Recap: Treatment Sequencing and Testing Strategies in HER2+ Colorectal Cancer

During an Around the Practice^® program hosted by CancerNetwork^®, a panel of experts discussed key treatment updates including testing for and treatment of metastatic colorectal cancer (CRC). They reviewed these updates in the context of the treatment landscape and how they might impact clinical practice. The discussion was led by Cathy Eng, MD, a professor of medicine and coleader of the Vanderbilt-Ingram Cancer Center Gastrointestinal Cancer Research Program at Vanderbilt University Medical Center in Nashville, Tennessee.

The panelists included Suneel Kamath, MD, assistant professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Ohio; Michael Foote, MD, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York; Arvind N. Dasari, MD, associate professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston; and Aparna Parikh, MD, a gastrointestinal oncologist at Mass General Cancer Center in Boston, Massachusetts.

Patient Case 1.

Testing Options in CRC

Eng: Can you briefly discuss the current epidemiology data and trends surrounding metastatic CRC in early-onset patients?

Kamath: Unfortunately, [early-]onset CRC [in young patients] is increasingly [becoming] a problem. We know that this is a relatively common disease with around 150,000 cases per year and 52,000 deaths per year.¹ [There is an] increasing share of incidence in young [patients]; 1 in 5 patients is under [50 years old], which is a very concerning trend that we don’t understand all that well, yet.² It is certainly a big area of investigation.

Eng: Can you briefly describe the landscape surrounding HER2-positive metastatic CRC?

Parikh: It’s an exciting time for biomarkers in colon cancer. I like to use a lot of subsets, and HER2 has stood out to be one of the most important subsets when you hear of an incidence of 150,000 cases. Although the HER2 prevalence in 3% to 5% of patients is quite low, it still is a substantial number of patients. For some of the features that we see with HER2 disease, we see patients who tend to have more left-sided disease. This case was a distal sigmoid with maybe high CRC. [This is] very consistent with the pathophysiology and the expectation that we would see with HER2 disease. We have many tools in our armamentarium to think about. As of January [2023], we have the FDA approval for tucatinib [Tukysa] plus trastuzumab [Herceptin] for this subset of patients, which is exciting.³

Eng: Can you very briefly mention your thoughts regarding anti-EGFR therapy when we’re considering treatment for patients with HER2?

Parikh: Early preclinical data from Europe initially suggested that HER2 amplification may be a negative predictive marker of anti-EGFR resistance. For patients who are HER2-amplified, that’s a subset of patients you would not want to necessarily think about starting with anti-EGFR therapy.

Eng: What are your recommendations for generalized biomarker testing for a patient with newly diagnosed metastatic CRC, and how do you incorporate it into your practice patterns?

Foote: For anyone with stage IV disease, we typically recommend comprehensive molecular profiling with one of the panels either institutionally or commercially available. There are a couple of actionable biomarkers we like to look for. Mismatch repair proficiency is important. Many patients will have their sample stained by immunohistochemistry [IHC], but evaluating it on a next-generation sequencing [NGS] test can also be helpful. For BRAF mutations, evaluating that as well as RAS [mutations] is also important specifically if a tumor is left-sided, because we do use EGFR inhibitors in RAS wild-type patients. Finally, there is HER2, a new biomarker [tucatinib; Tukysa] for which we’ve just heard there has been an FDA approval to indicate new therapy. That’s very appropriate [because] every patient at this stage should be evaluated for HER2 therapy. We should especially look at ones who have left-sided tumors because 85% of patients with HER2 amplification have left-sided cancers.

Eng: Would you do the testing early on when you meet a [patient who has just received a diagnosis], or would you wait?

Foote: I would do it right away. Most of the panels do evaluate for HER2 therapies, so if you’re using one, you’re probably going to end up getting the status.

Eng: Can you please discuss testing methods and scoring criteria when assessing HER2 status?

Dasari: HER2 as a biomarker was initially developed in breast cancer and later in gastric cancer. What we’re looking for is either overexpression of the protein done by IHC—that’s been the traditional way of evaluating—or looking at genomic amplification. That could be done by in situ hybridization or, more recently, NGS. The traditional criteria looking at IHC [considered] the intensity of staining, and tumors that had an intensity of 3 or more were positive, 0 or 1 were negative, and 2 or more were equivocal requiring additional investigation with in situ hybridization. With gastric cancer and breast cancer, the proportion of cells that needed to be positive was around 10% as compared with the HERACLES criteria, which needed about 50% or higher of the cells to be positive with IHC to be called positive.⁴ The bottom line is that there’s a wide variety of approaches that are currently available. In practice, we’re slowly moving from IHC to more NGS.

Treatment Sequencing

Eng: What is the current treatment landscape for HER2-positive metastatic CRC?

Kamath: What comes to mind, as we discussed in the first case, is the tucatinib and trastuzumab combination. It’s the first [regimen for HER2-positive metastatic CRC] to have an FDA approval in the United States. The strongest data are attractive as far as being a chemotherapy-free regimen with a great overall response rate [ORR] of about 38%.⁵ Of course, there’s certainly a number of other treatments in the market, as well. The next one that comes to mind is trastuzumab deruxtecan [T-DXd, Enhertu], which has made a lot of waves in breast cancer and gastric cancer, as well. That’s also a great option. That has a very similar ORR of around 37% and a similar disease control rate to the tucatinib and trastuzumab combination.

From a toxicity standpoint, that can be much harder in terms of mild suppression, gastrointestinal toxicity, and the interstitial lung disease that we see with those agents. Treatment selection and patient selection [are] critical. Certainly, there [have] been studies for many of the other tyrosine kinase inhibitors [TKIs], including lapatinib [Tykerb], trastuzumab, and fedratinib [Inrebic]. I look at those data and I see responses that are weaker, and [those agents] don’t seem to be quite as active. There is not that much room for those in this space. Similarly, trastuzumab emtansine [TDM-1, Kadcyla] has been looked at as well, and I find those data are not all that compelling, either.

Eng: Can you comment on the update to the National Comprehensive Cancer Network guidelines? Previously, pertuzumab [Perjeta] was listed as the first choice [therapy], and now we have this new FDA approval of tucatinib plus trastuzumab. How does somebody in practice incorporate these options?

Parikh: With the approval and the data that we have with the phase 2 MOUNTAINEER trial [NCT03043313],⁶ trastuzumab plus tucatinib will be your second-line [and beyond] HER2-directed therapy option in the guidelines, and we should confirm this.^7,8 In practice, it’s also listed for patients who are not only candidates for chemotherapy but are HER2-amplified. In the guidelines, there was the lapatinib option besides pertuzumab. Given MOUNTAINEER, trastuzumab plus tucatinib has come out in the front.

Eng: What other adverse effects would you be concerned about, and how would you recommend managing them for a new patient?

Kamath: Diarrhea is by far the biggest and most common toxicity. We certainly do see some fatigue, which is very mild. There is some skin toxicity, dryness, and palmar-plantar erythrodysesthesia, but those are usually rare and very easy to manage. The diarrhea is front and center, and I would say it’s certainly not the level of what you would see with neratinib [Nerlynx], where you want to prophylactically start [individuals] on antidiarrheals there. I have a very low threshold. It’s a situation where I try to touch base with patients very soon after initiating [treatment] because I often find they’re going to have significant grade 3 or higher diarrhea. It often happens quickly. Touching base with them quickly and intervening soon is key. Typically, it’s easy to manage with loperamide or agents of that nature. I also often find very brief dose holds, even just for a week or so, can often be great to reset the clock, and then you can resume even at the same dose many times.

Patient Case 2.

Managing Toxicity and the Possibility of Retesting

Eng: What are your next steps for a patient such as this who shows up in your clinic?

Parikh: This is such a provocative case on so many levels. There are so many things to discuss. The management [of the disease] is exactly what I would have done. It’s smart to be mindful of oligoprogression, too, when you’re on targeted therapies and not putting the targeted therapy on the back burner as you did and going ahead and giving ablative doses of radiation. That patient was able to regain response again for another 9 months. That’s an important teaching point from this case: that after potentially progressive sites of disease, you can still derive benefits with even mixed responses. With the development of new metastatic sites, you don’t necessarily give up your targeted therapy too early. Then, beyond that, it’s a rapidly evolving landscape in terms of what we’re going to be doing post initial HER2-directed therapy. One of the compelling things from the T-DXd data was that patients who had prior HER2-directed therapy still derive benefit from T-DXd. When I’m thinking about sequencing for patients knowing that we have the toxicity issue with the T-DXd, I like the TKI trastuzumab combination or antibody combination first and then reserving the T-DXd for later.

Eng: What is the toxicity that may be most concerning with T-DXd?

Parikh: The most concerning toxicity is interstitial lung disease. This is a class effect, and we know that this is an issue with these antibody-drug conjugates. Recognizing symptoms, asking patients about the shortness of breath, paying attention to their stats and their vitals, and making sure they’re not developing insidious hypoxia [are important]. Early CT scans can see [whether] you’re picking up any signs of this. Aggressive steroids early on can mitigate this, but it’s an important consideration for these patients. Besides that, there is also cytopenia with the T-DXd. You also get neutropenia and anemia. [You must] think carefully about your toxicity profile for sequencing. The other unique feature of T-DXd is some benefit for the RAS mutations, as well. That’s an important consideration. If you have a patient with RAS-mutated and HER2-positive disease, you could start with T-DXd, but I’m curious to see what other panelists’ thoughts are on that, too. Without the RAS mutation, the sequencing is, for me, at least starting with trastuzumab plus tucatinib and then moving to T-DXd later.

Eng: Can you mention the fact that we know that there appears to be activity for T-DXd in breast cancer and gastric cancer [called HER2 low], but not necessarily in CRC in that same fashion?

Foote: Unfortunately, it is hugely disappointing. There is no activity in those kinds of HER2-low patients. We looked at those low expressers as well, and we unfortunately didn’t see any activities. We’re not still seeing the bystander effect that we’re seeing in tumor types like breast cancer.

Eng: Should we be retesting patients for HER2 expression?

Parikh: This may be controversial. I retest before administering T-DXd, and I’m not sure how much change there is with HER2 in colon cancer, at least. Given the toxicity profile, it has always been my practice to rebiopsy.

Foote: I had a patient who was HER2 positive on a lymph node that we took out about a year and a half ago. We retested a surgical sample for her lung nodule, and she was HER2 negative. It was just a different subclone, but it was important to us because I would’ve put her on therapy. We ended up putting her on normal chemotherapy.

Moving Forward

Eng: What do you believe is an unmet need in CRC and future perspectives?

Kamath: To me, the biggest unmet need—and it’s shocking in 2023 to still be talking about—is the need to do biomarker testing consistently. There’s literature that seems like it was from the ’90s, but it was just published last year showing that testing rates are 60% to 70% in many settings. It’s just something we [must] do and learn to do consistently, especially as a number of targets evolve as were discussed here with HER2. It’s just something we must do early and consistently. That’s the greatest unmet need in my mind.

Foote: I envision a world where circulating tumor DNA [ctDNA] is going to help guide our management decisions. Maybe, provocatively, I could even say we might not need scans anymore. We might just go off the molecular burden of disease or which subclones tend to be the most active at any current time. It’s very difficult to study that sort of thing, but being able to use ctDNA intelligently is a big topic of discussion in our field.

Dasari: I’m going to take a step back and say that we’ve talked about treating patients with CRC that’s established or progressed today, but perhaps the key unmet need is increased and more efficient screening to prevent disease.

References

1. Cancer stat facts: colorectal cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed April 25, 2023. bit.ly/3oG3PQ6
2. Siegel RL, Jakubowski CD, Fedewa SA, Davis A, Azad NS. Colorectal cancer in the young: epidemiology, prevention, management. Am Soc Clin Oncol Educ Book. 2020;40:1-14. doi:10.1200/EDBK_279901
3. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. Seagen Inc. January 19, 2023. Accessed April 25, 2023. https://bwnews.pr/3Xpzbqn
4. Liu F, Ren C, Jin Y, et al. Assessment of two different HER2 scoring systems and clinical relevance for colorectal cancer. Virchows Arch. 2020;476(3):391-398. doi:10.1007/s00428-019-02668-9
5. Bakhtiar M, Gholami S, Saeed A. A systematic review to assess the efficacy of HER2-targeted treatment regimens in HER2-positive metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41(suppl 4):166. doi:10.1200/JCO.2023.41.4_suppl.166
6. Strickler JH, Cercek A, Siena S, et al. MOUNTAINEER: Open-label, phase 2 study of tucatinib in combination with trastuzumab for HER2-positive metastatic colorectal cancer. Presented at ESMO World Congress on Gastrointestinal Cancer 2022; June 29-July 2, 2022; Barcelona, Spain. Abstract LBA2.
7. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 2.2023. Accessed April 25, 2023. bit.ly/3oCtQQ1
8. NCCN. Clinical Practice Guidelines in Oncology. Rectal cancer, version 2.2023. Accessed April 25, 2023. bit.ly/40M6chG