Then and now: My take on individualizing therapy for progressive colorectal cancer in 2017

By Provided by Clinical Care Options, LLC
Published August 29, 2017

Key Takeaways

John L. Marshall, MD
Chief, Division of Hematology/Oncology
Department of Medicine
Georgetown University Hospital
Washington, DC
John L. Marshall, MD, has disclosed that he has received consulting fees from Amgen, Bayer, Celgene, Genentech, and Taiho and funds for research support from Amgen, Bayer, Genentech, and Taiho.

Case Scenario: Presentation

The patient was a 53-year-old man seeking a second opinion on therapeutic options for his progressive metastatic CRC. He was first diagnosed 3 years earlier with stage III colon cancer, which was treated with surgical resection and adjuvant 5-fluorouracil (5-FU). One year later, he developed a left RAS-mutated liver metastasis, which was resected; he then received 6 months of leucovorin/5-FU/oxaliplatin. However, he developed substantial neuropathy with this adjuvant regimen and discontinued oxaliplatin. One year after his resection, the disease progressed in his liver and he received leucovorin/5-FU/irinotecan plus bevacizumab, followed by 10 months of maintenance bevacizumab plus 5-FU.

When the man presented for my opinion, 2 small lung lesions had been detected 1 month previously. He had 2 high school–aged children and needed to continue working as long as possible. Because of his earlier side effects, he was reluctant to receive more chemotherapy—although he was open to aggressive treatment that would prolong his life. In 2015, I recommended regorafenib at a starting dose of 160 mg based on improved survival rates in the phase III CONCUR and CORRECT trials, as well as the patient's RAS mutation status, treatment history, experience, and preferences.

Treatment in 2017

In 2017, it is standard practice to evaluate microsatellite instability (MSI)/mismatch repair (MMR) deficiency, RAS, and BRAF in all patients diagnosed with CRC. Furthermore, emerging data support assessing HER2 expression.

Although this was not the situation in 2015, I now consider it essential to evaluate a patient's MSI status because this determines whether they could benefit from checkpoint inhibitor therapy. Presently, there are 2 checkpoint inhibitors approved for MSI-high/MMR deficiency CRC that has progressed after treatment with 5-FU, oxaliplatin, and irinotecan. The first is the anti–PD-1 antibody pembrolizumab, which was associated with an ORR of 40% among patients with MMR-deficient CRC vs 0% with MMR-proficient CRC. The second approved checkpoint inhibitor is the anti–PD-1 antibody nivolumab, which was associated with an ORR of 31% among patients with heavily pretreated MSI-high/MMR-deficient metastatic CRC. Based on these results and approvals, checkpoint inhibitor therapy would be appropriate if this patient has MSI-high CRC.

However, if testing reveals that his CRC is not MSI high, his RAS and BRAF status is important for determining whether he could benefit from anti-EGFR agents. When RAS is mutated, these agents should not be used. Furthermore, approximately 8% of patients with wild-type RAS have the BRAF V600E mutation and are therefore unlikely to benefit from anti-EGFR therapy. Testing shows that this patient has a RAS mutation. Because RAS and BRAF mutations are almost mutually exclusive, I would not look further at BRAF status. The RAS mutation rules out anti-EGFR therapy.

Although it is still being investigated, I also would evaluate HER2 for this patient. HER2 overexpression occurs in approximately 6% of CRC cases, and the phase II HERACLES-A trial reported that dual HER2 blockade with trastuzumab and lapatinib was associated with a disease control rate of 70% among 33 patients with heavily refractory, HER2-positive metastatic CRC. Similarly, the phase IIa basket study MyPathway reported that 9 of 13 patients with HER2-altered CRC achieved either a PR or stable disease on trastuzumab plus pertuzumab.

In the future, our treatment options may reflect results from ongoing biomarker-driven basket trials such as TAPUR and NCI-MATCH, which are recruiting participants to evaluate therapies targeted to specific genetic alterations across multiple cancers, including CRC. Both trials are evaluating regimens targeted to patients with a BRAF V600E mutation (eg, vemurafenib and cobimetinib). NCI-MATCH is also evaluating pertuzumab and trastuzumab among patients with HER2 amplification.

Case Scenario: Treatment Selection in 2017

Returning to this case, I would perform more extensive molecular profiling in 2017 (as described above) than was done in 2015. If this patient has non–MSI-high, RAS-mutated disease, I would still recommend treatment with the oral multikinase inhibitor regorafenib at the full dose of 160 mg. Regorafenib was approved in 2012 based on the phase III CORRECT trial, which reported that among patients with metastatic CRC progressing after all available standard therapy was given, regorafenib was associated with a significant improvement in median OS vs placebo (6.4 vs 5.0 months, respectively; P = 0.0052) and PFS (1.9 vs 1.7 months with placebo; P < 0.0001).

Case Scenario: Adverse Event Management

Continuing on with our case, the patient started on regorafenib and returned to the office after 2 weeks of therapy. Although his laboratory assessments were good, he had experienced a loss of appetite, fatigue, and tenderness of his hands and feet that caused him to miss several days of work. His symptoms worsened in the second week of therapy compared with the first.

Managing Adverse Events in 2017

This patient's experience is consistent with the safety profile for regorafenib. In the CORRECT trial, any-grade hand–foot skin reactions were observed in 47% of patients treated with regorafenib vs 8% with placebo. Fatigue and anorexia were also reported at elevated rates with regorafenib.

Because the patient is experiencing a hand–foot skin reaction of grade 2—symptoms that disrupt his normal activities—I would decrease regorafenib by 1 dose level (40 mg) to 120 mg/day and institute supportive measures. This is the same approach I would have taken in 2015 because there have not been any notable developments over the past 2 years in the standard management of adverse events associated with regorafenib.

That said, we anticipate that informative data will emerge from the ongoing phase II ReDOS study. The trial is comparing efficacy, safety, and quality of life among patients with refractory metastatic CRC who are randomly assigned to receive dose-escalated (80-160 mg) or standard-dose regorafenib. Within each arm, the patients are further randomly assigned to either a preemptive or reactive clobetasol arm for hand–foot skin reactions. Although we do not yet have the results, my hope is that the lower dose will maintain efficacy while offering improved tolerability for patients like this gentleman.

©2017 Clinical Care Options, LLC. All Rights Reserved.

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