Morse Gives His Perspective on Lines of Therapy for a Patient With Metastatic Colorectal Cancer

Michael A. Morse, MD

Michael A. Morse, MD

Michael A. Morse, MD, shared his treatment decision-making and the options for therapy for patients with metastatic colorectal cancer. Morse, a professor of medicine in the Department of Surgery at Duke University School of Medicine, explained his treatment decisions in 1 patient with metastatic colorectal cancer who progresses and requires second-line treatment during a recentTargeted Oncologylive case-based peer perspectives dinner.

October 2014

A 69-year-old Caucasian man presented with severe left lower quadrant pain and sought medical treatment after experiencing bloody diarrhea. His past medical history was remarkable for severe hypertension, managed with telmisartan. He is active and can perform daily activities without restrictions.His laboratory findings were remarkable for carcinoembryonic antigen, 6.5 ng/mL. A colonoscopy showed a fungating mass in the sigmoid colon which was biopsied and revealed an invasive poorly differentiated adenocarcinoma. A CT scan of the chest, abdomen, and pelvis showed a 3-cm mass in the right lobe of the liver, 2 masses (2.5 and 6 cm) in the left lobe abutting the left hepatic vein, and a 10-cm mass in the sigmoid colon. These findings were confirmed on FDG-PET scan. His metastatic disease was deemed borderline resectable. Additional molecular testing on the primary tumor was requested and showed that he had an NRAS mutation and was KRAS and BRAF wild-type, as well as microsatellite stable.

TARGETED ONCOLOGY: What are your initial impressions of this patient?

Morse:This patient’s case is one that should be reviewed in a multidisciplinary setting. The liver metastases were deemed borderline resectable after a multidisciplinary review. In this setting, one option is to choose a systemic therapy [that is] most likely to effect tumor regression to allow for an attempt at metastasectomy (so-called conversion therapy).

The second impression is that this is a sigmoid colon lesion (that is, a left-sided primary colon cancer). The patient has aKRASandBRAFwild-type tumor but it isNRAS-mutated, demonstrating the importance of extendedRASsequencing to identify one of the less common mutations. It is important for clinicians to know whatRASmutations are tested at their institution or send-out laboratory because, in some cases, onlyKRASor only codons 12 and 13 are analyzed for mutations, which will miss up to 10% to 15% ofRASmutations, all of which predict resistance to EGFR-targeted therapy.

Treatment was initiated with FOLFOXIRI (fluorouracil [5-FU], folinic acid, oxaliplatin, and irinotecan) plus bevacizumab (Avastin). His hypertension worsened while on bevacizumab, which was managed with the addition of amlodipine (Norvasc).

Following 6 doses of FOLFOXIRI/bevacizumab, the hepatic metastases became resectable. Bevacizumab was held with the last 2 cycles to avoid any risk of wound healing complications. A staged resection of the primary tumor and hepatic metastases was performed. Six doses of modified FOLFOX (mFOLFOX) were administered post-operatively.

TARGETED ONCOLOGY: Why is this patient considered to be borderline resectable?

Morse:He had metastases abutting the hepatic vein and right liver metastases. The surgeons indicated that they wanted to try to preserve that vein if possible and were also concerned about the synchronous presentation of metastases and whether there could be other metastases unappreciated at the time of his imaging. Therefore, the goal was to effect some regression of the known disease and prevent any new metastases from appearing in order to achieve resectability.

TARGETED ONCOLOGY: Why was this patient chosen for FOLFOXIRI/bevacizumab?

Morse:The highest response rates and chance of resectability have been reported with the combination of FOLFOXIRI/bevacizumab. [In the OLIVIA trial,] there was an 81% response rate with FOLFOXIRI/bevacizumab compared with 62% with modified FOLFOX6 [5-FU, folinic acid, oxaliplatin]/bevacizumab. The rate of proceeding to liver resection was 61% with FOLFOXIRI/bevacizumab compared with 49% with mFOLFOX6/bevacizumab. R0 resection—microscopic negative margins—was achieved in 49% with FOLFOXIRI/bevacizumab and in 23% with mFOLFOX6/bevacizumab.¹Further, if resectability was not achieved, it is also the case that the survival is longer in people receiving FOLFOXIRI plus bevacizumab compared with a dual agent chemotherapy plus bevacizumab regimen, such as FOLFIRI plus bevacizumab. For example, in the TRIBE study, the overall survival was greater with FOLFOXIRI/bevacizumab than with FOLFIRI/bevacizumab (29.8 versus 25.8 months).²Nonetheless, for patients who are not going to be candidates for resection, FOLFOX/bevacizumab or FOLFIRI/bevacizumab are still reasonable options because they are less toxic than FOLFOXIRI containing regimens.

August 2015

He continued to be observed following surgery. On restaging CT scans after 6 months, the patient was found to have new hepatic and pulmonary lesions and he reported right upper quadrant pain.

He began treatment with trifluridine/tipiracil (TAS-102; Lonsurf). On day 1 of the third cycle, his absolute neutrophil count (ANC) was 1100, and so he was dose-delayed for a week, at which point the ANC was 1900 and he continued treatment with TAS-102 at the same dose. A PET/CT scan at 3 months showed stable disease, and at 6 months, he reported improvement of his symptoms.

TARGETED ONCOLOGY: After the patient experienced disease progression, why was TAS-102 chosen as a second-line therapy?

Morse:He had received the standard intravenous chemotherapies (fluorouracil, irinotecan, and oxaliplatin) and the biologic bevacizumab. Because of theNRASmutation, they are not candidates for anti-EGFR therapy and there is no data for use of ziv-aflibercept [Zaltrap] or ramucirumab [Cyramza] with irinotecan in patients who have received prior irinotecan. They have a microsatellite stable tumor, so anti—PD-1 therapy with pembrolizumab [Keytruda] or nivolumab [Opdivo] would not be indicated. Selective internal radiation therapy with SIR-Spheres could address the liver metastases but not the lung metastases. Therefore, the remaining FDA-approved treatment options are TAS-102 and regorafenib [Stivarga].

Both have demonstrated prolongation of survival compared with best supportive care/placebo in patients who had progressed on fluoropyrimidines, irinotecan, oxaliplain, an anti-VEGF therapy, and if appropriate, an anti-EGFR therapy.^3,4Although one often thinks of these drugs as third, fourth, or fifth line, there are situations where they are appropriate as early as the second line. Another scenario could be in a person with aRAS-mutated tumor who has had adjuvant therapy with FOLFOX and then progresses and gets FOLFIRI/bevacizumab as their first-line metastatic therapy and progresses. They would also fit the indication for these oral drugs. Because the patient had difficult-to-control hypertension, regorafenib was not the preferred drug as it can cause hypertension, whereas TAS-102 does not.

TARGETED ONCOLOGY: What is your personal experience with TAS-102?

Morse:I have found its efficacy and tolerability very consistent with the FDA-approved labeling. The overall survival was 7.1 months versus 5.3 months [with placebo] in the pivotal trial³and this seems to be the case in our real-world use. TAS-102 has activity regardless of whether or not the colorectal cancer has aRASmutation, because about half the people in the pivotal RECOURSE trial hadRASmutations and still benefited about the same. Mild nausea, fatigue, and diarrhea are frequent, and neutropenia is common, and often requires dose-delays, but does not often require dose-reductions. In the case presented, there was neutropenia when a new cycle was to begin, but after a week, the neutrophil count was above the required threshold of 1500/mm³and they were treated with the same dose. Further, TAS-102 does not cause hand-foot syndrome and seems to have less stomatitis than fluorouracil so we have found it can be used even in people who have had tolerability issues with fluorouracil. TAS-102 also seems to slow the deterioration in performance status that otherwise accompanies progressive colorectal cancer. Our typical patient takes between 2 and 6 cycles and discontinuation is more typically due to progressive disease rather than toxicity.

TARGETED ONCOLOGY: What options are available for this patient should he progress on TAS-102?

Morse:If the patient progresses and still has an adequate performance status, they can still get regorafenib. However, it still might be an issue for this patient due to his hypertension. A clinical trial would be an option and this is a scenario when we frequently will obtain next-generation sequencing to try to identify targetable molecular abnormalities. If he didn’t have a good performance status, then palliative care would be appropriate. A clinical trial would not be an option if the patient has a declining performance status.

References

1. Gruenberger T, Bridgewater J, Chau I, et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial.Ann Oncol.2015;26(4):702-708. doi: 10.1093/annonc/mdu580.
2. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.Lancet Oncol.2015;16(13):1306-1315. doi: 10.1016/S1470-2045(15)00122-9.
3. Mayer RJ, Van Cutsem E, Falcone A, et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer.N Engl J Med. 2015;372(20):1909-1919. doi: 10.1056/NEJMoa1414325.
4. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.Lancet.2013;381(9863):303-312. doi: 10.1016/S0140-6736(12)61900-X.