Targeted Toxicities: Protocols for Monitoring the Adverse Events of Targeted Therapies Used in the Treatment of Non-Small Cell Lung Cancer

Targeted therapies have revolutionized the treatment for many patients with non-small cell lung cancer (NSCLC). Multiple new oral targeted therapies have been approved in the last decade; however, their overall efficacy may be reduced by poor adherence, treatment interruptions, or dose reductions due to adverse events. Most institutions lack standard monitoring protocols for toxicities from these targeted agents. This review describes important adverse events observed in clinical trials and reported by the U.S. Food and Drug Administration for both currently approved and upcoming promising therapies in the treatment of NSCLC. These agents cause a range of toxicities, including dermatologic, gastroenteric, pulmonary, and cardiac toxicities. This review proposes protocols for routine monitoring of these adverse events, both prior to initiation of therapy and while on treatment.


Introduction
Lung cancer remains the number one cause of cancer-related death worldwide. Nonsmall cell lung cancer (NSCLC) accounts for most lung cancer diagnoses (84%), and the identification of targetable driver mutations has changed treatment options dramatically over the last decade [1]. More than half of patients diagnosed with NSCLC have an actionable mutation [2]. The identification of driver mutations has resulted in the U.S. Food and Administration's (FDA) approval of multiple oral and intravenous therapies. The development of oral targeted therapies provides a clear advantage in terms of convenience to the patient but can also result in toxicity and non-adherence [3]. In recent years, the American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS) jointly published and recently updated guidelines on oral chemotherapy safety standards [4]. Patients receiving these oral anti-cancer therapies appear to have less contact with the treating providers than those receiving intravenous treatments [5]. Given patients receiving targeted agents may have less direct contact with healthcare teams, it is crucial to closely monitor side effects, adherence, and safety. Regular monitoring of oral drugs for cancer is a critical component of comprehensive patient care. It enables healthcare providers to detect and manage potential side effects early, which can help prevent complications, reduce the need for hospitalization, and improve patients' quality of life. By adjusting treatment as needed, healthcare providers can optimize outcomes and enhance the overall effectiveness of treatment.
CBC, amylase, and lipase: monthly for the first 3 months then every 3 months thereafter. CMP: every 2 weeks during the first 3 months, then monthly.

ERBB2 (HER 2) Mutation Positive
* This table represents the most common and clinically significant adverse events and is not a fully exhaustive list of potential toxicities.

Literature Search
Our recommendations were based predominantly on FDA prescribing information. We also evaluated landmark trials resulting in FDA approval, trials cited as providing evidence for the National Comprehensive Cancer Network (NCCN) recommendations in the treatment of NSCLC, related papers, and case reports via a PubMed search on 22 October 2022 using the relevant drugs and "adverse events" as keywords without restrictions to assess common toxicities. Toxicities that occurred in more than 10% of the patient population or that were of significant clinical concern in the landmark trials were included in our monitoring parameters. We also incorporated periodic monitoring parameters that were stated in the package insert.

Erlotinib + Ramucirumab
The results of the RELAY study led to the 2020 FDA approval of ramucirumab in combination with erlotinib for the first-line treatment of metastatic NSCLC for patients with EGFR exon 19 deletions or exon 21 L858R mutations. Similar toxicities to erlotinib monotherapy were observed. Adverse events that were described more frequently with the addition of ramucirumab included: hypertension (42%), proteinuria (35%), epistaxis (16%), peripheral edema (13%), and hepatotoxicity (42-43%). Hypertension and diarrhea were the most common grade 3-4 adverse events noted with the addition of ramucirumab (24% and 7%, respectively) [33,34].

Gefitinib
Gefitinib was initially approved in the European market in 2009, where it has seen the majority of its use. It has since been approved by the FDA in 2015 for the first-line treatment of metastatic NSCLC with EGFR 19 deletions or exon 21 L858R mutations. The common adverse events of any grade observed in trials included: rash (44.9-66.2%), diarrhea (30.8-44.6%), and nausea (10.3-16.6%) [7,35]. Other notable adverse events of any grade included: proteinuria (35%), ALT (38%), and AST (40%). ILD occurred in 1.3% and ocular disorders occurred in roughly 6.7% of patients. Grade 3-4 adverse events are uncommon with diarrhea (3%) and decreased appetite (2.3%) being reported most frequently [8].

Second Generation Afatinib
Afatinib is a tyrosine kinase inhibitor (TKI) that was first approved in July 2013 as first-line therapy for patients with metastatic NSCLC with EGFR exon 19 deletions or L858R substitutions. In a grouped analysis of the LUX-LUNG 3 and LUX-LUNG 6 trials, dermatologic toxicities, diarrhea, and nail changes were the most common adverse events overall (90%, 96%, and 58%, respectively), as well as the most common grade 3-4 adverse events (15-16%, 15%, and 13-14%, respectively) [36]. Other notable toxicities across all trials included: interstitial lung disease (ILD) in 1.6% of patients, keratitis in 0.7% of patients, and hepatic toxicity in 9.7% of patients [37]. Some online reference guides recommend left ventricular ejection fraction (LVEF) monitoring, though a review of cardiac safety across clinical trials did not show an association with heart failure or a decrease in LVEF [38].

Third Generation Osimertinib
Osimertinib was first approved for the use of T790M mutated NSCLC previously treated with first-generation TKIs after clinical trials demonstrated improved progressionfree survival (PFS) (10.1 months vs. 4.4 months) and objective response rate (ORR) (71% vs. 31%) compared to platinum therapy plus pemetrexed [12,13]. The subsequent FLAURA and ADURA trials, respectively, led to the FDA approval of osimertinib in the first-line treatment of metastatic NSCLC and as adjuvant therapy for patients with Stage IB-IIIA EGFR exon 19 deletions or exon 21 L858R mutations. Gastrointestinal and dermatologic toxicities were common in both studies (46-58% and 34-58%, respectively). ILD was observed in 3-4% of patients [39,40]. The FLAURA trial observed QTc changes in 10% of patients receiving osimertinib [39]. A post hoc analysis of the FLAURA and AURA3 trials observed a decrease in LVEF of ≥10 percentage points to an absolute value of <50% in 3.9% of patients [41]. The data did not demonstrate a significant causal relationship, though several recent case reports have observed reversible osimertinib-induced cardiomyopathy [14,15,42]. The most frequent grade 3-4 toxicities included: neutropenia (3.4%), lymphopenia (3.3%), and hyponatremia (3.4%).

Sotorasib
Sotorasib, an inhibitor of the RAS GTPase family, was the first FDA-approved therapy for KRAS G12C mutated NSCLC [46]. In CodeBreaK100, a phase II study of sotorasib in previously treated locally advanced or metastatic KRAS G12C mutated disease, the most common treatment-related adverse events were diarrhea (31.7%), nausea (19%), and increase in AST/ALT (15%). Edema of all grades occurred in 13% of patients, and 29% of patients experienced increased urine protein. Hepatotoxicity was the most common grade 3-4 adverse event, occurring in up to 5-6% of patients, and approximately 2.4% of patients experienced grade 3-4 pulmonary toxicities [19].

Ceritinib
In 2017, ceritinib was FDA-approved for patients with previously untreated metastatic NSCLC with an ALK rearrangement. This was a change from the original indication of patients whose disease had progressed or who were intolerant to crizotinib. This approval was based on the ASCEND-4 trial in which the most common toxicities included: diarrhea, nausea, abdominal pain, vomiting, and fatigue. Notable grade 3-4 toxicities included: ALT elevation (31%), AST elevation (17%), and diarrhea (5%) [18,22]. Similarly, the subsequent ASCEND-8 trial reported that a reduced dose of 450 mg in a fed state resulted in less GI toxicity when compared to a previously approved dose of 750 mg in a fasted state (65.9% vs. 80%), but maintained a relatively high level of ALT elevation (27.3%) [52].

ROS1 Rearrangement Crizotinib and Entrectinib
These drugs are currently approved for the treatment of ROS1 rearrangements [25,55]. Adverse events are described elsewhere in this manuscript.

Crizotinib
While crizotinib is FDA-approved for the treatment of ALK-positive and ROS1rearranged NSCLC as described above, there is a growing body of evidence that supports its use in MET exon 14 skipping mutations [61,64]. Adverse events in these studies were similar to those reported in other mutations.

Discussion
The ongoing identification of driver mutations in NSCLC has led to the development of a multitude of targeted therapies which bring new opportunities for treatment but can also cause a considerable degree of morbidity, dose interruptions, and treatment delays. Although the FDA includes recommendations for the monitoring of adverse events in the package insert, the degree to which these are followed is unclear. Through the assessment of clinical trial data, case reports, and other adverse events data provided by the FDA, we have developed much-needed protocols for laboratory assessment and clinical monitoring for the targeted therapies currently used in the treatment of NSCLC.
The ASCO/ONS guidelines highlight the importance of adherence and monitoring of patients on targeted therapy. It is essential to counsel a patient about the importance of adherence and signs or symptoms of toxicity upon initiation of therapy. Studies have shown that roughly half of the patients are fully adherent to prescribed oral chemotherapy regimens [70,71]. One of the major limiting factors to adherence is toxicity, which leads to dose reductions and treatment interruptions [2]. In a survey of 42 national cancer centers, it was established that 88% of adverse events were predictable and 50% were preventable [72]. Early identification of toxicity can lead to improved outcomes, reduced hospitalizations, and better quality of life for patients.
An important aspect of the implementation of these proposed monitoring protocols is the consideration of how to best translate the adverse events described in clinical trials into regular clinical practice. The patients studied in trials are meticulously observed in a manner that may not be feasible or realistic in actual practice. Similarly, patients must meet stringent criteria to allow participation in clinical trials. Investigational trials of new drugs across specialties may exclude 26.3-52.9% of the adult population of interest depending on age and other comorbidities; oncology trials specifically may have a median exclusion proportion of 26.4% [73]. The rates of adverse events in this curated population may not be representative of those in the real world. A retrospective study of oral medications in metastatic renal cell carcinoma demonstrated variability in the rates of adverse events reported in a clinical registry as compared to those in the FDA label and landmark trials [74]. As mentioned above, real-world experience with EGFR inhibitors such as osimertinib suggests additional cardiac toxicities, specifically late toxicities, that were not captured in the landmark trials [14,15,42,75]. It is therefore imperative that we update our screening guidelines to reflect these emerging discrepancies in actual clinical practice.
Another challenge stems from uncertainty about how these new therapies will affect an individual patient and the degree to which toxicity should be expected. Although providers may be inclined to encourage patients to make their own choices regarding different treatment options, based on the patient's tolerance for different side effects, many patients would prefer to eschew this responsibility and receive a clear recommendation from their provider [76]. Providing clear information to patients about the range of possible effects of therapy is important for establishing perceptions of competent care and building patient trust [77]. Nonetheless, transparent communication can be combined with clear recommendations to ease patients' psychological burdens.
Our hope is that the standardization of toxicity monitoring will help to minimize and address the above challenges and improve patient outcomes. Implementing and standardizing such a protocol requires a multidisciplinary approach involving collaboration between pharmacists, nurses, and physicians. Pharmacists can provide medication education, monitor for potential drug interactions, and make recommendations to physicians regarding dose adjustments or changes to the treatment plan. Nurses can assist in monitoring for potential side effects and providing ongoing support to patients, while physicians are responsible for prescribing appropriate oral drugs and monitoring patient progress throughout treatment. Similarly, local community and academic centers should work together to align monitoring protocols to help standardize patient care. More data are needed to determine the full extent of adverse events observed in patients longitudinally as well as which patients are more susceptible to certain toxicities in the presence of prior comorbidities.