Wainberg Considers More Aggressive Treatment for Patients With BRAF-Mutant CRC


Zev A. Wainberg, MD, recently discussed the treatment considerations and decisions he makes when treating patients with colorectal cancer and hepatocellular carcinoma. Wainberg, co-director of the Gastrointestinal Oncology Program, University of California Los Angeles, explained his treatment decisions based on 2 gastrointestinal case scenarios during a <em>Targeted Oncology</em> live case-based peer perspectives program.

Zev A. Wainberg, MD

Zev A. Wainberg, MD

Zev A. Wainberg, MD, recently discussed the treatment considerations and decisions he makes when treating patients with colorectal cancer and hepatocellular carcinoma. Wainberg, co-director of the Gastrointestinal Oncology Program, University of California Los Angeles, explained his treatment decisions based on 2 gastrointestinal case scenarios during aTargeted Oncologylive case-based peer perspectives program.

Case 1

February 2016

A 53-year-old Caucasian man without a previous colonoscopy presented to his primary care physician complaining of rectal bleeding and abdominal tenderness. His past medical history included hypertension, well controlled on a beta-blocker, and it was noted that his mother died from breast cancer from his family history.

He underwent colonoscopy with a biopsy and an ulcerated nonobstructive mass was noted in the right colon. His pathology results confirmed poorly differentiated adenocarcinoma. His molecular testing was BRAF-mutated, microsatellite stable.

A CT of abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. He was later diagnosed with metastatic adenocarcinoma of the right colon, TIVN0M1.

What factors do you consider when determining systemic therapy for this patient?

There are several options forBRAF-mutant colon cancer, which include FOLFOX-based treatment or fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)-based treatment. FOLFOXIRI is a more aggressive treatment regimen that is represented in the Italian TRIBE study.1We know the value of adding a 3-drug regimen upfront, FOLFOXIRI plus bevacizumab, and the survival advantage, and it should be discussed whether that survival advantage is worth the increase in toxicity. Personally, I think that withBRAF-mutant patients in particular, FOLFOXIRI needs to be considered as an upfront regimen. In the subset analysis of the TRIBE study, the FOLFOXIRI plus bevacizumab regimen was particularly effective in theBRAF-mutant group. Based on that, and the clear understanding thatBRAFis a poor prognostic sign, it is logical to consider a more aggressive treatment approach.

Should the patient have additional genetic testing?

No, he already has aBRAFmutation. Therefore, there is no real value, in this particular case, of adding more molecular data to what we already have.

What is the significance of a right-sided versus a left-sided tumor in terms of response to biologic therapy?

Independent of theBRAFmutation, we know that right-sided patients do more poorly than left-sided patients. That derives from the data of the CALGB/SWOG 80405 study, where you can see the retrospective but clear evidence that there is an improvement in survival in the patients with left-sided tumors.2Those data are compelling enough and we are pleased with those data. The idea that there is value in being more aggressive with the first-line therapy [is consistent with this group of patients], which is why we add irinotecan upfront. That is why FOLFOXIRI is the recommendation.

The patient was started on 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) and bevacizumab (Avastin). His therapy was well tolerated after management of grade 2 neutropenia.

Three months later, his second follow-up scan showed a 35% decrease in 2 of the liver lesions and stability in the lung lesion. He continued on FOLFOX for 6 months and then switched to capecitabine (Xeloda) and bevacizumab due to grade 1 neuropathy.

January 2017

The patient did well radiologically and biochemically; however, 11 months later, he developed intermittent shortness of breath, although he continued his normal activities and had an ECOG performance status of 1. Imaging showed a new 3-mm lung lesion, increased size of the pleural lesion, and stability in the liver lesions.

The patient was treated withirinotecan plus vemurafenib (Zelboraf) plus cetuximab (Erbitux) and did well for 4 months, but then progressed and was started on regorafenib (Stivarga).

What are the choices for therapy at this point?

For second-line treatment, an option could be FOLFIRI with or without bevacizumab. The idea of this would be that, based on the fact that the patient already received FOLFOX plus bevacizumab, you can continue them on second-line treatment with FOLFIRI plus bevacizumab. This concept is based on the TML study.3The study showed that patients who received bevacizumab plus FOLFIRI for second-line therapy did better than patients without bevacizumab.

Another option is FOLFIRI plus cetuximab. Several trials, including the FIRE-3 trial, showed that patients withKRASwild-type could be administered this regimen as an option.4However, theBRAF-mutant patients did not do as well on EGFR inhibitors as non—BRAF-mutated patients.

A third option is irinotecan plus vemurafenib, a BRAFinhibitor. This is an intriguing option because, based on the data from the SWOG 1406 trial, now on the National Comprehensive Cancer Network guidelines, although not approved, the irinotecan plus vemurafenib plus cetuximab did better than without the vemurafenib.5Therefore, that approach is also a very strong consideration.

Others include regorafenib and trifluridine/tipiracil (TAS-102), although I do not believe that this is an option yet at this point in time.

There is 1 international clinical trial that is ongoing, called the BEACON trial, and it is [evaluating encorafenib plus cetuximab plus or minus binimetinib versus investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab] (NCT02928224). It is a different way to blockBRAF-mutant colon cancer. It is a good option for this patient at this point as well.

What is the rationale for starting the patient on regorafenib and at what dose would you start?

At that point, the patient has been through all other approved treatments. He has progressed on irinotecan, vemurafenib, cetuximab, and FOLFOX. So, the rationale is to use regorafenib. The data from the ReDOS trial show that starting on 80-mg dose-escalation strategy was better than starting at a full dose of 160 mg in terms of toxicity.6It is an appropriate regimen, and the time to do it is now.

Case 2

February 2014

A 63-year-old Asian man with chronic hepatitis B virus infection was referred for further imaging studies after suspicious findings on routine ultrasound surveillance for hepatocellular carcinoma (HCC).

Laboratory findings showed: alpha-fetoprotein, 5400 IU/mL; platelets, 230,000 cells/mcL; bilirubin, 1.0 mg/dL; albumin, 3.5 g/dL. There was no hepatic encephalopathy and ascites were not present. His Child-Pugh class was A.

A CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm with no extrahepatic disease. Biopsy findings showed grade 2 HCC with moderate fibrosis. Both lesions were resected with R0 margin.

What is the prognosis of the patient?

The prognosis of the patient is a little better than the average patient with HCC because he has Child-Pugh class A and he is resectable. He also has good hepatic function. But there is no evidence of adjuvant use with HCC. In fact, the largest study that has been done with sorafenib in that setting was negative for any improvements. That was the premise for not administering sorafenib.

August 2016

Routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm and a chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung. The patient was started on sorafenib (Nexavar) 400 mg twice a day and tolerated therapy well after management of grade 1 diarrhea.

What factors do you consider when deciding when to initiate therapy with sorafenib?

When the disease recurred in this patent, and specifically when it metastasized, that is when I would start the patient on the standard of care. The standard of care at this point is sorafenib. The factors that I consider are performance status, whether there are any options available surgically, and what to hope for and achieve with treatment.

Is this patient a good candidate for sorafenib?

Yes, I consider this patient a candidate and [believe] that this is the right next step for this patient. His liver function is still intact, he has a good Child-Pugh A score, and he has evidence of spread of his cancer. All of these factors make this patient a good candidate and it is clear that there is no value in going on with procedures at this point.

How will this change with the availability of lenvatinib (Lenvima)?

Lenvatinib was shown to be noninferior to sorafenib in a recent study, and that will mean that there is now a second option for patients and it will be individualized based on adverse event (AE) profile, which is different between the 2 drugs. Sorafenib [is known for] fatigue, hand/foot syndrome, and things of that nature. Lenvatinib AEs are consistent with more hypertension and diarrhea. So, they have different safety profiles, and everyone is going to be individualizing them based on the AEs.

What are practical strategies to manage toxicities?

The best way to manage these AEs is proactively. So, for hand/foot syndrome, we can give out creams as a recommendation. For hypertension, we give hypertensive drugs as needed. For some of the other strategies, it is dose reduction or dose delays.

August 2017

The patient complains of increasing fatigue and CT scans show widely scattered lung nodules. He had an ECOG performance status of 1.

The patient was started on 160 mg of regorafenib, but he later complained of intermittent diarrhea.

What are the options for therapy?

The options are regorafenib and nivolumab (Opdivo), and both are approved. Regorafenib is proven to have a survival benefit from the RESORCE trial.7Nivolumab was approved based on the CheckMate 040 trial.8We don&rsquo;t have an answer as to which is best because nivolumab, at this point, is often compared with regorafenib. But, that study is ongoing. I can conclude that these are 2 reasonable options and every patient should get both at some point.

There is a question of whether or not the combination of immunotherapy plus these drugs is going to be the way moving forward. This could mean immunotherapy plus sorafenib, nivolumab plus sorafenib, or nivolumab plus regorafenib. These studies are ongoing and they will be coming out in the next year. We can expect some big changes.


  1. Cremolini A, 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.
  2. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1&deg;) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).J Clin Oncol.2016;34(15 suppl; abstr 3504).doi: 10.1200/JCO.2016.34.15_suppl.3504.
  3. Bennouna J, Sastre J, Arnold D, et al; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial. Lancet Oncol. 2013;14(1):29-37. doi: 10.1016/S1470-2045(12)70477-1.
  4. Stintzing S, Miller-Phillips, Modest DP, et al; FIRE-3 Investigators. Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study.Eur J Cancer. 2017;79:50-60. doi: 10.1016/j.ejca.2017.03.023.
  5. Kopetz S, McDonough SL, Karlyle Morris V, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib inBRAF-mutant metastatic colorectal cancer (SWOG 1406).J Clin Oncol. 2017;35(4 suppl; abstr 520).doi: 10.1200/JCO.2017.34_suppl.520.
  6. Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study.J Clin Oncol. 2018;36(4 suppl; abstr 611).doi: 10.1200/JCO.2018.36.4_suppl.611.
  7. Bruix J, Merle P, Granito A, et al. Survival by pattern of tumor progression during prior sorafenib (SOR) treatment in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial comparing second-line treatment with regorafenib (REG) or placebo.J Clin Oncol. 2017;35 (4 suppl; abstr 229). doi: 10.1200/JCO.20135.4_suppl.229.
  8. Crocenzi TS, El-Khoueiry AB, Cheung Yau T, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.J Clin Oncol.2017;35 (15 suppl; abstr 4013). doi: 10.1200/JCO.2017.35.15_suppl.4013.
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