients who have not had prior somatostatin [analog] exposure," he observed.

Dr. Yao also reported new analyses of the trial’s main results, showing that, when progression was assessed by local investigators instead of central reviewers, everolimus was associated with a 22% reduction in risk and the study met its statistical boundary (P = .018). The difference was due to 51 more events tallied by the local investigators vs. the central reviewers.

Additionally, the progression-free survival estimates for both treatment groups were longer with central review than with local investigator assessment. "These findings are actually hallmarks of informative censoring," he said. "The main source of informative censoring lies in the fact that patient management is based on investigator review, while the end point assessment is based on central review."

Issues arise when the local investigator calls progression before the central reviewer does. "In these cases, because of the crossover and change in therapy, the cases are censored. In fact, the central radiologist is effectively prevented from seeing the progression event," Dr. Yao explained. "This results in an inflation of PFS [progression-free survival] and reduced power in the study."

When the trial’s main analysis was repeated with correction for informative censoring, reduced power, and imbalances in randomization, the median progression-free survival was 13.8 months with everolimus and 8.3 months with placebo. That difference corresponds to a 40% reduction in risk and far exceeds the predefined boundary for significance (HR 0.60, P = .0014).

Commenting on the discrepancy between local and central review, discussant Dr. Mary F. Mulcahy said, "I think what this tells us ... is that progression-free survival may not be the right end point to be looking at when evaluating these diseases with secretory symptoms," because the symptoms may prompt investigators to switch treatment before radiographic progression occurs.

"So I think more so than these fancy calculations to try and rectify this, we need to maybe consider what our end point is for these very clinical syndromes that we see," she commented.

She called attention to the fact that the rate of discontinuation for progressive disease or adverse events was similarly high in the everolimus and placebo groups (70% and 75%), and median duration of treatment exposure was the same.

"So I have some concerns about the benefit of everolimus," said Dr. Mulcahy of the Robert H. Lurie Comprehensive Cancer Center in Chicago. "For the population studied, I think the benefit of everolimus with octreotide LAR is undefined. The activity of everolimus is demonstrated, but it’s associated with significant adverse events."

RADIANT-3: Pancreatic NET

The RADIANT-3 trial was conducted among 410 patients with progressive advanced pancreatic NET (pNET). It found a 65% reduction in the risk of progression with everolimus plus best supportive care, compared with placebo plus best supportive care (HR 0.35, P less than .0001).

Updated analyses showed that the benefit seen in the whole study population was also evident in subgroups stratified by patient and disease factors, and prior treatment, reported lead investigator Dr. Manisha H. Shah of the Ohio State University Comprehensive Cancer Center in Columbus.

"No matter how we slice the data based on different characteristics, we saw the significant benefit of everolimus compared to placebo," she commented. Some 50% of the patients had previously used somatostatin analogs, and 40% of patients used these agents concomitantly while in the trial.

In exploratory analyses, the progression-free survival benefit of everolimus was similar in subgroups of patients who had and had not previously used somatostatin analogs, and who did and did not use them concomitantly during the trial.

"Everolimus showed a consistent benefit in all subgroups regardless of presence or absence of somatostatin analog," commented Dr. Shah.

"RADIANT-3 is the largest randomized controlled trial ever completed in patients with progressive advanced pNET," she noted. "These data support the use of everolimus as the standard of care for patients with progressive advanced pNET."

In her discussion, Dr. Mulcahy noted that, in this trial, results were similar for central and local review. "That’s probably because these patients did not necessarily have the secretory symptoms of the patients in the RADIANT-2 study," she speculated.

The results are "strikingly similar" to those seen previously with the tyrosine kinase inhibitor sunitinib (Sutent) in patients with pNET. "We are seeing consistent results. How we are going to sequence these is something that needs to be further evaluated."

Her overall assessment of RADIANT-3 was more positive than that of RADIANT-2. "There is a significant and durable benefit of everolimus in previously treated [pNET] patients," she commented.

A variety of markers are being assessed in NET, including some associated with response to mTOR inhibitors, according to Dr. Mulcahy.

"This is hopefully the direction where we are going to be going, looking at these different prognostic and predictive markers, and assigning therapy and doing rationally designed clinical trials to find the best sequence of drugs," she concluded.

Novartis sponsored both trials. Dr. Yao and Dr. Shah reported being advisors to and receiving honoraria and research support from Novartis. Dr. Mulcahy did not report any relevant conflicts of interest.

SAN FRANCISCO – Everolimus improves progression-free survival in all subgroups of patients with progressive advanced neuroendocrine tumors, and does so regardless of prior use of somatostatin analogs, according to updated results of the randomized RADIANT-2 and RADIANT-3 trials.

Both trials showed that the reduced risk of progression seen with everolimus in their study populations overall also was present to some extent in subgroups stratified by patient and disease characteristics, and by prior use of somatostatin analogs.

The updates were reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"There is a significant unmet medical need for patients with advanced NETs [neuroendocrine tumors]," asserted RADIANT-2 lead investigator Dr. James C. Yao of the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. In particular, "there are currently no drugs approved by the health authorities for the oncologic therapy of advanced carcinoid tumors."

RADIANT-2: Unselected NETs

The RADIANT-2 trial was conducted among 429 patients with progressive advanced NETs of diverse primary sites who had carcinoid syndrome. It compared everolimus (Afinitor) plus octreotide LAR (Sandostatin LAR, or long-acting release) with placebo plus octreotide LAR.

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved by the Food and Drug Administration for the treatment of certain subependymal giant cell astrocytomas and advanced renal cell carcinoma.

Octreotide LAR is a somatostatin analog approved for symptom control in patients with metastatic carcinoid tumors, a subset of NETs that cause secretory symptoms.

The trial found a 23% reduction in the risk of progression, as assessed by independent central review, with everolimus vs. placebo (hazard ratio [HR] 0.77, P = .026), but it fell just short of its predefined statistical boundary for significance (P = .0246), according to Dr. Yao.

Updated analyses showed that the benefit seen in the entire study population was also evident in subgroups stratified by patient and disease factors, and by prior treatment, although most of the hazard ratios overlapped unity.

About 80% of patients in both treatment groups had previously used long-acting somatostatin analogs. In exploratory analyses, everolimus was associated a reduced risk of progression in previous users (HR 0.81, P = .077) and in previous nonusers (HR 0.63, P = .054). "However, the absolute and relative benefits were perhaps greater among patients who have not had prior somatostatin [analog] exposure," he observed.

Dr. Yao also reported new analyses of the trial’s main results, showing that, when progression was assessed by local investigators instead of central reviewers, everolimus was associated with a 22% reduction in risk and the study met its statistical boundary (P = .018). The difference was due to 51 more events tallied by the local investigators vs. the central reviewers.

Additionally, the progression-free survival estimates for both treatment groups were longer with central review than with local investigator assessment. "These findings are actually hallmarks of informative censoring," he said. "The main source of informative censoring lies in the fact that patient management is based on investigator review, while the end point assessment is based on central review."

Issues arise when the local investigator calls progression before the central reviewer does. "In these cases, because of the crossover and change in therapy, the cases are censored. In fact, the central radiologist is effectively prevented from seeing the progression event," Dr. Yao explained. "This results in an inflation of PFS [progression-free survival] and reduced power in the study."

When the trial’s main analysis was repeated with correction for informative censoring, reduced power, and imbalances in randomization, the median progression-free survival was 13.8 months with everolimus and 8.3 months with placebo. That difference corresponds to a 40% reduction in risk and far exceeds the predefined boundary for significance (HR 0.60, P = .0014).

Commenting on the discrepancy between local and central review, discussant Dr. Mary F. Mulcahy said, "I think what this tells us ... is that progression-free survival may not be the right end point to be looking at when evaluating these diseases with secretory symptoms," because the symptoms may prompt investigators to switch treatment before radiographic progression occurs.

"So I think more so than these fancy calculations to try and rectify this, we need to maybe consider what our end point is for these very clinical syndromes that we see," she commented.

She called attention to the fact that the rate of discontinuation for progressive disease or adverse events was similarly high in the everolimus and placebo groups (70% and 75%), and median duration of treatment exposure was the same.

"So I have some concerns about the benefit of everolimus," said Dr. Mulcahy of the Robert H. Lurie Comprehensive Cancer Center in Chicago. "For the population studied, I think the benefit of everolimus with octreotide LAR is undefined. The activity of everolimus is demonstrated, but it’s associated with significant adverse events."

RADIANT-3: Pancreatic NET

The RADIANT-3 trial was conducted among 410 patients with progressive advanced pancreatic NET (pNET). It found a 65% reduction in the risk of progression with everolimus plus best supportive care, compared with placebo plus best supportive care (HR 0.35, P less than .0001).

Updated analyses showed that the benefit seen in the whole study population was also evident in subgroups stratified by patient and disease factors, and prior treatment, reported lead investigator Dr. Manisha H. Shah of the Ohio State University Comprehensive Cancer Center in Columbus.

"No matter how we slice the data based on different characteristics, we saw the significant benefit of everolimus compared to placebo," she commented. Some 50% of the patients had previously used somatostatin analogs, and 40% of patients used these agents concomitantly while in the trial.

In exploratory analyses, the progression-free survival benefit of everolimus was similar in subgroups of patients who had and had not previously used somatostatin analogs, and who did and did not use them concomitantly during the trial.

"Everolimus showed a consistent benefit in all subgroups regardless of presence or absence of somatostatin analog," commented Dr. Shah.

"RADIANT-3 is the largest randomized controlled trial ever completed in patients with progressive advanced pNET," she noted. "These data support the use of everolimus as the standard of care for patients with progressive advanced pNET."

In her discussion, Dr. Mulcahy noted that, in this trial, results were similar for central and local review. "That’s probably because these patients did not necessarily have the secretory symptoms of the patients in the RADIANT-2 study," she speculated.

The results are "strikingly similar" to those seen previously with the tyrosine kinase inhibitor sunitinib (Sutent) in patients with pNET. "We are seeing consistent results. How we are going to sequence these is something that needs to be further evaluated."

Her overall assessment of RADIANT-3 was more positive than that of RADIANT-2. "There is a significant and durable benefit of everolimus in previously treated [pNET] patients," she commented.

A variety of markers are being assessed in NET, including some associated with response to mTOR inhibitors, according to Dr. Mulcahy.

"This is hopefully the direction where we are going to be going, looking at these different prognostic and predictive markers, and assigning therapy and doing rationally designed clinical trials to find the best sequence of drugs," she concluded.

Novartis sponsored both trials. Dr. Yao and Dr. Shah reported being advisors to and receiving honoraria and research support from Novartis. Dr. Mulcahy did not report any relevant conflicts of interest.