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Treating mCRC
Shifting Paradigms: Treating HER2-Positive or Microsatellite Unstable mCRC

Released: June 05, 2023

Robert Lentz
Robert Lentz, MD
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Key Takeaways
  • Immune checkpoint inhibitors are now the standard of care first-line treatment for microsatellite instability-high /mismatch repair deficient metastatic colorectal cancer (mCRC).   
  • Treatments for HER2+ mCRC include trastuzumab plus tucatinib, pertuzumab, or lapatinib, as well as trastuzumab deruxtecan.
  • Targeted therapies are associated with unique adverse event profiles compared with chemotherapy.

 


The approval of several novel targeted therapies metastatic colorectal cancer (mCRC) with specific molecular profiles has contributed to the growing complexity of managing patients with mCRC. In this commentary, Robert Lentz, MD, discusses key considerations with treatment options for patients with microsatellite unstable or HER2-positive (HER2+) mCRC.

Immunotherapy for MSI-H/dMMR mCRC

Appropriate molecular testing for patients with mCRC is essential to ensure that treatments are effectively tailored to each patient’s specific cancer. Regardless of stage, all patients with CRC should have testing for microsatellite instability (MSI) and/or mismatch repair (MMR). High microsatellite instability high (MSI-H) or deficiency in the mismatch repair proteins (dMMR) are biomarkers for a positive response to immune checkpoint inhibitors (ICIs) that target the PD-1 and/or CTLA-4 axes. MSI testing is performed via PCR and mismatch repair testing is performed via immunohistochemistry. Although MSI-H/dMMR is associated with a positive response to immune therapy, it is only present in 5% of mCRCs.

In most patients with microsatellite-stable disease, initial treatment includes a regimen that incorporates 2 chemotherapy agents—most commonly FOLFOX, although CAPEOX or FOLFIRI may also be used. All of these regimens are efficacious. In patients who are young and/or healthy and/or desire to be more aggressive with their treatment, a triple cytotoxic regimen such as FOLFIRINOX or FOLFOXIRI can be used. A biologic agent—either an EGFR inhibitor or the VEGF inhibitor bevacizumab—is typically added to the chemotherapy backbone. Patients are eligible for an EGFR inhibitor if they have left-sided, RAS/RAF wild-type disease.

For patients with MSI-H/dMMR cancer, ICIs have revolutionized treatment. These agents, including pembrolizumab or dostarlimab monotherapy or nivolumab with or without ipilimumab, have improved outcomes for patients with MSI-H/dMMR mCRC compared with chemotherapy.

KEYNOTE-177 was a randomized phase III trial comparing pembrolizumab with chemotherapy as first-line therapy for patients with MSI-H/dMMR mCRC. Data from this trial led to a paradigm shift from treating MSI-H mCRC with first-line chemotherapy to treating with first-line ICI therapy, which remains the current standard of care. In this study, pembrolizumab was associated with a 16.5-month median progression-free survival (PFS), which was twice as long as the 8.2-month median PFS associated with chemotherapy. Pembrolizumab was also associated with improved overall survival trends compared with chemotherapy, although the difference was not statistically significant. The lack of a statistically significant difference is likely due to the approximate 60% crossover rate to immune therapy among patients initially treated with chemotherapy, which narrows the difference between the treatment groups. Of importance, when compared with chemotherapy, pembrolizumab also improved quality of life. In the trial, patients receiving pembrolizumab experienced fewer severe adverse events compared with those receiving chemotherapy. Overall, pembrolizumab is usually well tolerated, even in patients who are older or have comorbidities.

Nivolumab with or without ipilimumab is another option for patients with MSI-H/dMMR mCRC based on results from CheckMate 142, an open-label, nonrandomized phase II study. This multicohort trial investigated a regimen of nivolumab plus ipilimumab as first-line therapy for patients with MSI-H/dMMR mCRC. In this cohort, nivolumab plus ipilimumab was associated with an objective response rate of 69%, a 2-year PFS of 75%, and a 2-year overall survival of 79%.

It is not known how the nivolumab plus ipilimumab combination compares with pembrolizumab, as there have been no direct comparisons between the 2 regimens. However, data from cross-trial comparisons—which obviously have limitations—have shown that the combination of nivolumab plus ipilimumab is associated with an objective response rate of 69%, which is higher than the 45.1% objective response rate associated with pembrolizumab. Therefore, for patients who are relatively young and healthy and who want a higher response rate, the nivolumab plus ipilimumab combination may be preferred over pembrolizumab. The trade-off is that the nivolumab plus ipilimumab combination has been associated with a higher rate of side effects, particularly colitis.

Like pembrolizumab and nivolumab, dostarlimab is another anti–PD-1 ICI. It is not commonly used, but is approved for patients with recurrent MSI-H/dMMR CRC.

It is not possible to predict which patients receiving ICI therapy will develop immune-related adverse events (irAEs), the severity of the events, or the organs that will be affected. IrAEs can occur at any time during immune therapy. Although onset typically occurs 2 or 3 months after initiating therapy, it may occur years later or even after therapy has been discontinued. Organs most commonly affected include the thyroid, in the form of hypothyroidism; the colon, in the form of colitis; and the skin, in the form of a low-grade maculopapular rash. Most events are mild and can be managed with oral therapy or creams. However, in approximately 10% to 20% of patients receiving immune therapy, these irAEs can be severe or life threatening.

It is important to inform patients that the side effect profile of ICIs is often very different than that associated with chemotherapy. Patients should be told to contact their physician if they begin experiencing any new symptoms because the earlier the symptoms are recognized, the easier it is to treat them. If irAEs are suspected, patients should undergo a complete workup that includes lab tests and other common causes for the observed symptoms should be ruled out.

Let’s look at immune-related colitis in terms of managing a common ICI-related adverse event. Grade 1 colitis or diarrhea is defined as an increase of fewer than 4 stools per day from baseline or a mild increase in ostomy output. In this case, it is important to rule out infection (most commonly Clostridioides difficile, or C. diff) and to continue ICI therapy while treating the colitis symptoms with fluids and agents such as loperamide. Some patients develop more severe diarrhea, which is defined as a stool increase from baseline ranging from an additional 4 or 6 stools per day to as many as an additional 10 or 15 stools per day. In these cases, it is important to temporarily withhold the ICI, seek a gastroenterology consult, and initiate steroids. A typical course of steroids includes 1 mg/kg daily of prednisone or a prednisone equivalent followed by a slow taper over 4 to 6 weeks. In addition, these patients should undergo a flexible sigmoidoscopy or colonoscopy to help microscopically evaluate the severity of the disease. Escalation of steroid dose and/or addition of a biologic agent (such as infliximab or vedolizumab) may be needed in severe or refractory cases.

Targeting HER2+ mCRC

HER2 amplification (ie, HER2 overexpression) occurs in approximately 3% of patients with mCRC. Patients with HER2+ mCRC are eligible for anti-HER2 therapy. Of importance, anti-HER2–directed therapies are only likely to be effective in mCRC characterized by wildtype RAS and BRAF. The 4 treatment options currently recommended for patients with HER2+ mCRC include trastuzumab plus lapatinib; trastuzumab plus pertuzumab; trastuzumab plus tucatinib; or trastuzumab deruxtecan, which is an antibody–drug conjugate (ADC). These are generally recommended in later-line settings following initial chemotherapy.

Trastuzumab and pertuzumab are anti-HER2 monoclonal antibodies, whereas lapatinib and tucatinib are oral tyrosine kinase inhibitors. Trastuzumab deruxtecan is an ADC that is composed of the anti-HER2 antibody trastuzumab attached to deruxtecan, a cytotoxic payload. After binding to the tumor cell, trastuzumab deruxtecan is internalized and the cytotoxic payload is released, thereby killing the tumor cell.

No head-to-head trials have compared the anti-HER2 combinations. However, separate trial data for each combination have shown promising response rates and survival. To date, the most promising data are from the phase II MOUNTAINEER trial, which examined the combination of trastuzumab plus tucatinib in patients with previously treated HER2+ mCRC. In the trial, the trastuzumab plus tucatinib combination was associated with a 38% response rate and a median overall survival of 24 months. In my practice, following progression on chemotherapy, I typically opt for the trastuzumab plus tucatinib combination for patients with RAS/BRAF wild-type, HER2+ mCRC who have not previously received an anti-HER2 therapy. However, the choice is empirical and patient-related factors need to be considered when selecting a HER2-targeted treatment. It is important to note that adding trastuzumab or pertuzumab alone to standard chemotherapy is ineffective, so for example, trastuzumab would not be added to a FOLFOX or FOLFIRI regimen.

Unique side effects can be associated with anti-HER2 therapies. Among these side effects is heart failure; therefore, it is recommended that echocardiograms be performed before initiating anti-HER2 therapy and periodically during treatment. Interstitial lung disease (ILD) is also an important toxicity in patients receiving trastuzumab deruxtecan, occurring in 9% of patients with mCRC in the DESTINY-CRC01 trial. For patients receiving trastuzumab deruxtecan who present with new pulmonary symptoms, trastuzumab deruxtecan should be temporarily withheld and the patient should be evaluated for suspected ILD. The evaluation should include high-resolution CT, a pulmonary consult, and should exclude infections. For grade 1 ILD, which is asymptomatic and diagnosed via imaging results, trastuzumab deruxtecan should be withheld until the ILD fully resolves and the patient should be treated with a regimen of steroids with a taper. For grade 2 or greater ILD, which is characterized by image findings plus symptoms related to ILD, trastuzumab deruxtecan should be permanently discontinued and the patient should receive a steroid regimen that typically includes prednisone 1 mg/kg daily followed by a taper over the period of at least 1 month.

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