Elle Charnisky, a patient with stage IV HER2+ metastatic colorectal cancer (mCRC), joins a panel of healthcare professionals to discuss how HER2 alternations are detected and how patients with HER2+ mCRC are optimally treated to improve outcomes.
At an Around the Practice® program hosted by CancerNetwork®, experts and patients spoke about the treatment of HER2- expressing metastatic colorectal cancer (mCRC). The discussion was led by John H. Strickler, MD, a medical oncologist and associate professor of medicine at the Duke Cancer Center in Durham, North Carolina.
Panelists included Tanios S. Bekaii-Saab, MD, FACP, leader of the Gastrointestinal Cancer Program, medical director of the Cancer Clinical Research Office, and vice chair and section chair for Medical Oncology in the Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona; Deanna A. Griffie, MSN, AGNP-BC, RN, OCN, a nurse practitioner working in gastrointestinal medical oncology at the Duke Cancer Center in Durham, North Carolina; and Elle Charnisky, a patient advocate from St Louis, Missouri.
STRICKLER: Could you provide a brief overview of mCRC? What does the typical patient with this disease look like in your clinic, and how are they diagnosed?
BEKAII-SAAB: With screening, there has been a downward trend in [the number of] older patients with CRC, but that has not been the case with younger patients, among whom there’s been a surge. Although this remains mostly a cancer of older patients, there’s been a disproportionate increase in younger patients over the last 10 or 20 years.
Family history and genetics account for about 15% to 20% of all patients with mCRC; most patients have no genetic link to their cancer. [However], we recently published a paper suggesting that in about a quarter of patients who would not [be selected for] genetic testing according to guidelines, we do detect [genetic indications], and so universal testing for genetic predisposition should be implemented.
CRC is preventable for some patients, and [for them] a colonoscopy is the best way to diagnose early or even prevent CRC by excising the affected polyps. Most patients present with a symptom relating to the early stages [of the disease]: usually either bleeding, a change in bowel movements, or melena—digestive blood that appears black in stools. Some patients present [with these symptoms] just after the screening colonoscopy that finds the cancer. For mCRC, which affects more than 50,000 US patients a year, those diagnosed typically present with symptoms depending on the organ affected: either the liver, lungs, or elsewhere. [Patients usually experience] a drop in hemoglobin counts, abnormal liver function [enzyme levels], weight loss, loss of appetite, and the typical changes in bowel movements.
STRICKLER: Elle, how did you know something was wrong? How did you know you needed to see a doctor?
CHARNISKY: The first symptom I noticed was a mucous discharge when I went to the bathroom, which was sometimes tinged with blood. Having had my son a little more than a year prior, I thought [these discharges might be due to] internal hemorrhoids or something like that, and my primary doctor agreed. I did contact her as soon as I noticed, and she said I was more than welcome to see a specialist at any time. I didn’t feel a specialist was necessary because I felt the cause was probably internal hemorrhoids or something like that.
The discharges never went away for any significant length of time. There were also times I noticed dark red blood in the stool, and then [I began to have] constipation, which is unusual for me. This is what made me assess how long it had been since those initial symptoms. After realizing that the symptoms had never gone away, I finally decided to see a specialist, and that’s when [the cancer] was detected.
STRICKLER: How did you educate yourself about the disease? Was it easy for you to find resources? Where did you seek information?
CHARNISKY: Initially I searched online and found some very sobering statistics. [However], I realized soon that those were outdated, as well as unnecessarily grim and discouraging [given] the advances [in treatment] that happen every year. The place I got the most valuable information was Facebook, actually. There was an online community—a Facebook group— that provided a wealth of information. So many people [in the community] are willing to share their experiences. It’s just so valuable to hear from people who have lived through the disease. [The Facebook community] was Colontown. There’s also a new one emerging called One Cancer Place, led by Erika Brown. She was the founder of Colontown.
STRICKLER: What is the prevalence of HER2-positive mCRC? How is it detected in the clinic?
BEKAII-SAAB: HER2-positive mCRC is a rare subtype of this disease, affecting about 3% to 4% of patients. HER2 expression usually occurs on the left side of the colon—the descending colon, the sigmoid colon, and the rectum.
[When considering HER2-positive CRC], it’s important to consider the presence or absence of another common mutation in colon cancer called RAS mutation. HER2 expression is not mutually exclusive with RAS mutation, which means that there’s also a chance of RAS alterations when you see overexpression of HER2. [The presence of RAS mutation] changes the optimal treatment; it affects the selection of certain therapies, such as HER2 inhibitors, and the exclusion of other therapies…such as EGFR inhibitors.
Importantly, 80% of HER2-amplified tumors are within the RAS wild-type genotype of CRC, and 20% are in the RAS-mutated group, which has significant implications. We do not yet know whether HER2 overexpression has any prognostic implications—any implications on the aggressiveness of the cancer. This is being studied. But we know that it favors certain therapies and excludes others.
STRICKLER: How was molecular testing done in your case, Elle?
CHARNISKY: My initial oncologist had biomarker testing done. Two different tests were performed, which was his standard procedure. I’ve [since] learned that this is not the case for everyone’s oncologist, so I’m very grateful for that.
STRICKLER: How were the results explained to you?
CHARNISKY: It was noted that I had a HER2 amplification [and that it] might open options down the road. I don’t think my oncologist was very familiar with what that might look like or what those options were.
STRICKLER: How should we as clinicians explain these tests to our patients? How should we explain the results?
GRIFFIE: It’s challenging and complex. It’s important to let patients know up front that this is a rapidly evolving field and that we have a rapidly evolving understanding of the disease and the treatment options. A 1-stop-shop education session [isn’t sufficient]; the conversation happens over time. I give the most pertinent information, [including] information about microsatellite instability and what it means regarding treatment.
It’s also important, especially when we get these tests up front, to explain that [the results] may not impact treatment today but will add to our options in the future. It’s important to let the patient know that our best evidence is in those frontline therapies, and [beyond that] we’ll need to customize treatment to meet their needs. [Any patient’s] cancer is not necessarily like their friend’s or neighbor’s cancer.
I strongly encourage patients not to [rely on] random Google searches, and to [share with us] any resources they encounter that seem unusual. I send patients to the CRC page maintained by the American Cancer Society and to the National Comprehensive Cancer Network website, [both of which] are vetted and up to date. It’s important for nurse practitioners and physician assistants, who tend to be more able to answer direct questions from the patient, to examine online resources together [with the patient] and decide which are reliable [and relevant].
STRICKLER: What are the barriers to molecular testing? How can we address them?
BEKAII-SAAB: The first and most important barrier is education, not only for care providers…but also for patients. Patients are sometimes their own best advocates; they themselves often ask about testing. Part of the [necessary] education for providers is to emphasize the importance of HER2 overexpression when deciding the best path forward for the patient. [For example], the presence of HER2 overexpression excludes [the possibility of treatment with] the EGFR inhibitors cetuximab [Erbitux] and panitumumab [Vectibix]. Most HER2 amplifications occur in the presence of RAS wild-type phenotype, which is usually treated with EGFR inhibitors. These inhibitors can be quite toxic; they can affect quality of life [QOL], they’re costly, and they’re frankly unnecessary in this setting. That’s one of the reasons we need to educate our peers about the importance of [HER2] testing when deciding what’s best for patients.
The second barrier is cost; many of these tests are not fully covered. We have recently [seen some improvement in this area]. I remember the days when it was an incredible battle to get the test covered, involving [a lot of] paperwork, and trying to get companies to help us. Part of the [necessary] education is informing our physicians, especially those in smaller practices, that many of these tests are now covered and are important when planning treatment. In fact, one can make a strong case that an [initially] expensive test [can lead to] reduced costs [by eliminating the need for] the more expensive and toxic drugs.
We [need to] remove these barriers in education and cost. These are the 2 most important barriers to widespread testing, and [their removal would allow] clinicians to help patients better trace their journey through treatment.
STRICKLER: How do you choose first-line treatments for mCRC? What are the common adverse effects and toxicities of the various options?
BEKAII-SAAB: The landscape of mCRC continues to become more complex, which is great because it means more options for patients.
Many elements help decide what type of treatment is best. [Clinicians have to account for] age, comorbidities, and other illnesses. Older patients, for example, don’t tolerate or benefit from aggressive treatment. Younger patients do benefit [from these aggressive therapies], but it’s important to remember that youth isn’t just [an invitation] for punishment. As oncologists, we sometimes forget that [the advantages of youth] don’t mean we have to punish the young. Many good strategies to tone the treatment down can help patients navigate aggressive treatment. How much is too much? [It’s important to have] good discussions with patients [so they can understand] the impacts [of various treatments] on the rest of their lives. That’s the most important aspect of our work: patient autonomy.
It’s also important to have the relevant genetic elements available from day 1. I [always] want to know if the patient is a candidate for a VEGF inhibitor or an EGFR inhibitor. Which side is their cancer on? What’s the genetic profile of their disease? Do they have RAS mutation? [RAS mutation] automatically excludes the possibility of EGFR inhibitors. Also, certain subtypes of RAS mutations are important in the planning process. Several trials are examining these new KRAS G12C inhibitors called adagrasib and sotorasib [Lumakras], [which may be effective] in combination in the second- and third-line settings for about 2% of patients. That’s a target we now know to be relevant in this disease. BRAF mutations would also exclude EGFR inhibitors and [wouldn’t favor] HER2 treatment in the rare patient with HER2 amplification [as well].
In terms of the chemotherapy backbone, there’s been about 20 years of argument over the most optimal [choice]. As it turns out, they’re all about the same [in terms of efficacy]. You choose the backbone based on the available trials and, more importantly, what the patient desires. [For example], if the patient is a golfer, or a pianist, or a guitarist, clinicians should avoid oxaliplatin [Eloxatin] [to minimize the risk of] neuropathy. Irinotecan [Camptosar], [meanwhile], carries the risk of diarrhea, [and so] for patients who already have issues with diarrhea, it may not be the best treatment option. They’re all relatively equivalent [otherwise]. For some patients, we administer the full-blown treatment regimen of all 3 drugs: irinotecan, oxaliplatin, and 5FU [fluorouracil]. I’ve used [this regimen] more and more in younger patients—those younger than 70 years—because we now know it’s not necessary to expose patients to more than 4 months of chemotherapy. I say 3; some say 4. [I tell my patients that] we’ll treat them with strong induction chemotherapy for 3 months in hopes of achieving maximum results and then tone it down to [only] oral capecitabine plus VEGF inhibitors. We have overwhelming data now showing that induction chemotherapy beyond 3 to 4 months achieves little aside from increased toxicities. I also like the concept of a holiday…[because] we know giving patients a holiday—[that is, a break from treatment]—after 3 or 4 months of aggressive treatment does not affect outcomes. Patients have families and vacations; they want to live their [normal] lives. We [therefore] have to plan treatments that extend life while preserving QOL.
Also, a subgroup exists of about 2% to 3% of patients with high microsatellite instability. Most of these cases are in a Lynch syndrome setting, but many others are somatic—[that is], random. These patients respond beautifully to immunotherapy using an agent called pembrolizumab [Keytruda]. Many of them, even with metastatic disease, are cured [using immunotherapy] without ever seeing chemotherapy in their lifetime.
That’s why it’s so important to have all these elements available to us from day 1 so we can figure out [the optimal treatment]. This landscape is growing richer as more [genetic] alterations are uncovered. That’s why it’s becoming complex, but I like complexity because, as I said, it gives our patients so many more options.
STRICKLER: Elle, when you were initially diagnosed, what did you receive? What were the adverse effects?
CHARNISKY: It’s been a little more than 6 years since my initial diagnosis. I was put on FOLFOX [leucovorin calcium, fluorouracil, and oxaliplatin] initially, and I experienced neuropathy [and] nausea. Part of the information I found in the online community revolved around long-term neuropathy effects from oxaliplatin, [and] community members were also sharing results from a conference indicating that any more than 3 or 4 rounds of oxaliplatin don’t seem to make a difference long-term. I decided to stop [treatment] after 6 rounds, which was against my oncologist’s wishes. His standard [protocol] was to administer 12 rounds of [FOLFOX] if it’s tolerated. I don’t know whether I would’ve tolerated 12 rounds or not, but I chose to stop after 6. I’ve never regretted that decision at all, especially given that my path [revolves around] HER2 positivity. I [often] share this story with other patients.
I was also on irinotecan for a time—I believe as part of FOLFIRI [leucovorin calcium, fluorouracil, irinotecan hydrochloride]—but I only received 1 or 2 rounds. I didn’t like the [associated] diuretic-type diarrhea. There was a watery feeling throughout my body which I didn’t like. I was also on Avastin [bevacizumab], which prevents scabs from doing their job, basically. [My wounds] would scab over, and then the scab would fall off [without] any healing. That was unpleasant. It’s not completely unmanageable, but it’s noticeable.
STRICKLER: How should physicians select patients for anti-HER2 therapies?
BEKAII-SAAB: First, what Elle has just discussed is exactly what clinicians must always be aware of. We do often underestimate those key toxicities, which end up limiting the patient’s QOL.
That’s why it’s important to understand the role of HER2-positive colon cancer…and [the potential benefits of] HER2-targeted therapy. A few combination therapies…[involving active agents] are approved for other indications but not for CRC. These agents include trastuzumab [Herceptin]—a monoclonal antibody commonly used in breast cancer, gastric cancer, and now HER2-positive colon cancer—as well as lapatinib [Tykerb], an oral tyrosine kinase inhibitor [TKI] that attacks the receptor from within the cell. Lapatinib is a HER2 inhibitor that also hits EGFR, and so its toxicities are not the typical HER2 toxicities—it [can cause] a rash or diarrhea. Some of these can be quite bothersome, but [the drug] has roughly a 30% response rate, and the work done by our Italian colleagues [showed this to be] the first valuable proof-of-concept targeting HER2-positive CRC.1
Two other [active agents] are trastuzumab and pertuzumab [Perjeta]. They’re both [adequate monoclonal antibodies], and they’re both approved for breast cancer. They haven’t shown much activity [in combination] in gastric cancers vs trastuzumab alone, but in CRC, a [phase 2] trial called MyPathway [NCT02091141] is examining trastuzumab and pertuzumab in combination.2
The combination of [trastuzumab and pertuzumab] showed a 30% response rate, roughly, across a small number of patients [in MyPathway]. But the trial didn’t examine colon cancer alone, [because it was a basket trial, and that limits its applicability].3 I also find this regimen to be quite tough on some patients; [it can cause] skin toxicities, diarrhea, and other bothersome effects.
Also, an agent called fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] takes advantage of the presence of the HER2 receptor, docks to it, has a linker, breaks the linker, [and then] chemotherapy rushes into the site of the cancer. That’s how you achieve the kill [of the cancer cell]: through local delivery of chemotherapy. This local delivery has not yet been perfected, and so a lot of [the chemotherapy] spills into circulation, which is why we see toxicities similar to those from chemotherapy— fatigue, nausea, vomiting, and diarrhea. I’ve used [T-DXd] quite a few times, and it can be tough [to tolerate]. The nice element of this treatment is that it provides another layer of activity when other regimens fail [because] it cares about the expression of the receptor [rather than] the receptor’s activity. If a patient is treated with trastuzumab plus lapatinib, trastuzumab plus pertuzumab, or trastuzumab plus tucatinib [Tukysa] first, the second layer [of treatment] could be T-DXd. The DESTINY-CRC01 trial [NCT03384940], which showed clinical activity with [this agent] regardless of a patient’s previous exposure to other anti-HER2 treatments, led to its inclusion in the guidelines. We now have 2 layers [of treatment] for patients with HER2-positive disease.4
STRICKLER: What is the main toxicity to look out for when administering T-DXd?
BEKAII-SAAB: The most concerning toxicity is a less common one: interstitial lung disease [ILD]. This [toxicity] isn’t uncommon when using other antibody-drug conjugates [ADCs], and it’s a little more common with T-DXd than with trastuzumab emtansine [T-DM1; Kadcyla] and other ADCs. It occurs in about 67% of patients with colon cancer [who are treated with this agent] and can even cause death.
The best way to avoid [this] is to diagnose it early. [Concerning] symptoms [that point to ILD] include shortness of breath or dyspnea on exertion. However, there’s no way to [reliably] catch ILD when it’s still reversible. Therefore, in my clinic, we [only] choose T-DXd after the other combinations [have failed]. It only tends to be active when the others fail [anyway], whereas it’s not yet known [if the inverse is true].
STRICKLER: Who do you call at our institution if a patient presents with shortness of breath or worsening oxygen status on this agent?
GRIFFIE: First and foremost, I try to get a scan on the patient to check for any effusions, because those will need to be managed. I also connect with our pulmonology colleagues sooner rather than later; thankfully, [they’re] right next door. If there are effusions—if there’s ILD—we need a pulmonologist on board quickly to minimize the impact and [hopefully] prevent it from becoming irreversible.
STRICKLER: How are you advising patients who struggle with this toxicity?
GRIFFIE: The patient has to be instructed from day 1, before [the toxicity] even occurs, that prompt identification is essential. [In other words], don’t wait until you’re dehydrated and falling at home, or struggling with many episodes [of toxicity] every day. We have to open the door to early communication. Patients are sometimes afraid to let us know just how badly they’re struggling because they don’t want us to hold back [or delay] any therapies. Some patients [have] a fear of being robustly honest about their struggles, so we have to demystify [the consequences] and explain that [dose reductions may not be necessary in all cases]. [Dose reductions] may become [necessary] if things get bad enough, but if we catch certain toxicities early, we can usually keep people on treatment.
We manage these toxicities the same way we manage our upfront chemotherapies; [we use] loperamide [in the form of] over-the-counter Imodium as robustly as needed. [I prescribe] 4 mg up to 4 times a day for a maximum of 8 tablets. If that fails, we combine it with prescription Lomotil [diphenoxylate plus atropine] or potentially even octreotide [Sandostatin] or a tincture of opium. I have not found those to be terribly helpful, but, as a caveat, we [tend to] blame everything on the therapy, and we need to perform clostridioides testing as well to ensure there’s not some other underlying [factor to blame]. Also, I always check a patient’s medication list to ensure no issues exist there, or any foods [they eat] that may be relevant.
STRICKLER: What is the safety profile of the chemotherapy-free MOUNTAINEER regimen of tucatinib and trastuzumab?
BEKAII-SAAB: The good news is that the most common toxicity [with this regimen] is diarrhea, which occurs in a little more than half of the patients. There are typically few instances of bad diarrhea, [and even those] are manageable with dose adjustments and skipping. Often, clinicians think of grade 2/3 diarrhea as not being too bad. Grade 2 diarrhea is unpleasant. [Grade 2 implies] multiple bowel movements a day, which can prevent patients from traveling and conducting normal activities. Clinicians have to be aware of that. The good news is that, if managed well, [diarrhea toxicities are] controllable, and patients can live with it. We [can sometimes] minimize the burden to just 2 or 3 bowel movements per day.
This point also again touches on [the importance of] education for both the provider and the patient. [The power of education] is amazing to me. We’ve done an ad hoc experiment in our clinic in which we gave patients very strict instructions on how to manage diarrhea when taking FOLFOX and FOLFIRI, and we found that the likelihood of patients going to the hospital from a diarrheal complication was close to 0. It’s amazing [that we accomplished this with] just with a single piece of paper, and by spending time with patients. That second part, [the spending of time], cannot be overemphasized.
All of these TKIs carry some risk of fatigue. It can be difficult to understand the [difference between] fatigue coming from the cancer vs the treatment, but [the risk] is undeniable. Thankfully, most of the fatigue [at my clinic] is very low grade, very manageable, involving very little nausea and low toxicity.
[Additionally], all these HER inhibitors, from HER1 to HER3, affect the skin. We’ve seen very few skin toxicities—mostly faint rashes that are usually not too bothersome for patients. We also keep an eye on liver function tests. In rare instances, [toxicities] can be elevated, but all in all, tucatinib plus trastuzumab remains a relatively tolerable regimen, conducive to a high QOL. In fact, we presented QOL data at the 2022 European Society for Medical Oncology Congress regarding tucatinib and trastuzumab, and [the regimen] did seem to preserve the QOL for patients.5 This is a regimen that can be tolerated for prolonged periods of time.
STRICKLER: How are the toxicities associated with tucatinib managed? How do you assist patients with mild, moderate, or severe diarrheal toxicities?
GRIFFIE: Hopefully [the patient] doesn’t ever experience a severe [toxicity] because we’ve done a good job upfront.
It’s important to know upfront what the [patient’s] baseline [activity] is. Some already have a [high] baseline frequency of stools, for example. There are also higher-risk patients, [such as those] with an ileostomy. All these things [need to be] on our radar upfront. I like to proactively give patients a list of the most expected adverse effects [AEs], [with the understanding that] just because it might be expected doesn’t mean we’ll ignore it.
First, identifying [the toxicity] sooner rather than later, and trying to keep bowel movements at grade 1, meaning only 1 or 2 bowel movements [per day] above baseline. [We also focus on] replacing fluids and electrolytes, [all the while] keeping a close eye on those elements [to prevent] acute kidney injury, hypertension, falls, and dehydration. [These AEs] can escalate quickly if we’re not proactive.
[It’s also important to] max out the loperamide [treatment], and if that doesn’t work, to move on to plan B, which [involves] layering in diphenoxylate/atropine followed by octreotide acetate if needed.
STRICKLER: What advice would you give patients and caregivers dealing with a new diagnosis of HER2-positive mCRC?
CHARNISKY: If you have a very strong HER2 amplification, avoid EGFR inhibitors. [This advice might not apply to everyone], such as those with a RAS mutation at play, but for me, EGFR inhibitors didn’t do any good and were extremely toxic, limiting my QOL. My main advice is to try to receive HER2 therapies as soon as possible. I would only caution that to be eligible for MOUNTAINEER, [patients] can’t have already been on prior HER2-targeted therapy. Aside from that, any kind of HER2-targeted therapy is in their best interest.
STRICKLER: Do you have any advice for patients regarding their diagnosis?
GRIFFIE: First, educate yourself with the help of your provider so that you know what the data say. It’s also important to connect with a support group, whether formal or informal, one that is therapeutic and that allows you the space to speak about your struggles and needs.
You also have to advocate for the right testing. We’ve already spoken about the need to educate our peers about [adequate testing]. Clinicians [need to] know what they’re dealing with upfront to provide the best possible treatment trajectory for patients. If you haven’t had this testing, ask your oncology team how you might have it.
STRICKLER: Do any other important unmet needs, or areas for improvement, exist in this space?
BEKAII-SAAB: mCRC has not been cured yet, but we’re getting closer thanks to patients like Elle who not only volunteer on studies but also advocate for other patients. We always have to remember [the difference] our patients make [when volunteering for studies]. [After all], these studies are how we learn, [and] this gives us the incentive to keep generating new ideas.
I’ve helped lead an effort called the COLOMATE trial [NCT03765736] which, [along with efforts by] our Japanese and European colleagues, will further break down CRC into small [genetic] subgroups like those HER2- and G12C-expressing groups. What other subgroups can we uncover and target? We’ve come a long way but there’s still a long road ahead. [Future advancements will] be very rewarding [because they’ll] move us closer to a cured cancer.
GRIFFIE: [I want to reinforce something] mentioned earlier: A patient being young and otherwise healthy does not [justify] an aggressive treatment. Clinicians have to recognize that QOL is just as important [as efficacy]. We [also] need to be better about giving [patients] breaks from treatment and moving to maintenance therapies to allow them some recovery time. We all need to better recognize that pain does not always equal progress.
CHARNISKY: I couldn’t agree more; the holidays [from treatment] are so important. There was so much fatigue [for me initially], and it’s amazing how your body bounces back [if given the chance to do so].
[It’s also important to adjust] the baseline [when necessary]. For someone like me, who’d never had a colon resection, the baseline needs to change after resection because it makes a huge difference. It’s important to make sure any diarrheal toxicity is not unfairly blamed on tucatinib when it might be an effect of resection.