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BERLIN — Re-treatment with an antiepidermal growth factor receptor (EGFR) agent is effective in patients with chemorefractory metastatic colorectal cancer (mCRC) with RAS and BRAF wild-type tumors confirmed on circulating tumor DNA (ctDNA), although the sequencing of therapy does not seem to matter, suggest overall survival results from the crossover trial PARERE.
The findings nevertheless indicate that anti-EGFR rechallenge with panitumumab may prolong progression-free survival (PFS) over the multiple kinase inhibitor regorafenib. This suggests that “the most pragmatic choice” would be to give the anti-EGFR before regorafenib, said study presenter Marco Maria Germani, MD, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
The caveat, however, is in patients who have an anti-EGFR interval since previously receiving the drugs of < 6 months. Those patients appeared to do better if they had regorafenib first and then anti-EGFR rechallenge.
Overall, Germani said that “since [trifluridine/tipiracil] plus bevacizumab is today the third-line standard of care” in this patient population, “anti-EGFR re-treatment might be considered after progression” on that combination.
Germani presented the research on October 18 at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, which was simultaneously published in the Annals of Oncology.
Michel P. Ducreux, MD, PhD, head of the Digestive Cancer Committee at Gustave Roussy, Villejuif, France, and invited discussant for the results, said, despite the study being negative, it is “very important to continue to perform this kind of trial to evaluate the [ideal] sequence in the treatment of our patients.”
He continued that the secondary endpoints in the trial of PFS and objective response and disease control rates were “fairly in favor of the use of rechallenge before regorafenib, and in my opinion, this is really quite convincing.”
Ducreux, who was not involved in PARERE trail, also pointed to the sex difference seen in the study, which suggested that women responded much better to having anti-EGFR retreatment before regorafenib than did men.
Similar findings have been reported in a number of other trials, and previous work has suggested that there are sex differences in the pharmacokinetics of several anticancer drugs. However, while this is “very important,” he said that “we never consider it, because we are not able to really explain [it].”
Overall, he concluded that, on the basis of these results, he would agree with the notion that it is better to propose a rechallenge with anti-EGFR treatment as the fourth-line therapy in this patient population, before administering regorafenib.
Ducreux explained that, after a partial response, tumors acquire resistance to EGFR inhibitors through alterations and mutations that occur during treatment, via nongenetic mechanisms, and through treatment-induced selection for preexisting mutations.
Previous work has shown that mutations, such as in the RAS gene, are detectable early during EGFR inhibitor therapy, but that they then decay exponentially once the drugs are stopped, with the potential that tumors regain their sensitivity to them.
Germani said that this means that ctDNA-guided retreatment with anti-EGFR therapies is a “promising approach” in pretreated patients with RAS and BRAF wild-type mCRC, and that the sequencing of the drugs may be important. Indeed, the REVERCE trial showed that giving regorafenib followed by the anti-EGFR drug cetuzximab was associated with longer overall survival than the other way around in anti-EGFR medication-naive patients.
Methods and Results
For PARERE, the researchers enrolled patients aged at least 18 years with RAS and BRAF wild-type mCRC who were previously treated with a first-line anti-EGFR-containing regimen and had at least a partial response or stable disease for at least 6 months.
The patients were also required to have had at least one intervening anti-EGFR-free line of therapy, and to have previously received treatment with fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenics. At least 4 months were required to have passed between the end of anti-EGFR administration and screening for the study.
In all, 428 patients were screened between December 2020 and December 2024, with 213 patients with RAS and BRAF wild-type mCRC, as detected on ctDNA, enrolled. They were randomized to panitumumab or regorafenib until first progression, followed by regorafenib, if they started on panitumumab, or panitumumab, if they started on regorafenib, until second progression.
The median age of the patients was 61 years among those who started on panitumumab and 64 years among those initially given regorafenib in the trial, and 63% and 57%, respectively, were male. The median number of prior lines of therapy was two in both groups, and 65% and 69%, respectively, had received pantitumumab as their first-line anti-EGFR.
Initial findings from the study presented at the 2025 ASCO Annual Meeting indicated that, after a median follow-up of 23.5 months, there was no significant difference in the median first PFS between the two treatment arms.
However, patients who started with panitumumab had a significant improvement in both the objective response and disease control rates (P < .001), as well as a signal for a potentially longer median second PFS, than those who started with regorafenib, particularly on the per-protocol analysis.
Presenting the overall survival results, Germani said that there was no significant difference between the groups on the intention-to-treat analysis, at a stratified hazard ratio of 1.13 (P = .440), or on the per-protocol analysis, at a hazard ratio of 1.07 (P = .730).
“We then ran a subgroup analysis,” he continued, “and we found out that an anti-EGFR-free interval before liquid biopsy shorter than 6 months was associated with less benefit from a panitumumab [first] sequence, which is biologically sound.”
It was also observed that women did significantly better when having panitumumab first, whereas men did not, for which “we do not have a clear biological explanation,” Germani added.
Confining the analysis to so-called “hyperselected” patients, who not only were RAS and BRAF wild type but also had no pathogenic mutations associated with anti-EGFR resistance, did not reveal any significant overall survival differences between the treatment groups.
However, Ducreux took issue with the way in which hyperselection, which is turning up more and more regularly in trials, is defined, as the choice of which mutations to include varies widely. He suggested that a consensus group be assembled to resolve this issue.
Looking more broadly, the researchers were able to show that, in this updated analysis, anti-EGFR re-treatment was superior to regorafenib regardless of the treatment sequence in terms of PFS, at 4.2 months vs 2.4 months (P = .103) when given first in the trial, and 3.9 months vs 2.7 months (P = .019) when given second in the trial, as well as in terms of objective response and disease control rates.
Adverse Events
In terms of safety, the results showed that, as expected, acneiform rash, fatigue, and hypomagnesemia were the most common adverse events associated with panitumumb, while those with regorafenib were fatigue, hand-foot skin reactions, and hypertension.
There were no notable differences in the number of patients receiving a post-study treatment nor in the post-study therapeutic choices, between the study arms.
The study was sponsored by GONO Foundation and partially supported by Amgen and Bayer. Germani declared having relationships with MSD and Amgen. Ducreux declared having relationships with Amgen, Bayer, BeiGene, Incyte, Jazz, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Roche, Servier, Keocyt, AbbVie, Abcely, Arcus, Bayer, BMS, Boehringer, GlaxoSmithKline, Sanofi, Scandion, and Zymeworks.
A version of this article first appeared on Medscape.com.
BERLIN — Re-treatment with an antiepidermal growth factor receptor (EGFR) agent is effective in patients with chemorefractory metastatic colorectal cancer (mCRC) with RAS and BRAF wild-type tumors confirmed on circulating tumor DNA (ctDNA), although the sequencing of therapy does not seem to matter, suggest overall survival results from the crossover trial PARERE.
The findings nevertheless indicate that anti-EGFR rechallenge with panitumumab may prolong progression-free survival (PFS) over the multiple kinase inhibitor regorafenib. This suggests that “the most pragmatic choice” would be to give the anti-EGFR before regorafenib, said study presenter Marco Maria Germani, MD, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
The caveat, however, is in patients who have an anti-EGFR interval since previously receiving the drugs of < 6 months. Those patients appeared to do better if they had regorafenib first and then anti-EGFR rechallenge.
Overall, Germani said that “since [trifluridine/tipiracil] plus bevacizumab is today the third-line standard of care” in this patient population, “anti-EGFR re-treatment might be considered after progression” on that combination.
Germani presented the research on October 18 at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, which was simultaneously published in the Annals of Oncology.
Michel P. Ducreux, MD, PhD, head of the Digestive Cancer Committee at Gustave Roussy, Villejuif, France, and invited discussant for the results, said, despite the study being negative, it is “very important to continue to perform this kind of trial to evaluate the [ideal] sequence in the treatment of our patients.”
He continued that the secondary endpoints in the trial of PFS and objective response and disease control rates were “fairly in favor of the use of rechallenge before regorafenib, and in my opinion, this is really quite convincing.”
Ducreux, who was not involved in PARERE trail, also pointed to the sex difference seen in the study, which suggested that women responded much better to having anti-EGFR retreatment before regorafenib than did men.
Similar findings have been reported in a number of other trials, and previous work has suggested that there are sex differences in the pharmacokinetics of several anticancer drugs. However, while this is “very important,” he said that “we never consider it, because we are not able to really explain [it].”
Overall, he concluded that, on the basis of these results, he would agree with the notion that it is better to propose a rechallenge with anti-EGFR treatment as the fourth-line therapy in this patient population, before administering regorafenib.
Ducreux explained that, after a partial response, tumors acquire resistance to EGFR inhibitors through alterations and mutations that occur during treatment, via nongenetic mechanisms, and through treatment-induced selection for preexisting mutations.
Previous work has shown that mutations, such as in the RAS gene, are detectable early during EGFR inhibitor therapy, but that they then decay exponentially once the drugs are stopped, with the potential that tumors regain their sensitivity to them.
Germani said that this means that ctDNA-guided retreatment with anti-EGFR therapies is a “promising approach” in pretreated patients with RAS and BRAF wild-type mCRC, and that the sequencing of the drugs may be important. Indeed, the REVERCE trial showed that giving regorafenib followed by the anti-EGFR drug cetuzximab was associated with longer overall survival than the other way around in anti-EGFR medication-naive patients.
Methods and Results
For PARERE, the researchers enrolled patients aged at least 18 years with RAS and BRAF wild-type mCRC who were previously treated with a first-line anti-EGFR-containing regimen and had at least a partial response or stable disease for at least 6 months.
The patients were also required to have had at least one intervening anti-EGFR-free line of therapy, and to have previously received treatment with fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenics. At least 4 months were required to have passed between the end of anti-EGFR administration and screening for the study.
In all, 428 patients were screened between December 2020 and December 2024, with 213 patients with RAS and BRAF wild-type mCRC, as detected on ctDNA, enrolled. They were randomized to panitumumab or regorafenib until first progression, followed by regorafenib, if they started on panitumumab, or panitumumab, if they started on regorafenib, until second progression.
The median age of the patients was 61 years among those who started on panitumumab and 64 years among those initially given regorafenib in the trial, and 63% and 57%, respectively, were male. The median number of prior lines of therapy was two in both groups, and 65% and 69%, respectively, had received pantitumumab as their first-line anti-EGFR.
Initial findings from the study presented at the 2025 ASCO Annual Meeting indicated that, after a median follow-up of 23.5 months, there was no significant difference in the median first PFS between the two treatment arms.
However, patients who started with panitumumab had a significant improvement in both the objective response and disease control rates (P < .001), as well as a signal for a potentially longer median second PFS, than those who started with regorafenib, particularly on the per-protocol analysis.
Presenting the overall survival results, Germani said that there was no significant difference between the groups on the intention-to-treat analysis, at a stratified hazard ratio of 1.13 (P = .440), or on the per-protocol analysis, at a hazard ratio of 1.07 (P = .730).
“We then ran a subgroup analysis,” he continued, “and we found out that an anti-EGFR-free interval before liquid biopsy shorter than 6 months was associated with less benefit from a panitumumab [first] sequence, which is biologically sound.”
It was also observed that women did significantly better when having panitumumab first, whereas men did not, for which “we do not have a clear biological explanation,” Germani added.
Confining the analysis to so-called “hyperselected” patients, who not only were RAS and BRAF wild type but also had no pathogenic mutations associated with anti-EGFR resistance, did not reveal any significant overall survival differences between the treatment groups.
However, Ducreux took issue with the way in which hyperselection, which is turning up more and more regularly in trials, is defined, as the choice of which mutations to include varies widely. He suggested that a consensus group be assembled to resolve this issue.
Looking more broadly, the researchers were able to show that, in this updated analysis, anti-EGFR re-treatment was superior to regorafenib regardless of the treatment sequence in terms of PFS, at 4.2 months vs 2.4 months (P = .103) when given first in the trial, and 3.9 months vs 2.7 months (P = .019) when given second in the trial, as well as in terms of objective response and disease control rates.
Adverse Events
In terms of safety, the results showed that, as expected, acneiform rash, fatigue, and hypomagnesemia were the most common adverse events associated with panitumumb, while those with regorafenib were fatigue, hand-foot skin reactions, and hypertension.
There were no notable differences in the number of patients receiving a post-study treatment nor in the post-study therapeutic choices, between the study arms.
The study was sponsored by GONO Foundation and partially supported by Amgen and Bayer. Germani declared having relationships with MSD and Amgen. Ducreux declared having relationships with Amgen, Bayer, BeiGene, Incyte, Jazz, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Roche, Servier, Keocyt, AbbVie, Abcely, Arcus, Bayer, BMS, Boehringer, GlaxoSmithKline, Sanofi, Scandion, and Zymeworks.
A version of this article first appeared on Medscape.com.
BERLIN — Re-treatment with an antiepidermal growth factor receptor (EGFR) agent is effective in patients with chemorefractory metastatic colorectal cancer (mCRC) with RAS and BRAF wild-type tumors confirmed on circulating tumor DNA (ctDNA), although the sequencing of therapy does not seem to matter, suggest overall survival results from the crossover trial PARERE.
The findings nevertheless indicate that anti-EGFR rechallenge with panitumumab may prolong progression-free survival (PFS) over the multiple kinase inhibitor regorafenib. This suggests that “the most pragmatic choice” would be to give the anti-EGFR before regorafenib, said study presenter Marco Maria Germani, MD, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
The caveat, however, is in patients who have an anti-EGFR interval since previously receiving the drugs of < 6 months. Those patients appeared to do better if they had regorafenib first and then anti-EGFR rechallenge.
Overall, Germani said that “since [trifluridine/tipiracil] plus bevacizumab is today the third-line standard of care” in this patient population, “anti-EGFR re-treatment might be considered after progression” on that combination.
Germani presented the research on October 18 at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, which was simultaneously published in the Annals of Oncology.
Michel P. Ducreux, MD, PhD, head of the Digestive Cancer Committee at Gustave Roussy, Villejuif, France, and invited discussant for the results, said, despite the study being negative, it is “very important to continue to perform this kind of trial to evaluate the [ideal] sequence in the treatment of our patients.”
He continued that the secondary endpoints in the trial of PFS and objective response and disease control rates were “fairly in favor of the use of rechallenge before regorafenib, and in my opinion, this is really quite convincing.”
Ducreux, who was not involved in PARERE trail, also pointed to the sex difference seen in the study, which suggested that women responded much better to having anti-EGFR retreatment before regorafenib than did men.
Similar findings have been reported in a number of other trials, and previous work has suggested that there are sex differences in the pharmacokinetics of several anticancer drugs. However, while this is “very important,” he said that “we never consider it, because we are not able to really explain [it].”
Overall, he concluded that, on the basis of these results, he would agree with the notion that it is better to propose a rechallenge with anti-EGFR treatment as the fourth-line therapy in this patient population, before administering regorafenib.
Ducreux explained that, after a partial response, tumors acquire resistance to EGFR inhibitors through alterations and mutations that occur during treatment, via nongenetic mechanisms, and through treatment-induced selection for preexisting mutations.
Previous work has shown that mutations, such as in the RAS gene, are detectable early during EGFR inhibitor therapy, but that they then decay exponentially once the drugs are stopped, with the potential that tumors regain their sensitivity to them.
Germani said that this means that ctDNA-guided retreatment with anti-EGFR therapies is a “promising approach” in pretreated patients with RAS and BRAF wild-type mCRC, and that the sequencing of the drugs may be important. Indeed, the REVERCE trial showed that giving regorafenib followed by the anti-EGFR drug cetuzximab was associated with longer overall survival than the other way around in anti-EGFR medication-naive patients.
Methods and Results
For PARERE, the researchers enrolled patients aged at least 18 years with RAS and BRAF wild-type mCRC who were previously treated with a first-line anti-EGFR-containing regimen and had at least a partial response or stable disease for at least 6 months.
The patients were also required to have had at least one intervening anti-EGFR-free line of therapy, and to have previously received treatment with fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenics. At least 4 months were required to have passed between the end of anti-EGFR administration and screening for the study.
In all, 428 patients were screened between December 2020 and December 2024, with 213 patients with RAS and BRAF wild-type mCRC, as detected on ctDNA, enrolled. They were randomized to panitumumab or regorafenib until first progression, followed by regorafenib, if they started on panitumumab, or panitumumab, if they started on regorafenib, until second progression.
The median age of the patients was 61 years among those who started on panitumumab and 64 years among those initially given regorafenib in the trial, and 63% and 57%, respectively, were male. The median number of prior lines of therapy was two in both groups, and 65% and 69%, respectively, had received pantitumumab as their first-line anti-EGFR.
Initial findings from the study presented at the 2025 ASCO Annual Meeting indicated that, after a median follow-up of 23.5 months, there was no significant difference in the median first PFS between the two treatment arms.
However, patients who started with panitumumab had a significant improvement in both the objective response and disease control rates (P < .001), as well as a signal for a potentially longer median second PFS, than those who started with regorafenib, particularly on the per-protocol analysis.
Presenting the overall survival results, Germani said that there was no significant difference between the groups on the intention-to-treat analysis, at a stratified hazard ratio of 1.13 (P = .440), or on the per-protocol analysis, at a hazard ratio of 1.07 (P = .730).
“We then ran a subgroup analysis,” he continued, “and we found out that an anti-EGFR-free interval before liquid biopsy shorter than 6 months was associated with less benefit from a panitumumab [first] sequence, which is biologically sound.”
It was also observed that women did significantly better when having panitumumab first, whereas men did not, for which “we do not have a clear biological explanation,” Germani added.
Confining the analysis to so-called “hyperselected” patients, who not only were RAS and BRAF wild type but also had no pathogenic mutations associated with anti-EGFR resistance, did not reveal any significant overall survival differences between the treatment groups.
However, Ducreux took issue with the way in which hyperselection, which is turning up more and more regularly in trials, is defined, as the choice of which mutations to include varies widely. He suggested that a consensus group be assembled to resolve this issue.
Looking more broadly, the researchers were able to show that, in this updated analysis, anti-EGFR re-treatment was superior to regorafenib regardless of the treatment sequence in terms of PFS, at 4.2 months vs 2.4 months (P = .103) when given first in the trial, and 3.9 months vs 2.7 months (P = .019) when given second in the trial, as well as in terms of objective response and disease control rates.
Adverse Events
In terms of safety, the results showed that, as expected, acneiform rash, fatigue, and hypomagnesemia were the most common adverse events associated with panitumumb, while those with regorafenib were fatigue, hand-foot skin reactions, and hypertension.
There were no notable differences in the number of patients receiving a post-study treatment nor in the post-study therapeutic choices, between the study arms.
The study was sponsored by GONO Foundation and partially supported by Amgen and Bayer. Germani declared having relationships with MSD and Amgen. Ducreux declared having relationships with Amgen, Bayer, BeiGene, Incyte, Jazz, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Roche, Servier, Keocyt, AbbVie, Abcely, Arcus, Bayer, BMS, Boehringer, GlaxoSmithKline, Sanofi, Scandion, and Zymeworks.
A version of this article first appeared on Medscape.com.
FROM ENDO 2025