Benjamin A. Weinberg, MD, FACP

Throughout the oncology landscape we are trying to incorporate immunotherapy into the treatment paradigm, and while this has been very successful in certain types of cancer (e.g. melanoma, lung cancer, and kidney cancer), colorectal cancer has been mostly left behind by the immunotherapy revolution to date. In a phase II single-arm study out of China, Lin and coworkers added camrelizumab, an anti-PD-1 monoclonal antibody, to neoadjuvant CAPOX chemotherapy following short-course radiation for patients with locally advanced rectal cancer. Of 27 evaluable patients, 13 had a pathological complete response (pCR, 48.1%), all but one of whom were mismatch repair proficient and unlikely to respond to immunotherapy. This small study laid the groundwork for an ongoing, randomized phase III study which is designed to demonstrate a significant increase in the pCR rate compared to standard neoadjuvant long-course chemoradiation and chemotherapy.

Finally, there has been excitement in the advanced setting of adding regorafenib, an oral poly-tyrosine kinase inhibitor, to immune checkpoint inhibitors for patients with mismatch repair proficient disease. Japanese data suggested a benefit from this combination which has not been fully borne out in the American experience. Yang and coauthors retrospectively analyzed the experience of regorafenib plus immune checkpoint inhibitors in mismatch repair proficient metastatic colorectal cancer patients at 14 Chinese medical centers and determined that the objective response rate in 82 patients was only 5% with a 45% stable disease rate. However, the median duration of disease control (stable disease or better) was 6.3 months which is clinically meaningful in this population. Moreover, 65% of patients have liver metastases which have proven to be more refractory to this combination in the American data. While we await more prospective studies of this combination, we continue to hold out hope that it may be a novel therapeutic option which is so desperately needed for patients with metastatic colorectal cancer.

Throughout the oncology landscape we are trying to incorporate immunotherapy into the treatment paradigm, and while this has been very successful in certain types of cancer (e.g. melanoma, lung cancer, and kidney cancer), colorectal cancer has been mostly left behind by the immunotherapy revolution to date. In a phase II single-arm study out of China, Lin and coworkers added camrelizumab, an anti-PD-1 monoclonal antibody, to neoadjuvant CAPOX chemotherapy following short-course radiation for patients with locally advanced rectal cancer. Of 27 evaluable patients, 13 had a pathological complete response (pCR, 48.1%), all but one of whom were mismatch repair proficient and unlikely to respond to immunotherapy. This small study laid the groundwork for an ongoing, randomized phase III study which is designed to demonstrate a significant increase in the pCR rate compared to standard neoadjuvant long-course chemoradiation and chemotherapy.

Finally, there has been excitement in the advanced setting of adding regorafenib, an oral poly-tyrosine kinase inhibitor, to immune checkpoint inhibitors for patients with mismatch repair proficient disease. Japanese data suggested a benefit from this combination which has not been fully borne out in the American experience. Yang and coauthors retrospectively analyzed the experience of regorafenib plus immune checkpoint inhibitors in mismatch repair proficient metastatic colorectal cancer patients at 14 Chinese medical centers and determined that the objective response rate in 82 patients was only 5% with a 45% stable disease rate. However, the median duration of disease control (stable disease or better) was 6.3 months which is clinically meaningful in this population. Moreover, 65% of patients have liver metastases which have proven to be more refractory to this combination in the American data. While we await more prospective studies of this combination, we continue to hold out hope that it may be a novel therapeutic option which is so desperately needed for patients with metastatic colorectal cancer.

Throughout the oncology landscape we are trying to incorporate immunotherapy into the treatment paradigm, and while this has been very successful in certain types of cancer (e.g. melanoma, lung cancer, and kidney cancer), colorectal cancer has been mostly left behind by the immunotherapy revolution to date. In a phase II single-arm study out of China, Lin and coworkers added camrelizumab, an anti-PD-1 monoclonal antibody, to neoadjuvant CAPOX chemotherapy following short-course radiation for patients with locally advanced rectal cancer. Of 27 evaluable patients, 13 had a pathological complete response (pCR, 48.1%), all but one of whom were mismatch repair proficient and unlikely to respond to immunotherapy. This small study laid the groundwork for an ongoing, randomized phase III study which is designed to demonstrate a significant increase in the pCR rate compared to standard neoadjuvant long-course chemoradiation and chemotherapy.

Finally, there has been excitement in the advanced setting of adding regorafenib, an oral poly-tyrosine kinase inhibitor, to immune checkpoint inhibitors for patients with mismatch repair proficient disease. Japanese data suggested a benefit from this combination which has not been fully borne out in the American experience. Yang and coauthors retrospectively analyzed the experience of regorafenib plus immune checkpoint inhibitors in mismatch repair proficient metastatic colorectal cancer patients at 14 Chinese medical centers and determined that the objective response rate in 82 patients was only 5% with a 45% stable disease rate. However, the median duration of disease control (stable disease or better) was 6.3 months which is clinically meaningful in this population. Moreover, 65% of patients have liver metastases which have proven to be more refractory to this combination in the American data. While we await more prospective studies of this combination, we continue to hold out hope that it may be a novel therapeutic option which is so desperately needed for patients with metastatic colorectal cancer.

The tide may finally be shifting as drugs targeting specific KRAS mutations have made their way into the clinic, and there is particular excitement around the oral WEE1 inhibitor, adavosertib (AZD1775). WEE1 is a cell cycle regulatory protein and WEE1 inhibition may have increased activity in tumors with DNA repair deficiency. In a phase 2 maintenance study, Seligmann and colleagues randomized 69 patients with RAS- and TP53-mutated mCRC with stable disease or better after 16 weeks of induction chemotherapy 2:1 to receive adavosertib vs active monitoring. Median progression-free survival (mPFS) was significant improved with adavosertib (3.61 vs 1.68 months), and patients with left-sided primary tumors appears to derive more benefit. While this finding needs to be further explored in larger clinical trials, it is exciting that there may finally be a new treatment option for patients with this specific molecular subtype of mCRC.

Another maintenance mCRC trial of interest is the PANAMA trial, a phase 2 study in which 248 patients with RAS wild-type mCRC were randomized 1:1 to 5-fluorouracil/leucovorin with or without panitumumab, an anti-epidermal growth factor receptor antibody, following induction chemotherapy with 6 cycles FOLFOX/panitumumab. Modest and co-workers report that mPFS was significantly improved with continuing panitumumab in the maintenance setting (8.8 vs. 5.7 months), and there was a trend towards an overall survival benefit as well. This study further supports continuing anti-EGFR therapy with maintenance chemotherapy for patients with RAS wild-type mCRC.

Finally, in stage III CRC, there is a big movement towards using circulating tumor DNA (ctDNA) as a method to monitor disease recurrence by detecting minimal residual disease based on tumor DNA being shed into the bloodstream. Henriksen et al. evaluated 168 patients with stage III CRC who underwent surgical resection and plasma ctDNA testing using 16 patient-specific DNA variants (tumor tissue-informed testing). The rates of recurrence were much higher in patients with detectable ctDNA post-operatively and/or after the completion of adjuvant chemotherapy, whereas those patients with persistently undetectable ctDNA did not recur. ctDNA is a powerful new technology that we are still learning how to best harness in the clinic, and this study demonstrates its prognostic value and potential ability to detect recurrence prior to standard imaging surveillance. Moreover, the rate of ctDNA rise was also prognostic of survival. ctDNA testing is likely to become standard of care in the management of stage II/III colorectal cancer in the very near future, and we hope that eventually it may be able to predict who needs to receive adjuvant chemotherapy and who does not.

The tide may finally be shifting as drugs targeting specific KRAS mutations have made their way into the clinic, and there is particular excitement around the oral WEE1 inhibitor, adavosertib (AZD1775). WEE1 is a cell cycle regulatory protein and WEE1 inhibition may have increased activity in tumors with DNA repair deficiency. In a phase 2 maintenance study, Seligmann and colleagues randomized 69 patients with RAS- and TP53-mutated mCRC with stable disease or better after 16 weeks of induction chemotherapy 2:1 to receive adavosertib vs active monitoring. Median progression-free survival (mPFS) was significant improved with adavosertib (3.61 vs 1.68 months), and patients with left-sided primary tumors appears to derive more benefit. While this finding needs to be further explored in larger clinical trials, it is exciting that there may finally be a new treatment option for patients with this specific molecular subtype of mCRC.

Another maintenance mCRC trial of interest is the PANAMA trial, a phase 2 study in which 248 patients with RAS wild-type mCRC were randomized 1:1 to 5-fluorouracil/leucovorin with or without panitumumab, an anti-epidermal growth factor receptor antibody, following induction chemotherapy with 6 cycles FOLFOX/panitumumab. Modest and co-workers report that mPFS was significantly improved with continuing panitumumab in the maintenance setting (8.8 vs. 5.7 months), and there was a trend towards an overall survival benefit as well. This study further supports continuing anti-EGFR therapy with maintenance chemotherapy for patients with RAS wild-type mCRC.

Finally, in stage III CRC, there is a big movement towards using circulating tumor DNA (ctDNA) as a method to monitor disease recurrence by detecting minimal residual disease based on tumor DNA being shed into the bloodstream. Henriksen et al. evaluated 168 patients with stage III CRC who underwent surgical resection and plasma ctDNA testing using 16 patient-specific DNA variants (tumor tissue-informed testing). The rates of recurrence were much higher in patients with detectable ctDNA post-operatively and/or after the completion of adjuvant chemotherapy, whereas those patients with persistently undetectable ctDNA did not recur. ctDNA is a powerful new technology that we are still learning how to best harness in the clinic, and this study demonstrates its prognostic value and potential ability to detect recurrence prior to standard imaging surveillance. Moreover, the rate of ctDNA rise was also prognostic of survival. ctDNA testing is likely to become standard of care in the management of stage II/III colorectal cancer in the very near future, and we hope that eventually it may be able to predict who needs to receive adjuvant chemotherapy and who does not.

The tide may finally be shifting as drugs targeting specific KRAS mutations have made their way into the clinic, and there is particular excitement around the oral WEE1 inhibitor, adavosertib (AZD1775). WEE1 is a cell cycle regulatory protein and WEE1 inhibition may have increased activity in tumors with DNA repair deficiency. In a phase 2 maintenance study, Seligmann and colleagues randomized 69 patients with RAS- and TP53-mutated mCRC with stable disease or better after 16 weeks of induction chemotherapy 2:1 to receive adavosertib vs active monitoring. Median progression-free survival (mPFS) was significant improved with adavosertib (3.61 vs 1.68 months), and patients with left-sided primary tumors appears to derive more benefit. While this finding needs to be further explored in larger clinical trials, it is exciting that there may finally be a new treatment option for patients with this specific molecular subtype of mCRC.

Another maintenance mCRC trial of interest is the PANAMA trial, a phase 2 study in which 248 patients with RAS wild-type mCRC were randomized 1:1 to 5-fluorouracil/leucovorin with or without panitumumab, an anti-epidermal growth factor receptor antibody, following induction chemotherapy with 6 cycles FOLFOX/panitumumab. Modest and co-workers report that mPFS was significantly improved with continuing panitumumab in the maintenance setting (8.8 vs. 5.7 months), and there was a trend towards an overall survival benefit as well. This study further supports continuing anti-EGFR therapy with maintenance chemotherapy for patients with RAS wild-type mCRC.

Finally, in stage III CRC, there is a big movement towards using circulating tumor DNA (ctDNA) as a method to monitor disease recurrence by detecting minimal residual disease based on tumor DNA being shed into the bloodstream. Henriksen et al. evaluated 168 patients with stage III CRC who underwent surgical resection and plasma ctDNA testing using 16 patient-specific DNA variants (tumor tissue-informed testing). The rates of recurrence were much higher in patients with detectable ctDNA post-operatively and/or after the completion of adjuvant chemotherapy, whereas those patients with persistently undetectable ctDNA did not recur. ctDNA is a powerful new technology that we are still learning how to best harness in the clinic, and this study demonstrates its prognostic value and potential ability to detect recurrence prior to standard imaging surveillance. Moreover, the rate of ctDNA rise was also prognostic of survival. ctDNA testing is likely to become standard of care in the management of stage II/III colorectal cancer in the very near future, and we hope that eventually it may be able to predict who needs to receive adjuvant chemotherapy and who does not.

Emerging data have helped to elucidate the real world experience of regorafenib vs trifluridine/tipiracil in the third-line setting. In a single-institution retrospective study, Patel and colleagues evaluated 126 patients who received trifluridine/tipiracil and 95 patients who received regorafenib. There were higher response and disease control rates seen with trifluridine/tipiracil, although median overall survival was similar (7.5 vs 7.1 months). These findings are limited by the single-institution, retrospective and non-randomized nature of the study. Also, the better-tolerated ReDOS dose-escalation schema for regorafenib was not utilized in this study, and it would be interesting to see how this novel dosing strategy compares to trifluridine/tipiracil in the real world setting.

Immunotherapy with anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibodies has proven to be very effective in the rare group of patients with mCRC harboring deficiencies in mismatch repair, but has unfortunately largely fallen short for the vast majority of patients with mismatch repair proficient cancers. Martinelli et al. looked at adding avelumab, and anti-PD-L1 antibody, to cetuximab in an effort to rechallenge patients with RAS wild-type disease to anti-EGFR therapy in the single-arm phase 2 CAVE trial. 77 patients were treated and the median overall survival was an impressive 11.6 months, increasing to 17.3 months in patients with circulating tumor DNA (ctDNA) that was wild-type for both RAS and BRAF. This study suggests that rechallenging with anti-EGFR therapy can be effective in a ctDNA-selected population and that immunotherapy may have a role to play in this setting, although these findings would need to be confirmed in a larger, randomized phase 3 trial.

Finally, the COVID-19 pandemic has upended medical care, including oncology care. Thierry and co-workers evaluated the effect on the pandemic lockdown in France by looking at the baseline levels of ctDNA in 80 patients with newly diagnosed mCRC presenting pre-lockdown vs. post-lockdown. They showed that median ctDNA was much higher post-lockdown (119.2 vs 17.3 ng/mL), implying that delays in diagnosis related to the pandemic led to more advanced mCRC, at least in terms of ctDNA level. This study adds to the growing literature demonstrating that COVID-19 will continue to have effects on cancer care and cancer-related mortality for years to come.

Emerging data have helped to elucidate the real world experience of regorafenib vs trifluridine/tipiracil in the third-line setting. In a single-institution retrospective study, Patel and colleagues evaluated 126 patients who received trifluridine/tipiracil and 95 patients who received regorafenib. There were higher response and disease control rates seen with trifluridine/tipiracil, although median overall survival was similar (7.5 vs 7.1 months). These findings are limited by the single-institution, retrospective and non-randomized nature of the study. Also, the better-tolerated ReDOS dose-escalation schema for regorafenib was not utilized in this study, and it would be interesting to see how this novel dosing strategy compares to trifluridine/tipiracil in the real world setting.

Immunotherapy with anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibodies has proven to be very effective in the rare group of patients with mCRC harboring deficiencies in mismatch repair, but has unfortunately largely fallen short for the vast majority of patients with mismatch repair proficient cancers. Martinelli et al. looked at adding avelumab, and anti-PD-L1 antibody, to cetuximab in an effort to rechallenge patients with RAS wild-type disease to anti-EGFR therapy in the single-arm phase 2 CAVE trial. 77 patients were treated and the median overall survival was an impressive 11.6 months, increasing to 17.3 months in patients with circulating tumor DNA (ctDNA) that was wild-type for both RAS and BRAF. This study suggests that rechallenging with anti-EGFR therapy can be effective in a ctDNA-selected population and that immunotherapy may have a role to play in this setting, although these findings would need to be confirmed in a larger, randomized phase 3 trial.

Finally, the COVID-19 pandemic has upended medical care, including oncology care. Thierry and co-workers evaluated the effect on the pandemic lockdown in France by looking at the baseline levels of ctDNA in 80 patients with newly diagnosed mCRC presenting pre-lockdown vs. post-lockdown. They showed that median ctDNA was much higher post-lockdown (119.2 vs 17.3 ng/mL), implying that delays in diagnosis related to the pandemic led to more advanced mCRC, at least in terms of ctDNA level. This study adds to the growing literature demonstrating that COVID-19 will continue to have effects on cancer care and cancer-related mortality for years to come.

Emerging data have helped to elucidate the real world experience of regorafenib vs trifluridine/tipiracil in the third-line setting. In a single-institution retrospective study, Patel and colleagues evaluated 126 patients who received trifluridine/tipiracil and 95 patients who received regorafenib. There were higher response and disease control rates seen with trifluridine/tipiracil, although median overall survival was similar (7.5 vs 7.1 months). These findings are limited by the single-institution, retrospective and non-randomized nature of the study. Also, the better-tolerated ReDOS dose-escalation schema for regorafenib was not utilized in this study, and it would be interesting to see how this novel dosing strategy compares to trifluridine/tipiracil in the real world setting.

Immunotherapy with anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibodies has proven to be very effective in the rare group of patients with mCRC harboring deficiencies in mismatch repair, but has unfortunately largely fallen short for the vast majority of patients with mismatch repair proficient cancers. Martinelli et al. looked at adding avelumab, and anti-PD-L1 antibody, to cetuximab in an effort to rechallenge patients with RAS wild-type disease to anti-EGFR therapy in the single-arm phase 2 CAVE trial. 77 patients were treated and the median overall survival was an impressive 11.6 months, increasing to 17.3 months in patients with circulating tumor DNA (ctDNA) that was wild-type for both RAS and BRAF. This study suggests that rechallenging with anti-EGFR therapy can be effective in a ctDNA-selected population and that immunotherapy may have a role to play in this setting, although these findings would need to be confirmed in a larger, randomized phase 3 trial.

Finally, the COVID-19 pandemic has upended medical care, including oncology care. Thierry and co-workers evaluated the effect on the pandemic lockdown in France by looking at the baseline levels of ctDNA in 80 patients with newly diagnosed mCRC presenting pre-lockdown vs. post-lockdown. They showed that median ctDNA was much higher post-lockdown (119.2 vs 17.3 ng/mL), implying that delays in diagnosis related to the pandemic led to more advanced mCRC, at least in terms of ctDNA level. This study adds to the growing literature demonstrating that COVID-19 will continue to have effects on cancer care and cancer-related mortality for years to come.