Grothey Discusses Evolving Treatment Options for Colon Cancer

Axel Grothey, MD

Axel Grothey, MD

Axel Grothey, MD, recently shared the treatment considerations and decisions he makes when treating patients with colon cancer. Grothey, a medical oncologist at the West Cancer Center, explained how he would treat these patients based on case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

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 revealed hypertension, which was well controlled on aβ-blocker. His family history revealed that his mother died from breast cancer.

He underwent a colonoscopy with biopsy and an ulcerated nonobstructive mass was noted in the right colon. His pathology results confirmed poorly differentiated adenocarcinoma and molecular testing showed that the tumor wasBRAFV600E mutated and microsatellite stable. A CT of abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. The patient was later diagnosed with metastatic adenocarcinoma of the right colon; T4N0M1.

What are your general impressions of this patient?

This is a 53-year-old patient with colorectal cancer (CRC)—a very young patient—who did not have a colonoscopy, which he probably should have had. He had rectal bleeding and was found to have a right colon mass with aBRAFV600E mutation and was shown to be microsatellite stable. He had multiple liver lesions. This is a case that is set up to be palliative, not surgical. 

His diagnosis is metastatic adenocarcinoma of the right colon, T4N0M1. This could make me believe that this a microsatellite-unstable tumor because the [right-sided] tumors are large, and they don’t necessarily metastasize—only in the later stages. Even if this was an early-stage cancer, we would still do microsatellite instability (MSI) testing.

Do you typically order next-generation sequencing for metastatic CRC?

At Mayo Clinic, most patients get molecular testing in the advanced stages. MSI, however, is considered standard for all patients. There is an adjuvant trial in planning forBRAFV600E—mutant stage III colon cancer led by Memorial Sloan Kettering Cancer Center negotiating whether molecular testing should be standard as well.

Do you wait for results to make first-line treatment decisions?

More and more research and clinical practice are molecularly driven. We try to be better than one-size-fits-all. A lot of people use folinic acid, fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab (Avastin) for these patients, and that is probably not right. We can do better than treating everyone the same way.

One of the reasons why we do molecular testing is to find subgroups like this patient. For example, if you look at patients with a tropomyosin receptor kinase (TRK) fusion in a phase I study, the responses are long lasting when treated with larotrectinib.¹In some responses, this single agent has lasted more than 4 years. That is remarkable. The duration of response has not yet been reached. That is 1 example of where we are with [molecular subgroups]. But the actual frequency of TRK fusions in colon cancer is 0.05%. It is going to be interesting to see how the FDA interprets the data.

We also had the approval of pembrolizumab (Keytruda) for MSI-high cancer—not just for MSI-high colon cancer—for adult and pediatric patients. But there were no kids treated with this agent. Still, the FDA was so bold to expand it to adult and pediatric patients. The FDA is doing things that they have never done before, which I think is remarkable.

When we treat patients with cancer, we move their molecular profiling in a certain direction. We see certain subgroups evolve, which might be tumor heterogenous.

What is the significance of thisBRAFmutation regarding whether to do surgery?

In this case, should we give everyone FOLFOX plus bevacizumab, or should we wait for the results to treat more specifically? Even if this were resectable or borderline-resectable disease, would thisBRAFmutation carry weight in the decision to do surgery? I think it does carry weight. One thing about biologic selection is response to therapy. If you give these patients treatment and they progress, surgery is not going to be helpful. Even if there was limited disease or potential respectability, we need to takeBRAFmutations into account.

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

The TRIBE study compared FOLFOXIRI plus bevacizumab versus folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFOXIRI) plus bevacizumab.²A subanalysis of the trial showed that—independent of the BRAF status—right-sided tumors had survival benefit with the triplet. This is because right-sided tumors have a bad prognosis. Even if you have a non—BRAF-mutant tumor, right-sided tumors still do well. Aggressive tumors need aggressive therapy. It is an unplanned subgroup and is considered exploratory data, but I think we are probably underusing triplets in our first-line management, especially for young patients, as in this case.

When you administer oxaliplatin-based chemotherapy, I will personally never give it more than 4 months or 8 cycles. I will then move to FOLFIRI or some type of maintenance because I am afraid of neurotoxicity. When you give chemotherapy, your first scan shows your best response. The second scan will show a little bit more of a response, and the third scan is typically stable disease. So why would you continue giving the treatment with toxicity and, later, not be able to give oxaliplatin? You have patients who come in with grade 1 toxicity, and the next time you see them, it is grade 3. This is because there is a certain threshold effect where people don’t report their symptoms. The other thing is this “coasting effect” where the patient gets worse when you stop for some time and then it gets better. In 20% to 40% of patients, this will happen. I am very mindful of that.

The patient was started on folinic acid, fluorouracil, irinotecan, and oxaliplatin and bevacizumab. His therapy was well tolerated after management of grade 2 neutropenia, and his second follow-up scan showed a 35% decrease in 2 of the liver lesions and stability in the lung lesion.

He continued on FOLFOXIRI plus bevacizumab for 4 months and then developed grade 1 neuropathy. He then switched to FOLFIRI plus bevacizumab. He did well radiologically and biochemically, but 4 months later he developed intermittent shortness of breath; he continued his normal activities.

Imaging showed a new 3-mm lung lesion with increased size of the pleural lesion and stability of the liver lesions and a pleural effusion. He had an ECOG performance status of 1.

What are the choices for therapy after disease progression?

This patient had some response for a little bit more than half of a year. The National Comprehensive Cancer Network (NCCN) guidelines say to use a BRAF inhibitor plus an anti-EGFR antibody. The committee was pushing to make data from the phase II S1406 trial part of the NCCN guidelines.³Vemurafenib (Zelboraf) is a first-generation BRAF inhibitor, and we know that it does not work as monotherapy for colon cancer. It does, however, work if you give cetuximab (Erbitux) in combination with the agent. Cetuximab alone also doesn’t work. But when you induce molecular biology to combine them, you see that the combination does work.

There was 50% crossover in the S1406 trial and no survival difference, and vemurafenib, I believe, is not the best drug. It is a first-generation BRAF inhibitor—full of sensitivity—and patients cannot go out in the sun. There is a better drug. There was a study that unfortunately never opened in the United States, the BEACON study.⁴The study looks at encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab. There is no chemotherapy at all but rather exploiting molecular biology. It is very interesting. It was compared with the doublet of encorafenib and cetuximab, and standard of care.

If you look at the data for the standard of care, 75% of patients had progression at the first scan. If you look at the survival, the survival of standard of care in the second and third lines is 6 months. That is the current regulatory standard, which is bad. The data for the safety lead-in of 29 patients is unbelievable [for the triplet combination]. There was a 48% response rate, and not a single patient progressed at the first scan. The median survival has not yet been reached. We are now trying to move this regimen to the frontline because chemotherapy doesn’t work as well. If it works that well in second and third lines, it should work even better in frontline. That is a great study, but it works only if we wait for the results from the analysis because if we start treatment with FOLFOX plus bevacizumab, patients don’t qualify for this study. And if they have aBRAFmutation, and that is about 10% to 12% of patients with metastatic colon cancer, I want [to give] this regimen. The toxicity is much less than with the FOLFOXIRI triplet. The interesting thing is that cetuximab has skin rash as one of the adverse events (AEs). But when you combine it with a BRAF inhibitor, there is less skin rash with this combination.

The patient received irinotecan, panitumumab (Vectibix), and vemurafenib. After 6 months, progressive disease was detected on imaging.

What are the choices for therapy at this point?

Clinical trial is always the right answer. The package insert for regorafenib (Stivarga) is wrong. We looked at toxicity and noticed a high rate of hand—foot skin reaction. And the question was, Can gastrointestinal oncologists handle hand–foot skin reaction? The first couple of patients I treated with this drug at a starting dose came back after 2 weeks with blisters on their feet, and they couldn’t walk anymore. It comes rapidly and is a completely different animal.

In the ReDOS study, we looked at lowering the dose.⁵We ran the phase III study with 123 patients treated with 80 mg daily with dose escalation compared with the initial starting dose of 160 mg. The primary endpoint was to see how many patients can stay on treatment longer. There were 2 criteria for patients to move on after 2 cycles: (1) Their 2-month scan was good and they didn’t have progression, and (2) they tolerated it because if they did not tolerate it they would have needed to stop the treatment.

The study met its primary endpoint, with 43% of patients in the dose-escalation arm moving to a third cycle compared with 25% of patients in the 160-mg arm. There is a huge difference. A lot more patients could stay on therapy in the dose-escalation arm. The difference in overall survival was also interesting, although not statistically significant. The current updated data are 10.3 versus 6.0 months, respectively. You can’t say that it is better in terms of survival, but it is definitely not worse. Additionally, the toxicity profile is more favorable. So I would never start the patient with 160 mg.

I would not treat a patient with an ECOG performance status of 2 with regorafenib. Trifluridine/tipiracil (TAS-102; Lonsurf) is easier on the patients, and patients don’t feel this drug [in terms of AEs]. What I worry about is if you give TAS-102 before regorafenib, and patients deteriorate on the therapy, they are no longer candidates for regorafenib. So if a patient is a candidate for regorafenib and TAS-102, I will give regorafenib first and then TAS-102. It makes sense because regorafenib is not a cytotoxic chemotherapy. It allows bone marrow to recover, and the main AE from TAS-102 is bone marrow toxicity.

At some point, there is also the discussion of hospice. It is the worst discussion that you can have with a patient but also the most important one. You need to know when you are done and not treat further. In the end, you are giving toxic placebos, which is not right. My philosophy for treating patients with metastatic colon cancer is, I want to keep you around in good quality of life as long as possible. When you use all the drugs we have, you can keep a patient alive for many years. For me, patients should get as many lines of therapy as make sense.

References:

1. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.
2. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colon 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. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.
4. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colon 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.
5. Kopetz S, McDonough SL, Lenz HJ, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).J Clin Oncol. 2017;35(suppl; abstr 3505). meetinglibrary.asco.org/record/147167/abstract.
6. Cutsem EV, Cuyle PJ, Huijberts S, et al. BEACON CRC study safety lead-in (SLI) in patients withBRAFV600E metastatic colorectal cancer (mCRC): efficacy and tumor markers.J Clin Oncol. 2018;36(suppl 4S; abstr 627). meetinglibrary.asco.org/record/155628/abstract.
7. 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(suppl 4S; abstr 611). meetinglibrary.asco.org/record/155600/abstract.