TBD Meeting (3660-24)

TOPLINE:

Tumor regrowth predicts distant metastases in patients with rectal cancer undergoing surveillance after complete clinical responses to neoadjuvant therapy.

METHODOLOGY:

• “Watch and wait” is generally offered to patients with rectal cancer who have a complete clinical response to neoadjuvant therapy.
• Up to 30% of tumors regrow within 3 years, and about 5% of patients develop distant metastases.
• To get a better handle on the risk factors, investigators identified 508 watch-and-wait patients from the International Watch & Wait database who had a local regrowth and underwent resection.
• The team compared them with 893 patients from a Spanish registry who had total mesorectal excisions after neoadjuvant therapy and who were found to have had a nearly complete response to neoadjuvant therapy, meaning that 90% or more of their tumor was gone.

TAKEAWAY:

• Three-year distant metastasis–free survival was 75% in the watch-and-wait/regrowth group vs 87% in the upfront surgery arm (P = .001); the results held when the two groups were stratified by pathological T stage and nodal status.
• Patients with local regrowth also had a higher risk of developing distant metastasis (22.8% vs 10.2% at 3 years).
• Local regrowth was an independent risk factor for distant metastasis, along with higher pathological T stage and positive nodal status on the resected regrowth specimen.
• Baseline clinical T stage and nodal status were not significantly associated with risk.

IN PRACTICE:

“Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes ... Efforts should be made to minimize the risk of local regrowth among patients undergoing watch and wait by the use of very stringent criteria for the identification of a clinical complete response.” There may be a role for ctDNA to improve patient selection for watch and wait.

SOURCE:

The study was led by Laura Melina Fernandez of the Champalimaud Foundation in Lisbon, Portugal, and presented on January 20, 2024, at the ASCO Gastrointestinal Cancers Symposium.

LIMITATIONS:

The definition of “complete clinical response” and selection of patients for watch and wait varied across International Watch & Wait database institutions. Recruitment occurred before implementation of total neoadjuvant therapy regimens.

DISCLOSURES:

There was no external funding for the work. The lead investigator didn’t have any disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Tumor regrowth predicts distant metastases in patients with rectal cancer undergoing surveillance after complete clinical responses to neoadjuvant therapy.

METHODOLOGY:

• “Watch and wait” is generally offered to patients with rectal cancer who have a complete clinical response to neoadjuvant therapy.
• Up to 30% of tumors regrow within 3 years, and about 5% of patients develop distant metastases.
• To get a better handle on the risk factors, investigators identified 508 watch-and-wait patients from the International Watch & Wait database who had a local regrowth and underwent resection.
• The team compared them with 893 patients from a Spanish registry who had total mesorectal excisions after neoadjuvant therapy and who were found to have had a nearly complete response to neoadjuvant therapy, meaning that 90% or more of their tumor was gone.

TAKEAWAY:

• Three-year distant metastasis–free survival was 75% in the watch-and-wait/regrowth group vs 87% in the upfront surgery arm (P = .001); the results held when the two groups were stratified by pathological T stage and nodal status.
• Patients with local regrowth also had a higher risk of developing distant metastasis (22.8% vs 10.2% at 3 years).
• Local regrowth was an independent risk factor for distant metastasis, along with higher pathological T stage and positive nodal status on the resected regrowth specimen.
• Baseline clinical T stage and nodal status were not significantly associated with risk.

IN PRACTICE:

“Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes ... Efforts should be made to minimize the risk of local regrowth among patients undergoing watch and wait by the use of very stringent criteria for the identification of a clinical complete response.” There may be a role for ctDNA to improve patient selection for watch and wait.

SOURCE:

The study was led by Laura Melina Fernandez of the Champalimaud Foundation in Lisbon, Portugal, and presented on January 20, 2024, at the ASCO Gastrointestinal Cancers Symposium.

LIMITATIONS:

The definition of “complete clinical response” and selection of patients for watch and wait varied across International Watch & Wait database institutions. Recruitment occurred before implementation of total neoadjuvant therapy regimens.

DISCLOSURES:

There was no external funding for the work. The lead investigator didn’t have any disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Tumor regrowth predicts distant metastases in patients with rectal cancer undergoing surveillance after complete clinical responses to neoadjuvant therapy.

METHODOLOGY:

• “Watch and wait” is generally offered to patients with rectal cancer who have a complete clinical response to neoadjuvant therapy.
• Up to 30% of tumors regrow within 3 years, and about 5% of patients develop distant metastases.
• To get a better handle on the risk factors, investigators identified 508 watch-and-wait patients from the International Watch & Wait database who had a local regrowth and underwent resection.
• The team compared them with 893 patients from a Spanish registry who had total mesorectal excisions after neoadjuvant therapy and who were found to have had a nearly complete response to neoadjuvant therapy, meaning that 90% or more of their tumor was gone.

TAKEAWAY:

• Three-year distant metastasis–free survival was 75% in the watch-and-wait/regrowth group vs 87% in the upfront surgery arm (P = .001); the results held when the two groups were stratified by pathological T stage and nodal status.
• Patients with local regrowth also had a higher risk of developing distant metastasis (22.8% vs 10.2% at 3 years).
• Local regrowth was an independent risk factor for distant metastasis, along with higher pathological T stage and positive nodal status on the resected regrowth specimen.
• Baseline clinical T stage and nodal status were not significantly associated with risk.

IN PRACTICE:

“Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes ... Efforts should be made to minimize the risk of local regrowth among patients undergoing watch and wait by the use of very stringent criteria for the identification of a clinical complete response.” There may be a role for ctDNA to improve patient selection for watch and wait.

SOURCE:

The study was led by Laura Melina Fernandez of the Champalimaud Foundation in Lisbon, Portugal, and presented on January 20, 2024, at the ASCO Gastrointestinal Cancers Symposium.

LIMITATIONS:

The definition of “complete clinical response” and selection of patients for watch and wait varied across International Watch & Wait database institutions. Recruitment occurred before implementation of total neoadjuvant therapy regimens.

DISCLOSURES:

There was no external funding for the work. The lead investigator didn’t have any disclosures.
 

A version of this article appeared on Medscape.com.

Circulating tumor DNA (ctDNA) has proven itself as a prognostic tool, but questions remain as to whether it can be used to guide the use of adjuvant chemotherapy in patients with colorectal cancer (CRC). Much of the uncertainty surrounds the sensitivity of ctDNA at the time when decisions regarding adjuvant therapy are being made.

Those were some of the key points made during a series of presentations and discussions on ctDNA at the ASCO Gastrointestinal Cancers Symposium.

In a morning session, Pashtoon Murtaza Kasi, MD, presented the first interim results from the multicenter, prospective observational BESPOKE CRC study, which included 689 patients with stage II or III colorectal cancer. The trial was designed to determine what effect ctDNA results would have on adjuvant chemotherapy treatment decisions. Over a median follow-up of 24.8 months, 623 patients had ctDNA results available. ctDNA positivity was associated with worse 2-year disease-free survival (DFS) at 29.86% versus 91.59% in the stage II/III combined group (hazard ratio [HR], 12.1; P < .0001) and in stage II (HR, 18.8; P < .0001) and stage III (HR, 9.9; P < .0001) analyzed separately.

In ctDNA-positive patients, adjuvant chemotherapy was associated with longer DFS than in those who did not undergo adjuvant chemotherapy (HR, 3.06; P = .0025), but there was no difference in DFS between ctDNA-negative patients who received adjuvant chemotherapy and those who didn’t. Patients who achieved ctDNA clearance had a longer median DFS (24.2 versus 13.8 months; HR, 0.4; P = .045).
 

Patient Anxiety Concerns

Dr. Kasi noted the importance of considering the patient’s view of ctDNA. There may be some concerns that such tests could cause patient anxiety, but he referenced a poster at ASCO GI which suggested the opposite. “It actually reduced anxiety, and 90% of the patients felt confident in the treatment they were receiving. They [said that] they will continue using the assay, and they value the additional information,” said Dr. Kasi, who is a medical oncologist at Weill Cornell Medicine in New York City.

During the Q&A after the talk, David Ellison, MD, a medical oncology and hematology specialist at Memorial Sloan Kettering Cancer Center, also in New York asked Dr. Kasi: “Did this [positive ctDNA] test just prompt earlier imaging? Was it any better than conventional surveillance like CEA (carcinoembryonic antigen) or imaging?” he asked.

Dr. Kasi responded that the data showed ctDNA positivity 6-9 months earlier than cancer detection through traditional imaging.

“It doesn’t necessarily replace the ongoing surveillance. This particular study did not guide or make it as a protocol as to what to do. Everything was done as part of standard of care, the usual surveillance that the cancer center follows, he said. “I think [ctDNA] would help complement the ongoing care and in conjunction with somebody who has, for example, an indeterminant lung nodule, but also has ctDNA positivity, I think it adds confidence to the decisions that one might be making.”

Eujung Kim, MD, PhD, an instructor of medicine at Harvard Medical School, Boston, Massachusetts, wondered if there might be chemoresistant tumor cells remaining that are not shedding DNA. “You have to keep the biology in mind as well make decisions in conjunction with the clinical situation, as opposed to in isolation with ctDNA results,” Dr. Kasi responded.

In the same session, Jeannie Tie, MD, described results from the AGITG DYNAMIC-Rectal trial, which was a randomized study to determine if ctDNA could inform adjuvant chemotherapy decisions in locally advanced rectal cancer. The analysis included 230 patients who were randomized to ctDNA-informed management (n = 155), with a positive test leading to adjuvant chemotherapy, or a standard arm where adjuvant therapy decisions were left to the physician (n = 75).

Adjuvant chemotherapy use was higher in the control arm (77% versus 46%; P < .001). Lymphovascular invasion was more common in the control arm (odds ratio [OR], 3.06; P = .023), and recurrence-free survival was higher in patients who remained ctDNA negative (HR, 0.29; P < .001) despite all ctDNA-positive patients and only 23% of ctDNA-negative patients undergoing chemotherapy.

The sites of relapses were also different, with 78% occurring in patients who were ctDNA negative after surgery occurring only in the lung, versus just 1% of metastases solely in the lung among those who were ctDNA positive.

In ctDNA-positive patients, 50% of relapses were only in the liver and 19% were in the liver and lung.

Over 36 months, 16% of ctDNA-negative patients developed distant relapses and 2.8% developed locoregional relapses, versus 36% and 7.1% in the ctDNA-positive group.

“Regrettably, we could not conclude about the noninferiority of [using ctDNA to guide adjuvant therapy decisions] due to the premature study closure and small sample size. We confirmed the significantly lower risk of recurrence in post-op ctDNA-negative patients compared to ctDNA-positive patients, as well as the differential pattern of relapse where lung metastases predominate in ctDNA-negative patients, while liver metastases were the dominant side of relapse in ctDNA-positive patients,” said Dr. Tie, who is a medical oncologist at the Peter MacCallum Cancer Centre, Victoria, Australia.
 

GALAXY Study Results Updated

In an afternoon session, Hiroki Yukami, MD, PhD, presented updated results of the GALAXY study, which examined 2998 patients with stage I-IV colorectal cancer who underwent ctDNA surveillance over a median 16.14 months following surgery. ctDNA-positive status was associated with worse DFS (HR, 10.53; P < .0001) in all stages as well as in stage II/III (HR, 12.05; P < .0001). The researchers also distinguished between patients with sustained ctDNA clearance and those with transient ctDNA clearance, in which a positive test occurred after an initial negative result. Recurrences occurred in 7.1% of patients with sustained ctDNA clearance, versus 85.2% of patients with transient clearance (P < .0001) and 89.4% of those with no clearance (P < .0001). “Sustained clearance indicates superior DFS compared to transient or no clearance,” said Dr. Yukami during his presentation.

Of 117 patients treated with adjuvant chemotherapy after testing ctDNA positive, subsequent ctDNA clearance was associated with better DFS (HR, 6.72; P < .0001). There were also better DFS outcomes among patients who saw a greater decline in ctDNA plasma levels after adjuvant chemotherapy (0%-50% versus 50%-100% reduction; HR, 2.41; P = .001).

Aparna Raj Parikh, MD, assistant professor of medicine at Harvard Medical School, served as a discussant for the GALAXY study. She acknowledged that ctDNA is the most powerful prognostic marker in oncology, but to be clinically useful it is necessary to consider its utility at the landmark time point, which is when decisions are made whether to treat with adjuvant chemotherapy. At that time point, the sensitivity of ctDNA is about 48% in the GALAXY study, which Dr. Parikh said is consistent with other data.
 

ctDNA ‘not sensitive enough’

“We know that postoperative ctDNA is only capturing 40%-50% of patients with recurrences in non–stage IV patients in multiple datasets to date. I think it’s really important to keep in mind the sensitivity of the different time points when you’re actually thinking about how to use this in clinic. The first generation of tests are certainly promising, but I would make the argument that these are just not sensitive enough,” said Dr. Parikh.

“Landmark testing is not yet sensitive enough to deescalate care in a patient where chemotherapy would otherwise be indicated, and surveillance testing has not yet demonstrated clinical utility. I think our goal to actually deescalate care would be to try to lower the ctDNA-negative population recurrence risk to akin to stage I patients, with that 5-year DFS of 93%-95%,” Dr. Parikh said.

Dr. Parikh offered some advice on how to use ctDNA outside of a clinical trial setting. She said that positive ctDNA results can help drive the decision to initiate adjuvant chemotherapy in concert with clinical and other factors.

“I’m pretty convinced by the data that ctDNA is prognostic, and though we still need outcomes data, in particular scenarios where I’m thinking of not giving chemotherapy, a positive test may sway me in that direction,” she said. She gave examples such as patients with a single high-risk feature, or a stage III patient with marginal performance status, or an elderly patient with low-risk stage III disease.

Dr. Kasi has financial relationships with Precision Biosensors, Elicio Therapeutics, Bayer, BostonGene, Daiichi Sankyo/AstraZeneca, Delcath Systems, Eisai, Elicio Therapeutics, Exact Sciences, Foundation Medicine, Guardant Health, Illumina, Ipsen, Lilly, MSD Oncology, Natera, NeoGenomics, QED Therapeutics, SAGA Diagnostics, Seagen, SERVIER, Taiho Oncology, Taiho Pharmaceutical, Advanced Accelerator Applications, Boston Scientific, and Tersera. Dr. Tie, Dr. Kim, Dr. Ellison, and Dr. Yukami did not disclose conflicts of interest. Dr. Parikh has financial relationships with Abbvie, Bayer, Biofidelity, CheckMate Pharmaceuticals, CVS, Delcath Systems, Foundation Medicine, Guardant Health, Illumina, Lily, SAGA Diagnostics, Scarce, Seagen, Taiho Oncology, Takeda, UpToDate, and Value Analytics Labs.

Circulating tumor DNA (ctDNA) has proven itself as a prognostic tool, but questions remain as to whether it can be used to guide the use of adjuvant chemotherapy in patients with colorectal cancer (CRC). Much of the uncertainty surrounds the sensitivity of ctDNA at the time when decisions regarding adjuvant therapy are being made.

Those were some of the key points made during a series of presentations and discussions on ctDNA at the ASCO Gastrointestinal Cancers Symposium.

In a morning session, Pashtoon Murtaza Kasi, MD, presented the first interim results from the multicenter, prospective observational BESPOKE CRC study, which included 689 patients with stage II or III colorectal cancer. The trial was designed to determine what effect ctDNA results would have on adjuvant chemotherapy treatment decisions. Over a median follow-up of 24.8 months, 623 patients had ctDNA results available. ctDNA positivity was associated with worse 2-year disease-free survival (DFS) at 29.86% versus 91.59% in the stage II/III combined group (hazard ratio [HR], 12.1; P < .0001) and in stage II (HR, 18.8; P < .0001) and stage III (HR, 9.9; P < .0001) analyzed separately.

In ctDNA-positive patients, adjuvant chemotherapy was associated with longer DFS than in those who did not undergo adjuvant chemotherapy (HR, 3.06; P = .0025), but there was no difference in DFS between ctDNA-negative patients who received adjuvant chemotherapy and those who didn’t. Patients who achieved ctDNA clearance had a longer median DFS (24.2 versus 13.8 months; HR, 0.4; P = .045).
 

Patient Anxiety Concerns

Dr. Kasi noted the importance of considering the patient’s view of ctDNA. There may be some concerns that such tests could cause patient anxiety, but he referenced a poster at ASCO GI which suggested the opposite. “It actually reduced anxiety, and 90% of the patients felt confident in the treatment they were receiving. They [said that] they will continue using the assay, and they value the additional information,” said Dr. Kasi, who is a medical oncologist at Weill Cornell Medicine in New York City.

During the Q&A after the talk, David Ellison, MD, a medical oncology and hematology specialist at Memorial Sloan Kettering Cancer Center, also in New York asked Dr. Kasi: “Did this [positive ctDNA] test just prompt earlier imaging? Was it any better than conventional surveillance like CEA (carcinoembryonic antigen) or imaging?” he asked.

Dr. Kasi responded that the data showed ctDNA positivity 6-9 months earlier than cancer detection through traditional imaging.

“It doesn’t necessarily replace the ongoing surveillance. This particular study did not guide or make it as a protocol as to what to do. Everything was done as part of standard of care, the usual surveillance that the cancer center follows, he said. “I think [ctDNA] would help complement the ongoing care and in conjunction with somebody who has, for example, an indeterminant lung nodule, but also has ctDNA positivity, I think it adds confidence to the decisions that one might be making.”

Eujung Kim, MD, PhD, an instructor of medicine at Harvard Medical School, Boston, Massachusetts, wondered if there might be chemoresistant tumor cells remaining that are not shedding DNA. “You have to keep the biology in mind as well make decisions in conjunction with the clinical situation, as opposed to in isolation with ctDNA results,” Dr. Kasi responded.

In the same session, Jeannie Tie, MD, described results from the AGITG DYNAMIC-Rectal trial, which was a randomized study to determine if ctDNA could inform adjuvant chemotherapy decisions in locally advanced rectal cancer. The analysis included 230 patients who were randomized to ctDNA-informed management (n = 155), with a positive test leading to adjuvant chemotherapy, or a standard arm where adjuvant therapy decisions were left to the physician (n = 75).

Adjuvant chemotherapy use was higher in the control arm (77% versus 46%; P < .001). Lymphovascular invasion was more common in the control arm (odds ratio [OR], 3.06; P = .023), and recurrence-free survival was higher in patients who remained ctDNA negative (HR, 0.29; P < .001) despite all ctDNA-positive patients and only 23% of ctDNA-negative patients undergoing chemotherapy.

The sites of relapses were also different, with 78% occurring in patients who were ctDNA negative after surgery occurring only in the lung, versus just 1% of metastases solely in the lung among those who were ctDNA positive.

In ctDNA-positive patients, 50% of relapses were only in the liver and 19% were in the liver and lung.

Over 36 months, 16% of ctDNA-negative patients developed distant relapses and 2.8% developed locoregional relapses, versus 36% and 7.1% in the ctDNA-positive group.

“Regrettably, we could not conclude about the noninferiority of [using ctDNA to guide adjuvant therapy decisions] due to the premature study closure and small sample size. We confirmed the significantly lower risk of recurrence in post-op ctDNA-negative patients compared to ctDNA-positive patients, as well as the differential pattern of relapse where lung metastases predominate in ctDNA-negative patients, while liver metastases were the dominant side of relapse in ctDNA-positive patients,” said Dr. Tie, who is a medical oncologist at the Peter MacCallum Cancer Centre, Victoria, Australia.
 

GALAXY Study Results Updated

In an afternoon session, Hiroki Yukami, MD, PhD, presented updated results of the GALAXY study, which examined 2998 patients with stage I-IV colorectal cancer who underwent ctDNA surveillance over a median 16.14 months following surgery. ctDNA-positive status was associated with worse DFS (HR, 10.53; P < .0001) in all stages as well as in stage II/III (HR, 12.05; P < .0001). The researchers also distinguished between patients with sustained ctDNA clearance and those with transient ctDNA clearance, in which a positive test occurred after an initial negative result. Recurrences occurred in 7.1% of patients with sustained ctDNA clearance, versus 85.2% of patients with transient clearance (P < .0001) and 89.4% of those with no clearance (P < .0001). “Sustained clearance indicates superior DFS compared to transient or no clearance,” said Dr. Yukami during his presentation.

Of 117 patients treated with adjuvant chemotherapy after testing ctDNA positive, subsequent ctDNA clearance was associated with better DFS (HR, 6.72; P < .0001). There were also better DFS outcomes among patients who saw a greater decline in ctDNA plasma levels after adjuvant chemotherapy (0%-50% versus 50%-100% reduction; HR, 2.41; P = .001).

Aparna Raj Parikh, MD, assistant professor of medicine at Harvard Medical School, served as a discussant for the GALAXY study. She acknowledged that ctDNA is the most powerful prognostic marker in oncology, but to be clinically useful it is necessary to consider its utility at the landmark time point, which is when decisions are made whether to treat with adjuvant chemotherapy. At that time point, the sensitivity of ctDNA is about 48% in the GALAXY study, which Dr. Parikh said is consistent with other data.
 

ctDNA ‘not sensitive enough’

“We know that postoperative ctDNA is only capturing 40%-50% of patients with recurrences in non–stage IV patients in multiple datasets to date. I think it’s really important to keep in mind the sensitivity of the different time points when you’re actually thinking about how to use this in clinic. The first generation of tests are certainly promising, but I would make the argument that these are just not sensitive enough,” said Dr. Parikh.

“Landmark testing is not yet sensitive enough to deescalate care in a patient where chemotherapy would otherwise be indicated, and surveillance testing has not yet demonstrated clinical utility. I think our goal to actually deescalate care would be to try to lower the ctDNA-negative population recurrence risk to akin to stage I patients, with that 5-year DFS of 93%-95%,” Dr. Parikh said.

Dr. Parikh offered some advice on how to use ctDNA outside of a clinical trial setting. She said that positive ctDNA results can help drive the decision to initiate adjuvant chemotherapy in concert with clinical and other factors.

“I’m pretty convinced by the data that ctDNA is prognostic, and though we still need outcomes data, in particular scenarios where I’m thinking of not giving chemotherapy, a positive test may sway me in that direction,” she said. She gave examples such as patients with a single high-risk feature, or a stage III patient with marginal performance status, or an elderly patient with low-risk stage III disease.

Dr. Kasi has financial relationships with Precision Biosensors, Elicio Therapeutics, Bayer, BostonGene, Daiichi Sankyo/AstraZeneca, Delcath Systems, Eisai, Elicio Therapeutics, Exact Sciences, Foundation Medicine, Guardant Health, Illumina, Ipsen, Lilly, MSD Oncology, Natera, NeoGenomics, QED Therapeutics, SAGA Diagnostics, Seagen, SERVIER, Taiho Oncology, Taiho Pharmaceutical, Advanced Accelerator Applications, Boston Scientific, and Tersera. Dr. Tie, Dr. Kim, Dr. Ellison, and Dr. Yukami did not disclose conflicts of interest. Dr. Parikh has financial relationships with Abbvie, Bayer, Biofidelity, CheckMate Pharmaceuticals, CVS, Delcath Systems, Foundation Medicine, Guardant Health, Illumina, Lily, SAGA Diagnostics, Scarce, Seagen, Taiho Oncology, Takeda, UpToDate, and Value Analytics Labs.

Circulating tumor DNA (ctDNA) has proven itself as a prognostic tool, but questions remain as to whether it can be used to guide the use of adjuvant chemotherapy in patients with colorectal cancer (CRC). Much of the uncertainty surrounds the sensitivity of ctDNA at the time when decisions regarding adjuvant therapy are being made.

Those were some of the key points made during a series of presentations and discussions on ctDNA at the ASCO Gastrointestinal Cancers Symposium.

In a morning session, Pashtoon Murtaza Kasi, MD, presented the first interim results from the multicenter, prospective observational BESPOKE CRC study, which included 689 patients with stage II or III colorectal cancer. The trial was designed to determine what effect ctDNA results would have on adjuvant chemotherapy treatment decisions. Over a median follow-up of 24.8 months, 623 patients had ctDNA results available. ctDNA positivity was associated with worse 2-year disease-free survival (DFS) at 29.86% versus 91.59% in the stage II/III combined group (hazard ratio [HR], 12.1; P < .0001) and in stage II (HR, 18.8; P < .0001) and stage III (HR, 9.9; P < .0001) analyzed separately.

In ctDNA-positive patients, adjuvant chemotherapy was associated with longer DFS than in those who did not undergo adjuvant chemotherapy (HR, 3.06; P = .0025), but there was no difference in DFS between ctDNA-negative patients who received adjuvant chemotherapy and those who didn’t. Patients who achieved ctDNA clearance had a longer median DFS (24.2 versus 13.8 months; HR, 0.4; P = .045).
 

Patient Anxiety Concerns

Dr. Kasi noted the importance of considering the patient’s view of ctDNA. There may be some concerns that such tests could cause patient anxiety, but he referenced a poster at ASCO GI which suggested the opposite. “It actually reduced anxiety, and 90% of the patients felt confident in the treatment they were receiving. They [said that] they will continue using the assay, and they value the additional information,” said Dr. Kasi, who is a medical oncologist at Weill Cornell Medicine in New York City.

During the Q&A after the talk, David Ellison, MD, a medical oncology and hematology specialist at Memorial Sloan Kettering Cancer Center, also in New York asked Dr. Kasi: “Did this [positive ctDNA] test just prompt earlier imaging? Was it any better than conventional surveillance like CEA (carcinoembryonic antigen) or imaging?” he asked.

Dr. Kasi responded that the data showed ctDNA positivity 6-9 months earlier than cancer detection through traditional imaging.

“It doesn’t necessarily replace the ongoing surveillance. This particular study did not guide or make it as a protocol as to what to do. Everything was done as part of standard of care, the usual surveillance that the cancer center follows, he said. “I think [ctDNA] would help complement the ongoing care and in conjunction with somebody who has, for example, an indeterminant lung nodule, but also has ctDNA positivity, I think it adds confidence to the decisions that one might be making.”

Eujung Kim, MD, PhD, an instructor of medicine at Harvard Medical School, Boston, Massachusetts, wondered if there might be chemoresistant tumor cells remaining that are not shedding DNA. “You have to keep the biology in mind as well make decisions in conjunction with the clinical situation, as opposed to in isolation with ctDNA results,” Dr. Kasi responded.

In the same session, Jeannie Tie, MD, described results from the AGITG DYNAMIC-Rectal trial, which was a randomized study to determine if ctDNA could inform adjuvant chemotherapy decisions in locally advanced rectal cancer. The analysis included 230 patients who were randomized to ctDNA-informed management (n = 155), with a positive test leading to adjuvant chemotherapy, or a standard arm where adjuvant therapy decisions were left to the physician (n = 75).

Adjuvant chemotherapy use was higher in the control arm (77% versus 46%; P < .001). Lymphovascular invasion was more common in the control arm (odds ratio [OR], 3.06; P = .023), and recurrence-free survival was higher in patients who remained ctDNA negative (HR, 0.29; P < .001) despite all ctDNA-positive patients and only 23% of ctDNA-negative patients undergoing chemotherapy.

The sites of relapses were also different, with 78% occurring in patients who were ctDNA negative after surgery occurring only in the lung, versus just 1% of metastases solely in the lung among those who were ctDNA positive.

In ctDNA-positive patients, 50% of relapses were only in the liver and 19% were in the liver and lung.

Over 36 months, 16% of ctDNA-negative patients developed distant relapses and 2.8% developed locoregional relapses, versus 36% and 7.1% in the ctDNA-positive group.

“Regrettably, we could not conclude about the noninferiority of [using ctDNA to guide adjuvant therapy decisions] due to the premature study closure and small sample size. We confirmed the significantly lower risk of recurrence in post-op ctDNA-negative patients compared to ctDNA-positive patients, as well as the differential pattern of relapse where lung metastases predominate in ctDNA-negative patients, while liver metastases were the dominant side of relapse in ctDNA-positive patients,” said Dr. Tie, who is a medical oncologist at the Peter MacCallum Cancer Centre, Victoria, Australia.
 

GALAXY Study Results Updated

In an afternoon session, Hiroki Yukami, MD, PhD, presented updated results of the GALAXY study, which examined 2998 patients with stage I-IV colorectal cancer who underwent ctDNA surveillance over a median 16.14 months following surgery. ctDNA-positive status was associated with worse DFS (HR, 10.53; P < .0001) in all stages as well as in stage II/III (HR, 12.05; P < .0001). The researchers also distinguished between patients with sustained ctDNA clearance and those with transient ctDNA clearance, in which a positive test occurred after an initial negative result. Recurrences occurred in 7.1% of patients with sustained ctDNA clearance, versus 85.2% of patients with transient clearance (P < .0001) and 89.4% of those with no clearance (P < .0001). “Sustained clearance indicates superior DFS compared to transient or no clearance,” said Dr. Yukami during his presentation.

Of 117 patients treated with adjuvant chemotherapy after testing ctDNA positive, subsequent ctDNA clearance was associated with better DFS (HR, 6.72; P < .0001). There were also better DFS outcomes among patients who saw a greater decline in ctDNA plasma levels after adjuvant chemotherapy (0%-50% versus 50%-100% reduction; HR, 2.41; P = .001).

Aparna Raj Parikh, MD, assistant professor of medicine at Harvard Medical School, served as a discussant for the GALAXY study. She acknowledged that ctDNA is the most powerful prognostic marker in oncology, but to be clinically useful it is necessary to consider its utility at the landmark time point, which is when decisions are made whether to treat with adjuvant chemotherapy. At that time point, the sensitivity of ctDNA is about 48% in the GALAXY study, which Dr. Parikh said is consistent with other data.
 

ctDNA ‘not sensitive enough’

“We know that postoperative ctDNA is only capturing 40%-50% of patients with recurrences in non–stage IV patients in multiple datasets to date. I think it’s really important to keep in mind the sensitivity of the different time points when you’re actually thinking about how to use this in clinic. The first generation of tests are certainly promising, but I would make the argument that these are just not sensitive enough,” said Dr. Parikh.

“Landmark testing is not yet sensitive enough to deescalate care in a patient where chemotherapy would otherwise be indicated, and surveillance testing has not yet demonstrated clinical utility. I think our goal to actually deescalate care would be to try to lower the ctDNA-negative population recurrence risk to akin to stage I patients, with that 5-year DFS of 93%-95%,” Dr. Parikh said.

Dr. Parikh offered some advice on how to use ctDNA outside of a clinical trial setting. She said that positive ctDNA results can help drive the decision to initiate adjuvant chemotherapy in concert with clinical and other factors.

“I’m pretty convinced by the data that ctDNA is prognostic, and though we still need outcomes data, in particular scenarios where I’m thinking of not giving chemotherapy, a positive test may sway me in that direction,” she said. She gave examples such as patients with a single high-risk feature, or a stage III patient with marginal performance status, or an elderly patient with low-risk stage III disease.

Dr. Kasi has financial relationships with Precision Biosensors, Elicio Therapeutics, Bayer, BostonGene, Daiichi Sankyo/AstraZeneca, Delcath Systems, Eisai, Elicio Therapeutics, Exact Sciences, Foundation Medicine, Guardant Health, Illumina, Ipsen, Lilly, MSD Oncology, Natera, NeoGenomics, QED Therapeutics, SAGA Diagnostics, Seagen, SERVIER, Taiho Oncology, Taiho Pharmaceutical, Advanced Accelerator Applications, Boston Scientific, and Tersera. Dr. Tie, Dr. Kim, Dr. Ellison, and Dr. Yukami did not disclose conflicts of interest. Dr. Parikh has financial relationships with Abbvie, Bayer, Biofidelity, CheckMate Pharmaceuticals, CVS, Delcath Systems, Foundation Medicine, Guardant Health, Illumina, Lily, SAGA Diagnostics, Scarce, Seagen, Taiho Oncology, Takeda, UpToDate, and Value Analytics Labs.

Although treatment of advanced gastroesophageal cancer is increasingly dependent on biomarkers, only about 40% of patients are tested.

For patients to fully benefit from the latest targeted therapies, biomarker testing needs to improve, explained Yelena Janjigian, MD, chief of gastrointestinal oncology at the Memorial Sloan Kettering Cancer Center in New York City.

“The biomarker revolution in this disease has been quite remarkable in the last 10 years, so it’s very important to routinely test for these biomarkers,” Dr. Janjigian said in a presentation at the 2024 ASCO Gastrointestinal Cancers Symposium.

Dr. Janjigian suspected that inertia and logistics are the main reasons biomarker testing rates have lagged. “Even at tertiary cancer centers like ours, we fall short,” she said. For practices that don’t see many patients with gastroesophageal cancer, the rates are probably worse.

Biomarker testing, however, is readily available, Dr. Janjigian said, and overall, it’s about “being obsessive about doing it and following up on it and training your staff.”

As for how to prioritize biomarker testing for treatment selection, Dr. Janjigian provided her top three picks.

Microsatellite instability (MSI) is the most important biomarker, followed by human epidermal growth factor receptor 2 (HER2) as well as tumors expressing programmed death–ligand 1 (PD-L1) with a combined positive score (CPS) of 5 or higher.

Claudin 18.2 testing is “a great newcomer” worth mentioning as well, she noted. Claudin 18.2 is “very druggable,” and several claudin-targeting drugs are currently being assessed, including zolbetuximab.

MSI testing earned the top spot for Dr. Janjigian given the overall survival results from the CHECKMATE 649 trial.

The trial, which Dr. Janjigian led, assessed treatment with first-line nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma.

Median overall survival among the small subset of patients with high MSI who received nivolumab plus chemotherapy (n = 23) was more than three times longer than that among those who received chemotherapy alone (n = 21) — 38.7 months vs 12.3 months. Median overall survival was not reached in patients with high MSI who received nivolumab plus ipilimumab at the trial’s 36-month follow-up.

Dr. Janjigian’s case for a PD-L1 CPS of 5 or higher also came, in part, from the CHECKMATE 649 trial. In a subgroup analysis, patients with a CPS of 5 or higher receiving nivolumab plus chemotherapy had a significantly higher median overall survival of 14.4 months vs 11.1 months with chemotherapy alone.

Dr. Janjigian made the case for HER2 testing based on outcomes from the KEYNOTE 811 trial.

This trial, also led by Dr. Janjigian, randomized HER2-positive patients with unresectable advanced gastroesophageal junction adenocarcinoma irrespective of PDL-1 status to pembrolizumab plus trastuzumab and chemotherapy or trastuzumab and chemotherapy alone.

Past studies have reported that targeting HER2 by itself is not a good idea, Dr. Janjigian said, but this trial demonstrated that dual PD-L1/HER2 blockade improves survival outcomes.

Median overall survival in HER2-positive patients with a PD-L1 CPS of 1 or more was 20.0 months vs 15.7 months (hazard ratio [HR], 0.81; 95% CI, 0.67-0.98) compared with 20.0 vs 16.8 months in the overall cohort (HR, 0.84; 95% CI, 0.70-1.01). However, patients with PD-L1 CPS below 1 showed limited benefit from pembrolizumab (HR, 1.41 for overall survival; 95% CI, 0.90-2.20).

To take advantage of the benefit, HER2 testing is “critical,” Dr. Janjigian said.

Overall, when it comes to targeted therapy for advanced disease, the evolution has been rapid. But “we are not done yet,” she said. “We need to be smarter about patient selection” by using biomarker testing.

Dr. Janjigian reported a range of industry ties, including travel expenses, honoraria, and research funding from nivolumab maker Bristol Myers Squibb and Merck, the maker of pembrolizumab. She also advises both companies.

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

Although treatment of advanced gastroesophageal cancer is increasingly dependent on biomarkers, only about 40% of patients are tested.

For patients to fully benefit from the latest targeted therapies, biomarker testing needs to improve, explained Yelena Janjigian, MD, chief of gastrointestinal oncology at the Memorial Sloan Kettering Cancer Center in New York City.

“The biomarker revolution in this disease has been quite remarkable in the last 10 years, so it’s very important to routinely test for these biomarkers,” Dr. Janjigian said in a presentation at the 2024 ASCO Gastrointestinal Cancers Symposium.

Dr. Janjigian suspected that inertia and logistics are the main reasons biomarker testing rates have lagged. “Even at tertiary cancer centers like ours, we fall short,” she said. For practices that don’t see many patients with gastroesophageal cancer, the rates are probably worse.

Biomarker testing, however, is readily available, Dr. Janjigian said, and overall, it’s about “being obsessive about doing it and following up on it and training your staff.”

As for how to prioritize biomarker testing for treatment selection, Dr. Janjigian provided her top three picks.

Microsatellite instability (MSI) is the most important biomarker, followed by human epidermal growth factor receptor 2 (HER2) as well as tumors expressing programmed death–ligand 1 (PD-L1) with a combined positive score (CPS) of 5 or higher.

Claudin 18.2 testing is “a great newcomer” worth mentioning as well, she noted. Claudin 18.2 is “very druggable,” and several claudin-targeting drugs are currently being assessed, including zolbetuximab.

MSI testing earned the top spot for Dr. Janjigian given the overall survival results from the CHECKMATE 649 trial.

The trial, which Dr. Janjigian led, assessed treatment with first-line nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma.

Median overall survival among the small subset of patients with high MSI who received nivolumab plus chemotherapy (n = 23) was more than three times longer than that among those who received chemotherapy alone (n = 21) — 38.7 months vs 12.3 months. Median overall survival was not reached in patients with high MSI who received nivolumab plus ipilimumab at the trial’s 36-month follow-up.

Dr. Janjigian’s case for a PD-L1 CPS of 5 or higher also came, in part, from the CHECKMATE 649 trial. In a subgroup analysis, patients with a CPS of 5 or higher receiving nivolumab plus chemotherapy had a significantly higher median overall survival of 14.4 months vs 11.1 months with chemotherapy alone.

Dr. Janjigian made the case for HER2 testing based on outcomes from the KEYNOTE 811 trial.

This trial, also led by Dr. Janjigian, randomized HER2-positive patients with unresectable advanced gastroesophageal junction adenocarcinoma irrespective of PDL-1 status to pembrolizumab plus trastuzumab and chemotherapy or trastuzumab and chemotherapy alone.

Past studies have reported that targeting HER2 by itself is not a good idea, Dr. Janjigian said, but this trial demonstrated that dual PD-L1/HER2 blockade improves survival outcomes.

Median overall survival in HER2-positive patients with a PD-L1 CPS of 1 or more was 20.0 months vs 15.7 months (hazard ratio [HR], 0.81; 95% CI, 0.67-0.98) compared with 20.0 vs 16.8 months in the overall cohort (HR, 0.84; 95% CI, 0.70-1.01). However, patients with PD-L1 CPS below 1 showed limited benefit from pembrolizumab (HR, 1.41 for overall survival; 95% CI, 0.90-2.20).

To take advantage of the benefit, HER2 testing is “critical,” Dr. Janjigian said.

Overall, when it comes to targeted therapy for advanced disease, the evolution has been rapid. But “we are not done yet,” she said. “We need to be smarter about patient selection” by using biomarker testing.

Dr. Janjigian reported a range of industry ties, including travel expenses, honoraria, and research funding from nivolumab maker Bristol Myers Squibb and Merck, the maker of pembrolizumab. She also advises both companies.

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

Although treatment of advanced gastroesophageal cancer is increasingly dependent on biomarkers, only about 40% of patients are tested.

For patients to fully benefit from the latest targeted therapies, biomarker testing needs to improve, explained Yelena Janjigian, MD, chief of gastrointestinal oncology at the Memorial Sloan Kettering Cancer Center in New York City.

“The biomarker revolution in this disease has been quite remarkable in the last 10 years, so it’s very important to routinely test for these biomarkers,” Dr. Janjigian said in a presentation at the 2024 ASCO Gastrointestinal Cancers Symposium.

Dr. Janjigian suspected that inertia and logistics are the main reasons biomarker testing rates have lagged. “Even at tertiary cancer centers like ours, we fall short,” she said. For practices that don’t see many patients with gastroesophageal cancer, the rates are probably worse.

Biomarker testing, however, is readily available, Dr. Janjigian said, and overall, it’s about “being obsessive about doing it and following up on it and training your staff.”

As for how to prioritize biomarker testing for treatment selection, Dr. Janjigian provided her top three picks.

Microsatellite instability (MSI) is the most important biomarker, followed by human epidermal growth factor receptor 2 (HER2) as well as tumors expressing programmed death–ligand 1 (PD-L1) with a combined positive score (CPS) of 5 or higher.

Claudin 18.2 testing is “a great newcomer” worth mentioning as well, she noted. Claudin 18.2 is “very druggable,” and several claudin-targeting drugs are currently being assessed, including zolbetuximab.

MSI testing earned the top spot for Dr. Janjigian given the overall survival results from the CHECKMATE 649 trial.

The trial, which Dr. Janjigian led, assessed treatment with first-line nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma.

Median overall survival among the small subset of patients with high MSI who received nivolumab plus chemotherapy (n = 23) was more than three times longer than that among those who received chemotherapy alone (n = 21) — 38.7 months vs 12.3 months. Median overall survival was not reached in patients with high MSI who received nivolumab plus ipilimumab at the trial’s 36-month follow-up.

Dr. Janjigian’s case for a PD-L1 CPS of 5 or higher also came, in part, from the CHECKMATE 649 trial. In a subgroup analysis, patients with a CPS of 5 or higher receiving nivolumab plus chemotherapy had a significantly higher median overall survival of 14.4 months vs 11.1 months with chemotherapy alone.

Dr. Janjigian made the case for HER2 testing based on outcomes from the KEYNOTE 811 trial.

This trial, also led by Dr. Janjigian, randomized HER2-positive patients with unresectable advanced gastroesophageal junction adenocarcinoma irrespective of PDL-1 status to pembrolizumab plus trastuzumab and chemotherapy or trastuzumab and chemotherapy alone.

Past studies have reported that targeting HER2 by itself is not a good idea, Dr. Janjigian said, but this trial demonstrated that dual PD-L1/HER2 blockade improves survival outcomes.

Median overall survival in HER2-positive patients with a PD-L1 CPS of 1 or more was 20.0 months vs 15.7 months (hazard ratio [HR], 0.81; 95% CI, 0.67-0.98) compared with 20.0 vs 16.8 months in the overall cohort (HR, 0.84; 95% CI, 0.70-1.01). However, patients with PD-L1 CPS below 1 showed limited benefit from pembrolizumab (HR, 1.41 for overall survival; 95% CI, 0.90-2.20).

To take advantage of the benefit, HER2 testing is “critical,” Dr. Janjigian said.

Overall, when it comes to targeted therapy for advanced disease, the evolution has been rapid. But “we are not done yet,” she said. “We need to be smarter about patient selection” by using biomarker testing.

Dr. Janjigian reported a range of industry ties, including travel expenses, honoraria, and research funding from nivolumab maker Bristol Myers Squibb and Merck, the maker of pembrolizumab. She also advises both companies.

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

Renewed interest in hepatic arterial chemotherapy infusion pumps may be on the horizon, given promising overall survival findings in patients with advanced, unresectable cholangiocarcinoma.

Dutch investigators reported a 3-year overall survival of 33% in patients with advanced, unresectable cholangiocarcinoma confined to the liver who received the infusion chemotherapy vs 3% in historical controls treated with standard systemic gemcitabine/cisplatin.

The response with the pump is “clearly superior” to systemic treatment, said investigator Bas Groot Koerkamp, MD, who presented the findings at the ASCO Gastrointestinal Cancers Symposium.

“I do share the enthusiasm of my colleagues about immunotherapy and targeted treatments for intrahepatic cholangiocarcinoma,” said Dr. Koerkamp, a hepato-pancreato-biliary surgeon at Erasmus University Medical Center, Rotterdam, the Netherlands. But “none of these treatments has shown a 3-year overall survival of one in three with advanced disease.”

The hepatic arterial infusion pump, a hockey puck-sized device that essentially bathes liver tumors in floxuridine for about 2 weeks, is not a new technology. The pump has been around since at least the 1990s, developed largely at Memorial Sloan Kettering Cancer Center, New York City, where Dr. Koerkamp trained.

Three previous small studies in cholangiocarcinoma reported outcomes similar to Dr. Koerkamp’s. Despite the strong survival outcomes, uptake of these pumps has lagged.

A key reason is likely the lack of phase 3 trials evaluating the technology, Laleh Melstrom, MD, chief of surgical oncology at City of Hope, outside of Los Angeles, Duarte, California, told this news organization.

Dr. Melstrom, who moderated Dr. Koerkamp’s presentation, also noted that using the pump requires special attention to bilirubin levels to prevent biliary toxicity and knowledge of pump placement.

The pump, placed subcutaneously on one side of the lower abdomen, is connected to a side branch of the hepatic artery and then filled with the chemotherapy agent floxuridine. Delivering floxuridine directly to the hepatic artery increases liver lesion exposure 200-fold over systemic delivery. The pump needs to be refilled after 2 weeks.

“It’s not difficult to place the pump, even doing it robotically,” which was how it was placed in over 40% of patients in the study, Dr. Koerkamp said.

As for biliary toxicity, only one patient in the current study developed biliary sclerosis, which was easily handled with a stent. “You just put in a stent and continue,” Dr. Koerkamp said.

The current single-arm phase 2 study included 50 patients implanted with the hepatic pump at three centers in the Netherlands. All patients had advanced, unresectable cholangiocarcinoma confined to the liver.

Ultimately, 48 of 50 patients received treatment after one patient died of unrelated causes and another had an arterial dissection.

Overall, 38 received gemcitabine/cisplatin concurrently, and the remaining had the pump treatment alone, having already received the systemic combination. Most (84%) received at least four cycles of chemotherapy infusion.

Almost half of patients (46%) had a partial response to treatment, and 88% exhibited disease control at 6 months. Four patients who responded underwent a liver resection, one of whom had a complete pathologic response.

Median overall survival was 22 months vs 12 months in historical controls. One-year median overall survival was 80% in the treatment group vs 47% in controls, and 3-year median overall survival was 33% in the pump group vs 3% in controls.

An audience member noted that similar results have been reported for transarterial Yttrium-90 radioembolization, another and newer option to treat intrahepatic cholangiocarcinoma.

“The Y90 results are quite impressive,” Dr. Koerkamp said, adding that he’d like to see a head-to-head comparison.

“The main advantage of the pump is that it treats the entire liver,” as opposed to one lesion at a time, “so if you have 10 lesions [the pump] makes a lot more sense,” he said.

There is “definitely a movement” to “reinvigorate” the hepatic artery infusion pump approach, Dr. Melstrom said.

The study was funded by the Dutch Cancer Society. Dr. Koerkamp disclosed research funding from Tricumed, a maker of implantable infusion pumps. Dr. Melstrom didn’t have any disclosures.

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

Renewed interest in hepatic arterial chemotherapy infusion pumps may be on the horizon, given promising overall survival findings in patients with advanced, unresectable cholangiocarcinoma.

Dutch investigators reported a 3-year overall survival of 33% in patients with advanced, unresectable cholangiocarcinoma confined to the liver who received the infusion chemotherapy vs 3% in historical controls treated with standard systemic gemcitabine/cisplatin.

The response with the pump is “clearly superior” to systemic treatment, said investigator Bas Groot Koerkamp, MD, who presented the findings at the ASCO Gastrointestinal Cancers Symposium.

“I do share the enthusiasm of my colleagues about immunotherapy and targeted treatments for intrahepatic cholangiocarcinoma,” said Dr. Koerkamp, a hepato-pancreato-biliary surgeon at Erasmus University Medical Center, Rotterdam, the Netherlands. But “none of these treatments has shown a 3-year overall survival of one in three with advanced disease.”

The hepatic arterial infusion pump, a hockey puck-sized device that essentially bathes liver tumors in floxuridine for about 2 weeks, is not a new technology. The pump has been around since at least the 1990s, developed largely at Memorial Sloan Kettering Cancer Center, New York City, where Dr. Koerkamp trained.

Three previous small studies in cholangiocarcinoma reported outcomes similar to Dr. Koerkamp’s. Despite the strong survival outcomes, uptake of these pumps has lagged.

A key reason is likely the lack of phase 3 trials evaluating the technology, Laleh Melstrom, MD, chief of surgical oncology at City of Hope, outside of Los Angeles, Duarte, California, told this news organization.

Dr. Melstrom, who moderated Dr. Koerkamp’s presentation, also noted that using the pump requires special attention to bilirubin levels to prevent biliary toxicity and knowledge of pump placement.

The pump, placed subcutaneously on one side of the lower abdomen, is connected to a side branch of the hepatic artery and then filled with the chemotherapy agent floxuridine. Delivering floxuridine directly to the hepatic artery increases liver lesion exposure 200-fold over systemic delivery. The pump needs to be refilled after 2 weeks.

“It’s not difficult to place the pump, even doing it robotically,” which was how it was placed in over 40% of patients in the study, Dr. Koerkamp said.

As for biliary toxicity, only one patient in the current study developed biliary sclerosis, which was easily handled with a stent. “You just put in a stent and continue,” Dr. Koerkamp said.

The current single-arm phase 2 study included 50 patients implanted with the hepatic pump at three centers in the Netherlands. All patients had advanced, unresectable cholangiocarcinoma confined to the liver.

Ultimately, 48 of 50 patients received treatment after one patient died of unrelated causes and another had an arterial dissection.

Overall, 38 received gemcitabine/cisplatin concurrently, and the remaining had the pump treatment alone, having already received the systemic combination. Most (84%) received at least four cycles of chemotherapy infusion.

Almost half of patients (46%) had a partial response to treatment, and 88% exhibited disease control at 6 months. Four patients who responded underwent a liver resection, one of whom had a complete pathologic response.

Median overall survival was 22 months vs 12 months in historical controls. One-year median overall survival was 80% in the treatment group vs 47% in controls, and 3-year median overall survival was 33% in the pump group vs 3% in controls.

An audience member noted that similar results have been reported for transarterial Yttrium-90 radioembolization, another and newer option to treat intrahepatic cholangiocarcinoma.

“The Y90 results are quite impressive,” Dr. Koerkamp said, adding that he’d like to see a head-to-head comparison.

“The main advantage of the pump is that it treats the entire liver,” as opposed to one lesion at a time, “so if you have 10 lesions [the pump] makes a lot more sense,” he said.

There is “definitely a movement” to “reinvigorate” the hepatic artery infusion pump approach, Dr. Melstrom said.

The study was funded by the Dutch Cancer Society. Dr. Koerkamp disclosed research funding from Tricumed, a maker of implantable infusion pumps. Dr. Melstrom didn’t have any disclosures.

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

Renewed interest in hepatic arterial chemotherapy infusion pumps may be on the horizon, given promising overall survival findings in patients with advanced, unresectable cholangiocarcinoma.

Dutch investigators reported a 3-year overall survival of 33% in patients with advanced, unresectable cholangiocarcinoma confined to the liver who received the infusion chemotherapy vs 3% in historical controls treated with standard systemic gemcitabine/cisplatin.

The response with the pump is “clearly superior” to systemic treatment, said investigator Bas Groot Koerkamp, MD, who presented the findings at the ASCO Gastrointestinal Cancers Symposium.

“I do share the enthusiasm of my colleagues about immunotherapy and targeted treatments for intrahepatic cholangiocarcinoma,” said Dr. Koerkamp, a hepato-pancreato-biliary surgeon at Erasmus University Medical Center, Rotterdam, the Netherlands. But “none of these treatments has shown a 3-year overall survival of one in three with advanced disease.”

The hepatic arterial infusion pump, a hockey puck-sized device that essentially bathes liver tumors in floxuridine for about 2 weeks, is not a new technology. The pump has been around since at least the 1990s, developed largely at Memorial Sloan Kettering Cancer Center, New York City, where Dr. Koerkamp trained.

Three previous small studies in cholangiocarcinoma reported outcomes similar to Dr. Koerkamp’s. Despite the strong survival outcomes, uptake of these pumps has lagged.

A key reason is likely the lack of phase 3 trials evaluating the technology, Laleh Melstrom, MD, chief of surgical oncology at City of Hope, outside of Los Angeles, Duarte, California, told this news organization.

Dr. Melstrom, who moderated Dr. Koerkamp’s presentation, also noted that using the pump requires special attention to bilirubin levels to prevent biliary toxicity and knowledge of pump placement.

The pump, placed subcutaneously on one side of the lower abdomen, is connected to a side branch of the hepatic artery and then filled with the chemotherapy agent floxuridine. Delivering floxuridine directly to the hepatic artery increases liver lesion exposure 200-fold over systemic delivery. The pump needs to be refilled after 2 weeks.

“It’s not difficult to place the pump, even doing it robotically,” which was how it was placed in over 40% of patients in the study, Dr. Koerkamp said.

As for biliary toxicity, only one patient in the current study developed biliary sclerosis, which was easily handled with a stent. “You just put in a stent and continue,” Dr. Koerkamp said.

The current single-arm phase 2 study included 50 patients implanted with the hepatic pump at three centers in the Netherlands. All patients had advanced, unresectable cholangiocarcinoma confined to the liver.

Ultimately, 48 of 50 patients received treatment after one patient died of unrelated causes and another had an arterial dissection.

Overall, 38 received gemcitabine/cisplatin concurrently, and the remaining had the pump treatment alone, having already received the systemic combination. Most (84%) received at least four cycles of chemotherapy infusion.

Almost half of patients (46%) had a partial response to treatment, and 88% exhibited disease control at 6 months. Four patients who responded underwent a liver resection, one of whom had a complete pathologic response.

Median overall survival was 22 months vs 12 months in historical controls. One-year median overall survival was 80% in the treatment group vs 47% in controls, and 3-year median overall survival was 33% in the pump group vs 3% in controls.

An audience member noted that similar results have been reported for transarterial Yttrium-90 radioembolization, another and newer option to treat intrahepatic cholangiocarcinoma.

“The Y90 results are quite impressive,” Dr. Koerkamp said, adding that he’d like to see a head-to-head comparison.

“The main advantage of the pump is that it treats the entire liver,” as opposed to one lesion at a time, “so if you have 10 lesions [the pump] makes a lot more sense,” he said.

There is “definitely a movement” to “reinvigorate” the hepatic artery infusion pump approach, Dr. Melstrom said.

The study was funded by the Dutch Cancer Society. Dr. Koerkamp disclosed research funding from Tricumed, a maker of implantable infusion pumps. Dr. Melstrom didn’t have any disclosures.

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

In patients with colorectal cancer bearing the KRAS G12C mutation, a combination of the Kirsten rat sarcoma viral oncogene homologue (KRAS) G12C inhibitor sotorasib and the epidermal growth factor receptor inhibitor panitumumab led to an improvement in quality of life (QoL) measures compared with standard therapy.

Dominik Modest, MD, presented these new results of the phase 3 CodeBreaK 300 trial at the 2024 ASCO Gastrointestinal Cancers Symposium.

The KRAS G12C mutation occurs in 3%-4% of metastatic colorectal cancer cases, according to Dr. Modest and the other authors of a paper published in the New England Journal of Medicine describing the primary outcome of the trial. The study included 160 patients who were randomized to once daily sotorasib (960 mg) plus panitumumab (Soto960), once daily sotorasib (240 mg) plus panitumumab (Soto240), or investigator’s choice of trifluridine–tipiracil or regorafenib.

The December 2023 paper described improvements in median progression-free survival, progression or death, and objective response (OR). The authors described statistically significant improvements in disease progression or death in the Soto960 group (hazard ratio [HR], 0.49; P = .006) and the Soto240 group (HR, 0.58; P = .03). The objective response rate was highest in the Soto960 group (26.4%; 95% CI, 15.3%-40.3%), followed by the Soto240 group (5.7%; 95% CI, 1.2%-15.7%), and the control group (0%; 95% CI, 0.0%-6.6%). Grade 3 or higher treatment-related adverse events were generally similar at 35.8% (Soto960), 30.2% (Soto240), and 43.1% (control) in each group. The most common adverse events associated with sotorasib-panitumumab were skin-related toxicity and hypomagnesemia.

The new analysis showed that both doses of sotorasib also improved patient-reported outcomes from baseline to week 8, Dr. Modest, professor of medicine at Charité University of Medicine in Berlin, said at the meeting.

Compared with the chemotherapy group, there were statistically significant differences in least square mean change from baseline to week 8 for: pain at its worst in the Soto240 group (Brief Pain Inventory [BPI], –1.18; 95% CI, –2.05 to –0.32) and the Soto960 group (BPI, –1.49; 95% CI, –2.36 to –0.61); and physical functioning, as measured by the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire, in the Soto240 (7.95; 95% CI, 2.39-13.51) and Soto960 (6.73; 95% CI, 1.05-12.41) groups. Nearly all other measures trended toward favoring the sotorasib/panitumumab groups, but did not reach statistical significance. A similar pattern was seen in time to deterioration measures. Among adverse events, diarrhea trended toward being more frequent in the intervention arms.

At week 9, 63% of patients in Soto960 and 84% in Soto240 reported improvement in the Patient Global Impression of Change score (PGI-C), versus 37% in the chemotherapy arm. At week 17, the percentages were 77%, 59%, and 21%, respectively.

“The clinical benefits and the better quality of life outcomes associated with sotorasib at the high dose of 960 milligrams plus panitumumab establishes this combination as a potential new standard [therapy] for patients with chemorefractory KRAS G12C mutant colorectal cancer, and I think it’s quite reassuring that even if you compare two active drugs versus one active drug, this does not necessarily translate into impaired quality of life assessments by the patients,” Dr. Modest said during his presentation.

CodeBreaK 300 may point the way to other dual therapies involving kinase inhibitors, according to Rona Yaeger, MD, who wrote an accompanying editorial to the NEJM paper. Dr. Yaeger noted that clinical and preclinical studies had shown that targeted oncogenes like KRAS G12C and BRAF V600E alone would be insufficient in colorectal cancer.

When combined with KRAS G12C inhibitors, EGFR inhibitors prevent EGFR from participating in negative feedback loops that can otherwise lead to drug resistance. “Whether targeting [receptor tyrosine kinases like EGFR] in epithelial tumors other than those associated with colorectal cancers would improve the incidence of response to KRAS G12C inhibitors remains unknown,” wrote Dr. Yaeger, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. There is an ongoing clinical trial evaluating KRAS G12C inhibitors combined with EGFR antibodies in both lung and pancreatic cancer.

She noted that colorectal tumors have high levels of receptor tyrosine kinases, and argued that this will require higher doses of KRAS G12C inhibitors or novel drugs with higher activity. This is supported by the higher frequency of response and longer PFS at the higher dose in CodeBreaK 300, but could present a challenge: “Lowering the drug dose to manage toxic effects may limit the efficacy of the drug against some cancers,” she wrote.

Dr. Yaeger highlighted the KRYSTAL-10 phase 3 randomized trial, which is assessing the KRAS G12C inhibitor adagrasib in combination with the EGFR antibody cetuximab versus chemotherapy in advanced solid tumors with the KRAS G12C mutation.

“The CodeBreaK 300 trial is an exciting first step for targeting KRAS in colorectal cancer,” Dr. Yaeger wrote.

Dr. Modest has financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Incyte, Lily, Merck Serono, Merck Sharp & Dohme, Onkowissen, Pierre Fabre, Roche, and SERVIER. Dr. Yaeger has financial relationships with Amgen, Boehringer Ingelheim, Daiichi Sankyo, Mirati, Pfizer, and Zai Lab.

In patients with colorectal cancer bearing the KRAS G12C mutation, a combination of the Kirsten rat sarcoma viral oncogene homologue (KRAS) G12C inhibitor sotorasib and the epidermal growth factor receptor inhibitor panitumumab led to an improvement in quality of life (QoL) measures compared with standard therapy.

Dominik Modest, MD, presented these new results of the phase 3 CodeBreaK 300 trial at the 2024 ASCO Gastrointestinal Cancers Symposium.

The KRAS G12C mutation occurs in 3%-4% of metastatic colorectal cancer cases, according to Dr. Modest and the other authors of a paper published in the New England Journal of Medicine describing the primary outcome of the trial. The study included 160 patients who were randomized to once daily sotorasib (960 mg) plus panitumumab (Soto960), once daily sotorasib (240 mg) plus panitumumab (Soto240), or investigator’s choice of trifluridine–tipiracil or regorafenib.

The December 2023 paper described improvements in median progression-free survival, progression or death, and objective response (OR). The authors described statistically significant improvements in disease progression or death in the Soto960 group (hazard ratio [HR], 0.49; P = .006) and the Soto240 group (HR, 0.58; P = .03). The objective response rate was highest in the Soto960 group (26.4%; 95% CI, 15.3%-40.3%), followed by the Soto240 group (5.7%; 95% CI, 1.2%-15.7%), and the control group (0%; 95% CI, 0.0%-6.6%). Grade 3 or higher treatment-related adverse events were generally similar at 35.8% (Soto960), 30.2% (Soto240), and 43.1% (control) in each group. The most common adverse events associated with sotorasib-panitumumab were skin-related toxicity and hypomagnesemia.

The new analysis showed that both doses of sotorasib also improved patient-reported outcomes from baseline to week 8, Dr. Modest, professor of medicine at Charité University of Medicine in Berlin, said at the meeting.

Compared with the chemotherapy group, there were statistically significant differences in least square mean change from baseline to week 8 for: pain at its worst in the Soto240 group (Brief Pain Inventory [BPI], –1.18; 95% CI, –2.05 to –0.32) and the Soto960 group (BPI, –1.49; 95% CI, –2.36 to –0.61); and physical functioning, as measured by the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire, in the Soto240 (7.95; 95% CI, 2.39-13.51) and Soto960 (6.73; 95% CI, 1.05-12.41) groups. Nearly all other measures trended toward favoring the sotorasib/panitumumab groups, but did not reach statistical significance. A similar pattern was seen in time to deterioration measures. Among adverse events, diarrhea trended toward being more frequent in the intervention arms.

At week 9, 63% of patients in Soto960 and 84% in Soto240 reported improvement in the Patient Global Impression of Change score (PGI-C), versus 37% in the chemotherapy arm. At week 17, the percentages were 77%, 59%, and 21%, respectively.

“The clinical benefits and the better quality of life outcomes associated with sotorasib at the high dose of 960 milligrams plus panitumumab establishes this combination as a potential new standard [therapy] for patients with chemorefractory KRAS G12C mutant colorectal cancer, and I think it’s quite reassuring that even if you compare two active drugs versus one active drug, this does not necessarily translate into impaired quality of life assessments by the patients,” Dr. Modest said during his presentation.

CodeBreaK 300 may point the way to other dual therapies involving kinase inhibitors, according to Rona Yaeger, MD, who wrote an accompanying editorial to the NEJM paper. Dr. Yaeger noted that clinical and preclinical studies had shown that targeted oncogenes like KRAS G12C and BRAF V600E alone would be insufficient in colorectal cancer.

When combined with KRAS G12C inhibitors, EGFR inhibitors prevent EGFR from participating in negative feedback loops that can otherwise lead to drug resistance. “Whether targeting [receptor tyrosine kinases like EGFR] in epithelial tumors other than those associated with colorectal cancers would improve the incidence of response to KRAS G12C inhibitors remains unknown,” wrote Dr. Yaeger, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. There is an ongoing clinical trial evaluating KRAS G12C inhibitors combined with EGFR antibodies in both lung and pancreatic cancer.

She noted that colorectal tumors have high levels of receptor tyrosine kinases, and argued that this will require higher doses of KRAS G12C inhibitors or novel drugs with higher activity. This is supported by the higher frequency of response and longer PFS at the higher dose in CodeBreaK 300, but could present a challenge: “Lowering the drug dose to manage toxic effects may limit the efficacy of the drug against some cancers,” she wrote.

Dr. Yaeger highlighted the KRYSTAL-10 phase 3 randomized trial, which is assessing the KRAS G12C inhibitor adagrasib in combination with the EGFR antibody cetuximab versus chemotherapy in advanced solid tumors with the KRAS G12C mutation.

“The CodeBreaK 300 trial is an exciting first step for targeting KRAS in colorectal cancer,” Dr. Yaeger wrote.

Dr. Modest has financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Incyte, Lily, Merck Serono, Merck Sharp & Dohme, Onkowissen, Pierre Fabre, Roche, and SERVIER. Dr. Yaeger has financial relationships with Amgen, Boehringer Ingelheim, Daiichi Sankyo, Mirati, Pfizer, and Zai Lab.

In patients with colorectal cancer bearing the KRAS G12C mutation, a combination of the Kirsten rat sarcoma viral oncogene homologue (KRAS) G12C inhibitor sotorasib and the epidermal growth factor receptor inhibitor panitumumab led to an improvement in quality of life (QoL) measures compared with standard therapy.

Dominik Modest, MD, presented these new results of the phase 3 CodeBreaK 300 trial at the 2024 ASCO Gastrointestinal Cancers Symposium.

The KRAS G12C mutation occurs in 3%-4% of metastatic colorectal cancer cases, according to Dr. Modest and the other authors of a paper published in the New England Journal of Medicine describing the primary outcome of the trial. The study included 160 patients who were randomized to once daily sotorasib (960 mg) plus panitumumab (Soto960), once daily sotorasib (240 mg) plus panitumumab (Soto240), or investigator’s choice of trifluridine–tipiracil or regorafenib.

The December 2023 paper described improvements in median progression-free survival, progression or death, and objective response (OR). The authors described statistically significant improvements in disease progression or death in the Soto960 group (hazard ratio [HR], 0.49; P = .006) and the Soto240 group (HR, 0.58; P = .03). The objective response rate was highest in the Soto960 group (26.4%; 95% CI, 15.3%-40.3%), followed by the Soto240 group (5.7%; 95% CI, 1.2%-15.7%), and the control group (0%; 95% CI, 0.0%-6.6%). Grade 3 or higher treatment-related adverse events were generally similar at 35.8% (Soto960), 30.2% (Soto240), and 43.1% (control) in each group. The most common adverse events associated with sotorasib-panitumumab were skin-related toxicity and hypomagnesemia.

The new analysis showed that both doses of sotorasib also improved patient-reported outcomes from baseline to week 8, Dr. Modest, professor of medicine at Charité University of Medicine in Berlin, said at the meeting.

Compared with the chemotherapy group, there were statistically significant differences in least square mean change from baseline to week 8 for: pain at its worst in the Soto240 group (Brief Pain Inventory [BPI], –1.18; 95% CI, –2.05 to –0.32) and the Soto960 group (BPI, –1.49; 95% CI, –2.36 to –0.61); and physical functioning, as measured by the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire, in the Soto240 (7.95; 95% CI, 2.39-13.51) and Soto960 (6.73; 95% CI, 1.05-12.41) groups. Nearly all other measures trended toward favoring the sotorasib/panitumumab groups, but did not reach statistical significance. A similar pattern was seen in time to deterioration measures. Among adverse events, diarrhea trended toward being more frequent in the intervention arms.

At week 9, 63% of patients in Soto960 and 84% in Soto240 reported improvement in the Patient Global Impression of Change score (PGI-C), versus 37% in the chemotherapy arm. At week 17, the percentages were 77%, 59%, and 21%, respectively.

“The clinical benefits and the better quality of life outcomes associated with sotorasib at the high dose of 960 milligrams plus panitumumab establishes this combination as a potential new standard [therapy] for patients with chemorefractory KRAS G12C mutant colorectal cancer, and I think it’s quite reassuring that even if you compare two active drugs versus one active drug, this does not necessarily translate into impaired quality of life assessments by the patients,” Dr. Modest said during his presentation.

CodeBreaK 300 may point the way to other dual therapies involving kinase inhibitors, according to Rona Yaeger, MD, who wrote an accompanying editorial to the NEJM paper. Dr. Yaeger noted that clinical and preclinical studies had shown that targeted oncogenes like KRAS G12C and BRAF V600E alone would be insufficient in colorectal cancer.

When combined with KRAS G12C inhibitors, EGFR inhibitors prevent EGFR from participating in negative feedback loops that can otherwise lead to drug resistance. “Whether targeting [receptor tyrosine kinases like EGFR] in epithelial tumors other than those associated with colorectal cancers would improve the incidence of response to KRAS G12C inhibitors remains unknown,” wrote Dr. Yaeger, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. There is an ongoing clinical trial evaluating KRAS G12C inhibitors combined with EGFR antibodies in both lung and pancreatic cancer.

She noted that colorectal tumors have high levels of receptor tyrosine kinases, and argued that this will require higher doses of KRAS G12C inhibitors or novel drugs with higher activity. This is supported by the higher frequency of response and longer PFS at the higher dose in CodeBreaK 300, but could present a challenge: “Lowering the drug dose to manage toxic effects may limit the efficacy of the drug against some cancers,” she wrote.

Dr. Yaeger highlighted the KRYSTAL-10 phase 3 randomized trial, which is assessing the KRAS G12C inhibitor adagrasib in combination with the EGFR antibody cetuximab versus chemotherapy in advanced solid tumors with the KRAS G12C mutation.

“The CodeBreaK 300 trial is an exciting first step for targeting KRAS in colorectal cancer,” Dr. Yaeger wrote.

Dr. Modest has financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Incyte, Lily, Merck Serono, Merck Sharp & Dohme, Onkowissen, Pierre Fabre, Roche, and SERVIER. Dr. Yaeger has financial relationships with Amgen, Boehringer Ingelheim, Daiichi Sankyo, Mirati, Pfizer, and Zai Lab.

SAN FRANCISCO — The immunotherapy combination nivolumab plus ipilimumab rivals chemotherapy as well as pembrolizumab monotherapy in the first-line treatment of metastatic colorectal cancer (CRC), new data indicated.

Findings from the CHECKMATE-8HW trial revealed that first-line nivolumab plus ipilimumab led to a significant improvement in progression-free survival (PFS) compared with chemotherapy among patients with metastatic CRC.

More specifically, at 2 years, PFS was 72% among patients with microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) randomized to the immunotherapy combination compared with just 14% among those randomized to chemotherapy with or without targeted therapy.

The magnitude of the benefit was unexpected, especially considering patients received only four cycles of the immunotherapy combination in the trial. “It’s a good surprise,” said lead investigator Thierry Andre, MD, who presented the findings at the 2024 ASCO Gastrointestinal Cancers Symposium.

The findings indicate that nivolumab plus ipilimumab should really be “a new standard,” said Andre, a medical oncologist at Sorbonne University, Paris.

The combination as well as nivolumab alone has received US Food and Drug Administration’s (FDA’s) approval to treat MSI-H or dMMR metastatic CRC in the second line, following chemotherapy failure.

The FDA also approved pembrolizumab as first-line monotherapy for this CRC indication in 2020. The KEYNOTE-177 trial, which led to the pembrolizumab approval, reported a 2-year PFS of 48% among patients receiving the monotherapy. Andre was the lead investigator on KEYNOTE-177.

To compare PFS results for pembrolizumab and nivolumab alone, the CHECKMATE-8HW trial included a nivolumab monotherapy arm, but these results are pending, as are the overall survival findings, Andre said.

Overall, CHECKMATE-8HW must be taken into context with KEYNOTE-177, and “we need a little bit more trial data” for oncologists to decide between the two options, said Neil Newman, MD, a radiation oncologist at the University of Texas Health Science Center, San Antonio, Texas, who co-moderated Dr. Andre’s presentation.

Andre noted, however, that if the nivolumab and pembrolizumab monotherapy results are similar, most patients will likely receive the nivolumab/ipilimumab combination, given the improved PFS outcomes.

In CHECKMATE-8HW, patients were randomized to three regimens. The 202 patients in the combination arm received nivolumab 240 mg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks. The 101 patients in the chemotherapy group received investigator’s choice of mFOLFOX6 or FOLFIRI with or without bevacizumab or cetuximab. And the nivolumab monotherapy arm received nivolumab 240 mg every 2 weeks for six doses, followed by nivolumab 480 mg every 4 weeks.

Treatment continued until disease progression or unacceptable toxicity over a maximum of 2 years. The median duration of treatment was 13.5 months in the nivolumab/ipilimumab arm vs 4 months in the chemotherapy arm.

PFS curves started to separate between nivolumab/ipilimumab and chemotherapy at about 3 months.

Patients receiving the combination exhibited a 79% reduction in the risk for disease progression or death at 2 years (72% vs 14%; hazard ratio, 0.21; P < .0001). The median PFS was not reached with the combination vs 5.9 months with chemotherapy. The PFS benefit of nivolumab/ipilimumab held across various subgroups, including patients with KRAS or NRAS mutations and baseline lung, liver, or peritoneal metastases.

The incidence of grade 3/4 treatment-related adverse events was 23% with nivolumab/ipilimumab vs 48% in the chemotherapy arm. The most common grade 3/4 events with nivolumab/ipilimumab were diarrhea/colitis (5%), adrenal insufficiency (4%), hepatitis (3%), and inflammation of the pituitary gland (3%).

Two treatment-related deaths occurred in the combination arm — one from pneumonitis and the second from myocarditis — and none occurred in the chemotherapy arm.

Mark A. Lewis, MD, a gastrointestinal oncologist at Intermountain Healthcare in Murray, Utah, was impressed with the CHECKMATE-8HW findings. The data are shaping up to make nivolumab/ipilimumab “the next great step in metastatic CRC management beyond KEYNOTE-177,” Dr. Lewis said.

Dr. Lewis noted that the new trial makes it “imperative” to standardize testing for immunotherapy candidacy upfront. “It is completely unacceptable for any patient with metastatic CRC to not have their MMR/MSI status assessed,” he said. “Much as no oncologist would dare treat breast cancer without testing ER, PR, HER2 status, biomarkers cannot be a later-line afterthought in stage IV CRC.”

Drugmaker Bristol-Myers Squibb told this news organization that the company will be seeking a first-line indication for the combination, and anticipates approval early next year or possibly sooner, if the FDA grants a priority review.

The work was funded by Bristol-Myers Squibb and the ONO Pharmaceutical Company. Dr. Andre had numerous industry ties, including being a consultant for both BMS and Merck. He also reported honoraria from both companies. Dr. Newman and Dr. Lewis didn’t have any disclosures.

A version of this article appeared on Medscape.com.

SAN FRANCISCO — The immunotherapy combination nivolumab plus ipilimumab rivals chemotherapy as well as pembrolizumab monotherapy in the first-line treatment of metastatic colorectal cancer (CRC), new data indicated.

Findings from the CHECKMATE-8HW trial revealed that first-line nivolumab plus ipilimumab led to a significant improvement in progression-free survival (PFS) compared with chemotherapy among patients with metastatic CRC.

More specifically, at 2 years, PFS was 72% among patients with microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) randomized to the immunotherapy combination compared with just 14% among those randomized to chemotherapy with or without targeted therapy.

The magnitude of the benefit was unexpected, especially considering patients received only four cycles of the immunotherapy combination in the trial. “It’s a good surprise,” said lead investigator Thierry Andre, MD, who presented the findings at the 2024 ASCO Gastrointestinal Cancers Symposium.

The findings indicate that nivolumab plus ipilimumab should really be “a new standard,” said Andre, a medical oncologist at Sorbonne University, Paris.

The combination as well as nivolumab alone has received US Food and Drug Administration’s (FDA’s) approval to treat MSI-H or dMMR metastatic CRC in the second line, following chemotherapy failure.

The FDA also approved pembrolizumab as first-line monotherapy for this CRC indication in 2020. The KEYNOTE-177 trial, which led to the pembrolizumab approval, reported a 2-year PFS of 48% among patients receiving the monotherapy. Andre was the lead investigator on KEYNOTE-177.

To compare PFS results for pembrolizumab and nivolumab alone, the CHECKMATE-8HW trial included a nivolumab monotherapy arm, but these results are pending, as are the overall survival findings, Andre said.

Overall, CHECKMATE-8HW must be taken into context with KEYNOTE-177, and “we need a little bit more trial data” for oncologists to decide between the two options, said Neil Newman, MD, a radiation oncologist at the University of Texas Health Science Center, San Antonio, Texas, who co-moderated Dr. Andre’s presentation.

Andre noted, however, that if the nivolumab and pembrolizumab monotherapy results are similar, most patients will likely receive the nivolumab/ipilimumab combination, given the improved PFS outcomes.

In CHECKMATE-8HW, patients were randomized to three regimens. The 202 patients in the combination arm received nivolumab 240 mg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks. The 101 patients in the chemotherapy group received investigator’s choice of mFOLFOX6 or FOLFIRI with or without bevacizumab or cetuximab. And the nivolumab monotherapy arm received nivolumab 240 mg every 2 weeks for six doses, followed by nivolumab 480 mg every 4 weeks.

Treatment continued until disease progression or unacceptable toxicity over a maximum of 2 years. The median duration of treatment was 13.5 months in the nivolumab/ipilimumab arm vs 4 months in the chemotherapy arm.

PFS curves started to separate between nivolumab/ipilimumab and chemotherapy at about 3 months.

Patients receiving the combination exhibited a 79% reduction in the risk for disease progression or death at 2 years (72% vs 14%; hazard ratio, 0.21; P < .0001). The median PFS was not reached with the combination vs 5.9 months with chemotherapy. The PFS benefit of nivolumab/ipilimumab held across various subgroups, including patients with KRAS or NRAS mutations and baseline lung, liver, or peritoneal metastases.

The incidence of grade 3/4 treatment-related adverse events was 23% with nivolumab/ipilimumab vs 48% in the chemotherapy arm. The most common grade 3/4 events with nivolumab/ipilimumab were diarrhea/colitis (5%), adrenal insufficiency (4%), hepatitis (3%), and inflammation of the pituitary gland (3%).

Two treatment-related deaths occurred in the combination arm — one from pneumonitis and the second from myocarditis — and none occurred in the chemotherapy arm.

Mark A. Lewis, MD, a gastrointestinal oncologist at Intermountain Healthcare in Murray, Utah, was impressed with the CHECKMATE-8HW findings. The data are shaping up to make nivolumab/ipilimumab “the next great step in metastatic CRC management beyond KEYNOTE-177,” Dr. Lewis said.

Dr. Lewis noted that the new trial makes it “imperative” to standardize testing for immunotherapy candidacy upfront. “It is completely unacceptable for any patient with metastatic CRC to not have their MMR/MSI status assessed,” he said. “Much as no oncologist would dare treat breast cancer without testing ER, PR, HER2 status, biomarkers cannot be a later-line afterthought in stage IV CRC.”

Drugmaker Bristol-Myers Squibb told this news organization that the company will be seeking a first-line indication for the combination, and anticipates approval early next year or possibly sooner, if the FDA grants a priority review.

The work was funded by Bristol-Myers Squibb and the ONO Pharmaceutical Company. Dr. Andre had numerous industry ties, including being a consultant for both BMS and Merck. He also reported honoraria from both companies. Dr. Newman and Dr. Lewis didn’t have any disclosures.

A version of this article appeared on Medscape.com.

SAN FRANCISCO — The immunotherapy combination nivolumab plus ipilimumab rivals chemotherapy as well as pembrolizumab monotherapy in the first-line treatment of metastatic colorectal cancer (CRC), new data indicated.

Findings from the CHECKMATE-8HW trial revealed that first-line nivolumab plus ipilimumab led to a significant improvement in progression-free survival (PFS) compared with chemotherapy among patients with metastatic CRC.

More specifically, at 2 years, PFS was 72% among patients with microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) randomized to the immunotherapy combination compared with just 14% among those randomized to chemotherapy with or without targeted therapy.

The magnitude of the benefit was unexpected, especially considering patients received only four cycles of the immunotherapy combination in the trial. “It’s a good surprise,” said lead investigator Thierry Andre, MD, who presented the findings at the 2024 ASCO Gastrointestinal Cancers Symposium.

The findings indicate that nivolumab plus ipilimumab should really be “a new standard,” said Andre, a medical oncologist at Sorbonne University, Paris.

The combination as well as nivolumab alone has received US Food and Drug Administration’s (FDA’s) approval to treat MSI-H or dMMR metastatic CRC in the second line, following chemotherapy failure.

The FDA also approved pembrolizumab as first-line monotherapy for this CRC indication in 2020. The KEYNOTE-177 trial, which led to the pembrolizumab approval, reported a 2-year PFS of 48% among patients receiving the monotherapy. Andre was the lead investigator on KEYNOTE-177.

To compare PFS results for pembrolizumab and nivolumab alone, the CHECKMATE-8HW trial included a nivolumab monotherapy arm, but these results are pending, as are the overall survival findings, Andre said.

Overall, CHECKMATE-8HW must be taken into context with KEYNOTE-177, and “we need a little bit more trial data” for oncologists to decide between the two options, said Neil Newman, MD, a radiation oncologist at the University of Texas Health Science Center, San Antonio, Texas, who co-moderated Dr. Andre’s presentation.

Andre noted, however, that if the nivolumab and pembrolizumab monotherapy results are similar, most patients will likely receive the nivolumab/ipilimumab combination, given the improved PFS outcomes.

In CHECKMATE-8HW, patients were randomized to three regimens. The 202 patients in the combination arm received nivolumab 240 mg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks. The 101 patients in the chemotherapy group received investigator’s choice of mFOLFOX6 or FOLFIRI with or without bevacizumab or cetuximab. And the nivolumab monotherapy arm received nivolumab 240 mg every 2 weeks for six doses, followed by nivolumab 480 mg every 4 weeks.

Treatment continued until disease progression or unacceptable toxicity over a maximum of 2 years. The median duration of treatment was 13.5 months in the nivolumab/ipilimumab arm vs 4 months in the chemotherapy arm.

PFS curves started to separate between nivolumab/ipilimumab and chemotherapy at about 3 months.

Patients receiving the combination exhibited a 79% reduction in the risk for disease progression or death at 2 years (72% vs 14%; hazard ratio, 0.21; P < .0001). The median PFS was not reached with the combination vs 5.9 months with chemotherapy. The PFS benefit of nivolumab/ipilimumab held across various subgroups, including patients with KRAS or NRAS mutations and baseline lung, liver, or peritoneal metastases.

The incidence of grade 3/4 treatment-related adverse events was 23% with nivolumab/ipilimumab vs 48% in the chemotherapy arm. The most common grade 3/4 events with nivolumab/ipilimumab were diarrhea/colitis (5%), adrenal insufficiency (4%), hepatitis (3%), and inflammation of the pituitary gland (3%).

Two treatment-related deaths occurred in the combination arm — one from pneumonitis and the second from myocarditis — and none occurred in the chemotherapy arm.

Mark A. Lewis, MD, a gastrointestinal oncologist at Intermountain Healthcare in Murray, Utah, was impressed with the CHECKMATE-8HW findings. The data are shaping up to make nivolumab/ipilimumab “the next great step in metastatic CRC management beyond KEYNOTE-177,” Dr. Lewis said.

Dr. Lewis noted that the new trial makes it “imperative” to standardize testing for immunotherapy candidacy upfront. “It is completely unacceptable for any patient with metastatic CRC to not have their MMR/MSI status assessed,” he said. “Much as no oncologist would dare treat breast cancer without testing ER, PR, HER2 status, biomarkers cannot be a later-line afterthought in stage IV CRC.”

Drugmaker Bristol-Myers Squibb told this news organization that the company will be seeking a first-line indication for the combination, and anticipates approval early next year or possibly sooner, if the FDA grants a priority review.

The work was funded by Bristol-Myers Squibb and the ONO Pharmaceutical Company. Dr. Andre had numerous industry ties, including being a consultant for both BMS and Merck. He also reported honoraria from both companies. Dr. Newman and Dr. Lewis didn’t have any disclosures.

A version of this article appeared on Medscape.com.