Research summary edited by Pierre Fabre. Common toxicities associated with immune checkpoint inhibitors and targeted therapy in the treatment of melanoma: A systematic scoping review1
The introduction of immune checkpoint inhibitors (ICI) such as the cytotoxic T-lymphocyte-associated antigen 4 inhibitors (CTLA-4) and programmed death 1 inhibitors (PD-1), as well as targeted therapies (TT) exemplified by BRAF and MEK inhibitors have significantly altered the treatment paradigm for people with advanced melanoma. Both ICI and TT are associated with a wide range of adverse events (AEs). AEs significantly affect a patient’s quality of life (QoL) and present new challenges for clinical practice. Advancing the knowledge of the occurrence and frequency of specific AEs will aid in the selection of appropriate treatment and design of toxicity management for the individual patient.
Methods
A recently published scoping review1 compares reported toxicity profiles during ICI and TT treatment in patients with stage III (resected and unresectable) and stage IV melanoma, published in multiple phase III studies between 2010 and 2021. Initially 13,292 reports were identified, duplicates were removed and the remaining 8,006 were screened using title and abstract. Of these 635, were further assessed for eligibility using full reports and the final review included 24 reports. ICI was evaluated in 14 reports and TT in 10, a total of 11,208 patients were included. Eighteen of the trials included patients with unresectable or metastatic melanoma (N = 7,994). The median age of patients ranged from 50 to 63 years and distribution of sex ranged from 45% to 65% male.
Toxicity reporting varied between reports and between ICI and TT. The most common practice for ICI trials was to report any treatment related AEs with an incidence rate of ≥ 10% (5 trials, N = 2,234). TT trials maintained an incidence rate of ≥10% but included AEs deemed important even if incidence rate was lower than 10% (3 trials, N = 1025). Tables in this summary have set the inclusion level for severe adverse events (SAE) at 5%, tables for AEs (grade 1/2) can be found in the original paper.1
ICI treatment
Most AEs reported during ICI treatment were grade 1–2, but a substantial proportion of these continued after treatment discontinuation. Frequencies of severe AEs (grade 3–4), during treatment with anti-CTLA-4 and anti-PD-1 monotherapies are presented in table 1. The evaluated clinical trials using anti-PD1 monotherapies showed tolerable toxicity profiles, with fatigue reported as the only common AE (11–58% for Pembrolizumab and 20–34% for Nivolumab). Combination ICI treatment increased incidence rates of all toxicities compared to ICI monotherapy. With one in three patients reporting diarrhea and one in four, rash, pruritus, and fatigue.
Table 1. Frequencies of severe AEs (grade 3/4) reported during monotherapy and combination therapy with checkpoint inhibitors (ICI).*
* The frequency of AEs is reported as in the Egeler et al.1 and is lower than reported in SmPCs of Braftovi and Mektovi. Please see SmPCs for very common and common AEs related to Braftovi and Mektovi.
| Anti-CTLA-4 monotherapy | Anti-PD-1 monotherapy | ||
|---|---|---|---|
| Ipilimumab | Nivolumab | Pembrolizumab | |
| Hypophysis | 6% | – | – |
| Diarrhea | 3–10% | 1–2% | 0–3% |
| Rash | 0–2% | 0–3% | 0–2% |
| Fatigue | 0–7% | 0–1%pi | 0–1% |
| Increased ALT | 5% | – | 3% |
| Increased AST | 5% | – | 2% |
| Impaired liver function | 6% | – | – |
Only frequencies where severe AE reached 5% are included in the table and frequencies are grouped from lowest reported to highest reported across all included studies, regardless of specific treatment regime. “–” not reported, ALT, alanine aminotransferase; AST, aspartate aminotransferase, IPI, ipilimumab; NIVO, nivolumab; PEMBRO, pembrolizumab; RET, relatlimab. Table modified by Pierre Fabre from 1.
TT treatment
While administration of TT was associated with a high incidence rate of AEs compared to ICI, most of these resolved after discontinuation of treatment. The most common severe AEs with BRAFi or MEKi monotherapy and BRAFi or MEKi combination therapies are presented in Table 2. Combination therapy had lower frequencies of cutaneous and musculoskeletal AEs than monotherapy with BRAF inhibitors. The new Columbus part 2 study likewise, highlights the importance of combining a MEK inhibitor with a BRAF inhibitor in the treatment of patients with BRAFV600– mutant melanoma.2
Table 2. Frequencies of severe AEs (SAE grade 3/4) reported during monotherapy and combination therapy with targeted treatments (TT).*
* The frequency of AEs is reported as in the Egeler et al.1 and is lower than reported in SmPCs of Braftovi and Mektovi. Please see SmPCs for very common and common AEs related to Braftovi and Mektovi.
| BRAFi or MEKi monotherapy | BRAFi plus MEKi combination therapy | |||||
|---|---|---|---|---|---|---|
| VEMU | DABRA | TRAM | DABRA + TRAM | VEMU + COBI | ENCO + BINI | |
| Hypertension | – | – | 12% | – | – | – |
| Diarrhea | 0–2% | – | 0% | 0–1% | 3–6% | 3% |
| Rash | 3–10% | <1% | 8% | 0–1% | 6–9% | 1% |
| Maculopapular rash | 4% | – | – | – | 10% | – |
| Pruritus | 1–10% | 0% | – | – | <1% | 1% |
| Alopecia | 0–6% | 0% | <1% | – | <1% | 0% |
| Arthralgia | 3–7% | 0% | – | 0–1% | 2% | 1% |
| Pyrexia | 0–1% | 2% | – | 4–7% | 1–2% | 4% |
| Increased ALT | 6% | – | – | 4% | – | – |
| Increased AST | 2% | – | – | 4% | 2–9% | – |
| Increased AT | 6% | – | – | 4% | – | – |
| Increased bCPK | – | – | – | – | 15% | 7% |
| Increased lipase | – | – | – | – | 21% | – |
| KA | 10% | – | – | – | – | – |
| cSCC or KA | 17% | – | – | – | – | – |
| cSCC | 11–12% | – | – | – | – | – |
Only frequencies where severe AE reached 5% are included in the table and frequencies are grouped from lowest reported to highest reported across all included studies, regardless of specific treatment regime. “–” not reported, ALT, alanine aminotransferase; AST, aspartate aminotransferase, AT, aminotransferase; AP, alkaline phosphatase; bAP, blood AP; bCPK, blood creatine phosphokinase; bCR, blood creatine; KA keratoacanthoma; cSCC, cutaneous squamous cell carcinoma; VEMU, vemurafenib; DABRA, dabrafenib, TRAM, trametinib; COBI, cobimetinib; ENCO, Encorafenib; BINI, binimetinib. Table modified by Pierre Fabre from 1.
Conclusion
The review provides a comprehensive overview of the frequency and severity of AEs that advanced melanoma patients experience during ICI and TT. It showed that ICIs are associated with lower rates of AEs compared to TT. However, the ICI toxicity profiles showed higher rates of potentially chronic AEs. The toxicity profiles associated with TT were generally short-term and reversible with treatment discontinuation.
Providing an overview of the different toxicity profiles of ICI and TT can aid clinicians in the selection of appropriate treatments. This may be especially relevant for patients with a lower performance status, as they are often more vulnerable to treatment toxicities. Understanding the potential implications of treatment can also help patients engage in a shared decision making during their melanoma treatment.
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