Bekaii-Saab Covers Trials in the Second Line for a Patient With CRC

During a Targeted Oncology^TM Case-Based Roundtable event, Tanios S. Bekaii-Saab, MD, professor, Mayo Clinic College of Medicine and Science, discussed the factors that may influence treatment for a 50-year-old patient with KRAS/BRAF wild-type colorectal cancer as well as the treatment options available.

Targeted Oncology^TM: What are the elements that influence your treatment choices for metastatic colorectal cancer?

BEKAII-SAAB: There are a number of elements, starting with patient-related characteristics: comorbidities, prior adjuvant therapy, age. Patients above the age of 70 may have issues with more aggressive chemotherapy, and we have to be careful with how we treat them. That doesn’t mean they wouldn’t benefit from more intense chemotherapy, but FOLFOXIRI [fluorouracil, leucovorin, oxaliplatin, and irinotecan] would not be indicated for someone above the age of 75.

Tumor location [right-sided vs left-sided], resectability, and tumor burden are also characteristics to be considered.

The presence of certain molecular characteristics also influences treatment decisions. My preference is to do complete next-generation sequencing [NGS], but if you had to have the 4 most important genetic elements, they would be RAS [and KRAS], BRAF, HER2, and microsatellite instability [MSI]. For example, MSI determines who receives immunotherapy in the first line.

HER2 amplifications are very important, and their importance is not just linked to the fact that they may help you assess the need for HER2-targeted therapies at some point beyond first-line treatment. They are useful in the first line, because most overexpression of HER2 is on the left side, where EGFR inhibitors may [be effective]. HER2-amplified tumors do not respond to EGFR inhibitors. If anything, there are hints that there may be some detrimental effect from HER2-targeted therapy, similar to EGFR inhibitors in RAS-mutated tumors. So EGFR inhibitors may do worse in the context of HER2 amplification.

Can you comment on the different NGS tests?

The FoundationOne [sequencing test] is great, but it misses about 25% of fusions. If you were to be lucky enough in the next year to encounter an NTRK fusion, there’s a good chance you may miss it, using this test. This is because FoundationOne does not include RNA-sequencing, while Tempus, Caris, and others do. Commercially, it’s more challenging for them to do it.

What is your opinion about using circulating tumor DNA (ctDNA) tests to assess for response to treatment?

I obtain both a tissue sample and a liquid sample at the same time, right away, for every patient I see. I do have concern for the timeliness of the tests. There are limitations with the reimbursements; however, the Guardant360 [ctDNA sequencing test] has an approval now, which allows us to use it. For the common mutations [RAS, RAF, and HER2], it’s highly sensitive. For MSI, it’s less sensitive, and that is where you want to wait for results from tissue. With ctDNA testing, fusions are completely missed, because they don’t assess RNA and are not highly sensitive for fusions.

Once you have treated a patient, you can certainly assess for ctDNA sequentially. The challenge is, how do you make sense out of the data clinically? It can be difficult if you don’t have trials that are guided by ctDNA. It is probably less useful as the disease progresses, but it is still feasible. Sequential ctDNA assessments may signal an opportunity when you can rechallenge with EGFR inhibitors. On rare occasions, I have found emerging treatment targets while employing this method.

Do you obtain these when you find radiographic progression, or on a set interval?

Only on progression, not at set intervals; it would probably be quite a waste if we did that. I obtain them at disease progression because some of the clonal changes may be indicative. For example, sometimes you lose HER2 amplification, or part of HER2 amplification. We’ve sometimes seen MET amplification go up, which can predict for resistance for EGFR [inhibitors], even in the RAS wild-type. There’s quite a bit of utility to it in some ways. But overall, especially in a busy practice, unless you have access to additional trials, it may be tough to make sense out of the data.

The National Comprehensive Cancer Network [NCCN] guidelines pretty much summarize everything I’ve discussed.¹ Pembrolizumab [Keytruda] is listed as the first-line treatment for MSI-high tumors.

What treatment would you consider next, and what influences your decision?

Everyone relies a little bit differently on scans, CEA [carcinoembryonic antigen], and symptoms; and everyone weighs 1 parameter a bit more heavily than the others.

This next step is technically third-line treatment, because the patient had prior CAPEOX and FOLFOXIRI; however, you could argue that this is second line in metastatic cancer.

In the poll, 80% of participants said you would start regorafenib [Stivarga], and 20% would start an EGFR inhibitor.

What data back up the use of regorafenib for this patient?

A study that contributed to the approval of regorafenib is the CORRECT trial [NCT01103323]. It showed a median overall survival [mOS] advantage over placebo [mOS 6.4 vs 5.0 months (HR, 0.77; 95% CI, 0.64-0.94; P = .0052)], and a median progression-free survival [mPFS] advantage [mPFS, 1.9 vs 1.7 months (HR, 0.49; 95% CI, 0.42-0.58; P < .0001)].2 Some of the limiting factors with regorafenib are its toxicities, specifically hand-foot syndrome, fatigue, and gastrointestinal toxicities, which have limited the usage of the 160-mg dose.

We’ve had the discussion about how especially on the right side, EGFR inhibitors appear to be less effective even in the refractory setting; in fact, they may be harmful in the early stage. There is a Japanese study called REVERCE—a large study, but not large enough—which randomized patients to regorafenib followed by cetuximab [Erbitux], or cetuximab followed by regorafenib. It showed if you treat with regorafenib first, you end up with a survival benefit over if you treat with cetuximab first [mOS, 17.4 vs 11.6 months (HR, 0.61; 95% CI, 0.39-0.96; P < .0293)].3 Other parameters were close to a wash. We have a study ongoing in the United States called REVERCE II [NCT04117945] that is looking at the same question, accruing data nicely through our research network. We may have some United States-based data in the next year and a half or so.

Would you ever consider using an EGFR inhibitor for a right-sided tumor, further down the line?

Yes, I would, after regorafenib, whether before TAS-102 [Lonsurf] or not. I’ve done it both ways, and most patients haven’t had a response, but a couple of patients had nice responses. For those patients, after chemotherapy, after regorafenib, I would challenge them with cetuximab first, before going to TAS-102. [I would] keep them on it for 2 months and then scan. But if they’re deteriorating more quickly, I may scan, if the insurance allows it, in 6 weeks.

What is your protocol in dosing regorafenib?

We published a study addressing this question a couple of years ago, in Lancet Oncology. It’s called ReDOS, which is a regorafenib dose-optimization study [NCT02368886].⁴ For arm A, we started regorafenib 80 mg daily for one week, then increased the daily dose by 40 mg each week, as tolerated, up to 160 mg. The other arm [B] was given a standard dose of 160 mg per day. Medication was given for 21 days of the 28-day cycle. Whatever dose the patients best tolerated on arm A was the dose they took going into cycle 2 and beyond, so there was no further escalation. The primary end point of the study was the proportion of patients who completed 2 cycles, and then started the third cycle. The point of this study was to assess if patients would better tolerate the treatment, and would have some measurable benefit. Our statistics supported arm A being superior, meaning the dose-escalation strategy was superior in terms of what percentage of patients ended up in cycle 3, vs the standard 160 mg dosing strategy. This was a positive study, with 43% of the patients—almost half— being able to start cycle 3 on the dose escalation strategy vs only a quarter of the patients started on 160 mg [P = .028].⁴ We were pleasantly surprised to see that the OS was also better with the dose escalation strategy, 10 vs 6 months with standard dosing. It was very intriguing, and it also makes sense in some ways. These are agents that have a short half-life, and during the first 2 months of therapy you need some predictable dosing to have an effect. When you start high, you lose quite a bit of the predictability of the continuous dosing, and this where, I think, patients may lose in terms of outcome. This has been integrated into the NCCN guidelines1, and I know that the company has been trying to put it in the label.

When do you consider using TAS-102?

TAS-102 is part of the superfamily of fluoropyrimidines. The tipiracil component protects trifluridine, a fluoropyrimidine, from degradation. It essentially supports its use beyond 5-FU failure. The study that led to the approval of this agent is the RECOURSE trial [NCT01607957], showing a mOS that was favorable for TAS-102 vs placebo [mOS, 7.1 vs 5.3 months (HR, 0.68; 95% CI, 0.58-0.81; P < .001)]; same for PFS [mPFS, 2.0 vs 1.7 months (HR 0.48; 95% CI, 0.41-0.57; P < .001)].^5,6

The toxicities were primarily neutropenia, leukopenia, and thrombocytopenia. In fact, 4% of patients had febrile neutropenia and were admitted and treated with antibiotics.⁵ So, this is a cytotoxic agent. Regorafenib has a different profile, as it is a multi-kinase inhibitor. This one seems to do what you would expect from chemotherapy, the other one seems to do what you expect from tyrosine kinase inhibitors.

We recently published a network meta-analysis in the Oncologist that made indirect comparisons among all the randomized studies with regorafenib and TAS-102, based on the control arms. What we found is that regorafenib, dosed at 160 mg, and TAS-102 have about the same efficacy, which was not surprising. Of note, we found that the dose escalation strategy for regorafenib, as described in the ReDOS study, is superior to best supportive care, regorafenib 160 mg, or TAS-102.⁷ In our clinic, that has become the preferred way to administer regorafenib and move forward.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 2.2021. Accessed July 28, 2021. https://bit.ly/3lEhx2q}

_{2. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomized, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X}

_{3. Shitara K, Yamanaka T, Denda T, et al. REVERCE: a randomized phase II study of regorafenib followed by cetuximab vs the reverse sequence for previously treated metastatic colorectal cancer patients. Ann Oncol. 2019;30(2):259-265. doi:10.1093/annonc/mdy526}

_{4. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4}

_{5. Mayer RJ, Van Cutsem E, Falcone A, et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi:10.1056/NEJMAoa1414325}

_{6. Van Cutsem E, Mayer RJ, Laurent S, et al; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) vs placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018;90:63-72. doi:10.1016/j.ejca.2017.10.009}

_{7. Sonbol MB, Benkhadra R, Wang Z, et al. A systematic review and network meta-analysis of regorafenib and TAS-102 in refractory metastatic colorectal cancer. Oncologist. 2019;24(9):1174-1179. doi:10.1634/theoncologist.2019-0189}