Exploring New Frontiers in Non-Small Cell Lung Cancer Treatment

The following article features coverage from the 2022 Oncology Nurse Advisor Summit. Click here to read more of Oncology Nurse Advisor‘s conference coverage.

Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer cases. Understanding of its histology has evolved from classifying it into a handful of subtypes to identifying the disease by its driver mutation. The largest subtype of NSCLC is adenocarcinoma (40% of patients); the remaining subtypes are squamous cell carcinoma (25%), large cell carcinoma (10%), others (20%), and not otherwise specified (NOS; 5%). Adenocarcinomas are now further identified by more than a dozen driver mutations that rarely overlap and also help inform selection of optimal treatment.

In a presentation at the 2022 Oncology Nurse Advisor Summit, Marianne Davies, DNP, AOCNP, FAAN, associate professor, Yale School of Nursing, and thoracic oncology nurse practitioner at Smilow Cancer Hospital Yale Comprehensive Cancer Center in New Haven, Connecticut, described the various adenocarcinoma driver mutations and their recommended treatments. The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and others, including European associations, are recommending that all people with a lung cancer diagnosis undergo broad molecular testing preferably within 10 days of diagnosis, for potentially targetable biomarkers, including EGFR, ALK, ROS1, BRAF, KRAS, RET, MET, exon 14, NTRK 1/2/3, and PD-L1.

It can take a long time for patients to receive their testing results, Dr Davies explained; therefore, broad testing with next generation sequencing (NGS) is a valuable option. NGS RNA tumor sequencing is most sensitive for all the biomarkers listed above except MET amplification and PD-L1. Fluorescence in situ hybridization (FISH) testing is most sensitive for MET amplification; immunohistochemistry (IHC) testing is most sensitive for PD-L1. However, all of these tests require a specific number of tumor cells. Liquid biopsies are an option if an adequate tissue sample cannot be obtained. These tests have a high correlation with tissue samples (sensitivity, 70% to 80%; specificity, nearly 100%), require a smaller sample, and have a faster turnaround time, which reduces the time to treatment.

One in four cases of NSCLC have KRAS mutation, with 1 in 8 of those cases having KRAS G12C. “This population tends to be smokers with a high mutation burden,” noted Dr Davies. Sotorasib is US Food and Drug Administration (FDA)-approved in the second-line setting. Adverse effects (AEs) to watch for include diarrhea, joint and muscle pain, nausea, fatigue, cough, swelling, pneumonitis, hepatotoxicity, and interstitial lung disease (ILD); patients should be monitored for decreased lymphocytes, hemoglobin, sodium; and increased urine protein.

EGFR mutations occur in 15% of NSCLC cases. These patients tend to be nonsmokers, younger, and female. The mutation also is common in the Asian population. Trans-member ligand binding receptor on the surface of epithelial cells plays a role in cellular proliferation and differentiation. The most common mutations are exon 19 deletion (40% to 50%) and exon 21-point mutation (L858R; 30% to 40%).

Five drugs are FDA-approved for treatment of NSCLC with EGFR mutations: osimertinib is a third-generation, irreversible EGFR inhibitor; afatinib and dacomitinib are second-generation, also irreversible; erlotinib and gefitinib are first-generation inhibitors, EGFR inhibition is reversible. Common AEs include leukopenia, thrombocytopenia, diarrhea, rash, myalgias, dry skin, and fatigue. These agents may cause ILD and pneumonitis. Cardiac AEs include QTc interval prolongation, cardiomyopathy (monitor LVEF), and vasculitis. Additional AEs include erythema multiforme, Stevens-Johnson syndrome, and keratitis.

Exon 20 insertion accounts for 10% to 12% of EGFR mutations, which tend to be nonresponsive to EGFR inhibitors. Dr Davies described a new area of treatment for these patients, with amivantamab being one of the few monoclonal antibodies used to treat NSCLC. It is administered in split doses and requires premedication. AEs include infusion reactions, ILD, pneumonitis, and ocular effects; dermatologic AEs include rash, paronychia, and stomatitis. Patients should be monitored for decreased lymphocytes, albumin, and potassium; and increased glucose. Mobocertinib is approved as a second-line therapy after a platinum-based regimen. Patients should be monitored for QTc prolongation, ILD, and diarrhea. Common AEs are rash, nausea, stomatitis, paronychia, and myalgias.

ALK translocations (5% to 7% of EGFR mutations) result in uncontrolled growth and proliferation, occurring most commonly in nonsmokers, male patients, and younger patients, Dr Davies explained. One of the first treatments to receive approval is alectinib, a highly selective, second-generation therapy. Liver functions must be monitored every 2 weeks for the first 3 months of treatment, then monthly. AEs include ILD, renal impairment, bradycardia, severe myalgias, and hemolytic anemia. Crizotinib is a multitargeted therapy, with reported AEs being visual disturbance/loss, hepatotoxicity, prolonged QTc, edema, ILD, bradycardia, nausea, vomiting, diarrhea, and stomatitis. Ceritinib, another second-generation therapy, lists hepatotoxicity, elevation pancreatic enzymes, hyperglycemia, pneumonitis, QTc prolongation, bradycardia, hepatotoxicity as AEs to watch for.

Brigatinib, a second-generation therapy, and lorlatinib, a third-generation therapy, are ALK/ROS1 inhibitors that penetrate the CNS. Reported AEs include hypertension, hyperglycemia, bradycardia, elevated pancreatic enzymes, elevated CPK, ILD, and pneumonitis; and weight gain, hypercholesterolemia, mood disorders, prolonged PR interval, AV block, and pneumonitis, respectively.

ROS1 rearrangements comprise 1% to 2% of NSCLC mutations. Patients tend to be younger, never smokers, Asian, and have more advanced disease, explained Dr Davies. Crizotinib, ceritinib, and lorlatinib are also indicated for treatment of these patients. Entrectinib also shares this indication, with chronic heart failure (assess LVEF), CNS effects (cognitive, mood), skeletal fractures, hepatotoxicity, hyperuricemia, QTc prolongation, visual disorders, dysgeusia, edema, dyspnea, myalgias, and weight gain as reported AEs.

Five percent of NSCLC cases have a BRAF mutation, of those 40% to 50% will have BRAF V600E, a point mutation. Recommended therapies are dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. Notable AEs Dr Davies discussed are serious febrile reaction with dabrafenib and colitis and gastric perforation with trametinib, as well as cardiac toxicity and other AEs that occur with other EGFR inhibitors.

RET fusion (1% to 2%) tend to be patients who are younger and never smokers. Approved treatments include selpercatinib (AEs of note hepatotoxicity, hypertension, QTc prolongation, hypersensitivity reaction, and others) and pralsetinib (AEs include ILD, hypertension, hemorrhage, impaired wound healing, constipation, myalgias).

MET exon 14 skipping mutations occur in 3% to 4% of cases, and most commonly in the elderly. Therapies are capmatinib and tepotinib, as well as crizotinib. AEs include hepatotoxicity and ILD, as well as photosensitivity, peripheral edema, nausea, emesis, dyspnea, and anorexia with capmatinib, and edema, fatigue, myalgias, diarrhea, decreased albumin, and increased amylase with tepotinib.

Although NTRK occurs in a small percentage of NSCLS cases (0.3%), it is also present in many other cancers that occur throughout the body. Therefore, Dr Davies explained, treatment could be beneficial across other systems. Approved treatments are larotrectinib and entrectinib. Notable AEs are their CNS effects such as mood disorders and cognitive dysfunction. Other AEs include hepatotoxicity, skeletal fractures, GI issues, and myalgias.

No NSCLC mutations are targetable for immunotherapy. PD-L1 levels are measured as negative (<1%), low (1% to 49%), and high (≥50%). The standard of care is a combination of immune checkpoint inhibitor (ICI) plus chemotherapy for PD-L1 low or negative. For high PD-L1, treatment is choice of a single-agent ICI or ICI plus chemotherapy. Although single-agent ICI is approved for 1% or more of cases, it is not broadly recommended, concluded Dr Davies.

Read more of Oncology Nurse Advisor’s coverage of 2022 Oncology Nurse Advisor Summit by visiting the conference page.

Reference

Davies M. Targeted therapy for NSCLC: new frontiers. Oral presentation at: 2022 Oncology Nurse Advisor Summit; March 25-27, 2022.