Dear Editor:
Among cutaneous adverse events (CAEs) from immune checkpoint inhibitors (ICIs), rash and pruritus are the most common1. It is unknown if concurrent ICIs and radiotherapy (RT) increase their frequency and severity. We performed a systematic review and meta-analysis to characterize the incidence of all-grade and severe (grade 3 or 4) rash and pruritus in patients on concurrent ICI and RT regimens.
Studies published on or before March 20, 2020, were identified using the following search term on PubMed: “(ipilimumab OR yervoy OR pembrolizumab OR keytruda OR cemiplimab OR libtayo OR nivolumab OR opdivo OR tremelimumab OR ticilimumab OR atezolizumab OR tecentriq OR avelumab OR bavencio OR durvalumab OR imfinzi) AND (radiotherapy OR radiation) AND (adverse events OR adverse effects OR toxicity OR safety).”
The inclusion criteria were as follows: 1) clinical trial, 2) concurrent ICIs and RT, and 3) outcomes examined included CAEs. Studies were excluded if they did not specify the type of CAE.
There were 424 eligible articles (Figure 1). A total of 23 articles, including 12 phase I, 7 phase II, 2 phase I/II, and 2 phase III trials, were included, totaling 1504 patients (Table 1). The most common cancers per study were non-small cell lung cancer (26%) and various cancers (17%). The most common ICI classes were PD-1 inhibitors (48%) and CTLA-4 inhibitors (35%). The equivalent radiation dose if administered in 2 Gray fractions was calculated and classified as “high” or “low” using a cutoff of 50 Gray. Time between ICI and RT administration was 0–42 days.
Figure 1.
Flow diagram of study selection.
Table 1.
Characteristics of 23 studies included in analysis of rash and pruritus from concurrent treatment of advanced-stage malignancies with immune checkpoint inhibitors and radiation therapy.
| Study | Design | Cancer Type | Intervention | ICI Dose | EQD2 | Timing | Follow-Up |
|---|---|---|---|---|---|---|---|
| Antonia et al. 2018 | Phase III | NSCLC | Durvalumab + RT | 10mg/kg q2w | 54–74 Gy | RT then ICI within 42 days | 25.2 (range, 0.2 to 43.1 months) |
| Barroso-Sousa et al. 2020 | Phase II | Breast | Pembrolizumab + RT | 200mg q3w | 23 Gy | ICI then RT 2–7 days after | - |
| Elbers et al. 2020 | Phase I | H&N | Avelumab + RT | 10mg/kg q2w | 70 Gy | ICI then RT 7 days after | 12 (range, 8– 26) months |
| Formenti et al. 2018 | Phase II | NSCLC | Ipilimumab + RT | 3mg/kg q3w | 40 Gy (phase I) 46 Gy (phase II) | Both ICI and RT started on Day 1 | survivors: 43 (range, 38–47 months) |
| Ho et al. 2020 | Phase II | Breast | Pembrolizumab + RT | 200mg q3w | 40 Gy | RT and then ICI 1–3 days after | 34.5 (range, 2.1–108.3 weeks) |
| Jabbour et al. 2020 | Phase I | NSCLC | Pembrolizumab + RT | 100mg or 200mg q3w | 60 Gy | ICI given Day 1 or Day 29 of RT | 16.0 (95% CI: 12.0–22.6) months |
| Jiang et al. 2019 | Phase I | Breast | Tremelimumab + RT | 3, 6, 10, or 15 mg/kg | 23 Gy | RT then ICI on Day 3 | 27.0 (4.8–101.7) months |
| Kwon et al. 2014 | Phase III | Prostate | Ipilimumab + RT | 10mg/kg q3w | 12 Gy | RT then ICI within 2 days | 9.9 (IQR 4.3-16.7) months |
| Levy et al. 2016 | Phase I/II | Multiple | Durvalumab + RT | 10mg/kg q2w | 24 Gy | ICI then RT 1–35 days after | 15.6 (range, 2.5–27.6) months |
| Lin, J. et al. 2020 | Phase I | RCC | Pembrolizumab + RT | 200mg q3w | 8 Gy or 23 Gy | RT then ICI within 1 week | 32.3 (range, 9.3 to 46.6) months |
| Lin, S. et al. 2020 | Phase II | NSCLC | Atezolizumab + RT | 1200mg q3w | 60–66 Gy | RT then ICI after 3 weeks (Part 1) or at the same time (Part 2) | Part 1: 22.5 months (IQR 19.0–29.1) months; Part 2: 15.3 (IQR 10.9–19.4) months |
| Maity et al. 2018 | Phase I | Multiple | Pembrolizumab + RT | 200mg q3w | 36 Gy or 38 Gy | ICI then RT 1 week after | - |
| Miyamoto et al. 2018 | Phase I | NSCLC | Nivolumab + RT | 3mg/kg q2w | 54 Gy | ICI within 2 weeks of RT | - |
| Papadopoulos et al. 2020 | Phase I | Multiple | Cemiplimab + RT +/− CPA | 1, 3, or 10 mg/kg q2weeks | 40 Gy or 43 Gy | 1 week after ICI | 19.3 (range, 2.3–84.3) weeks |
| Peters et al. 2019 | Phase II | NSCLC | Nivolumab + RT | 360mg q3w x4 then 480mg q4w | 66 Gy or 72 Gy | Both ICI and RT on Day 1 | 13.4 (IQR: 9.0–18.4) months |
| Slovin et al. 2013 | Phase I/II | Prostate | Ipilimumab + RT | 3 mg/kg or 10 mg/kg q3w | 12 Gy | RT 2 days before ICI | 15.7 (range, 1.1–57.3) months |
| Sundahl et al. 2018 | Phase I | Melanoma | Ipilimumab + RT | 3mg/kg q3w | 36 Gy or 50 Gy or 66 Gy | RT then ICI 1 day after | - |
| Sundahl and Seremet et al. 2019 | Phase II | Melanoma | Nivolumab + RT | 3mg/kg q2w | 36 Gy | RT then ICI 1 day after | 13.1 (IQR: 7.5–19.2) months |
| Sundahl and Vandekerkhove et al. 2019 | Phase I | Urothelial | Pembrolizumab + RT | 200mg q3w | 36 Gy | RT then ICI 1 day after | - |
| Welsh and Heymach et al. 2020 | Phase I | SCLC | Pembrolizumab + RT | 100mg, 150mg, 200mg | 51 Gy | Both ICI and RT on Day 1 | 7.3 (range: 1–13) months |
| Welsh and Tang et al. 2019 | Phase II | Multiple | Ipilimumab + RT | 3mg/kg q3w | 94 Gy or 80 Gy | ICI then RT within 10 days after | 10.5 months |
| Williams et al. 2017 | Phase I | Melanoma | Ipilimumab + RT | 3mg/kg | 33 Gy or 60 Gy | ICI 2 days after RT | WBRT: 8.0 (range 3.5– 24.1) months; SRS: 10.5 (range 1.836.8) months |
| Xie et al. 2020 | Phase I | Pancreas | Durvalumab + RT | durvalumab 10mg/kg q2w | 12 Gy or 33 Gy | Both ICI and RT on Day 1 | - |
Abbreviations: chemoRT: chemoradiation; CI: confidence interval, EQD2: equivalent dose in 2 Gray per fraction; Gy: Gray; H&N: head and neck; ICI: immune checkpoint inhibitor; IQR: interquartile range; mg/kg: milligram per kilogram; NSCLC: non-small cell lung cancer; q#w: every # weeks; RCC: renal cell carcinoma; RT: radiation therapy; SCLC: small cell lung cancer; SRS: stereotactic radiosurgery; WBRT: whole brain radiotherapy
Using random-effects models, the overall incidence of all-grade and severe rash was 22% (95% confidence interval (CI): 16–29%) and 3% (95%CI: 2–5%), respectively. This is comparable to reported incidences of 14.3–24.3% and 1.2–2.4%, respectively, with ICI monotherapy2,3. Differences in rash incidence with varying ICI classes (p=0.47) or radiation dose (p=0.29) were not found.
The pooled incidence of all-grade and severe pruritus was 14% (95%CI: 10–19%) and 2% (95%CI: 1–3%), respectively, using random-effects models. Previous studies have reported similar rates of all-grade (13.2–30.7%) and severe (0.5–2.3%) pruritus with ICIs alone3,4. Differences in pruritus incidence did not vary among ICI classes (p=0.25). Subgroup analysis revealed a lower pruritus incidence (p=0.009) with higher radiation doses (8%, 95%CI: 4–14%) compared to lower doses (14%, 95%CI: 11–20%). A possible explanation may be that higher RT doses have a smaller target volume focused on deeper tumors, with a resultant lower effective dose to the skin.
This is the first meta-analysis reporting on the incidence of CAEs in patients concurrently treated with ICIs and RT in clinical trials. We did not find an increased incidence of all-grade or severe rash or pruritus with concurrent therapy. Limitations include the lack of patient-level data, nonspecific characterization of “rash” and “pruritus”, and significant heterogeneity of the included studies. Given the relatively high incidence of rash and pruritus and their known negative effects on the quality of life of patients with cancer5, continued care must be taken to monitor for and treat CAEs resulting from ICIs and RT.
Acknowledgments
Conflict of Interest Disclosure / Funding Sources:
MEL has consulted for Janssen, Seattle Genetics. MEL is funded by a NIH/NIAMS grant U01 AR077511. CAB reports grants from Merck, grants from Amgen, grants from Elekta, personal fees and non-financial support from Driver Group, personal fees and non-financial support from Regeneron, personal fees and non-financial support from Pfizer, grants and non-financial support from Alpha Tau Medical, outside the submitted work. This study was also funded in part by a grant from the National Cancer Institute / National Institutes of Health (P30-CA008748) made to the Memorial Sloan Kettering Cancer Center.
Abbreviations used:
- CAE
cutaneous adverse events
- CI
confidence interval
- ICI
immune checkpoint inhibitor
- RT
radiotherapy
Footnotes
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References
- 1.Geisler AN, Phillips GS, Barrios DM, et al. CME Part II: Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol. doi: 10.1016/j.jaad.2020.03.132 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME. The risk of rash associated with ipilimumab in patients with cancer: A systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2013;69(3):e121–e128. doi: 10.1016/j.jaad.2012.12.963 [DOI] [PubMed] [Google Scholar]
- 3.Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer Oxf Engl 1990. 2016;60:12–25. doi: 10.1016/j.ejca.2016.02.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ensslin CJ, Rosen AC, Wu S, Lacouture ME. Pruritus in patients treated with targeted cancer therapies: systematic review and meta-analysis. J Am Acad Dermatol. 2013;69(5):708–720. doi: 10.1016/j.jaad.2013.06.038 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Rosen AC, Case EC, Dusza SW, et al. Impact of Dermatologic Adverse Events on Quality of Life in 283 Cancer Patients: A Questionnaire Study in a Dermatology Referral Clinic. Am J Clin Dermatol. 2013;14(4):327–333. doi: 10.1007/s40257-013-0021-0 [DOI] [PubMed] [Google Scholar]