Managing Side Effects of Targeted Therapies for NSCLC May Improve Outcomes

Mark G. Kris, MD

Oncogenic driver mutations have been detected in over 60% of the non-small cell lung cancer (NSCLC) tumor samples surveyed by the Lung Cancer Mutation Consortium (LCMC).¹The increasing use of targeted drugs in the clinic has raised the potential for effective treatment of metastatic NSCLC with fewer side effects than traditional chemotherapeutic drugs.

“When we find these specific genetic changes, the doctor can choose drugs and clinical trials specifically targeting those oncogenic drivers,” wrote Mark G. Kris, MD, in a press release. Kris, lead author of the LCMC study and the Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Institute in New York City, explained, “When that happens, the chance of shrinkage is much higher than with standard chemotherapies. The side effects are much less because the cancer cells are much more dependent on these oncogenes than normal cells.”

However, while there are definite advantages to using targeted therapies, the reality is that these agents are associated with toxicities and adverse reactions that must be anticipated and managed by clinicians in order to maximize the benefit to their patients. A variety of side effects have been associated with these agents, including rash, diarrhea, hypertension, hepatotoxicity, and ocular toxicities, among others.²The majority of these side effects can be grouped into general categories, including mechanism-associated toxicities and off-target toxicities. Determining to which category a given side effect belongs is important for choosing an appropriate management strategy.

Mechanism-Associated Toxicities

Targeted therapies typically work by disrupting, in a selective manner, cell-signaling pathways that drive tumor growth. New agents in NSCLC have often targeted the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that is expressed in more than 60% of NSCLCs.³Tyrosine kinase inhibitors (TKIs) targeting EGFR that are approved for use in NSCLC include erlotinib and gefitinib.

Under normal circumstances, EGFR is expressed primarily in epithelial cells of the skin and digestive tract; therefore, rash and diarrhea constitute the most common side effects associated with EGFR inhibitors.⁴Because these side effects are associated with the mechanism of action of the drug (ie, inhibition of EGFR signaling), they may also serve as surrogate markers for an effective antitumor response.

The severity of rash in patients taking erlotinib has indeed been correlated with polymorphisms in theEGFRgene itself.⁵Furthermore, in a meta-analysis examining the association between skin rash and disease prognosis in patients with NSCLC who were treated with either erlotinib or gefitinib, the occurrence of rash was a predictive factor for improved response rate, progression-free survival (PFS), and overall survival (OS).⁶

Another target of molecular therapies in NSCLC is angiogenesis, specifically signaling by vascular endothelial growth factor (VEGF). Bevacizumab is a monoclonal antibody that binds to VEGF-A and is approved for use in patients with metastatic NSCLC in combination with cytotoxic chemotherapy. Studies have revealed a high incidence (23.6%) of hypertension in patients with cancer who are treated with this drug, including a significant number of grade 3/4 events (7.9%).⁷Similar to the incidence of rash in EGFR inhibitors, hypertension has been found to be associated with positive outcomes in patients with NSCLC.^8,9

When dealing with adverse events caused by on-target effects that are correlated with efficacy, it is better for clinicians to pursue a strategy of toxicity management rather than dose reduction, which would reduce the beneficial effects of the drug as well as the toxicities. This is particularly important in the context of metastatic disease, in which few effective alternatives are available.

Ocular Toxicities

Side effects involving the eyes are also common with EGFR inhibitors, such as erlotinib and the anti-EGFR antibody, cetuximab. The most common ocular toxicities include blepharitis, trichomegaly, meibomitis, and dysfunctional tear syndrome.

These side effects are often unfamiliar to oncologists and are underreported due to a lack of existing recommendations on routine ophthalmological monitoring regimens.¹⁰Ophthalmologic examination before treatment is recommended to enable the identification of ocular toxicities during treatment. Management strategies that avoid dose modifications or interruptions include the use of topical lubricants, anti-inflammatory agents, and corticosteroids.

Immune-Mediated Pneumonitis

There are chronic inflammatory and immunologic changes that occur in the lungs in NSCLC that encourage tumor growth. In some cases, these changes can cause severe pneumonitis, and even death, in reaction to TKIs or agents targeting immune checkpoint molecules, such as the programmed cell death-1 receptor (PD-1).¹¹This toxicity is commonly dealt with by cessation of treatment and administration of steroids in severe cases.

MPDL3280A, an antibody targeting the PD-1 ligand (PD-L1), has been the subject of a phase I trial in patients with metastatic NSCLC. Results presented in 2013 indicated that, although grade 3/4 adverse events occurred in 34% of participants, no cases of grade 3-5 pneumonitis were observed,¹²suggesting that PD-L1 inhibitors might avoid this serious side effect.

In a press release, study author Jean-Charles Soria, MD, PhD, from the Institut Gustave Roussy in France, expressed optimism about anti—PD-L1 immunotherapy in advanced NSLC. “A new therapy, with few serious adverse sideeffects, that is easy to use — one intravenous infusion every 3 weeks – and a robust clinical activity as a single agent should soon be available.”

Conclusion

Clinical Pearls

• Targeted agents for NSCLC may be associated with toxicities and adverse reactions and these must be anticipated and managed by clinicians to maximize benefit to patients.
• Rash and diarrhea constitute the most common side effects associated with EGFR inhibitors.
• When dealing with adverse events caused by effects correlated with efficacy, clinicians may pursue a strategy of toxicity management rather than dose reduction, which would reduce the beneficial effects of the drug as well as the toxicities.
• Side effects involving the eyes are also common with EGFR inhibitors.
• Management strategies that avoid dose modifications or interruptions include the use of topical lubricants, anti-inflammatory agents, and corticosteroids.
• Results presented in 2013 indicated that, although grade 3/4 adverse events occurred in 34% of participants taking PD-L1 inhibitors, no cases of grade 3-5 pneumonitis were observed, suggesting that PD-L1 inhibitors might avoid this side effect.

Although targeted therapies offer the potential for effective treatment of metastatic NSCLC with better safety profiles than conventional chemotherapy, side effects still occur with these agents. In the case of toxicities associated with the mechanism of action of the drug, symptom management should be attempted and dose reductions avoided, if possible.

References

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