First-Line mCRC Treatment Must Encompass Individualized Approach

Axel Grothey, MD

In an effort to improve patient outcomes and develop a clearer understanding of the biology of metastatic colorectal cancer (mCRC), researchers are working on more individualized approaches that will increase efficacy yet also aid in quality of life.

“We tailor our treatment approach according to the needs of the patient,” explained Axel Grothey, MD. “We utilize the different treatments we have to serve different purposes.”

Grothey lectured on frontline therapy and maintenance strategies in mCRC during the 2017 OncLive State of the Science Summit (SOSS) on Gastrointestinal Malignancies.

One innovative approach was discussed during the 2017 Gastrointestinal Cancers Symposium, where results of a randomized phase II trial demonstrated that the addition of vemurafenib (Zelboraf) to the standard combination of irinotecan and cetuximab (Erbitux) prolonged progression-free survival (PFS) in patients with BRAF-mutant mCRC.

In the study, which evaluated 106 patients, the median PFS improved from 2.0 months in the arm randomized to cetuximab and irinotecan to 4.4 months in patients assigned to the combination plus vemurafenib. Future analyses will include overall survival.

OncLive: Please provide an overview of your presentation on mCRC.

In an interview with OncLive during the SOSS meeting, Grothey, a medical oncologist at Mayo Clinic, expressed the need for tailoring treatments for patients with mCRC in the first-line setting, the debate over tumor sidedness in mCRC, and what ongoing research in the field might reveal over the next year.Grothey: There are a great variety of different agents that we have available right now. We need to make sense of which combinations we use for which clinical setting. Not every patient needs the same treatment, and we’ve known this for quite some time.

Obviously, individualized therapy did not start with the KRAS mutational analysis. We need to tailor our therapies according to patient needs, and we make use of treatment combinations that we have available in our armamentarium.

Before we start treatment for a patient with palliative intent, we have to keep in mind that the goal of palliation is to keep patients alive with a good quality of life for as long as possible. Treatment intensity is very important; first-line therapy is the longest time the patient is on therapy. When I talk to patients, I explain treatment algorithms and plan for the future because metastatic disease patients will more or less be on therapy for the rest of their life with breaks in between. I tell them, “This is not a sprint; it’s a marathon.”

What is the importance of molecular testing in this field?

We should not burn bridges early on by blasting a patient with too much treatment unnecessarily; we tailor treatment according to patient needs. In an elderly patient with low-volume disease, we don’t need a response to make a difference. Patients can benefit from something as easy as capecitabine/bevacizumab (Avastin) versus a more aggressive combination therapy. For other patients who have disease that is symptomatic where we need a response, we might need a chemotherapy triplet. BRAF-mutant tumors need to be counteracted by more aggressive therapy. This all needs to be taken into account.We do test patients’ tumors routinely for KRAS, NRAS, and HRAS mutations. We know that, in patients who have activating mutations, these genes do not benefit from EGFR antibodies. Cetuximab and panitumumab (Vectibix) do not work in these BRAF V600E-mutant tumors. We refine the treatment approach in the first-line setting according to individual patient characteristics, molecular tumor characteristics and, most recently, sidedness.

We know that right-sided and left-sided tumors have different prognoses. Right-sided tumors do poorer than left-sided tumors, but there is also a predictive component in all of this—not just prognostic. The right-sided tumors do not benefit from EGFR therapy and that is on top of the mutational analysis we are doing. We have right-sided tumors that are RAS wild-type and BRAF wild-type.

What highlights came out of the 2017 Gastrointestinal Cancers Symposium?

In some ways, it’s a little bit embarrassing that, in the area of next-generation sequencing, we come down to right versus left as a factor to determine our treatment decisions. Just from an intellectual curiosity, it would be nice to see why right-sided tumors are not responsive to this antibody therapy. We will probably see some more data coming out in the future that will, hopefully, go beyond just right versus left. That is embarrassing for the 21st century. The highlight really was the presentation by Dr Scott Kopetz in BRAF V600E tumors, which make up 8% to 10% of mCRCs. We recently did a Mayo Clinic analysis that showed the median survival with BRAF V600E tumors is about 14 months compared with 40 months in those who did not have those mutant tumors. It’s a big difference; that is a patient population with an unmet need.

We have the same population in melanoma and thyroid cancers. At least in melanoma, you have a BRAF inhibitor and it works. You have 80% responses that are not necessarily longer lasting; however, when you combine BRAF inhibition with MEK inhibition, it sometimes has longer-lasting responses.

We used the same approach in CRC with the same mutation and same drugs, and it doesn’t work. We have learned that it’s not just the mutation, but also the histologic contexts that can influence what you really need to do to inhibit this pathway.

What do you think we might know a year from now in terms of the discussion of tumor sidedness?

The first randomized trial looked at vemurafenib added to cetuximab and irinotecan in BRAF-mutant mCRC. With the addition of this drug, all of a sudden, the PFS doubled with a hazard ratio of 0.42. That’s a pretty impressive biologic effect. Having said that, the median improvement was only 2 months so we’re still at an unmet need situation. In this 100-patient, phase II study, there is a proof of principle, but we need to do better. We need to use this platform to rationally design treatment approaches for these patients. In 1 year from now, I hope that we will find the molecular basis for these sidedness results. Right now, it’s frustrating to see that it is a sidedness issue. But, in all honesty, if you look at the beauty of sidedness, it’s such an easy biomarker. You don’t need gene expression profiling or a complicated genetic mutation analysis. You would have a marker of information that can guide your therapy.

What are the most important things for community oncologists to take away from this area of research?

The data that we have right now—the lack of efficacy of an EGFR antibody—only applies to first-line treatment. The NCCN adopted this and put in the guideline that right-sided tumors should not be treated with an EGFR antibody in the first-line setting. From a biologic perspective, why would it be better in second- and third-line treatment? But, the guidelines committee was leaving a door open. There might be some patients who have right-sided tumors and might benefit, so we can’t completely close the door right now unless you have a better way to identify these patients. If we have a patient who is asymptomatic from the disease, we don’t need a tumor response; we can ride the wave of less toxic or a nontoxic therapy. In contrast, for patients who need a response, we might use an EGFR antibody or a triplet approach. Those are important decisions for patients—keeping in mind that quality of life is a very important point.

There are about 15% to 20% of patients right now where we identify for certain molecular markers that might be candidates for more targeted approaches. That includes immunotherapy, which we know is active in mismatch repair (MMR)-deficient and microsatellite instability-high tumors. I can easily see that, in a short time, these approaches will move into first-line treatment.

Since these only affect 15% to 20% of patients right now, the majority will still rely on good old chemotherapy and anti-VEGF therapy in frontline. Hopefully, we will chip away on this empirical approach and refine a patient population that can benefit from these targeted approaches.

What ongoing trials are you looking forward to seeing the results of?

There is a big discussion between when to use EGFR-targeted and when to use VEGF-targeted therapies. We have refined the patient population that can benefit from cetuximab and panitumumab based on mutation status. It’s important that we do that because with the side effects of the treatment—rash and diarrhea—there is a stigmatization of patients. They lose their normal appearance and they’re stigmatized in their social environment; that is not easy to justify unless it serves a purpose. We need to make a case for EGFR antibodies: when do they need to be used?Right now, there are a lot of trials moving into first-line treatment. There is a trial in development from the National Cancer Institute looking at immunotherapy with or without chemotherapy as first-line treatment. There are trials that look at HER2-targeted agents. We are also looking at these agents in the adjuvant setting, which is very interesting.

We just completed accrual for the large phase III IDEA (International Duration Evaluation of Adjuvant Chemotherapy; NCT00958737) Collaboration trial of adjuvant therapy of 12,000 patients to do a non-inferiority analysis of 6 months versus 3 months of combination chemotherapy.

We will have that at the 2017 ASCO Annual Meeting, which will hopefully show that half the duration of adjuvant therapy is noninferior to the longer duration that we normally try to administer to patients. That could cut down on side effects, health costs, and it would really change the standard of care for adjuvant therapy. Let’s cross our fingers and hope that this is true.

Kopetz S, McDonough S, Morris V, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 2017;35 (suppl 6S; abstr 520).