Oncology Overview: Safe Use of Oral Tyrosine Kinase Inhibitors in Thoracic Oncology

SAP Partners | Health System / Oncology | <b>Roswell Park Comprehensive Cancer Center</b>

Pharmacists have the potential to help optimize treatment and maximize supportive care management for targeted therapies.

Lung cancer is the leading cause of estimated cancer deaths in the United States.1,2 Fortunately, advances are being made within this disease state allowing for the incorporation of targeted therapies into the treatment landscape.

Patients with metastatic non-small cell lung cancer (NSCLC) who are candidates for treatment with targeted therapy are living longer, with some 5-year survival rates being up to 50% depending on the oncogenic driver alteration.2 Further understanding of disease biology and identification of driver mutations in NSCLC has resulted in a surge of new targeted therapies, particularly tyrosine kinase inhibitors (TKIs).2,3

First-generation epidermal growth factor receptor (EGFR) TKIs were among the initial breakthroughs driving precision medicine within the NSCLC treatment landscape. Personalized medicine in NSCLC has continued to expand with the development of novel small molecule therapies for various targets.

Some of the most recent actionable genomic alterations include rearranged during transfection (RET) rearrangements, mesenchymal-epithelial transition (MET) exon 14 skipping variants, and EGFR exon 20 insertion mutations.3

RET Kinase Inhibitors

Selpercatinib

Selpercatinib is 1 of 2 preferred TKIs for the treatment of metastatic RET fusion-positive NSCLC.2 The FDA approval of this indication was based on results from the LIBRETTO-001 trial.

This phase 1-2 trial included 105 patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and 39 patients who were previously untreated. The objective response rate was 64% in those who had previously received platinum-based chemotherapy and 85% in those who were previously untreated. The median duration of response was 17.5 months in previously treated patients and not reached in the treatment naïve group.4

The most common adverse events (AEs) and laboratory abnormalities are increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased alkaline phosphatase, increased glucose, decreased leukocytes, decreased platelets, decreased albumin, decreased calcium, dry mouth, diarrhea, constipation, increased creatinine, hypertension, fatigue, edema, increased total cholesterol, rash, and decreased sodium.5

Warnings and precautions exist for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, tumor lysis syndrome, risk of impaired wound healing, and embryo-fetal toxicity.5 Recommended monitoring for selpercatinib can be seen in Table 1.

The National Comprehensive Cancer Center (NCCN) recommends selpercatinib use in the first line setting for RET rearrangement-positive NSCLC or as subsequent therapy if not used first line.2 The recommended dosage is based on a patient’s body weight.

Those weighing less than 50 kg should take 120 mg orally twice daily, while those who are 50 kg or greater should take 160 mg orally twice daily. The TKI may be taken with or without food unless co-administration with a proton pump inhibitor as described below.5

Drug-drug interactions to be aware of with selpercatinib include co-administration with acid reducing agents. Ideally concomitant administration with these drugs should be avoided. However, if this cannot be avoided, patients should be counseled to take selpercatinib with food when also taking a proton pump inhibitor (PPI).

Selpercatinib should be administered 2 hours before or 10 hours after administration of an H2 receptor antagonist and 2 hours before or 2 hours after administration of a locally acting antacid.5

Table 2 lists recommended dosage modifications for concomitant use of selpercatinib with CYP3A inhibitors. 

Pralsetinib

Pralsetinib is another TKI approved for the treatment of metastatic, RET fusion-positive NSCLC. The FDA approval of this indication was based on results from the ARROW trial.6

This multi-cohort, open-label, phase 1-2 study included 233 patients with RET fusion-positive NSCLC. The RET fusion-positive measurable disease population included 87 patients who previously received platinum-based chemotherapy and 27 patients who were treatment naïve. The overall response rate was 61% in those who had previously received platinum-based chemotherapy and 70% in those who were previously untreated.6

The most common AEs and laboratory abnormalities are constipation, diarrhea, hypertension, fatigue, musculoskeletal pain, decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelets, decreased phosphate, decreased calcium, decreased sodium, increased AST, increased ALT, and increased alkaline phosphatase.7 Warnings and precautions exist for interstitial lung disease (ILD)/pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, tumor lysis syndrome, impaired wound healing, and embryo-fetal toxicity.7 Recommended monitoring for pralsetinib can be seen in Table 3.

The NCCN recommends pralsetinib use in the first line setting for RET rearrangement-positive NSCLC or as subsequent therapy if not used first line.2 The recommended dosage is 400 mg orally once daily on an empty stomach.

Drug-drug interactions to be aware of with pralsetinib include co-administration with strong CYP3A inducers and inhibitors, as well as combined P-gp and strong CYP3A inhibitors. Ideally concomitant administration with these drugs should be avoided. However, if this cannot be avoided recommended dosage modifications are as described in Table 4.7

MET Inhibitors

Capmatinib

Capmatinib is 1 of 2 preferred TKIs for the treatment of metastatic NSCLC with a MET exon 14 skipping mutation.2 The FDA approval of this indication was based on results from the GEOMETRY mono-1 study.

This multi-cohort, phase 2 study included 364 patients with MET-dysregulated advanced NSCLC. Cohort assignment was based on previous lines of therapy and MET status specified as MET exon 14 skipping mutation or MET amplification. The overall response rate seen in patients with a MET exon 14 skipping mutation was 41% in those who previously received 1 or 2 lines of therapy and 68% in those who were treatment naïve.8

The most common AEs are peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.9 Warnings and precautions exist for ILD/pneumonitis, hepatotoxicity, photosensitivity, and embryo-fetal toxicity.9 Recommended monitoring for capmatinib can be seen in Table 5.

The NCCN guidelines list capmatinib as a preferred agent in the first line setting for NSCLC with a MET exon 14 skipping mutation or as subsequent therapy if not used in first line.2 The recommended dosage is 400 mg orally twice daily with or without food. Co-administration with moderate or strong CYP3A inducers should be avoided.9

Tepotinib

Tepotinib is another small molecule TKI approved for the treatment of metastatic NSCLC with a MET exon 14 skipping mutation.11 This indication was granted based off results from the VISION trial.

The open-label, phase 2 trial included 152 patients with a MET exon 14 skipping mutation. Response was assessed based on identification of MET alterations through liquid biopsy, tissue biopsy, or combined (liquid and tissue) biopsy. Among the combined-biopsy group, the objective response rate by independent review was 46% with a median duration of response of 11.1 months.10

The most common AEs and grade 3 to 4 laboratory abnormalities are edema, fatigue, nausea, diarrhea, musculoskeletal pain, dyspnea, decreased lymphocytes, decreased hemoglobin, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, and increased AST.11 Warnings and precautions for tepotinib include ILD/pneumonitis, hepatotoxicity, and embryo-fetal toxicity.11 Recommended monitoring for the MET targeted TKI is listed in Table 6.

Tepotinib is recommended by the NCCN as a preferred agent in the first line setting for NSCLC with a MET exon 14 skipping mutation or subsequent line therapy if not previously used.2 The recommended dosage is 450 mg orally once daily with food.

Concomitant use with strong CYP3A inducers, dual strong CYP3A inhibitors and P-gp inhibitors, and P-gp substrates where minimal concentration changes can lead to serious toxicity should be avoided.11

EGFR Exon 20 Insertion Mutation Inhibitor

Mobocertinib is the first oral therapy for the treatment of advanced NSCLC with EGFR exon 20 insertion mutations. This novel targeted therapy received FDA approval based on results from an open-label, phase 1-2 study.12

The trial was multi-cohort with dose escalation/dose expansion cohorts and a single arm extension cohort (EXCLAIM). The study included 114 patients with advanced, EGFR exon 20 insertion mutation-positive NSCLC previously treated with platinum-based chemotherapy. The overall response rate was 28% with a median duration of response of 17.5 months.12

The most common AEs and grade 3 to 4 laboratory abnormalities are diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, musculoskeletal pain, decreased lymphocytes, decreased hemoglobin, increased amylase, increased lipase, decreased potassium, increased creatinine, and decreased magnesium. Listed warnings and precautions include ILD/pneumonitis, cardiac toxicity, diarrhea, and embryo-fetal toxicity.13

Recommended monitoring for mobocertinib can be seen in Table 7.

The NCCN recommends mobocertinib as subsequent therapy after progression on first-line systemic therapy in patients with EGFR exon 20 insertion mutation positive NSCLC.2 The recommended dosage is 160 mg orally once daily with or without food.

Concomitant use with moderate or strong CYP3A inducers and drugs that prolong the QTc interval should be avoided if possible.13 Consider more frequent monitoring of the QTc interval if there are risk factors for QTc prolongation.13

Table 8 lists recommended dosage modifications for concomitant use of mobocertinib with CYP3A inhibitors.

There will be an increasing number of targeted therapies emerging as more is discovered on driver mutations within NSCLC. Each TKI has its own toxicity profile and recommended monitoring parameters.

Drug-drug interactions should always be considered when prescribing these novel agents. Pharmacists have the potential to help optimize treatment and maximize supportive care management for these targeted therapies.

About the Author

Christina Billias, PharmD, BOCP, is a Clinical Pharmacist–Specialist with Roswell Park Comprehensive Cancer Center in Buffalo, NY.

References

  1. American Cancer Society. Cancer Facts & Figures 2022. Atlanta: American Cancer Society; 2022.
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  3. Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. 2022; 40:611-625. doi: 10.1200/JCO.21.01626
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  6. Gainor JF, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22:959-69. doi.org/10.1016/ S1470-2045(21)00247-3
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  9. Tabrecta (capmatinib). Package Insert. Novartis; 2020.
  10. Paik PK, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383:931-43. doi: 10.1056/NEJMoa2004407
  11. Tepmetko (tepotinib). Package Insert. EMD Serono, Inc.; 2021.
  12. Zhou C, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761
  13. Exkivity (mobocertinib) Package Insert. Takeda Pharmaceuticals; 2021.