Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies-pharmacovigilance database analysis with real-world data validation

Abstract

Background: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized.

Methods: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation.

Results: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference.

Conclusions: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.

Keywords: Conventional therapy; Immune checkpoint inhibitors; Interstitial pneumonitis; Non-small cell lung cancer; Radiation therapy.

Fig. 1

Flow chart of the study population. In this study, 10,678,588 reports were retrieved from the FAERS database during the first quarter of 2015 to the second quarter of 2020. By using NSCLC-related MedDRA preferred terms, 95,795 reports were selected. Omitting the 49,668 duplicates, 46,127 reports of NSCLC which consist of 3830 IP cases and 42,297 non-cases were enrolled finally

Fig. 2

Relative risk of interstitial pneumonitis under different therapies in non-small cell lung cancer patients. Each cell contains the adjusted ROR and its 95% confidence interval of IP under treatment in the rows using that in the column as a reference. All of the numbers in bold were statistically significant. The P-value for the adjusted ROR was calculated using a multivariable logistic regression model and was adjusted by using the “p.adjusted()” command in R. Abbreviations: ROR, reporting odds ratio; OTHER, all the other therapies except the listed therapies; RT, radiation therapy; ICI, immune checkpoint inhibitor therapy; CHEMO, chemotherapy; TARGET, targeted therapy

Fig. 3

Relative risk of interstitial pneumonitis under different ICI drugs in non-small cell lung cancer patients. Each cell contains the adjusted ROR and its 95% confidence interval of IP under treatment in the rows using that in the column as a reference. All of the number in bold were statistically significant. Since only one case received IPIL combined with RT and no case received AVEL combined with RT, these regimens were not invested further. The P-value for adjusted ROR was calculated using a multivariable logistic regression model and was adjusted by using the “p.adjusted()” command in R. Abbreviations: ROR, reporting odds ratio; RT, radiation therapy; ICI, immune checkpoint inhibitor therapy; NIVO, nivolumab; PEMB, pembrolizumab; DURV, durvalumab; ATEZ, atezolizumab; AVEL, avelumab; IPIL, ipilimumab

Fig. 4

Relative risk of interstitial pneumonitis under different therapies in non-small cell lung cancer patients from a validation cohort. A Each cell contains the odds ratio and its 95% confidence interval of IP under treatment in the rows using that in the column as a reference. All of the numbers in bold were statistically significant. B The black bar stands for all patients with any grade IP under different therapies and the red bar for patients with grade 3 or higher IP and treated by certain therapy. The P-value for adjusted ROR was calculated using a multivariable logistic regression model and was adjusted by using the “p.adjusted()” command in R. Abbreviations: RT, radiation therapy; ICI, immune checkpoint inhibitor therapy; CHEMO, chemotherapy; TARGET, targeted therapy; poly, multiple kinds of treatments; multitherapy, all the other multimodal therapies except the listed therapies