Preventing infusion-related reactions: the lessons learn with the use of amivantamab

Infusion-related reactions (IRRs), according to the National Cancer Institute, are defined as unfavorable reactions to the infusion of biological or pharmacological substances. IRRs may occur with several parenterally delivered anticancer therapies, i.e., cytotoxic chemotherapy, immune checkpoint inhibitors, and, more recently, bispecific antibodies and antibody-drug conjugates (1). The frequency and severity of IRRs in these newer drug classes have brought significant attention to this side effect, which is quite old. The incidence of IRRs has been difficult to ascertain due to historical inconsistencies and discrepancies in the terminology used for grading and reporting (2-5). Although the literature on this subject is sparse, studies show that the incidence of IRRs fluctuates according to anticancer therapy, cancer type, and administration practices (1). Other risk factors associated were previous allergic reactions (particularly seafood allergies), asthma, female sex, higher drug doses, iodine, and pre-existing cardiac or pulmonary dysfunction, concomitant β-adrenergic blocker therapy, and concurrent autoimmune disease (1). The pathogenesis of IRRs is not clearly established; the incidence is higher, and the IRR is more severe when the lymphocyte count is high, but neither the stage of the disease nor the tumor burden appears to play a significant role. The frequency of IRRs varies widely, depending on the patient’s condition, particularly the presence or absence of an autoimmune disease, the type of cancer, and the prevention methods used, as well as the specific drug (1). In a systematic review (4,5), the incidence of IRRs associated with chemotherapy ranged from 0% to 71% for all-grade reactions and from 0% to 15% for grades 3–4 reactions. Incidences of all-grade and grades 3–4 IRRs were 0–4% and 0–1% with panitumumab, 1.6–11% and 0–4% with bevacizumab, and 7.6–33% and 0–22% with cetuximab, respectively. With tarlatamab, a first-in-class DLL3-targeted bispecific T-cell engager, the incidence exceeded 53% in the DELLphi-304 trial (6).

IRRs can occur by one of two mechanisms, immune-mediated or non-immune-mediated, and be broadly classified as non-immune-mediated (or non-allergic) reactions or immune [generally immunoglobulin E (IgE)-mediated (or true allergic)] reactions to foreign proteins. The symptoms of both types of IRRs overlap, but their timing is typically different. True allergic responses typically manifest in subsequent exposures and are most observed with chemotherapy, particularly platinum. Non-immune-mediated, or non-allergic, reactions include cytokine-release syndrome (CRS; a cytokine-mediated hypersensitivity reaction) occurring within the first hours after infusion and characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia, idiosyncratic reactions (uncommon and unpredictable reactions unrelated to the drug’s pharmacological action) (1). The reaction may be IgE-mediated hypersensitivity or an anaphylactic reaction; this may also be related to the immunogenicity of the treatments. IgE mediated issue has been previously well studied with cetuximab (7). For newer drug classes, the IRRs-related symptomatology might differ significantly in severity, also affecting physiological systems differently. In most cases, the prevention and management of IRRs is empirical, and few prospective studies demonstrate the benefit of specific management of this side effect (1).

The phase 2 trial, SKIPPirr (8), confirmed the value of a standardized management approach to reduce the rate and severity of IRRs with intravenous amivantamab. Amivantamab (9-12) is an epidermal growth factor receptor (EGFR)-mesenchymal-epithelial transition (MET) bispecific antibody with immune cell-directing activity. Intravenous amivantamab has shown significant clinical efficacy and received regulatory approval in combination with lazertinib for first-line treatment of common EGFR-mutated advanced non-small cell lung cancer (NSCLC), and in combination with chemotherapy, for second-line treatment, after disease progression on EGFR-tyrosine kinase inhibitors. Amivantamab also had an approval in combination with chemotherapy for first-line treatment or as monotherapy after progression on platinum-based chemotherapy for NSCLC with EGFR exon 20 insertion mutations. The particularly high rate of adverse drug reactions in the early clinical trials, affecting nearly two-thirds of patients, led to a strategy of splitting the first dose over 2 days and premedication with antihistamines, antipyretics, and glucocorticoids. These reactions also resulted in recommendations for prolonged patient monitoring in hospital settings, complicating the use of amivantamab in certain structures.

Based on empirical clinical data from preventive management implemented by certain teams, the phase 2 SKIPPirr study (8) prospectively investigated four strategies for preventing IRRs) in patients initiating amivantamab treatment (Figure 1): (I) oral dexamethasone 4 mg twice daily given on cycle (C) 1 day (D) 1 (two doses); (II) oral dexamethasone 8 mg twice daily given on C1D2 and C1D1 and another dose 1 hour before amivantamab infusion on C1D1 (five doses); (III) oral montelukast 10 mg once daily given on C1D4, C1D3, C1D2, C1D1, and C1D1 (five doses); or (IV) a single dose of subcutaneous methotrexate 25 mg given anytime between C1D7 and C1D3. All participants also received standard premedication with antihistamines, antipyretics, and intravenous dexamethasone 10 mg (Figure 1). The dexamethasone 4 mg and methotrexate cohorts both had 5 of 6 participants (83.3%) who experienced IRRs and did not pass stage 1. The montelukast cohort had 10 of 15 participants (66.7%) who experienced IRRs and did not pass stage 2. The dexamethasone 8 mg twice daily cohort passed stages 1 and 2 and proceeded to the expansion stage, where 24 additional participants were enrolled and treated. On C1D1, 9/40 participants (22.5%) in this dexamethasone 8 mg cohort reported an IRR, and all were grades 1 to 2. The most frequent adverse events in the overall population were rash, paronychia, and hypoalbuminemia without differences between cohorts. Adverse events reported as potentially related to dexamethasone prophylaxis occurred in three participants receiving dexamethasone 8 mg (one event each: gastroesophageal reflux disease, muscle atrophy, somnolence) and were all grades 1 to 2.

Figure 1.

Design of the phase 2 SKIPPirr study. BID, twice daily; C, cycle; D, day; EGFR, epidermal growth factor receptor; IRR, infusion-related reaction; IV, intravenous; NSCLC, non-small cell lung cancer; PO, per os; SC, subcutaneous.

Clearly, the most effective prevention strategy is the one using dexamethasone 8 mg twice daily, reducing the number of IRRs by a factor of three compared to the historical control (22.5% vs. 67.4%). The value of this study is the fact that strategies for preventing the side effects of anticancer drugs are rarely studied prospectively, providing for these strategies a high level of evidence-based medicine.

But beyond premedication, IRRs prevention requires a multidisciplinary approach (13,14), including training for healthcare professionals involved in patient care (nursing assistants, nurses, and physicians) who must be aware of these side effects, more particularly of the timing of these side effects, generally during the first injections. Additionally, nurses, pharmacists, and others involved in patient care also had an important role in training and educating patients and family members on IRR symptoms and on the anticipated frequency and length of clinic visits, preparing patients physically and mentally for their treatment. Nurses should partner closely with patients and check on them often during the infusion to identify and report early and timely symptoms, allowing for rapid interruption of the infusion. Clear communication between nurses and physicians is important to ensures each step of the infusion, from order execution to discharge instructions, reducing the risk of IRRs and other complications of the infusion, such as extravasation at the infusion site and development of infection A peripheral line, rather than a central line, is recommended for the C1D1, C1D2, and C1D8 infusions to reduce drug exposure in the event of an IRR (13). However, nurses may utilize central lines starting on C1D15. Additionally, intravenous (IV) administration sets should be primed with 15 to 25 mL of 5% dextrose or 0.9% sodium chloride solution prior to infusing amivantamab (14). At the end of the infusion, 10 mL of blood should be withdrawn before flushing the catheter with the 5% dextrose or 0.9% sodium chloride solution to avoid rapid infusion of residual amivantamab (14). When a patient reports signs and symptoms of an IRR, the team should collaborate with to carefully evaluate the patient and determine the grade of IRR and adjust, or temporarily interrupt, the dose and administer supportive medications as appropriate. Even though the availability of subcutaneous amivantamab (15) will allow for a significant reduction in these IRRs, this study demonstrates the value of prospectively, high-quality studies, strategies for preventing adverse events and side effects of systemic anticancer treatments.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.