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ONCAlert | Upfront Therapy for mRCC

Case 3: KRAS-Mutated Metastatic Colon Cancer

Targeted Oncology
Published Online:1:31 PM, Wed November 21, 2018

Michael Morse, MD: For the third case, I’d like to present a woman with metastatic colorectal cancer that was KRAS-mutated. In March of 2016, she presented, otherwise healthy, on a referral to a gastroenterologist for a colonoscopy, which showed a 2-cm mass in the sigmoid colon that was invading the muscularis propria into the adjacent pericolorectal tissue. A biopsy confirmed it was poorly differentiated and was felt to be stage III. Molecular testing showed it to be positive for a KRAS exon 2 codon 12 mutation, but there were no mutations in NRAS, BRAF, or PIK3CA, and this was microsatellite stable. Shortly thereafter, she underwent a resection, with complete resection of disease. Following that, she received 6 months of adjuvant CAPEOX [capecitabine plus oxaliplatin].

In May of 2017, at her 12-month follow-up, it was noted that her CEA [carcinoembryonic antigen] level was 146. A CT scan of the abdomen, pelvis, and chest showed multiple small bilateral lung nodules, less than 5 mm. Her performance status [PS] remained at 0. She was then initiated with FOLFOX [folinic acid, fluorouracil, and oxaliplatin] plus bevacizumab, which she was tolerating well, and she subsequently continued maintenance bevacizumab.

Six months further, her CEA level was now normalized to 2.2 and a CT scan showed a reduction in the lung lesions. Subsequently, she began complaining of a dry cough and shortness of breath on exertion. Her CEA had increased to 25.3. A CT scan of the chest, abdomen, and pelvis showed that there was progression of 2 lung lesions in the right pulmonary lobe. FOLFIRI [folinic acid, fluorouracil, and irinotecan] was initiated while bevacizumab was continued.

Unfortunately, the CEA continued to rise and was now 99. A CT scan of the chest, abdomen, and pelvis showed progression of lung disease, a new lesion in the liver that was in close proximity to the bile duct, and diffuse peritoneal disease. Her performance status had now declined to a PS of 1. Nonetheless, she continued to work but sometimes had to leave early because of fatigue. She’d now like to know her options for additional therapy. She would like to avoid infusion-based therapy and its associated toxicities.

Let’s first look at some data around next-generation sequencing. This study asked whether it was actually beneficial or just an economic burden in the community oncology practice setting. This was a retrospective chart analysis of cancer patients treated at a large community practice. The data were collected on 209 patients who had next-generation sequencing in 2015 and 2016. Thirty-one of these patients had colorectal cancer. The question was whether there was a change in management based on the NGS testing. The results demonstrated that there was, in fact, not a change in management. In some cases, there was no change in management because patients had a poor performance status and, therefore, were not going to be candidates for additional therapies. But in the large majority of cases, there was a lack of a target or a drug that could be used to treat those patients.

The next study is a therapeutic one. This is the regorafenib pivotal trial, the CORRECT trial, which was a multicenter, randomized, placebo-controlled phase III clinical trial that compared regorafenib plus best supportive care with placebo in patients who had progressed on a standard chemotherapy such as fluorouracil, oxaliplatin, irinotecan, anti-VEGF therapy, and, if appropriate, anti-EGFR therapy.

The results showed that there was a median overall survival of 6.4 months for regorafenib versus 5 months for placebo, which was statistically significant. Of course, adverse events were seen in a large number of patients in both arms of the study. The most common grade 3 adverse events were hand–foot skin reaction, fatigue, diarrhea, hypertension, and rash. Because of these toxicities, the question has been asked: Is there an alternate strategy for initiating regorafenib that might be more tolerable for patients and allow them to continue on the drug longer? So this study, which was performed in the ACCRU Network, was a randomized phase II trial that looked at 2 different dosing strategies for regorafenib in patients with refractory metastatic colorectal cancer. It was called the ReDOS trial. In this study, patients were randomized to start regorafenib at 80 mg a day and increase weekly to eventually reach the full dose, 160 mg, if they had no toxicities, or to start at the standard dose of 160 mg. Both strategies gave patients the standard 3-weeks-on, 1-week-off regimen of regorafenib.

There was a further randomization that looked at whether preemptive clobetasol or reactive clobetasol would also alter the hand–foot skin reaction. In this study, it was called the palmar-plantar erythrodysesthesia syndrome. However, the primary endpoint for the study was the proportion of patients who had completed 2 cycles of regorafenib and were able to initiate the third cycle.

Interestingly, and this was not a primary endpoint of the trial, there was a trend toward better overall survival for the patients who initiated the regorafenib at 80 mg and escalated to tolerance compared to those patients who started at the full dose. The interpretation of this was that starting at a lower dose and escalating was certainly no worse for patients; it might even be better. Regarding toxicities, the severest of toxicities were less common in patients who had the full dose.

The take-home message of this study was that dose escalation of the regorafenib was certainly not inferior to using a full dose to start, and more patients were able to get to the third cycle of regorafenib if they used the dose-escalation strategy. From a tolerability standpoint, it was well tolerated to use the dose escalation strategy.

I’d also like to address the other oral therapy that is available for patients who have progressed through the standard fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and, if appropriate, anti-VEGF therapy—TAS-102 [trifluridine/tipiracil].

In the RECOURSE trial, a randomized phase III clinical trial, patients with advanced colorectal cancer with a good performance status of 0 or 1 who had received at least 2 prior regimens of standard chemotherapy and were refractory to or were failing all the of the following therapies—fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy—if they were RAS wild-type, they were randomized to TAS-102, which is a combination of trifluridine/tipiracil, plus best supportive care versus placebo plus best supportive care. The primary endpoint was overall survival and secondary endpoints were progression-free survival, safety, and tolerability.

The results of the study showed that the overall survival favored TAS-102, with a 7.2-month median overall survival compared to a 5.2-month median survival for placebo, with a hazard ratio of 0.69. The toxicities of this drug are primarily related to bone marrow and neutropenia. Thirty-eight percent of patients had grade 3/4 neutropenia with TAS-102 versus, of course, none with best supportive care. Also, 18% of patients had grade 3/4 anemia and 5% had grade 3/4 thrombocytopenia with TAS-102.

Transcript edited for clarity.

Michael Morse, MD: For the third case, I’d like to present a woman with metastatic colorectal cancer that was KRAS-mutated. In March of 2016, she presented, otherwise healthy, on a referral to a gastroenterologist for a colonoscopy, which showed a 2-cm mass in the sigmoid colon that was invading the muscularis propria into the adjacent pericolorectal tissue. A biopsy confirmed it was poorly differentiated and was felt to be stage III. Molecular testing showed it to be positive for a KRAS exon 2 codon 12 mutation, but there were no mutations in NRAS, BRAF, or PIK3CA, and this was microsatellite stable. Shortly thereafter, she underwent a resection, with complete resection of disease. Following that, she received 6 months of adjuvant CAPEOX [capecitabine plus oxaliplatin].

In May of 2017, at her 12-month follow-up, it was noted that her CEA [carcinoembryonic antigen] level was 146. A CT scan of the abdomen, pelvis, and chest showed multiple small bilateral lung nodules, less than 5 mm. Her performance status [PS] remained at 0. She was then initiated with FOLFOX [folinic acid, fluorouracil, and oxaliplatin] plus bevacizumab, which she was tolerating well, and she subsequently continued maintenance bevacizumab.

Six months further, her CEA level was now normalized to 2.2 and a CT scan showed a reduction in the lung lesions. Subsequently, she began complaining of a dry cough and shortness of breath on exertion. Her CEA had increased to 25.3. A CT scan of the chest, abdomen, and pelvis showed that there was progression of 2 lung lesions in the right pulmonary lobe. FOLFIRI [folinic acid, fluorouracil, and irinotecan] was initiated while bevacizumab was continued.

Unfortunately, the CEA continued to rise and was now 99. A CT scan of the chest, abdomen, and pelvis showed progression of lung disease, a new lesion in the liver that was in close proximity to the bile duct, and diffuse peritoneal disease. Her performance status had now declined to a PS of 1. Nonetheless, she continued to work but sometimes had to leave early because of fatigue. She’d now like to know her options for additional therapy. She would like to avoid infusion-based therapy and its associated toxicities.

Let’s first look at some data around next-generation sequencing. This study asked whether it was actually beneficial or just an economic burden in the community oncology practice setting. This was a retrospective chart analysis of cancer patients treated at a large community practice. The data were collected on 209 patients who had next-generation sequencing in 2015 and 2016. Thirty-one of these patients had colorectal cancer. The question was whether there was a change in management based on the NGS testing. The results demonstrated that there was, in fact, not a change in management. In some cases, there was no change in management because patients had a poor performance status and, therefore, were not going to be candidates for additional therapies. But in the large majority of cases, there was a lack of a target or a drug that could be used to treat those patients.

The next study is a therapeutic one. This is the regorafenib pivotal trial, the CORRECT trial, which was a multicenter, randomized, placebo-controlled phase III clinical trial that compared regorafenib plus best supportive care with placebo in patients who had progressed on a standard chemotherapy such as fluorouracil, oxaliplatin, irinotecan, anti-VEGF therapy, and, if appropriate, anti-EGFR therapy.

The results showed that there was a median overall survival of 6.4 months for regorafenib versus 5 months for placebo, which was statistically significant. Of course, adverse events were seen in a large number of patients in both arms of the study. The most common grade 3 adverse events were hand–foot skin reaction, fatigue, diarrhea, hypertension, and rash. Because of these toxicities, the question has been asked: Is there an alternate strategy for initiating regorafenib that might be more tolerable for patients and allow them to continue on the drug longer? So this study, which was performed in the ACCRU Network, was a randomized phase II trial that looked at 2 different dosing strategies for regorafenib in patients with refractory metastatic colorectal cancer. It was called the ReDOS trial. In this study, patients were randomized to start regorafenib at 80 mg a day and increase weekly to eventually reach the full dose, 160 mg, if they had no toxicities, or to start at the standard dose of 160 mg. Both strategies gave patients the standard 3-weeks-on, 1-week-off regimen of regorafenib.

There was a further randomization that looked at whether preemptive clobetasol or reactive clobetasol would also alter the hand–foot skin reaction. In this study, it was called the palmar-plantar erythrodysesthesia syndrome. However, the primary endpoint for the study was the proportion of patients who had completed 2 cycles of regorafenib and were able to initiate the third cycle.

Interestingly, and this was not a primary endpoint of the trial, there was a trend toward better overall survival for the patients who initiated the regorafenib at 80 mg and escalated to tolerance compared to those patients who started at the full dose. The interpretation of this was that starting at a lower dose and escalating was certainly no worse for patients; it might even be better. Regarding toxicities, the severest of toxicities were less common in patients who had the full dose.

The take-home message of this study was that dose escalation of the regorafenib was certainly not inferior to using a full dose to start, and more patients were able to get to the third cycle of regorafenib if they used the dose-escalation strategy. From a tolerability standpoint, it was well tolerated to use the dose escalation strategy.

I’d also like to address the other oral therapy that is available for patients who have progressed through the standard fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and, if appropriate, anti-VEGF therapy—TAS-102 [trifluridine/tipiracil].

In the RECOURSE trial, a randomized phase III clinical trial, patients with advanced colorectal cancer with a good performance status of 0 or 1 who had received at least 2 prior regimens of standard chemotherapy and were refractory to or were failing all the of the following therapies—fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy—if they were RAS wild-type, they were randomized to TAS-102, which is a combination of trifluridine/tipiracil, plus best supportive care versus placebo plus best supportive care. The primary endpoint was overall survival and secondary endpoints were progression-free survival, safety, and tolerability.

The results of the study showed that the overall survival favored TAS-102, with a 7.2-month median overall survival compared to a 5.2-month median survival for placebo, with a hazard ratio of 0.69. The toxicities of this drug are primarily related to bone marrow and neutropenia. Thirty-eight percent of patients had grade 3/4 neutropenia with TAS-102 versus, of course, none with best supportive care. Also, 18% of patients had grade 3/4 anemia and 5% had grade 3/4 thrombocytopenia with TAS-102.

Transcript edited for clarity.
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