Biologics are credited with increasing median overall survival in colorectal cancer to approximately 30 months. Their optimal use was discussed by Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, in an article he coauthored for the Journal of Oncology Practice 1 with Amit Mahipal, MBBS, MPH, and in an interview with The ASCO Post.
Selecting Patients for Treatment
Biologics are given on top of a chemotherapy backbone. What guides your selection of this backbone?
In older patients, we look at patient characteristics—performance status, comorbidities—and in all patients, we look at whether they had adjuvant therapy. If they were previously treated with oxaliplatin, they may have developed neuropathy, and we would not use this drug again as our first choice. We also wouldn’t want to use oxaliplatin in a patient with underlying diabetic neuropathy. And in a patient with inflammatory bowel disease, we would stay away from irinotecan, which can cause severe diarrhea in some patients.
Amit Mahipal, MBBS, MPH
It’s also important for physicians to be familiar with the regimen and know how to handle it. For example, patients can tolerate first-line oxaliplatin for about 4 to 6 months before developing neuropathy, but progression-free survival after first-line therapy is typically 9 to 11 months, so you should not treat with oxaliplatin until disease progression. You have to find a way to mitigate toxicity, and for this we implement a “stop and go” strategy, in which we stop the oxaliplatin and put the patient on maintenance with fluorouracil (5-FU) or capecitabine and commonly bevacizumab (Avastin). If patients experience disease progression, we can reintroduce oxaliplatin or switch to irinotecan. It depends on when disease progression occurs. If maintenance therapy controls the disease longer—for 6 months or more—and patients don’t have neuropathy, you may be able to safely reuse oxaliplatin.
Who Benefits From EGFR Inhibitors?
The main biologics are the epidermal growth factor receptor (EGFR) inhibitors and bevacizumab. How do you choose between them?
Two large head-to-head phase III trials and one smaller phase II trial attempted to answer this question, and their outcomes were conflicting.2-4 If efficacy is roughly the same, we have to rely on certain parameters in selecting one or the other. First, mutually exclusive molecular markers can identify patients who will not benefit from EGFR antagonists: RAS mutations (50%–55% of patients), BRAF mutations (8%–10%), and HER2 amplification (2%). Therefore, you simply cannot give EGFR antibodies to more than 60% of patients because they don’t benefit.
Sidedness is now playing a role in the selection of biologics, thus raising the percentage of patients we eliminate from a first-line EGFR antibody to about 70%.— Axel Grothey, MD
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A second group of patients who do not benefit from EGFR inhibitors are those with tumors located in the right side of the colon. This discovery was revolutionary! I personally did not believe these data initially, because I thought this idea was implausible, but it has been a consistent finding.
We are now diving deeper into the molecular pathways that are activated in right- vs left-sided tumors and have also found the microbiome is probably different, as well as immunogenicity (right-sided tumors appear to be more immunogenic). So, sidedness is now playing a role in the selection of biologics, thus raising the percentage of patients we eliminate from a first-line EGFR antibody to about 70%.
These factors aside, in your article you noted that bevacizumab tends to be your preferred treatment. When do you opt for an EGFR antibody?
Interestingly, for the 25% of patients in whom we can use EGFR inhibitors, we are likely to see a larger delta in terms of benefit, because it’s a refined population. EGFR antibodies do work in the right population, as characterized by higher response rates and more anatomic tumor shrinkage than we see with bevacizumab. This can play a role in the patient with symptomatic disease and a large tumor volume who needs a response or in the patient with almost an obstructing tumor where surgery is warranted, since you can’t use bevacizumab in these patients (or in those with a propensity for bleeding). In these situations, EGFR antibodies can be considered the default treatment, but it’s not the only choice.
In the right patient population—left-sided, wild-type RAS and BRAF, and HER2-negative tumors—it’s probably better to use an EGFR antibody….— Axel Grothey, MD
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The European guidelines more or less mandate EGFR antibodies for patients with left-sided RAS/BRAF wild-type tumors, but the National Comprehensive Cancer Network® (NCCN®) leaves this open. Personally, I’m in between these two approaches. In the right patient population—left-sided, wild-type RAS and BRAF, and HER2-negative tumors—it’s probably better to use an EGFR antibody, unless the situation is clearly palliative or the patient has low-volume metastatic disease.
For patients who are not threatened by metastatic disease and have a good chance at long-term survival, using initial chemotherapy plus bevacizumab and incorporating maintenance, with bevacizumab used beyond disease progression (shown to improve outcomes), is an effective, usually well-tolerated treatment strategy.
Treatment Beyond Disease Progression
Can you tell us more about treatment beyond disease progression?
The toxicity profile of bevacizumab lends itself to continued treatment, and its clinical synergy with fluoropyrimidines is an ideal prerequisite for an induction/maintenance approach. We don’t have similar data for EGFR antibodies as maintenance therapy and also see skin rash with these drugs, which makes them difficult to use in the long term.
We also are beginning to see data suggesting that continued treatment with cetuximab (Erbitux) in RAS wild-type patients can trigger selection pressure on the tumor and the development of RAS mutations. Cancers are genetically unstable and can mutate over time, or subclones that carry RAS/BRAF mutations obtain a growth advantage and populate the tumor. There are clones that evade treatment, so EGFR antibodies stop working. We don’t yet know whether these mutations will disappear when we take away the selection pressure and whether we then can use an EGFR antibody again.
When to Avoid EGFR Inhibitors
It is recommended to avoid the use of EGFR antibodies with capecitabine. Do you agree?
Yes. The interesting thing is that bevacizumab is combination-agnostic: It doesn’t matter what fluoropyrimidine you use it with. But there are studies with EGFR antibodies showing they may be antagonistic when added to capecitabine. Most notably, the COIN trial, which evaluated the addition of cetuximab to FOLFOX (5-FU, leucovorin, oxaliplatin) and CAPOX (capecitabine, oxaliplatin), found a benefit to adding cetuximab to FOLFOX but not CAPOX.5 A Scandinavian trial also found no benefit in adding cetuximab to bolus 5-FU.6
I wrote an editorial for the Journal of Clinical Oncology trying to explain the unexplainable.7 Is it about overlapping toxicity or pharmacokinetic factors? We haven’t teased this out, but we just don’t use an EGFR antibody with capecitabine.
Cetuximab or Panitumumab?
How do you choose between cetuximab and -panitumumab?
The package inserts are different regarding dosing. For cetuximab, it says to give a loading dose, then administer it weekly, but in practice we give cetuximab every other week to level these doses out. Panitumumab (Vectibix) is approved by the U.S. Food and Drug Administration for every-other-week dosing. Cetuximab is a chimeric antibody, whereas panitumumab is a fully human antibody, so there are some differences in allergic reactions to these drugs, particularly in the “tobacco belt.” There is a local antigen that primes these patients, and they can be tested for it.
Treatment of BRAF-Mutated Tumors
How do you treat BRAF-mutated patients?
BRAF V600E–mutated tumors are associated with a very poor prognosis, and they need aggressive treatment, as they don’t normally respond to second- and third-line therapies. We want to make all drugs available to all patients, but we can’t really sequence them in this subset. FOLFOXIRI (5-FU, leucovorin, oxaliplatin, irinotecan) plus bevacizumab is a “poor man’s choice.”
We have very exciting data for immunotherapy in the 4% to 5% of patients with mismatch repair–deficient or microsatellite instability–high tumors.— Axel Grothey, MD
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There are some data on an all-targeted triplet that tries to block the MAP kinase signaling pathway, which is activated in this tumor. But although a BRAF inhibitor plus a MEK inhibitor can produce long-term survival in melanoma, in colon cancer it doesn’t work so well because when you block BRAF, there’s a feedback loop back up to the EGFR (which is not present on the surface of melanoma cells). EGFR is then activated, and it overrides the pathway.
We have had success, in the BEACON trial, in patients with BRAF V600E mutations with binimetinib, a MEK inhibitor, plus encorafenib, a BRAF inhibitor, and adding cetuximab.8 We have treated 29 patients, and none have had disease progression. The response rate was 48%, including 3 complete responses. Historically, the median overall survival for patients with BRAF-mutant colon cancer is about 5 to 6 months after second- and third-line treatments. Here, the median progression-free survival was more than 8 months.
Newest Biologics and Immunotherapy
How do you position the newest biologics?
Ramucirumab (Cyramza) and ziv-aflibercept (Zaltrap) are antiangiogenic agents that are—in my eyes—“me too” drugs for bevacizumab. They are approved in the second-line setting, so they compete with bevacizumab beyond disease progression. In the NCCN Guidelines, these options are listed but not preferred over bevacizumab, which is familiar to us and less expensive. Regorafenib (Stivarga), a multikinase inhibitor, is used as salvage therapy, as is TAS-102 (trifluridine and tipiracil, Lonsurf), a cytotoxic agent with which it now “competes.”
What is on the horizon in metastatic colorectal cancer?
We have very exciting data for immunotherapy in the 4% to 5% of patients with mismatch repair–deficient or microsatellite instability–high tumors. At the 2018 ASCO Gastrointestinal Cancers Symposium, we saw data suggesting the combination of checkpoint inhibitors—in this study nivolumab (Opdivo) plus ipilimumab (Yervoy)—may be even better.9
These drugs work quite well in this patient population, and their toxicity profile is relatively benign, so we (and patients) are now questioning whether we should use them in the first-line setting. I have two patients who negotiated with their insurance companies to pay for pembrolizumab (Keytruda) in the first-line setting, and both had complete responses. The ATOMIC study has been initiated to evaluate atezolizumab (Tecentriq) in the adjuvant setting, to see whether it can improve disease-free survival in mismatch repair–deficient colon cancers. This is a very exciting development in colon cancer. ■
DISCLOSURE: Dr. Grothey has had a consulting/advisory role with Genentech, Bayer HealthCare Pharmaceuticals, Sanofi, -Bristol-Myers Squibb, Eli Lilly, Boston Biomedical, and Amgen; has received institutional research funding from Genentech, Bayer HealthCare Pharmaceuticals, Pfizer, Eisai, Sanofi, Eli Lilly, Boston Biomedical, and Boehringer Ingelheim; and has been reimbursed for travel/accommodation expenses from Genentech, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Boston Biomedical, Amgen, and Boehringer Ingelheim.
REFERENCES
1. Mahipal A, Grothey A: Role of biologics in first-line treatment of colorectal cancer. J Oncol Pract 12:1219-1229, 2016.
2. Heinemann V, von Weikersthal LF, Decker T, et al: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3). Lancet Oncol 15:1065-1075, 2014.
3. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. 2014 ASCO Annual Meeting. Abstract LBA3.
4. Schwartzberg LS, Rivera F, Karthaus M, et al: PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin -(mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously treated unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 32:2240-2247, 2014.
5. Maughan TS, Adams RA, Smith CG, et al: Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial. Lancet 377:2103-2114, 2011.
6. Tveit KM, Guren T, Glimelius B, et al: Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: The NORDIC-VII study. J Clin Oncol 30:1755-1762, 2012.
7. Grothey A, Lenz HJ: Explaining the unexplainable: EGFR antibodies in colorectal cancer. J Clin Oncol 30:1735-1737, 2012.
8. Van Cutsem E, Cuyle P-J, Huijberts S, et al: BEACON CRC study safety lead-in in patients with BRAF V600E metastatic colorectal cancer. 2018 Gastrointestinal Cancers Symposium. Abstract 627. Presented January 20, 2018.
9. André T, Lonardi S, Wong M, et al: Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer: First report of the full cohort from CheckMate-142. 2018 Gastrointestinal Cancers Symposium. Abstract 553. Presented January 20, 2018.
