TBD Meeting (3660-21)

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Shaukat has relationships with Freenome and Iterative Scopes.

Help your patients understand colorectal cancer prevention, and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

A version of this article first appeared on Medscape.com.

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Shaukat has relationships with Freenome and Iterative Scopes.

Help your patients understand colorectal cancer prevention, and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

A version of this article first appeared on Medscape.com.

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Shaukat has relationships with Freenome and Iterative Scopes.

Help your patients understand colorectal cancer prevention, and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

A version of this article first appeared on Medscape.com.

Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.

At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.

“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).

The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.

The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:

• Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
• Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
• Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).

Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
 

Four years on

“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.

The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.

The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.

The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
 

Safety

Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.

Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.

“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
 

Best combination?

“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.

Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.

Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.

At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.

“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).

The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.

The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:

• Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
• Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
• Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).

Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
 

Four years on

“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.

The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.

The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.

The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
 

Safety

Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.

Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.

“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
 

Best combination?

“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.

Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.

Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.

At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.

“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).

The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.

The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:

• Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
• Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
• Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).

Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
 

Four years on

“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.

The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.

The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.

The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
 

Safety

Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.

Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.

“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
 

Best combination?

“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.

Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.

Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining transcatheter arterial chemoembolization (TACE) therapy with sorafenib improved progression-free survival (PFS), but not overall survival (OS), when compared with TACE alone in patients with unresectable hepatocellular carcinoma (HCC), final results from the phase 2 TACTICS trial showed.

The lack of a statistically significant difference in OS may have been due to the fact that patients randomized to receive TACE alone had more frequent post-trial therapies compared with patients assigned to TACE plus sorafenib, said study investigator Masatoshi Kudo, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan.

“These subsequent anticancer procedures and active systemic therapies have potentially diluted OS benefit in TACE plus sorafenib by extending post-progression survival and confounding survival analysis, implying the OS endpoint is not feasible anymore for TACE combination trials in the era of multitargeted agents and immune checkpoint inhibitors,” Dr. Kudo said at the 2021 Gastrointestinal Cancers Symposium (abstract 270).
 

Unresectable HCC

The TACTICS trial was launched in October 2010. Investigators enrolled 156 patients with unresectable HCC, Child-Pugh scores of 7 or less, treatable tumors (10 or fewer nodules of 10 cm or less) and adequate organ function.

Patients were randomized to receive TACE alone or with sorafenib. Sorafenib was delivered at a dose of 400 mg daily starting 2-3 weeks before the first TACE procedure to assess tolerability, followed by 800-mg daily doses. Sorafenib was interrupted for 2 days before and 3 days after each TACE session.

The trial had a gate-keeping design, which specified that OS would be formally analyzed only if PFS results were positive.

As reported in GUT in 2020, the trial met its PFS coprimary endpoint, with a median PFS of 25.2 months for the combination, compared with 13.5 months for TACE alone, at a median follow-up of 122.3 weeks. The hazard ratio (HR) for progression with the combination was 0.59 (P = .006).
 

Updated results

At the symposium, Dr. Kudo presented updated PFS results. At a median follow-up for all randomized patients of 33.4 months, the median PFS with the combination was 22.8 months, compared with 13.5 months for TACE alone (HR, 0.661; P­ = .02).

However, OS did not differ significantly between the groups, with a median of 36.2 months for the combination and 30.8 months for TACE alone (HR, 0.861; P = .40)

In a subgroup analysis of OS, there were small trends in favor of the combination compared with TACE alone in most categories, but the benefit of the combination was statistically significant only for the 12 patients with HCC of hepatitis B virus etiology (HR, 0.72; 95% CI, 0.006-0.808).

There were also trends favoring TACE plus sorafenib for PFS in a subgroup analysis, but none of the differences were statistically significant, except for patients who had received one or two TACE treatments prior to study entry (HR, 0.474; 95% CI, 0.276-0.812).

Treatment-emergent adverse events were consistent with those seen in the primary analysis, with no new safety signals seen at the last follow-up, Dr. Kudo said.

A majority of patients in both arms had subsequent anticancer therapy – 76.3% of the TACE-alone arm and 58.8% of the combination arm.

Patients in the TACE-alone arm were more likely than were those in the combination arm to have ablation (22.4% vs. 14.9%) or additional sorafenib (50% vs. 10.6%). Patients in the TACE-alone arm were also more likely to receive hepatic artery infusion chemotherapy a single time (27.6% vs. 19.1%) but less likely to receive it continuously (10.3% vs. 19.1%).

Dr. Kudo noted that in six trials in which TACE was combined with another agent, the correlation coefficient between PFS and OS was low, and the slope of weighted linear regression was more gentle than that seen in trials of other therapies for advanced HCC, “suggesting that long post-progression survivals strongly affected the OS in TACE combination trials.”

The TACTICS study was funded by the Japan Liver Oncology Group. Dr. Kudo disclosed relationships with Bayer, codeveloper of sorafenib, and multiple other companies.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining transcatheter arterial chemoembolization (TACE) therapy with sorafenib improved progression-free survival (PFS), but not overall survival (OS), when compared with TACE alone in patients with unresectable hepatocellular carcinoma (HCC), final results from the phase 2 TACTICS trial showed.

The lack of a statistically significant difference in OS may have been due to the fact that patients randomized to receive TACE alone had more frequent post-trial therapies compared with patients assigned to TACE plus sorafenib, said study investigator Masatoshi Kudo, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan.

“These subsequent anticancer procedures and active systemic therapies have potentially diluted OS benefit in TACE plus sorafenib by extending post-progression survival and confounding survival analysis, implying the OS endpoint is not feasible anymore for TACE combination trials in the era of multitargeted agents and immune checkpoint inhibitors,” Dr. Kudo said at the 2021 Gastrointestinal Cancers Symposium (abstract 270).
 

Unresectable HCC

The TACTICS trial was launched in October 2010. Investigators enrolled 156 patients with unresectable HCC, Child-Pugh scores of 7 or less, treatable tumors (10 or fewer nodules of 10 cm or less) and adequate organ function.

Patients were randomized to receive TACE alone or with sorafenib. Sorafenib was delivered at a dose of 400 mg daily starting 2-3 weeks before the first TACE procedure to assess tolerability, followed by 800-mg daily doses. Sorafenib was interrupted for 2 days before and 3 days after each TACE session.

The trial had a gate-keeping design, which specified that OS would be formally analyzed only if PFS results were positive.

As reported in GUT in 2020, the trial met its PFS coprimary endpoint, with a median PFS of 25.2 months for the combination, compared with 13.5 months for TACE alone, at a median follow-up of 122.3 weeks. The hazard ratio (HR) for progression with the combination was 0.59 (P = .006).
 

Updated results

At the symposium, Dr. Kudo presented updated PFS results. At a median follow-up for all randomized patients of 33.4 months, the median PFS with the combination was 22.8 months, compared with 13.5 months for TACE alone (HR, 0.661; P­ = .02).

However, OS did not differ significantly between the groups, with a median of 36.2 months for the combination and 30.8 months for TACE alone (HR, 0.861; P = .40)

In a subgroup analysis of OS, there were small trends in favor of the combination compared with TACE alone in most categories, but the benefit of the combination was statistically significant only for the 12 patients with HCC of hepatitis B virus etiology (HR, 0.72; 95% CI, 0.006-0.808).

There were also trends favoring TACE plus sorafenib for PFS in a subgroup analysis, but none of the differences were statistically significant, except for patients who had received one or two TACE treatments prior to study entry (HR, 0.474; 95% CI, 0.276-0.812).

Treatment-emergent adverse events were consistent with those seen in the primary analysis, with no new safety signals seen at the last follow-up, Dr. Kudo said.

A majority of patients in both arms had subsequent anticancer therapy – 76.3% of the TACE-alone arm and 58.8% of the combination arm.

Patients in the TACE-alone arm were more likely than were those in the combination arm to have ablation (22.4% vs. 14.9%) or additional sorafenib (50% vs. 10.6%). Patients in the TACE-alone arm were also more likely to receive hepatic artery infusion chemotherapy a single time (27.6% vs. 19.1%) but less likely to receive it continuously (10.3% vs. 19.1%).

Dr. Kudo noted that in six trials in which TACE was combined with another agent, the correlation coefficient between PFS and OS was low, and the slope of weighted linear regression was more gentle than that seen in trials of other therapies for advanced HCC, “suggesting that long post-progression survivals strongly affected the OS in TACE combination trials.”

The TACTICS study was funded by the Japan Liver Oncology Group. Dr. Kudo disclosed relationships with Bayer, codeveloper of sorafenib, and multiple other companies.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining transcatheter arterial chemoembolization (TACE) therapy with sorafenib improved progression-free survival (PFS), but not overall survival (OS), when compared with TACE alone in patients with unresectable hepatocellular carcinoma (HCC), final results from the phase 2 TACTICS trial showed.

The lack of a statistically significant difference in OS may have been due to the fact that patients randomized to receive TACE alone had more frequent post-trial therapies compared with patients assigned to TACE plus sorafenib, said study investigator Masatoshi Kudo, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan.

“These subsequent anticancer procedures and active systemic therapies have potentially diluted OS benefit in TACE plus sorafenib by extending post-progression survival and confounding survival analysis, implying the OS endpoint is not feasible anymore for TACE combination trials in the era of multitargeted agents and immune checkpoint inhibitors,” Dr. Kudo said at the 2021 Gastrointestinal Cancers Symposium (abstract 270).
 

Unresectable HCC

The TACTICS trial was launched in October 2010. Investigators enrolled 156 patients with unresectable HCC, Child-Pugh scores of 7 or less, treatable tumors (10 or fewer nodules of 10 cm or less) and adequate organ function.

Patients were randomized to receive TACE alone or with sorafenib. Sorafenib was delivered at a dose of 400 mg daily starting 2-3 weeks before the first TACE procedure to assess tolerability, followed by 800-mg daily doses. Sorafenib was interrupted for 2 days before and 3 days after each TACE session.

The trial had a gate-keeping design, which specified that OS would be formally analyzed only if PFS results were positive.

As reported in GUT in 2020, the trial met its PFS coprimary endpoint, with a median PFS of 25.2 months for the combination, compared with 13.5 months for TACE alone, at a median follow-up of 122.3 weeks. The hazard ratio (HR) for progression with the combination was 0.59 (P = .006).
 

Updated results

At the symposium, Dr. Kudo presented updated PFS results. At a median follow-up for all randomized patients of 33.4 months, the median PFS with the combination was 22.8 months, compared with 13.5 months for TACE alone (HR, 0.661; P­ = .02).

However, OS did not differ significantly between the groups, with a median of 36.2 months for the combination and 30.8 months for TACE alone (HR, 0.861; P = .40)

In a subgroup analysis of OS, there were small trends in favor of the combination compared with TACE alone in most categories, but the benefit of the combination was statistically significant only for the 12 patients with HCC of hepatitis B virus etiology (HR, 0.72; 95% CI, 0.006-0.808).

There were also trends favoring TACE plus sorafenib for PFS in a subgroup analysis, but none of the differences were statistically significant, except for patients who had received one or two TACE treatments prior to study entry (HR, 0.474; 95% CI, 0.276-0.812).

Treatment-emergent adverse events were consistent with those seen in the primary analysis, with no new safety signals seen at the last follow-up, Dr. Kudo said.

A majority of patients in both arms had subsequent anticancer therapy – 76.3% of the TACE-alone arm and 58.8% of the combination arm.

Patients in the TACE-alone arm were more likely than were those in the combination arm to have ablation (22.4% vs. 14.9%) or additional sorafenib (50% vs. 10.6%). Patients in the TACE-alone arm were also more likely to receive hepatic artery infusion chemotherapy a single time (27.6% vs. 19.1%) but less likely to receive it continuously (10.3% vs. 19.1%).

Dr. Kudo noted that in six trials in which TACE was combined with another agent, the correlation coefficient between PFS and OS was low, and the slope of weighted linear regression was more gentle than that seen in trials of other therapies for advanced HCC, “suggesting that long post-progression survivals strongly affected the OS in TACE combination trials.”

The TACTICS study was funded by the Japan Liver Oncology Group. Dr. Kudo disclosed relationships with Bayer, codeveloper of sorafenib, and multiple other companies.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Pancreatic enzyme replacement therapy (PERT) is often an essential component of the treatment regimen for patients with pancreatic cancer, but it can be very pricey.

“Out-of-pocket costs for a 30-day supply of enzymes for Medicare beneficiaries can be as high as $1,000,” commented Arjun Gupta, MD, an oncology fellow at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

This can contribute to financial toxicity for patients who already have a high symptom burden and distress. The high cost of this supportive care has been underappreciated, he said.

In addition to its use for patients with pancreatic cancer, PERT is also prescribed to patients with chronic pancreatitis and cystic fibrosis. These enzymes can reduce symptoms of indigestion and improve nutrition for patients with exocrine pancreatic insufficiency, he explained.

“Out-of-pocket costs for two large pancreas enzyme capsules, which are often required for a meal, may be $15. And these need to be taken at every meal and may be more expensive than the meal itself,” he said in an interview.

Dr. Gupta led a new study which showed that, among Medicare beneficiaries, the expected out-of-pocket costs for a 30-day supply of optimally dosed PERT averaged $999 across formulations. Patients’ costs, including deductibles and coinsurance, ranged from $853 to $1,536.

The out-of-pocket costs were lower after patients met the deductible ($673; range, $527-$1,210) and continued to decrease after reaching catastrophic coverage ($135; range, $105-$242).

The findings were presented at the 2021 Gastrointestinal Cancers Symposium.

Dr. Gupta noted that there has been a lot of publicity about very expensive anticancer drugs, but little has been said about the costs of products used in supportive care. “While it’s true that many patients cannot afford the drugs, there are patient-assistance programs where they can often get them free of charge,” he said. “But supportive care agents, such as those for constipation or the enzymes – all of those can nickel and dime you and end up being very costly.”

These agents add substantially to the drug cost burden. “Some patients also need insulin, which is also insanely expensive,” he said.

One of the reasons for the high cost of PERT is that there are very few options, and all the available products are brand-name agents. Dr. Gupta noted that clinicians often underprescribe pancreatic enzymes in clinical practice. “Because of this, we wanted to look at what are the estimated out-of-pocket costs for patients directly when they’re prescribed an optimal regimen of pancreatic enzymes,” he said.
 

Study details

For their study, Dr. Gupta and colleagues assessed PERT costs using the Medicare Part D formulary and pricing files for the first quarter of 2020. Point-of-sale and out-of-pocket costs for each PERT formulation were calculated among Part D standalone and Medicare Advantage prescription drug plans.

Costs were then assessed using three scenarios: the standard-benefit design, with a $435 deductible and 25% coinsurance after the deductible is met; 25% coinsurance to fill a prescription after the deductible while in the coverage gap until the patient spends $6,350 out of pocket; and 5% coinsurance once catastrophic coverage is reached.

Across 3,974 plans nationwide, four formulations in 17 different doses were covered by Medicare plans during the study period. Doses ranged from 3,000 to 40,000 lipase units, and the per-unit list price ranged from $1.44 to $13.89.

The point-of-sale price for a 30-day supply of optimally dosed PERT ranged from $2,109 to $4,840.

Dr. Gupta noted that a “good-sized meal often requires 80,000 units of lipase, or two of the very largest pills. Of note, these pills need to be taken meal after meal every meal throughout a patient’s life.”

Prescribers and dietitians try to find the least expensive options, including patient-assistance programs, but in the end, they are sometimes forced to underprescribe. “Some patients will go and buy over-the-counter pancreatic enzyme supplements, and it seems like a good way to cut costs,” said Dr. Gupta, “but it is not recommended for people with pancreatic cancer.”

The problem with these formulations is that they are not regulated. “The enzyme content in them is also minuscule, in the range of hundreds of units instead of the 50,000 units needed per meal,” he said. “Patients end up spending much more for ineffective therapies.”

The study received no outside funding. Dr. Gupta disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pancreatic enzyme replacement therapy (PERT) is often an essential component of the treatment regimen for patients with pancreatic cancer, but it can be very pricey.

“Out-of-pocket costs for a 30-day supply of enzymes for Medicare beneficiaries can be as high as $1,000,” commented Arjun Gupta, MD, an oncology fellow at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

This can contribute to financial toxicity for patients who already have a high symptom burden and distress. The high cost of this supportive care has been underappreciated, he said.

In addition to its use for patients with pancreatic cancer, PERT is also prescribed to patients with chronic pancreatitis and cystic fibrosis. These enzymes can reduce symptoms of indigestion and improve nutrition for patients with exocrine pancreatic insufficiency, he explained.

“Out-of-pocket costs for two large pancreas enzyme capsules, which are often required for a meal, may be $15. And these need to be taken at every meal and may be more expensive than the meal itself,” he said in an interview.

Dr. Gupta led a new study which showed that, among Medicare beneficiaries, the expected out-of-pocket costs for a 30-day supply of optimally dosed PERT averaged $999 across formulations. Patients’ costs, including deductibles and coinsurance, ranged from $853 to $1,536.

The out-of-pocket costs were lower after patients met the deductible ($673; range, $527-$1,210) and continued to decrease after reaching catastrophic coverage ($135; range, $105-$242).

The findings were presented at the 2021 Gastrointestinal Cancers Symposium.

Dr. Gupta noted that there has been a lot of publicity about very expensive anticancer drugs, but little has been said about the costs of products used in supportive care. “While it’s true that many patients cannot afford the drugs, there are patient-assistance programs where they can often get them free of charge,” he said. “But supportive care agents, such as those for constipation or the enzymes – all of those can nickel and dime you and end up being very costly.”

These agents add substantially to the drug cost burden. “Some patients also need insulin, which is also insanely expensive,” he said.

One of the reasons for the high cost of PERT is that there are very few options, and all the available products are brand-name agents. Dr. Gupta noted that clinicians often underprescribe pancreatic enzymes in clinical practice. “Because of this, we wanted to look at what are the estimated out-of-pocket costs for patients directly when they’re prescribed an optimal regimen of pancreatic enzymes,” he said.
 

Study details

For their study, Dr. Gupta and colleagues assessed PERT costs using the Medicare Part D formulary and pricing files for the first quarter of 2020. Point-of-sale and out-of-pocket costs for each PERT formulation were calculated among Part D standalone and Medicare Advantage prescription drug plans.

Costs were then assessed using three scenarios: the standard-benefit design, with a $435 deductible and 25% coinsurance after the deductible is met; 25% coinsurance to fill a prescription after the deductible while in the coverage gap until the patient spends $6,350 out of pocket; and 5% coinsurance once catastrophic coverage is reached.

Across 3,974 plans nationwide, four formulations in 17 different doses were covered by Medicare plans during the study period. Doses ranged from 3,000 to 40,000 lipase units, and the per-unit list price ranged from $1.44 to $13.89.

The point-of-sale price for a 30-day supply of optimally dosed PERT ranged from $2,109 to $4,840.

Dr. Gupta noted that a “good-sized meal often requires 80,000 units of lipase, or two of the very largest pills. Of note, these pills need to be taken meal after meal every meal throughout a patient’s life.”

Prescribers and dietitians try to find the least expensive options, including patient-assistance programs, but in the end, they are sometimes forced to underprescribe. “Some patients will go and buy over-the-counter pancreatic enzyme supplements, and it seems like a good way to cut costs,” said Dr. Gupta, “but it is not recommended for people with pancreatic cancer.”

The problem with these formulations is that they are not regulated. “The enzyme content in them is also minuscule, in the range of hundreds of units instead of the 50,000 units needed per meal,” he said. “Patients end up spending much more for ineffective therapies.”

The study received no outside funding. Dr. Gupta disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pancreatic enzyme replacement therapy (PERT) is often an essential component of the treatment regimen for patients with pancreatic cancer, but it can be very pricey.

“Out-of-pocket costs for a 30-day supply of enzymes for Medicare beneficiaries can be as high as $1,000,” commented Arjun Gupta, MD, an oncology fellow at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

This can contribute to financial toxicity for patients who already have a high symptom burden and distress. The high cost of this supportive care has been underappreciated, he said.

In addition to its use for patients with pancreatic cancer, PERT is also prescribed to patients with chronic pancreatitis and cystic fibrosis. These enzymes can reduce symptoms of indigestion and improve nutrition for patients with exocrine pancreatic insufficiency, he explained.

“Out-of-pocket costs for two large pancreas enzyme capsules, which are often required for a meal, may be $15. And these need to be taken at every meal and may be more expensive than the meal itself,” he said in an interview.

Dr. Gupta led a new study which showed that, among Medicare beneficiaries, the expected out-of-pocket costs for a 30-day supply of optimally dosed PERT averaged $999 across formulations. Patients’ costs, including deductibles and coinsurance, ranged from $853 to $1,536.

The out-of-pocket costs were lower after patients met the deductible ($673; range, $527-$1,210) and continued to decrease after reaching catastrophic coverage ($135; range, $105-$242).

The findings were presented at the 2021 Gastrointestinal Cancers Symposium.

Dr. Gupta noted that there has been a lot of publicity about very expensive anticancer drugs, but little has been said about the costs of products used in supportive care. “While it’s true that many patients cannot afford the drugs, there are patient-assistance programs where they can often get them free of charge,” he said. “But supportive care agents, such as those for constipation or the enzymes – all of those can nickel and dime you and end up being very costly.”

These agents add substantially to the drug cost burden. “Some patients also need insulin, which is also insanely expensive,” he said.

One of the reasons for the high cost of PERT is that there are very few options, and all the available products are brand-name agents. Dr. Gupta noted that clinicians often underprescribe pancreatic enzymes in clinical practice. “Because of this, we wanted to look at what are the estimated out-of-pocket costs for patients directly when they’re prescribed an optimal regimen of pancreatic enzymes,” he said.
 

Study details

For their study, Dr. Gupta and colleagues assessed PERT costs using the Medicare Part D formulary and pricing files for the first quarter of 2020. Point-of-sale and out-of-pocket costs for each PERT formulation were calculated among Part D standalone and Medicare Advantage prescription drug plans.

Costs were then assessed using three scenarios: the standard-benefit design, with a $435 deductible and 25% coinsurance after the deductible is met; 25% coinsurance to fill a prescription after the deductible while in the coverage gap until the patient spends $6,350 out of pocket; and 5% coinsurance once catastrophic coverage is reached.

Across 3,974 plans nationwide, four formulations in 17 different doses were covered by Medicare plans during the study period. Doses ranged from 3,000 to 40,000 lipase units, and the per-unit list price ranged from $1.44 to $13.89.

The point-of-sale price for a 30-day supply of optimally dosed PERT ranged from $2,109 to $4,840.

Dr. Gupta noted that a “good-sized meal often requires 80,000 units of lipase, or two of the very largest pills. Of note, these pills need to be taken meal after meal every meal throughout a patient’s life.”

Prescribers and dietitians try to find the least expensive options, including patient-assistance programs, but in the end, they are sometimes forced to underprescribe. “Some patients will go and buy over-the-counter pancreatic enzyme supplements, and it seems like a good way to cut costs,” said Dr. Gupta, “but it is not recommended for people with pancreatic cancer.”

The problem with these formulations is that they are not regulated. “The enzyme content in them is also minuscule, in the range of hundreds of units instead of the 50,000 units needed per meal,” he said. “Patients end up spending much more for ineffective therapies.”

The study received no outside funding. Dr. Gupta disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

First-line trifluridine/tipiracil plus bevacizumab (TT-B) offered a slight survival benefit over capecitabine plus bevacizumab (C-B) in patients with unresectable metastatic colorectal cancer in the final analysis of the TASCO1 trial.

The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.

The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.

Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).

Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
 

About trifluridine/tipiracil

Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.

Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).

In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
 

TASCO1 details

In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.

After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).

TT-B consisted of oral trifluridine/tipiracil at 35 mg/m² twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.

C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m² twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
 

Final results

The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.

The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).

Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.

He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”

Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.

Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.

At the study cutoff date in September 2020, 66 patients in each arm had died.

Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
 

‘The jury is still out’

The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.

The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.

“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.

He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.

“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.

The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

First-line trifluridine/tipiracil plus bevacizumab (TT-B) offered a slight survival benefit over capecitabine plus bevacizumab (C-B) in patients with unresectable metastatic colorectal cancer in the final analysis of the TASCO1 trial.

The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.

The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.

Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).

Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
 

About trifluridine/tipiracil

Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.

Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).

In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
 

TASCO1 details

In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.

After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).

TT-B consisted of oral trifluridine/tipiracil at 35 mg/m² twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.

C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m² twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
 

Final results

The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.

The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).

Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.

He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”

Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.

Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.

At the study cutoff date in September 2020, 66 patients in each arm had died.

Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
 

‘The jury is still out’

The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.

The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.

“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.

He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.

“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.

The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

First-line trifluridine/tipiracil plus bevacizumab (TT-B) offered a slight survival benefit over capecitabine plus bevacizumab (C-B) in patients with unresectable metastatic colorectal cancer in the final analysis of the TASCO1 trial.

The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.

The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.

Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).

Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
 

About trifluridine/tipiracil

Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.

Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).

In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
 

TASCO1 details

In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.

After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).

TT-B consisted of oral trifluridine/tipiracil at 35 mg/m² twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.

C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m² twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
 

Final results

The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.

The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).

Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.

He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”

Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.

Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.

At the study cutoff date in September 2020, 66 patients in each arm had died.

Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
 

‘The jury is still out’

The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.

The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.

“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.

He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.

“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.

The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Despite standard blood monitoring and routine imaging, patients with colorectal cancer (CRC) tend to have multiple, incurable metastases when relapse occurs.

A new study indicates that postsurgical circulating tumor DNA (ctDNA) testing may improve our ability to predict relapse in patients with stage I-III CRC.

ctDNA testing outperformed carcinoembryonic antigen (CEA) testing in predicting relapse-free survival, and ctDNA was detected about 8 months prior to relapse detection via CT.

Tenna V. Henriksen, of Aarhus University in Denmark, presented these results at the 2021 Gastrointestinal Cancers Symposium (abstract 11).

The multi-institutional study included 260 patients with CRC – 4 with stage I disease, 90 with stage II, and 166 with stage III disease.

Patients were monitored with plasma ctDNA testing within 2 months of primary surgery. Some patients were monitored with follow-up ctDNA sampling every 3 months for an additional 3 years.

Individual tumors and matched germline DNA were interrogated with whole-exome sequencing, and somatic single nucleotide variants were identified. Personalized multiplex PCR assays were developed to track tumor-specific single nucleotide variants via the Signatera® ctDNA assay.

The researchers retrospectively assessed ctDNA’s performance in:

• Stratifying the postoperative risk of relapse.
• Quantifying the benefit of adjuvant chemotherapy in patients who had or did not have ctDNA in plasma.
• Efficiently detecting relapse, in comparison with standard surveillance tests.

Surveillance CT scans were performed at 12 and 36 months but not at the frequency recommended in NCCN guidelines.

In all, 165 patients received adjuvant chemotherapy. The decision to give chemotherapy was made on a clinical basis by treating physicians who were blinded to the results of ctDNA testing.
 

Results

Of the 260 patients analyzed, 48 relapsed. The median follow-up was 28.4 months overall and 29.9 months in the nonrelapse cases.

The researchers assessed postoperative ctDNA status prior to adjuvant chemotherapy in 218 patients and after adjuvant chemotherapy in 108 patients.

In the prechemotherapy group, 20 patients were ctDNA positive, and 80% of them relapsed. In contrast, 13% of the 198 ctDNA-negative patients relapsed. The hazard ratio (HR) for relapse-free survival was 11 (95% confidence interval, 5.9-21; P < .0001).

After adjuvant chemotherapy, 12.5% of the ctDNA-negative patients relapsed, compared with 83.3% of the ctDNA-positive patients. The HR for relapse-free survival was 12 (95% CI, 4.9-27; P < .0001).

Results from longitudinal ctDNA testing in 202 patients suggested that serial sampling is more useful than sampling at a single point in time. The recurrence rate was 3.4% among patients who remained persistently ctDNA negative, compared with 89.3% in patients who were ctDNA positive. The HR for relapse-free survival was 51 (95% CI, 20-125; P < .0001).

In a subgroup of 29 patients with clinical recurrence detected by CT imaging, ctDNA detection occurred a median of 8.1 months earlier than radiologic relapse.

Among the 197 patients who had serial CEA and ctDNA measurements, longitudinal CEA testing correlated with relapse-free survival (HR, 4.9; 95% CI, 3.2-15, P < .0001) but not nearly as well as ctDNA testing (HR, 95.7; 95% CI, 28-322, P < .0001) in a univariable analysis.

In a multivariable analysis, the HR for relapse-free survival was 1.8 (95% CI, 0.77-4.0; P = .184) for longitudinal CEA and 80.55 (95% CI, 23.1-281; P < .0001) for longitudinal ctDNA.

“[W]hen we pit them against each other in a multivariable analysis, we can see that all the predictive power is in the ctDNA samples,” Ms. Henriksen said. “This indicates that ctDNA is a stronger biomarker compared to CEA, at least with relapse-free survival.”

Availability is not actionability

Study discussant Michael J. Overman, MD, of MD Anderson Cancer Center in Houston, acknowledged that this research substantiates the ability of postoperative ctDNA detection to risk stratify patients with stage III CRC, the predominant stage of participants in the study.

The current results reinforce the researchers’ previously published work (JAMA Oncol. 2019;5[8]:1124-31) and affirm similar findings by other groups (JAMA Oncol. 2019;5[12]:1710-17 and JAMA Oncol. 2019;5[8]:1118-23).

However, Dr. Overman cautioned that “availability is not the same as actionability.”

He also said the “tumor-informed mutation” approach utilized in the Signatera assay differs from the simpler “panel-based” approach, which is also undergoing clinical testing and offers the additional opportunity to test potentially actionable epigenetic targets such as DNA methylation.

Furthermore, the practicality of integrating the tumor-informed mutation approach into the time constraints required in clinical practice was not evaluated in the current analysis.

Dr. Overman pointed out that 16 of the 20 ctDNA-positive patients who received adjuvant chemotherapy sustained a recurrence, so the chemotherapy benefit was lower than expected.

Finally, although ctDNA outperformed CEA in detecting relapse, the greatest impact of ctDNA is its potential to inform the clinician’s decision to escalate and deescalate treatment with impact on survival – a potential that remains unfulfilled.

Next steps

Ms. Henriksen closed her presentation with the perspective that, for serial ctDNA monitoring to be implemented in clinical settings, testing in randomized clinical trials will be needed.

In Denmark, the IMPROVE-IT study is enrolling patients with stage I or low-risk stage II CRC. In this trial, ctDNA-positive patients will receive adjuvant chemotherapy, and ctDNA-negative patients will have longitudinal ctDNA testing but no adjuvant chemotherapy.

A second study, IMPROVE-IT2, will assess the value of ctDNA to direct intensified radiologic surveillance to improve the application of potentially curative treatment for patients with stage II (high-risk) or stage III CRC. Patients with negative ctDNA tests will be followed with longitudinal ctDNA testing only.

In his talk, Dr. Overman highlighted several prospective studies assessing the value of ctDNA testing.

One of these is the ongoing COBRA study (NRG-GI-005), which uses a ctDNA assay (Guardant Lunar-1) for patients with stage IIA CRC for whom standard adjuvant chemotherapy is not indicated.

The patients in COBRA are randomized to active surveillance or assay-directed therapy. Patients assigned to assay-directed therapy have samples analyzed for ctDNA, which would guide the decision about adjuvant chemotherapy. If the postoperative sample is ctDNA positive and the patient accepts adjuvant chemotherapy, the patient could receive one of two standard adjuvant chemotherapy regimens. If ctDNA negative, the patient would be followed with active surveillance alone.

Dr. Overman also highlighted the planned CIRCULATE US trial (NRG-GI008). The aim of this trial is to test intensified adjuvant treatment for stage III CRC patients with positive ctDNA tests. It will employ the Signatera assay.

Ideally, these ongoing trials will provide the evidence base needed for clinicians to optimize adjuvant therapy and surveillance using ctDNA technology.

The current study was sponsored by the Danish Council for Independent Research, The Novo Nordisk Foundation, The Danish Cancer Society, and Natera Inc. Ms. Henriksen disclosed no conflicts of interest. Dr. Overman disclosed relationships with Array BioPharma, Bristol-Myers Squibb, Gritstone Oncology, Janssen, MedImmune, Merck, Novartis, Pfizer, Promega, Roche/Genentech, and Spectrum Pharmaceuticals.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
 

Despite standard blood monitoring and routine imaging, patients with colorectal cancer (CRC) tend to have multiple, incurable metastases when relapse occurs.

A new study indicates that postsurgical circulating tumor DNA (ctDNA) testing may improve our ability to predict relapse in patients with stage I-III CRC.

ctDNA testing outperformed carcinoembryonic antigen (CEA) testing in predicting relapse-free survival, and ctDNA was detected about 8 months prior to relapse detection via CT.

Tenna V. Henriksen, of Aarhus University in Denmark, presented these results at the 2021 Gastrointestinal Cancers Symposium (abstract 11).

The multi-institutional study included 260 patients with CRC – 4 with stage I disease, 90 with stage II, and 166 with stage III disease.

Patients were monitored with plasma ctDNA testing within 2 months of primary surgery. Some patients were monitored with follow-up ctDNA sampling every 3 months for an additional 3 years.

Individual tumors and matched germline DNA were interrogated with whole-exome sequencing, and somatic single nucleotide variants were identified. Personalized multiplex PCR assays were developed to track tumor-specific single nucleotide variants via the Signatera® ctDNA assay.

The researchers retrospectively assessed ctDNA’s performance in:

• Stratifying the postoperative risk of relapse.
• Quantifying the benefit of adjuvant chemotherapy in patients who had or did not have ctDNA in plasma.
• Efficiently detecting relapse, in comparison with standard surveillance tests.

Surveillance CT scans were performed at 12 and 36 months but not at the frequency recommended in NCCN guidelines.

In all, 165 patients received adjuvant chemotherapy. The decision to give chemotherapy was made on a clinical basis by treating physicians who were blinded to the results of ctDNA testing.
 

Results

Of the 260 patients analyzed, 48 relapsed. The median follow-up was 28.4 months overall and 29.9 months in the nonrelapse cases.

The researchers assessed postoperative ctDNA status prior to adjuvant chemotherapy in 218 patients and after adjuvant chemotherapy in 108 patients.

In the prechemotherapy group, 20 patients were ctDNA positive, and 80% of them relapsed. In contrast, 13% of the 198 ctDNA-negative patients relapsed. The hazard ratio (HR) for relapse-free survival was 11 (95% confidence interval, 5.9-21; P < .0001).

After adjuvant chemotherapy, 12.5% of the ctDNA-negative patients relapsed, compared with 83.3% of the ctDNA-positive patients. The HR for relapse-free survival was 12 (95% CI, 4.9-27; P < .0001).

Results from longitudinal ctDNA testing in 202 patients suggested that serial sampling is more useful than sampling at a single point in time. The recurrence rate was 3.4% among patients who remained persistently ctDNA negative, compared with 89.3% in patients who were ctDNA positive. The HR for relapse-free survival was 51 (95% CI, 20-125; P < .0001).

In a subgroup of 29 patients with clinical recurrence detected by CT imaging, ctDNA detection occurred a median of 8.1 months earlier than radiologic relapse.

Among the 197 patients who had serial CEA and ctDNA measurements, longitudinal CEA testing correlated with relapse-free survival (HR, 4.9; 95% CI, 3.2-15, P < .0001) but not nearly as well as ctDNA testing (HR, 95.7; 95% CI, 28-322, P < .0001) in a univariable analysis.

In a multivariable analysis, the HR for relapse-free survival was 1.8 (95% CI, 0.77-4.0; P = .184) for longitudinal CEA and 80.55 (95% CI, 23.1-281; P < .0001) for longitudinal ctDNA.

“[W]hen we pit them against each other in a multivariable analysis, we can see that all the predictive power is in the ctDNA samples,” Ms. Henriksen said. “This indicates that ctDNA is a stronger biomarker compared to CEA, at least with relapse-free survival.”

Availability is not actionability

Study discussant Michael J. Overman, MD, of MD Anderson Cancer Center in Houston, acknowledged that this research substantiates the ability of postoperative ctDNA detection to risk stratify patients with stage III CRC, the predominant stage of participants in the study.

The current results reinforce the researchers’ previously published work (JAMA Oncol. 2019;5[8]:1124-31) and affirm similar findings by other groups (JAMA Oncol. 2019;5[12]:1710-17 and JAMA Oncol. 2019;5[8]:1118-23).

However, Dr. Overman cautioned that “availability is not the same as actionability.”

He also said the “tumor-informed mutation” approach utilized in the Signatera assay differs from the simpler “panel-based” approach, which is also undergoing clinical testing and offers the additional opportunity to test potentially actionable epigenetic targets such as DNA methylation.

Furthermore, the practicality of integrating the tumor-informed mutation approach into the time constraints required in clinical practice was not evaluated in the current analysis.

Dr. Overman pointed out that 16 of the 20 ctDNA-positive patients who received adjuvant chemotherapy sustained a recurrence, so the chemotherapy benefit was lower than expected.

Finally, although ctDNA outperformed CEA in detecting relapse, the greatest impact of ctDNA is its potential to inform the clinician’s decision to escalate and deescalate treatment with impact on survival – a potential that remains unfulfilled.

Next steps

Ms. Henriksen closed her presentation with the perspective that, for serial ctDNA monitoring to be implemented in clinical settings, testing in randomized clinical trials will be needed.

In Denmark, the IMPROVE-IT study is enrolling patients with stage I or low-risk stage II CRC. In this trial, ctDNA-positive patients will receive adjuvant chemotherapy, and ctDNA-negative patients will have longitudinal ctDNA testing but no adjuvant chemotherapy.

A second study, IMPROVE-IT2, will assess the value of ctDNA to direct intensified radiologic surveillance to improve the application of potentially curative treatment for patients with stage II (high-risk) or stage III CRC. Patients with negative ctDNA tests will be followed with longitudinal ctDNA testing only.

In his talk, Dr. Overman highlighted several prospective studies assessing the value of ctDNA testing.

One of these is the ongoing COBRA study (NRG-GI-005), which uses a ctDNA assay (Guardant Lunar-1) for patients with stage IIA CRC for whom standard adjuvant chemotherapy is not indicated.

The patients in COBRA are randomized to active surveillance or assay-directed therapy. Patients assigned to assay-directed therapy have samples analyzed for ctDNA, which would guide the decision about adjuvant chemotherapy. If the postoperative sample is ctDNA positive and the patient accepts adjuvant chemotherapy, the patient could receive one of two standard adjuvant chemotherapy regimens. If ctDNA negative, the patient would be followed with active surveillance alone.

Dr. Overman also highlighted the planned CIRCULATE US trial (NRG-GI008). The aim of this trial is to test intensified adjuvant treatment for stage III CRC patients with positive ctDNA tests. It will employ the Signatera assay.

Ideally, these ongoing trials will provide the evidence base needed for clinicians to optimize adjuvant therapy and surveillance using ctDNA technology.

The current study was sponsored by the Danish Council for Independent Research, The Novo Nordisk Foundation, The Danish Cancer Society, and Natera Inc. Ms. Henriksen disclosed no conflicts of interest. Dr. Overman disclosed relationships with Array BioPharma, Bristol-Myers Squibb, Gritstone Oncology, Janssen, MedImmune, Merck, Novartis, Pfizer, Promega, Roche/Genentech, and Spectrum Pharmaceuticals.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
 

Despite standard blood monitoring and routine imaging, patients with colorectal cancer (CRC) tend to have multiple, incurable metastases when relapse occurs.

A new study indicates that postsurgical circulating tumor DNA (ctDNA) testing may improve our ability to predict relapse in patients with stage I-III CRC.

ctDNA testing outperformed carcinoembryonic antigen (CEA) testing in predicting relapse-free survival, and ctDNA was detected about 8 months prior to relapse detection via CT.

Tenna V. Henriksen, of Aarhus University in Denmark, presented these results at the 2021 Gastrointestinal Cancers Symposium (abstract 11).

The multi-institutional study included 260 patients with CRC – 4 with stage I disease, 90 with stage II, and 166 with stage III disease.

Patients were monitored with plasma ctDNA testing within 2 months of primary surgery. Some patients were monitored with follow-up ctDNA sampling every 3 months for an additional 3 years.

Individual tumors and matched germline DNA were interrogated with whole-exome sequencing, and somatic single nucleotide variants were identified. Personalized multiplex PCR assays were developed to track tumor-specific single nucleotide variants via the Signatera® ctDNA assay.

The researchers retrospectively assessed ctDNA’s performance in:

• Stratifying the postoperative risk of relapse.
• Quantifying the benefit of adjuvant chemotherapy in patients who had or did not have ctDNA in plasma.
• Efficiently detecting relapse, in comparison with standard surveillance tests.

Surveillance CT scans were performed at 12 and 36 months but not at the frequency recommended in NCCN guidelines.

In all, 165 patients received adjuvant chemotherapy. The decision to give chemotherapy was made on a clinical basis by treating physicians who were blinded to the results of ctDNA testing.
 

Results

Of the 260 patients analyzed, 48 relapsed. The median follow-up was 28.4 months overall and 29.9 months in the nonrelapse cases.

The researchers assessed postoperative ctDNA status prior to adjuvant chemotherapy in 218 patients and after adjuvant chemotherapy in 108 patients.

In the prechemotherapy group, 20 patients were ctDNA positive, and 80% of them relapsed. In contrast, 13% of the 198 ctDNA-negative patients relapsed. The hazard ratio (HR) for relapse-free survival was 11 (95% confidence interval, 5.9-21; P < .0001).

After adjuvant chemotherapy, 12.5% of the ctDNA-negative patients relapsed, compared with 83.3% of the ctDNA-positive patients. The HR for relapse-free survival was 12 (95% CI, 4.9-27; P < .0001).

Results from longitudinal ctDNA testing in 202 patients suggested that serial sampling is more useful than sampling at a single point in time. The recurrence rate was 3.4% among patients who remained persistently ctDNA negative, compared with 89.3% in patients who were ctDNA positive. The HR for relapse-free survival was 51 (95% CI, 20-125; P < .0001).

In a subgroup of 29 patients with clinical recurrence detected by CT imaging, ctDNA detection occurred a median of 8.1 months earlier than radiologic relapse.

Among the 197 patients who had serial CEA and ctDNA measurements, longitudinal CEA testing correlated with relapse-free survival (HR, 4.9; 95% CI, 3.2-15, P < .0001) but not nearly as well as ctDNA testing (HR, 95.7; 95% CI, 28-322, P < .0001) in a univariable analysis.

In a multivariable analysis, the HR for relapse-free survival was 1.8 (95% CI, 0.77-4.0; P = .184) for longitudinal CEA and 80.55 (95% CI, 23.1-281; P < .0001) for longitudinal ctDNA.

“[W]hen we pit them against each other in a multivariable analysis, we can see that all the predictive power is in the ctDNA samples,” Ms. Henriksen said. “This indicates that ctDNA is a stronger biomarker compared to CEA, at least with relapse-free survival.”

Availability is not actionability

Study discussant Michael J. Overman, MD, of MD Anderson Cancer Center in Houston, acknowledged that this research substantiates the ability of postoperative ctDNA detection to risk stratify patients with stage III CRC, the predominant stage of participants in the study.

The current results reinforce the researchers’ previously published work (JAMA Oncol. 2019;5[8]:1124-31) and affirm similar findings by other groups (JAMA Oncol. 2019;5[12]:1710-17 and JAMA Oncol. 2019;5[8]:1118-23).

However, Dr. Overman cautioned that “availability is not the same as actionability.”

He also said the “tumor-informed mutation” approach utilized in the Signatera assay differs from the simpler “panel-based” approach, which is also undergoing clinical testing and offers the additional opportunity to test potentially actionable epigenetic targets such as DNA methylation.

Furthermore, the practicality of integrating the tumor-informed mutation approach into the time constraints required in clinical practice was not evaluated in the current analysis.

Dr. Overman pointed out that 16 of the 20 ctDNA-positive patients who received adjuvant chemotherapy sustained a recurrence, so the chemotherapy benefit was lower than expected.

Finally, although ctDNA outperformed CEA in detecting relapse, the greatest impact of ctDNA is its potential to inform the clinician’s decision to escalate and deescalate treatment with impact on survival – a potential that remains unfulfilled.

Next steps

Ms. Henriksen closed her presentation with the perspective that, for serial ctDNA monitoring to be implemented in clinical settings, testing in randomized clinical trials will be needed.

In Denmark, the IMPROVE-IT study is enrolling patients with stage I or low-risk stage II CRC. In this trial, ctDNA-positive patients will receive adjuvant chemotherapy, and ctDNA-negative patients will have longitudinal ctDNA testing but no adjuvant chemotherapy.

A second study, IMPROVE-IT2, will assess the value of ctDNA to direct intensified radiologic surveillance to improve the application of potentially curative treatment for patients with stage II (high-risk) or stage III CRC. Patients with negative ctDNA tests will be followed with longitudinal ctDNA testing only.

In his talk, Dr. Overman highlighted several prospective studies assessing the value of ctDNA testing.

One of these is the ongoing COBRA study (NRG-GI-005), which uses a ctDNA assay (Guardant Lunar-1) for patients with stage IIA CRC for whom standard adjuvant chemotherapy is not indicated.

The patients in COBRA are randomized to active surveillance or assay-directed therapy. Patients assigned to assay-directed therapy have samples analyzed for ctDNA, which would guide the decision about adjuvant chemotherapy. If the postoperative sample is ctDNA positive and the patient accepts adjuvant chemotherapy, the patient could receive one of two standard adjuvant chemotherapy regimens. If ctDNA negative, the patient would be followed with active surveillance alone.

Dr. Overman also highlighted the planned CIRCULATE US trial (NRG-GI008). The aim of this trial is to test intensified adjuvant treatment for stage III CRC patients with positive ctDNA tests. It will employ the Signatera assay.

Ideally, these ongoing trials will provide the evidence base needed for clinicians to optimize adjuvant therapy and surveillance using ctDNA technology.

The current study was sponsored by the Danish Council for Independent Research, The Novo Nordisk Foundation, The Danish Cancer Society, and Natera Inc. Ms. Henriksen disclosed no conflicts of interest. Dr. Overman disclosed relationships with Array BioPharma, Bristol-Myers Squibb, Gritstone Oncology, Janssen, MedImmune, Merck, Novartis, Pfizer, Promega, Roche/Genentech, and Spectrum Pharmaceuticals.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
 

Combining an EGFR inhibitor with a pair of checkpoint inhibitors can produce “promising” activity in certain patients with colorectal cancer (CRC), according to an investigator from a phase 2 trial.

The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.

Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).

Immune activation?

The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.

In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.

“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.

In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.

“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.

Single-arm study

Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.

The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.

Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.

As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.

Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.

The best response rate (confirmed and unconfirmed) at any time was 41%.

At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.

There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.

Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).

‘Disappointing PFS’

In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”

“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.

He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.

Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.

Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.

The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining an EGFR inhibitor with a pair of checkpoint inhibitors can produce “promising” activity in certain patients with colorectal cancer (CRC), according to an investigator from a phase 2 trial.

The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.

Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).

Immune activation?

The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.

In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.

“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.

In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.

“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.

Single-arm study

Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.

The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.

Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.

As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.

Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.

The best response rate (confirmed and unconfirmed) at any time was 41%.

At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.

There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.

Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).

‘Disappointing PFS’

In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”

“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.

He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.

Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.

Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.

The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining an EGFR inhibitor with a pair of checkpoint inhibitors can produce “promising” activity in certain patients with colorectal cancer (CRC), according to an investigator from a phase 2 trial.

The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.

Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).

Immune activation?

The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.

In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.

“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.

In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.

“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.

Single-arm study

Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.

The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.

Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.

As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.

Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.

The best response rate (confirmed and unconfirmed) at any time was 41%.

At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.

There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.

Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).

‘Disappointing PFS’

In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”

“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.

He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.

Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.

Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.

The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Dr. Shaukat has relationships with Freenome and Iterative Scopes.

This article was updated 2/2/21.

A version of this article first appeared on Medscape.com.

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Dr. Shaukat has relationships with Freenome and Iterative Scopes.

This article was updated 2/2/21.

A version of this article first appeared on Medscape.com.

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Dr. Shaukat has relationships with Freenome and Iterative Scopes.

This article was updated 2/2/21.

A version of this article first appeared on Medscape.com.

Combining standard neoadjuvant chemotherapy for locally advanced esophageal cancer with either radiation or docetaxel did not increase the risk of surgical complications, investigators in the JCOG1109 trial reported.

The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.

Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.

Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.

“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
 

Trial details

The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.

Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.

The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.

A total of 601 patients were enrolled and randomized to receive one of the following treatments:

• CF, with cisplatin at a dose of 80 mg/m² on day 1 and 5-fluorouracil at 800 mg/m² on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
• DCF, with cisplatin at 70 mg/m² on day 1, 5-fluorouracil at 750 mg/m² on days 1-5, and docetaxel at 70 mg/m² on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
• CF-RT, with cisplatin at 75 mg/m² on day 1, 5-fluorouracil at 1,000 mg/m² on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).

Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.

Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
 

Results

Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.

The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.

The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)

In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:

• Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
• DCF (RR, 0.79; P = .02)
• A thoracoscopic vs. open approach (RR, 0.77; P = .002).

The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).

Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
 

CROSS talk

“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.

The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m² for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.

Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.

He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.

“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.

A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.

“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.

JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining standard neoadjuvant chemotherapy for locally advanced esophageal cancer with either radiation or docetaxel did not increase the risk of surgical complications, investigators in the JCOG1109 trial reported.

The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.

Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.

Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.

“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
 

Trial details

The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.

Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.

The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.

A total of 601 patients were enrolled and randomized to receive one of the following treatments:

• CF, with cisplatin at a dose of 80 mg/m² on day 1 and 5-fluorouracil at 800 mg/m² on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
• DCF, with cisplatin at 70 mg/m² on day 1, 5-fluorouracil at 750 mg/m² on days 1-5, and docetaxel at 70 mg/m² on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
• CF-RT, with cisplatin at 75 mg/m² on day 1, 5-fluorouracil at 1,000 mg/m² on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).

Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.

Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
 

Results

Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.

The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.

The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)

In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:

• Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
• DCF (RR, 0.79; P = .02)
• A thoracoscopic vs. open approach (RR, 0.77; P = .002).

The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).

Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
 

CROSS talk

“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.

The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m² for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.

Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.

He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.

“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.

A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.

“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.

JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining standard neoadjuvant chemotherapy for locally advanced esophageal cancer with either radiation or docetaxel did not increase the risk of surgical complications, investigators in the JCOG1109 trial reported.

The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.

Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.

Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.

“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
 

Trial details

The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.

Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.

The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.

A total of 601 patients were enrolled and randomized to receive one of the following treatments:

• CF, with cisplatin at a dose of 80 mg/m² on day 1 and 5-fluorouracil at 800 mg/m² on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
• DCF, with cisplatin at 70 mg/m² on day 1, 5-fluorouracil at 750 mg/m² on days 1-5, and docetaxel at 70 mg/m² on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
• CF-RT, with cisplatin at 75 mg/m² on day 1, 5-fluorouracil at 1,000 mg/m² on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).

Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.

Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
 

Results

Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.

The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.

The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)

In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:

• Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
• DCF (RR, 0.79; P = .02)
• A thoracoscopic vs. open approach (RR, 0.77; P = .002).

The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).

Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
 

CROSS talk

“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.

The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m² for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.

Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.

He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.

“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.

A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.

“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.

JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.

Results from the Alliance A021501 study suggest the reference regimen should be neoadjuvant therapy with modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours), according to Matthew Katz, MD, FACS, chief of the pancreatic surgery service at the University of Texas MD Anderson Cancer Center, Houston.

This regimen improved survival for patients with PDAC, relative to historical data. For patients who received mFOLFIRINOX, the overall 18-month survival rate was 66.4%. However, when this regimen was combined with hypofractionated radiotherapy, the survival benefit was significantly lower, at 47.3%.

These findings were presented at the 2021 Gastrointestinal Cancers Symposium (GICS), which was held online this year.

“ASCO guidelines recommend that preoperative therapy be administered to patients with localized pancreatic adenocarcinoma who have tumors that have a significant radiographic interface with the major mesenteric blood vessels, as these patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz explained.

Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.

The goal of Alliance A021501 “was to define a reference preoperative regimen for future trials of preoperative therapy,” he said.

The cohort included 126 patients who were randomly assigned to receive either mFOLFIRINOX (arm A) or mFOLFIRINOX plus radiotherapy (arm B).

Patients in arm A received eight cycles of neoadjuvant mFOLFIRINOX. Patients in arm B received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiotherapy with either stereotactic body radiotherapy or hypofractionated image-guided radiotherapy.

In either arm, patients who did not experience disease progression underwent pancreatectomy followed by four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours).

The study’s primary endpoint was 18-month overall survival in comparison to a historical control of 50%. “An interim futility analysis was scheduled to be conducted following treatment of 30 patients on each arm,” Dr. Katz said. “Either arm in which 11 or fewer patients underwent [curative] R0 resection on protocol was to be declared futile and closed to further enrollment.

“With 62 evaluable patients in each arm, the final efficacy analysis was powered to detect an improvement in 18-month overall survival of 13% over the historical rate of 50%,” said Dr. Katz. “The two arms would be compared only if both were declared efficacious.”

At the interim analysis, 57% of the first 30 patients in arm A had undergone a resection, vs. 33% in arm B. Therefore, arm B was considered futile and was closed to accrual.

The median overall survival in arm A was 29.8 months. The median event-free survival was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pathologic complete response rate was 0%, and the 18-month overall survival rate was 93.1%.

For the patients in arm B, which had been closed to accrual, the median overall survival was 17.1 months, and the median event-free survival was 10.2 months. About one-third (35%) of patients were able to proceed to pancreatectomy. The R0 resection rate was 74%, the pathologic complete response rate was 11%, and the 18-month overall survival rate was 78.9%.

“Preoperative mFOLFIRINOX was associated with favorable overall survival relative to historical criteria in patients with borderline resectable PDAC, and mFOLFIRINOX with radiation therapy met the predefined futility boundary for R0 resection at interim analysis,” Dr. Katz concluded. “Therefore, mFOLFIRINOX represents a reference perioperative regimen for patients with borderline resectable PDAC.”
 

Further investigation needed

The paper’s discussant, Rebecca A. Snyder, MD, MPH, of the Brody School of Medicine, East Carolina University, Greenville, N.C., emphasized that this study was not designed or powered to directly compare chemotherapy alone with chemotherapy plus radiotherapy in the neoadjuvant setting.

She noted that it is surprising that the radiotherapy arm was closed early. She said the reasons for this remain unclear, although a few possible reasons can be speculated.

“Based on multiple studies in both the adjuvant and neoadjuvant setting, including the Alliance [A021501] trial presented today, there is no convincing randomized data that radiation therapy prolongs survival in any population of unselected patients with pancreatic cancer,” said Dr. Snyder.

“Certainly, follow-up questions still remain, specifically regarding the role for non-SBRT radiation in the preoperative setting, which may be answered by the ongoing PREOPANC-2 and PRODIGE 44 trials,” she said.

She added that the “addition of SBRT in the preoperative setting does not appear to be justified.”

The role of radiotherapy for subsets of patients remains unknown, and future investigation should focus on patient-centered endpoints, such as symptomatic local control rates, Dr. Snyder concluded.

The study was funded by the National Institutes of Health. Dr. Katz has had a consulting or advisory role for AbbVie and Alcresta Therapeutics. Dr. Snyder has disclosed no relevant financial relationships.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

A version of this article first appeared on Medscape.com.

Patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.

Results from the Alliance A021501 study suggest the reference regimen should be neoadjuvant therapy with modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours), according to Matthew Katz, MD, FACS, chief of the pancreatic surgery service at the University of Texas MD Anderson Cancer Center, Houston.

This regimen improved survival for patients with PDAC, relative to historical data. For patients who received mFOLFIRINOX, the overall 18-month survival rate was 66.4%. However, when this regimen was combined with hypofractionated radiotherapy, the survival benefit was significantly lower, at 47.3%.

These findings were presented at the 2021 Gastrointestinal Cancers Symposium (GICS), which was held online this year.

“ASCO guidelines recommend that preoperative therapy be administered to patients with localized pancreatic adenocarcinoma who have tumors that have a significant radiographic interface with the major mesenteric blood vessels, as these patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz explained.

Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.

The goal of Alliance A021501 “was to define a reference preoperative regimen for future trials of preoperative therapy,” he said.

The cohort included 126 patients who were randomly assigned to receive either mFOLFIRINOX (arm A) or mFOLFIRINOX plus radiotherapy (arm B).

Patients in arm A received eight cycles of neoadjuvant mFOLFIRINOX. Patients in arm B received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiotherapy with either stereotactic body radiotherapy or hypofractionated image-guided radiotherapy.

In either arm, patients who did not experience disease progression underwent pancreatectomy followed by four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours).

The study’s primary endpoint was 18-month overall survival in comparison to a historical control of 50%. “An interim futility analysis was scheduled to be conducted following treatment of 30 patients on each arm,” Dr. Katz said. “Either arm in which 11 or fewer patients underwent [curative] R0 resection on protocol was to be declared futile and closed to further enrollment.

“With 62 evaluable patients in each arm, the final efficacy analysis was powered to detect an improvement in 18-month overall survival of 13% over the historical rate of 50%,” said Dr. Katz. “The two arms would be compared only if both were declared efficacious.”

At the interim analysis, 57% of the first 30 patients in arm A had undergone a resection, vs. 33% in arm B. Therefore, arm B was considered futile and was closed to accrual.

The median overall survival in arm A was 29.8 months. The median event-free survival was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pathologic complete response rate was 0%, and the 18-month overall survival rate was 93.1%.

For the patients in arm B, which had been closed to accrual, the median overall survival was 17.1 months, and the median event-free survival was 10.2 months. About one-third (35%) of patients were able to proceed to pancreatectomy. The R0 resection rate was 74%, the pathologic complete response rate was 11%, and the 18-month overall survival rate was 78.9%.

“Preoperative mFOLFIRINOX was associated with favorable overall survival relative to historical criteria in patients with borderline resectable PDAC, and mFOLFIRINOX with radiation therapy met the predefined futility boundary for R0 resection at interim analysis,” Dr. Katz concluded. “Therefore, mFOLFIRINOX represents a reference perioperative regimen for patients with borderline resectable PDAC.”
 

Further investigation needed

The paper’s discussant, Rebecca A. Snyder, MD, MPH, of the Brody School of Medicine, East Carolina University, Greenville, N.C., emphasized that this study was not designed or powered to directly compare chemotherapy alone with chemotherapy plus radiotherapy in the neoadjuvant setting.

She noted that it is surprising that the radiotherapy arm was closed early. She said the reasons for this remain unclear, although a few possible reasons can be speculated.

“Based on multiple studies in both the adjuvant and neoadjuvant setting, including the Alliance [A021501] trial presented today, there is no convincing randomized data that radiation therapy prolongs survival in any population of unselected patients with pancreatic cancer,” said Dr. Snyder.

“Certainly, follow-up questions still remain, specifically regarding the role for non-SBRT radiation in the preoperative setting, which may be answered by the ongoing PREOPANC-2 and PRODIGE 44 trials,” she said.

She added that the “addition of SBRT in the preoperative setting does not appear to be justified.”

The role of radiotherapy for subsets of patients remains unknown, and future investigation should focus on patient-centered endpoints, such as symptomatic local control rates, Dr. Snyder concluded.

The study was funded by the National Institutes of Health. Dr. Katz has had a consulting or advisory role for AbbVie and Alcresta Therapeutics. Dr. Snyder has disclosed no relevant financial relationships.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

A version of this article first appeared on Medscape.com.

Patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.

Results from the Alliance A021501 study suggest the reference regimen should be neoadjuvant therapy with modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours), according to Matthew Katz, MD, FACS, chief of the pancreatic surgery service at the University of Texas MD Anderson Cancer Center, Houston.

This regimen improved survival for patients with PDAC, relative to historical data. For patients who received mFOLFIRINOX, the overall 18-month survival rate was 66.4%. However, when this regimen was combined with hypofractionated radiotherapy, the survival benefit was significantly lower, at 47.3%.

These findings were presented at the 2021 Gastrointestinal Cancers Symposium (GICS), which was held online this year.

“ASCO guidelines recommend that preoperative therapy be administered to patients with localized pancreatic adenocarcinoma who have tumors that have a significant radiographic interface with the major mesenteric blood vessels, as these patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz explained.

Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.

The goal of Alliance A021501 “was to define a reference preoperative regimen for future trials of preoperative therapy,” he said.

The cohort included 126 patients who were randomly assigned to receive either mFOLFIRINOX (arm A) or mFOLFIRINOX plus radiotherapy (arm B).

Patients in arm A received eight cycles of neoadjuvant mFOLFIRINOX. Patients in arm B received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiotherapy with either stereotactic body radiotherapy or hypofractionated image-guided radiotherapy.

In either arm, patients who did not experience disease progression underwent pancreatectomy followed by four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours).

The study’s primary endpoint was 18-month overall survival in comparison to a historical control of 50%. “An interim futility analysis was scheduled to be conducted following treatment of 30 patients on each arm,” Dr. Katz said. “Either arm in which 11 or fewer patients underwent [curative] R0 resection on protocol was to be declared futile and closed to further enrollment.

“With 62 evaluable patients in each arm, the final efficacy analysis was powered to detect an improvement in 18-month overall survival of 13% over the historical rate of 50%,” said Dr. Katz. “The two arms would be compared only if both were declared efficacious.”

At the interim analysis, 57% of the first 30 patients in arm A had undergone a resection, vs. 33% in arm B. Therefore, arm B was considered futile and was closed to accrual.

The median overall survival in arm A was 29.8 months. The median event-free survival was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pathologic complete response rate was 0%, and the 18-month overall survival rate was 93.1%.

For the patients in arm B, which had been closed to accrual, the median overall survival was 17.1 months, and the median event-free survival was 10.2 months. About one-third (35%) of patients were able to proceed to pancreatectomy. The R0 resection rate was 74%, the pathologic complete response rate was 11%, and the 18-month overall survival rate was 78.9%.

“Preoperative mFOLFIRINOX was associated with favorable overall survival relative to historical criteria in patients with borderline resectable PDAC, and mFOLFIRINOX with radiation therapy met the predefined futility boundary for R0 resection at interim analysis,” Dr. Katz concluded. “Therefore, mFOLFIRINOX represents a reference perioperative regimen for patients with borderline resectable PDAC.”
 

Further investigation needed

The paper’s discussant, Rebecca A. Snyder, MD, MPH, of the Brody School of Medicine, East Carolina University, Greenville, N.C., emphasized that this study was not designed or powered to directly compare chemotherapy alone with chemotherapy plus radiotherapy in the neoadjuvant setting.

She noted that it is surprising that the radiotherapy arm was closed early. She said the reasons for this remain unclear, although a few possible reasons can be speculated.

“Based on multiple studies in both the adjuvant and neoadjuvant setting, including the Alliance [A021501] trial presented today, there is no convincing randomized data that radiation therapy prolongs survival in any population of unselected patients with pancreatic cancer,” said Dr. Snyder.

“Certainly, follow-up questions still remain, specifically regarding the role for non-SBRT radiation in the preoperative setting, which may be answered by the ongoing PREOPANC-2 and PRODIGE 44 trials,” she said.

She added that the “addition of SBRT in the preoperative setting does not appear to be justified.”

The role of radiotherapy for subsets of patients remains unknown, and future investigation should focus on patient-centered endpoints, such as symptomatic local control rates, Dr. Snyder concluded.

The study was funded by the National Institutes of Health. Dr. Katz has had a consulting or advisory role for AbbVie and Alcresta Therapeutics. Dr. Snyder has disclosed no relevant financial relationships.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

A version of this article first appeared on Medscape.com.