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In the later-line treatment of metastatic colorectal cancer (CRC), options become more limited and are often guided by prior therapies and biomarker status. Michael J. Overman, MD, associative vice president of research, Cancer Network, Division of Cancer Medicine and professor at The University of Texas MD Anderson Cancer Center, moderated the discussion at a live Case-Based Roundtable event in Dallas, Texas. Overman detailed the use of liquid and tumor biopsies for rapid molecular profiling to inform frontline decisions. He also reviewed key third-line regimens, and the consideration of anti-EGFR rechallenge in selected patients.

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CASE SUMMARY

• A 58-year-old female teacher was diagnosed with metastatic CRC 3 years ago. The primary tumor was in the sigmoid colon with metastatic lesions in the liver and peritoneal implants.
• Tumor genomics: microsatellite stable (MSS), RAS wild type, BRAF wild type, HER2 negative, low tumor mutational burden
• Medical history: controlled hypertension, type 2 diabetes, and history of deep vein thrombosis 5 years ago

Treatment

• Received folinic acid/fluorouracil/oxaliplatin/bevacizumab in first line with initial partial response; progression after 11 months of therapy; during treatment patient experienced grade 2 peripheral neuropathy, which stabilized with oxaliplatin dose reduction
• Received folinic acid/fluorouracil/irinotecan/cetuximab in second line with initial disease control; progression after 8 months of therapy; patient experienced grade 1 skin rash that was managed with topical treatments
• Currently, patient reports grade 1 fatigue that worsens toward the end of each treatment cycle and grade 1 myelosuppression. Last imaging showed mixed response with no new lesions.
• ECOG performance status: 1 (intermittently grade 2 for several days after each chemotherapy cycle)

Laboratory results

• White blood cell count: 3.2 x 10⁹/L
• Hemoglobin: 10.2 g/dL
• Platelets: 95 x 10⁹/L
• Alanine aminotransferase: 65 U/L
• Aspartate aminotransferase: 58 U/L

Targeted Oncology: What testing do you normally get for patients with CRC such as this?

Michael J. Overman, MD: At MD Anderson Cancer Center, we do a lot of testing, but we do liquid biopsy to get at that issue so that we get a molecular test back quickly. We also do the tumor because it’s bigger, so we do both. That’s not [the most] health economic but that’s our approach to getting it because of the issue of, by the time you get your NGS, you already started therapy…. I don’t know if a lot of people do that, if you have the same issue in the front line for liquid biopsy these days. I think it’s even more relevant now because of the BRAF mutations. Now BRAF [inhibition] is frontline therapy.

How does circulating tumor DNA (ctDNA) factor in in these kinds of cases where there’s mixed response?

For colon cancer, we have carcinoembryonic antigen [CEA], which is a pretty good surrogate. I think ctDNA would probably be a more accurate surrogate, if you had it, but you’d have to be tracking it over time. We do a ton of minimal residual disease testing.

The best data, I think, on treatment, is immunotherapy [IO]-based data. There are some really good IO data with ctDNA, I think a good early predictor of IO benefit and addresses that pseudo-progression issue that sometimes can come up. The data are really good there. I think on systemic therapy, it’s a good readout. It’s just a more accurate CEA, to some degree. Right now, how much is it an aid to what you already have? I don’t know if we do it in the metastatic setting for following; we do it for profiling up front. That’s where we try to get our HER2 amplification, BRAF, or NRAS testing, and be able to make a frontline decision by doing liquid biopsy. But it does get you to where you end up doing both. If we have time to wait, then just do tumor biopsy and wait. That’s fine, but often they don’t want to wait 3 to 4 weeks.

What are the second-line therapy options for this patient with metastatic CRC?

In the NCCN, we have the biomarker-directed therapies for HER2, KRAS G12C, BRAF, and more in the frontline. For previous therapy [with oxaliplatin and irinotecan], we have fruquintinib [Fruzaqla], regorafenib [Stivarga], trifluridine/tipiracil [Lonsurf], and trifluridine/tipiracil/bevacizumab. That would be the third-line options.

The treatment here that I don’t think they list that we sometimes do is the anti-EGFR re-challenge. In this case, the patient had second-line EGFR treatment, but if they had frontline EGFR, [it might be an option]. There are small data sets for EGFR rechallenge. They’re smaller randomized studies, but there are some; the data are definitely much more solid for treatments such as trifluridine/tipiracil/bevacizumab or fruquintinib. I can talk about regorafenib, but regorafenib has some issues.

We would say our approach would be time off from prior EGFR treatment, and then we often do a liquid biopsy to make sure they don’t have any persistent MAP kinase alterations. The data are clear that if a patient has a persistent RAS or MAP kinase alteration, they don’t get benefit. So that would be our approach, and response rates have been pretty consistent, [up to] 20% for EGFR rechallenge in that setting.¹ It’s something we do consider in a certain setting. But I would probably put it later [rather] than earlier. The one thing where we do use it is that EGFR rechallenge does give them a response, whereas some of these agents are…more cytostatic, so you get more survival benefit, but not response benefit. So if you really need a response, then that sometimes is something we consider for that sole reason.

How often are you seeing KRAS G12C and NTRK mutations in these patients?

It’s rare; it’s [around 3%].² It’s a rare kind of KRAS variant in colon cancer. The NTRK and the other fusions are really rare. The fusions tend to be more common in patients with microsatellite instability [MSI].³ So MSI patients tend to have a much higher fusion rate than MSS. In standard colon cancer, it’s less than 1% but it’d be a little more common in MSI. I have seen them. NTRK [inhibitors] do work, but it’s super rare.

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_{DISCLOSURES: Overman previously reported consulting for 3T Biosciences, Agenus, Array, Bayer, Gritstone, Janssen, Merck, Merus, Pfizer, Summit Therapeutics, and Takeda, and grants/research support from Bristol Myers Squibb, Lilly, Medimmune, Merck, Nouscom, Phanes, Roche, and Takeda.}

_References:

_{1. Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat Med. 2022;28(8):1612-1618. doi:10.1038/s41591-022-01886-0}

_{2. Strickler JH, Yoshino T, Stevinson K, et al. Prevalence of KRAS G12C mutation and co-mutations and associated clinical outcomes in patients with colorectal cancer: A systematic literature review. Oncologist. 2023;28(11):e981-e994. doi:10.1093/oncolo/oyad138}

_{3. Wang H, Li ZW, Ou Q, et al. NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability. Cancer Med. 2022;11(13):2541-2549. doi:10.1002/cam4.4561}