The relative risk of pneumonitis associated with neoadjuvant chemoimmunotherapy use in early-stage triple-negative breast cancer: A systematic review and meta-analysis

Abstract Background: Pneumonitis is significant toxicity of immune checkpoint inhibitors (ICIs). Lately, multiple clinical trials have demonstrated that neoadjuvant chemoimmunotherapy improves pathological complete response rate in high-risk early-stage triple-negative breast cancer (TNBC), an exciting development in breast oncology. In this systematic review and meta-analysis, we attempt to determine the risk of pneumonitis associated with the use of chemoimmunotherapy in early-stage TNBC. Methods: We conducted a systematic search in the PUBMED, MEDLINE, EMBASE, American Society of Clinical Oncology, and San Antonio Breast Cancer Symposium meeting abstracts as per PRISMA guidelines from inception through May 30, 2021. Published phase 2 and 3 randomized control trials (RCTs) using neoadjuvant ICI plus chemotherapy (ICI+C) in the study arm for early-stage TNBC and reporting the number of events for pneumonitis were included in the analyses. We used the Mantel-Haenszel method and random-effects model to calculate the estimated pooled risk ratio (RR) with a 95% confidence interval (CI). Heterogeneity was tested with the I2 value and Cochran’s Q-test. Results: Two phase 3 RCTs (IMpassion031 and KEYNOTE-522) and Two phase 2 RCTs (GeparNuevo and I-SPY2) were included in the final analysis. These RCTs randomized 1,106 patients in the ICI+C arm and 819 patients in the placebo + chemotherapy (P+C) arm. We have included some essential characteristics of these studies, such as the number of patients and chemotherapy regimen used in table 1. Any grade pneumonitis was reported in 1.90% of patients in the ICI+C arm versus 1.47% of patients in the P+C arm. The relative risk of any grade pneumonitis was not significantly different between the arms (the pooled RR = 1.29, 95% CI: 0.64-2.63, P = 0.48, I2 = 0%). Grade 3/4 pneumonitis was reported in 0.54% of patients in the ICI+C arm and 0.37% of patients in the P+C arm. The relative risk of grade 3/4 pneumonitis was also not significantly different between the arms (the pooled RR = 1.36, 95% CI: 0.36-5.13, P = 0.65, I2 = 0%). One grade 5 pneumonitis was reported in the KEYNOTE-522 trial in the ICI+C arm. Conclusions: Neoadjuvant chemoimmunotherapy does not significantly increase any grade and grade 3/4 pneumonitis risk in early-stage triple-negative breast cancer patients compared to chemotherapy. This finding is reassuring and clinically relevant. However, clinical vigilance is necessary. Table 1.Characteristics of the studies included in the meta-analysisStudyPhaseICI usedC usedNo. of patients (ICI+C)No. of patients (P+C)GaperNuevo2DurvalumabNab-paclitaxel + EC9282I-SPY22PembrolizumabPaclitaxel + AC69181IMpassion0313AtezolizumabNab-paclitaxel + AC164167KEYNOTE-5223PembrolizumabPaclitaxel + carboplatin + AC/EC781389AC: doxorubicin + cyclophosphamide; C: chemotherapy; EC: epirubicin + cyclophosphamide; ICI: immune checkpoint inhibitor; P: placebo Citation Format: Nusrat Jahan, Shabnam Rehman, Srikala Meda, Lukman Tijani. The relative risk of pneumonitis associated with neoadjuvant chemoimmunotherapy use in early-stage triple-negative breast cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-14.