CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit
Released: May 02, 2023
Expiration: May 01, 2024
Although patients derive some benefit from subsequent lines of chemotherapy with or without targeted therapies after progression of metastatic disease, the advent of newer therapies has expanded options and improved outcomes. Choice of second-line and subsequent-line therapy is based on patient history and previous therapy as well as the molecular characteristics of the individual’s disease, as summarized in Table 6.
Table 6. Preferred Subsequent Therapy for mCRC Based on Molecular Profile4,5
Standard chemotherapy with or without a VEGF inhibitor (bevacizumab preferred) or an EGFR inhibitor (if not received in the first-line setting) is still an option for those without actionable mutations or MSI-high/dMMR. The type of chemotherapy depends on previous regimens (oxiplatin- or irinotecan-based, whichever was not received in the first-line setting), and retreatment after progression on a regimen other than bevacizumab is not recommended. Patients who have progressed through all standard lines of therapy may receive regorafenib or trifluridine plus tipiracil with or without bevacizumab. Clinical trials should be considered.
The BRAF V600E mutation is found in 8% to 12% of mCRC and associated with poor prognosis.8 The phase III BEACON study compared treatment with the BRAF inhibitor encorafenib plus cetuximab (with or without the MEK inhibitor binimetinib) against standard chemotherapy plus cetuximab in previously treated patients with BRAF V600E–mutated mCRC. For the study’s primary outcome of OS, both the doublet and triplet regimens with encorafenib were superior to chemotherapy, each reducing risk of death by approximately 40% (Figure 3), and both regimens also improved PFS. However, the addition of binimetinib added considerable toxicity.31 Currently, encorafenib plus an EGFR inhibitor is the recommended standard of care for patients with the BRAF V600E mutation who have progressed after earlier treatment.4,5,8
Figure 3. Second-line and subsequent line treatment for BRAF-mutated mCRC.8,31
Because of downstream signaling pathways, patients’ tumors must be wild type for both RAS and BRAF to derive benefit from HER2-directed therapies.4,5 Table 7 summarizes recent data from clinical trials of HER2-directed therapies in treatment of HER2-amplified m CRC.32-38 Two newer options are trastuzumab plus oral tucatinib (MOUNTAINEER trial) and trastuzumab deruxtecan (T-DXd) (DESTINY-CRC01 trial).35,38 Both MOUNTAINEER and DESTINY-CRC01 are phase II studies without comparator arms, conducted in patients with multiple previous lines of therapy. The studies have reported impressive ORR (38.1% with tucatinib and 45.3% with T-DXd) and matured enough to include median PFS and OS. Between-trial comparison suggests median OS and ORR with tucatinib/trastuzumab or T-DXd is improved compared with previous options, suggesting a benefit with the newer therapies.35,38 Of note, T-DXd was effective in patients with previous exposure to HER2-directed therapy; in such patients, ORR was 43.8% and comparable to the 45.3% ORR in the overall population.38
Table 7. Recent Data With HER2-Targeted Regimens for mCRC32,34,35,37,38
The safety profiles of these newer HER2-directed agents are different than with cytotoxic chemotherapy. Healthcare professionals should be aware of increased risk for LVEF decreases in patients treated with any HER2-directed therapy. Risk factors for cardiotoxicity with trastuzumab regimens include aged older than 50 years, previous or concurrent anthracycline therapy, preexisting cardiac dysfunction, and obesity. Patients should have a transthoracic echocardiogram at baseline and periodically during treatment, and treatment withheld if significant LVEF decline occurs.32-38
T-DXd is an antibody–drug conjugate that leverages HER2 overexpression to deliver a cytotoxic payload into tumor cells. The development of ILD/pneumonitis is a special concern with this treatment. ILD can be severe or fatal, and treatment is permanently discontinued if grade ≥2 ILD occurs. T-DXd prescribing information carries a boxed warning about ILD development and recommends regular monitoring for symptoms of cough, dyspnea, or fever.34,39
Several of the targeted therapies used in later lines for patients with mCRC have received tumor agnostic approvals based on the presence of the specific genetic alteration rather than the type of cancer. NTRK inhibitors and selpercatinib are approved by the FDA for patients who have progressed on previous lines of treatment and have limited alternative options, while KRAS G12C inhibitors which are currently approved for NSCLC offer another option in metastatic CRC.
NTRK Fusions
Currently, 2 NTRK inhibitors, entrectinib and larotrectinib, are approved for use in patients with advanced solid tumors and NTRK gene fusions who have progressed following previous treatment or who have no satisfactory alternative options. Each is administered orally. Both entrectinib and larotrectinib were studied in phase I/II basket trials that included small numbers of heavily pretreated patients with mCRC. The drugs produced objective responses: ORR of 25% (1/4) with entrectinib and 50% (4/8) with larotrectinib.40,41 Grade ≥3 adverse events included anemia, weight gain, neutropenia, and liver enzyme decreases. Warnings carried by these drugs include central nervous system effects, hepatotoxicity, and skeletal fractures (both drugs), as well as worsening QT prolongation, hyperuricemia, and vision disturbances with entrectinib.42,43
RET Fusions
Currently, selpercatinib is the only approved tumor agnostic treatment for patients with locally advanced or metastatic solid tumors with a RET gene fusion who have progressed on or after previous systemic therapy or who have no satisfactory alternative options. It was approved based on ORR in the phase I/II LIBRETTO-001 trial, which included heavily pretreated patients with RET fusion–positive solid tumors (N = 45), including mCRC (n = 10). ORR, the primary outcome, was 44% in all patients, and clinical benefit rate (complete response plus partial response plus stable disease) was 63%. Median PFS with selpercatinib was 13.2 months, and 34.1% of patients were alive and disease free at 16.4 months.44,45 Potential toxicities of selpercatinib include ILD, QT prolongation, worsening hypertension (22% grade ≥3), hemorrhagic events or impaired wound healing, and tumor lysis syndrome. However, frequent adverse events are usually manageable and include edema, diarrhea, fatigue, dry mouth, constipation, rash and nausea.46
KRAS G12C–Mutated CRC
While KRAS mutations are common in CRC, the KRAS G12C mutation is present in only 3% to 4% of patients with CRC. Sotorasib was studied as monotherapy in CodeBreaK100, which included patients with previously treated mCRC (N = 62). The ORR was 9.7% (all partial responses), with median response duration of 4.2 months and 2 of 6 responding patients remaining on treatment with ongoing responses of more than 11 months as of the data cutoff date.47 Adagrasib was studied in KRYSTAL-1 as monotherapy (n = 44) or in combination with cetuximab (n = 32). The ORR as monotherapy was 19%; in combination with cetuximab, ORR was 46%, with median duration of response 7.6 months.48 Gastrointestinal toxicities occur frequently with these drugs; 3% of patients in CodeBreak100 had grade ≥3 diarrhea.47 Ongoing studies with combined KRAS G12C and EGFR inhibitors currently are recruiting: adagrasib plus cetuximab (KRYSTAL-10; NCT04793958) and sotorasib plus panitumumab (NCT05198934). KRAS G12C inhibitors can be used off-label or through a clinical trial in metastatic CRC.
Patients progressing after ≥3 previous therapies and without other options may benefit from regorafenib or trifluridine/tipiracil, and the latter can be combined with bevacizumab, which improves OS rates versus trifluridine/tipiracil alone. Response rates with these therapies are <5%.50,51 Toxicity tends to occur early and diminish over time with regorafenib, and a dose-escalation strategy at initiation is used to reduce incidence. Grade ≥3 AE include diarrhea, hypertension, and hand–foot skin reaction, which can be minimized by careful examination of hands and feet before treatment and by avoiding constricting clothing or other friction on the skin.52 Trifluridine/tipiracil is associated with neutropenia and anemia (grade ≥3: 38% and 18%, respectively). Severe gastrointestinal events are infrequent. Patients treated with trifluridine/tipiracil should be monitored closely for hematologic toxicity and educated to keep antidiarrheals on hand.50
With many of these drugs administered orally, it is important to identify patients at risk for nonadherence and to develop a strategy to support adherence, including education of patients, caregivers, and support staff on potential toxicities and preventive strategies. It also helps to provide tools for managing medication schedules and provide access to patient portals.
Finally, patients may appreciate the potential for treatment holidays—taking a break from systemic therapy after achieving stable disease—vs continuous maintenance therapy. Recent clinical trials suggest that taking a break has little impact on OS or quality of life and is associated with fewer toxicities. However, shorter PFS times are seen.53,54
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