Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis

Introduction

Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors are thriving in anti-cancer treatment. PD-1 was expressed by activated T lymphocytes. It combines with its ligands PD-L1 to restrict the activation of T lymphocytes and prevent autoimmune disease. Monoclonal antibodies targeting PD-1 and PD-L1 can block the immune checkpoint and eliminate the inhibition of T lymphocytes activation. As a result, they largely enhance immune reactions to fight against malignant tumors (1,2). Several PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) are showing distinct activities and efficacy in treatment of advanced melanoma, renal cell carcinoma and non-small cell lung cancer (NSCLC) or Hodgkin lymphoma.

However, for its character of blocking inhibitory regulation and leading to unregulated activation of immune reaction, when the potency of fighting against cancer increased significantly, it may also affect other organs and injure normal tissues, which consequently lead to immune-related adverse effects (IRAEs) (3). A wide range of organs and systems may be involved, and skin, gastrointestinal tract and liver are the most commonly affected. Preclinical researches, animal experiments and pathological specimens of clinical patients found abundant infiltration of activated T CD8 positive lymphocytes in involved organs. Usually, IRAEs of checkpoint inhibitors are mild and could be managed by clinicians. However, some serious adverse effects must be controlled by discontinuation of drugs, temporarily or even permanently. Pneumonitis is one of the IRAEs that reported by most clinical trials, and severe cases may lead to death. Besides, some rare toxic effects affecting cardiovascular and respiratory systems should raise our concern because they may be deadly once occur and possibly unrecognized as immune-related adverse effects. Incidence of pneumonitis in PD-1 and PD-L1 inhibitor therapy has been reported in several metanalysis, as well as differences in incidence between NSCLC and melanoma, and PD-1 and PD-L1 inhibitors (4,5). However, no metanalysis explored the incidence of these rare but life-threatening IRAEs, such as immune related myocarditis.

The objective of this study was to investigate the incidence of pneumonitis and other rare but life-threatening adverse effects, as well as treatment related deaths in PD-1 and PD-L1 inhibitor therapy for treatment of NSCLC. Meanwhile, we compare differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitor therapy and standard-of-care chemotherapy.

Methods

Search methods and study selection

Clinical trials of PD-1 and PD-L1 inhibitors for treatment of lung neoplasms were searched through PubMed, using the key words of PD-1 and PD-L1 monoclonal antibody, nivolumab, pembrolizumab, atezolizumab, avelumab and durvalumab. Besides, references of relevant articles were searched for meeting abstracts and possible omission. Articles meeting the following criteria were included: (I) phases I–III clinical trials; (II) measure the safety profile of PD-1 and PD-L1 inhibitors; (III) single-arm trials of PD-1 and PD-L1 inhibitors or PD-1 and PD-L1 inhibitors versus chemotherapy. Trials of combined therapy of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) inhibitors and PD-1 and PD-L1 inhibitors were excluded for that they would increase the incidence of pneumonitis and we may fail to distinguish the adverse effects of which drug. When results of the same clinical trial were reported at different time, only the most recent, or the most complete report was included. All the articles were screened independently by two authors (YB Hu and Q Zhang).

Data extraction

Data including clinical trial information of the study, first author, year of publication, trial phases, study drugs, total number of patients evaluated for safety, number of patients with pneumonitis, other rare but life-threatening adverse effects including cardiac failure, cardiorespiratory arrest, myocardial infarction, stroke, disease progression, pancreatitis, severe skin reactions, sepsis, pulmonary embolism, respiratory arrest, respiratory failure, constrictive pericarditis, cardiac tamponade, pericardial effusion, encephalitis, myocarditis, sarcoidosis, endophthalmitis, and myasthenia gravis, as well as treatment related deaths were extracted. Infectious related pneumonia was not included. Because phase I trials were commonly dose escalation, the number of an adverse event which developed from the study drug were counted together, regardless of doses. Any data not reported in the primary articles were represented as “not applicable”. We didn’t contact the author for detailed information. The main outcomes were incidence of pneumonitis and other rare but life-threatening adverse effects in PD-1 and PD-L1 inhibitor therapy, cases of treatment related deaths, and differences in incidence of pneumonitis between checkpoint inhibitor therapy and chemotherapy.

Statistical analysis

Review manager version 5.3 was used for statistical analysis. For trials with control groups, data type of dichotomous was selected to compare the incidence of pneumonitis between PD-1 and PD-L1 inhibitor therapy and standard-of-care chemotherapy. For single arm trials, data type of generic inverse variance was selected.

For the outcome of incidence, if P value was not close to 0 or 1 and both n*P and n*(1–P) were more than 5, P could be calculated by n/X [1], in which n and X referred to the number of patients with pneumonitis and total number of patients evaluated for safety, respectively. Standard error (SE) could be calculated using the formula of (P(1–P)/n)^1/2 [2], in which P and n had the same meaning with above. On the other hand, if the above condition could not be met, P and SE must be calculated by the below formulas: P= ln(odds) = ln[X/(n–X)] [3], SE(P) = SE[ln(odds)] = [1/X+1/(n–X)]^1/2[4]. Significantly, this is the method used for categorical data, thus the calculations OR should be transformed using the following formula: Pf = OR/(1+ OR) [5], lower limit (LL) of 95% confidence interval (CI) = LL_OR/(1+ LL_OR) [6], upper limit (UL) = UL_OR/(1+ UL_OR) [7]. Due to the low incidence of adverse effects in our study, the latter method was adopted.

Heterogeneity was evaluated by Cochran chi-square test and the I² test. Heterogeneity was thought to be exist if P value was less than 0.05. If the homogeneity of ORs were fine (P>0.05), a fixed effect model was used; if not (P<0.05), a random effect model was used. I²<30% represented a slight level of heterogeneity, 30–60% was moderate while I²>60% meant the heterogeneity was high. Chi-square test was performed for rate differences between two or more categorical data by SPSS version 20.0.

Results

Eligible studies and characteristics

Totally, 1,956 publications were searched on PubMed up to 24 March 2017 and 61 abstracts were identified from reference lists of relevant articles. A total of 1,554 texts were screened after duplications removed, and 1,526 were excluded for reasons of not clinical trials, not of PD-1 and PD-L1 inhibitor therapy, not for treatment of NSCLC, and no information of adverse effects. Consequently, 28 articles were assessed for eligibility, and six were excluded, with one had no numerical data of adverse effects, one of combined therapy of CTLA-4 and PD-L1 inhibitor, and the left four had no data of pneumonitis and other needed information. Finally, 22 trials were included (6-27), 14 with data of pneumonitis were included for meta-analysis (6-10,12-18,20,21) (Figure 1). Five had control groups, with two of nivolumab vs. docetaxel (13,14), one of pembrolizumab vs. docetaxel (16), one of pembrolizumab vs. chemotherapy (pemetrexed plus carboplatin) (15) and one of pembrolizumab plus chemotherapy vs. chemotherapy (11). Nineteen reported other rare but life-threatening IRAEs and data of treatment related deaths (6-13,15-17,19,20,22-27).

Figure 1 Flow diagram of study selection. NSCLC, non-small cell lung cancer.

Tables 1,2 are summary of the characteristics of all the included trials. Among them, 11 were phase I trials, 6 were phase II, 3 phase III, 1 phase II/III and the last one was phase IIIB/IV trial; 17 were PD-1 inhibitors (10 nivolumab and 7 pembrolizumab), and 5 were PD-L1 inhibitors (4 atezolizumab and 1 avelumab).

Table1 Characteristics of all included studies
Full table

Table2 Characteristics of all included studies
Full table

Incidence of pneumonitis

Incidence of all-grade pneumonitis (n=3,542) was 2.9% (95% CI, 2.0–4.8%, P=0.0003, I²=66%) (Figure 2A), and it was 2.0% (95% CI, 1.0–2.0%, P=0.30, I²=14%) of grade 3–5 pneumonitis (Figure 2B). Considering of the high heterogeneity, incidence of pneumonitis in full texts and abstracts were analyzed respectively. Results revealed that incidence of pneumonitis was 4.8% (95% CI, 3.8–5.7%, P=0.13, I²=34%) of all-grade (Figure 2C) and 2.0% (95% CI, 2.0–2.9%, P=0.64, I²=0) of grade 3–5 (Figure 2D) in published full texts (n=2,361). On the other hand, it was 1.0% (95% CI, 1.0–2.0%, P=0.66, I²=0) of all-grade (Figure 2E) and 1.0% (95% CI, 0–2.0%, P=0.63, I²=0) (Figure 2F) in reported abstracts (n=1,181).

Figure 2 Forest plots of incidence of pneumonitis. (A) Incidence of all-grade pneumonitis; (B) incidence of grades 3–5 pneumonitis; (C) incidence of all-grade pneumonitis in published full-texts; (D) incidence of grades 3–5 pneumonitis in published full-texts; (E) incidence of all-grade pneumonitis in reported abstracts; (F) incidence of grades 3–5 pneumonitis in reported abstracts.

Incidence of pneumonitis in PD-1 and PD-L1 inhibitor therapy vs. standard-of-care chemotherapy

In the five trials with control groups, incidence of any grade pneumonitis in PD-1 and PD-L1 inhibitor therapy (n=1,313) was significantly higher than that in chemotherapy (n=918) (OR=2.35, 95%CI, 1.32–4.20, P=0.004) ( Figure 3A) . However, in the case of grade 3–5 pneumonitis, it was higher in PD-1 and PD-L1 inhibitor therapy, but was not statistically significant (P=0.24) (Figure 3B).

Figure 3 Forest plots of differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitors and chemotherapy. (A) Difference in incidence of all-grade pneumonitis between PD-1 and PD-L1 inhibitors and chemotherapy; (B) difference in incidence of grades 3–5 pneumonitis between PD-1 and PD-L1 inhibitors and chemotherapy. PD-1, programmed death-1; PD-L1, programmed death ligand-1

Incidence of other rare but life-threatening adverse effects

Incidence of some other rare adverse effects were 1.0% (95% CI, 0–2.0%) of cardiorespiratory arrest (n=537) (Figure 4A), 2.0% (95% CI, 1.0–5.7%) of cardiac failure (n=214) (Figure 4B), 1.0% (95% CI, 0–3.8%) of myocardial infarction (n=402) (Figure 4C), 2.0% (95% CI, 0–13.0%) of stroke (n=135) (Figure 4D), 1.0% (95% CI, 0–2.9%) of disease progression (n=391) (Figure 4E), 1.0% (95% CI, 0–2.0%) of pancreatitis (n=700) (Figure 4F) and 2.0% (95% CI, 1.0–3.8%) of severe skin reactions (n=836) (Figure 4G).

Figure 4 Forest plots of incidence of some rare but severe adverse effects. (A) Cardiorespiratory arrest; (B) cardiac failure; (C) myocardial infarction; (D) stroke; (E) disease progression; (F) pancreatitis; (G) severe skin reactions.

Two cases of sepsis were reported and one of them led to death (n=59). Cases of pulmonary embolism, respiratory arrest, respiratory failure, constrictive pericarditis, cardiac tamponade, pericardial effusion, encephalitis, myocarditis, sarcoidosis, endophthalmitis and myasthenia gravis were reported each by one case. Three cases of respiratory arrest, respiratory failure and constrictive pericarditis had led to deaths of patients (treated with pembrolizumab, avelumab and atezolizumab respectively). All the other cases were treated with nivolumab. What’s more, except for myocarditis of grades 1–2, all the others were grades 3–4 in severity (Table 3).

Table 3 Incidence of other rare but life-threatening IRAEs
Full table

Treatment related deaths

Totally, 29 deaths related to treatment were reported (n=4,160). There was no significant difference between the rate of death in PD-1 and PD-L1 inhibitors (P=0.626). Four deaths were attribute to pneumonitis, four pneumonias and another one radiation pneumonitis. Other causes leading to deaths included cardiac failure, respiratory failure, respiratory arrest, constrictive pericarditis, encephalitis, ischemic stroke, myocardial infarction, sepsis (each n=1), and interstitial lung disease (ILD) and cardiorespiratory arrest (each n=2), as well as disease progression (n=3) and unknown causes (n=5) (Table 4).

Table 4 Trials reporting treatment-related deaths and causes of deaths
Full table

Discussion

This metanalysis revealed in patients with lung cancer treated with PD-1 and PD-L1 inhibitors the overall incidence of pneumonitis was 2.9% for all-grade and 2.0% for grade 3–5. Nishino et.al summarized in NSCLC treated with PD-1 inhibitor monotherapy the incidence of pneumonitis was 4.1% for all-grade and 1.8% for grade 3–5, both of which were significantly higher than that in melanoma (4). Besides, Khunger et al. found incidence of all-grade pneumonitis is 3.6% in PD-1 inhibitors and 1.3% in PD-L1 inhibitors, while it was 1.1% and 0.4% of grade 3–5 pneumonitis (5). Cardiovascular toxicities associated with immune checkpoint inhibitors have been serially reported mainly related to CTLA-4 inhibitors or combined therapy with PD-1 and PD-L1 antibodies, such as myocarditis, heart failure, cardiomyopathy, myocardial fibrosis, cardiac arrest, and complete heart block (28-31). Information of cardiac side effects of anti-PD-1 and anti-PD-L1 on patients with lung cancer were limited. Laubli et al. reported a case of heart failure due to autoimmune myocarditis after treating melanoma with pembrolizumab. Cardiac biopsy showed infiltration of CD8 positive T lymphocytes and a reduction of FOXP3 positive regulatory T cells (32). Semper et al. made known a patient with lung squamous cell carcinoma developed myocarditis after treatment of nivolumab (33); and Behling et al. gave an account of a case of myositis with treatment of nivolumab for metastatic melanoma, which then developed to third-degree atrioventricular block (34). Despite of the low incidence, they should be brought to the forefront. Any symptoms and signs should give rise to rapid and comprehensive cardiovascular evaluation, and prompt and effective therapeutic approaches are dictated, such as respiratory and hemodynamic support, even heart transplant if necessary.

Clinical trials demonstrated treatment-related adverse effects in PD-1 and PD-L1 inhibitors were fewer than that in docetaxel or chemotherapy (13-15). However, we proved patients treated with PD-1 and PD-L1 inhibitors had higher incidence of pneumonitis than chemotherapy. Nishijima et al. compared the safety and tolerability of PD-1 and PD-L1 inhibitors with chemotherapy and demonstrated incidence of any adverse effects of checkpoint inhibitors were significantly lower than chemotherapy, both all-grade and high grade, as well as the frequency of discontinued treatment for toxicity. However, PD-1 and PD-L1 inhibitors were associated with higher risk of all-grade rash, colitis, hypothyroidism, hyperthyroidism, and aminotransferase elevations, and all- and high-grade pneumonitis (35).

IRAEs were normal mild and could be managed by clinicians. However, some severe cases may be deadly and lead to deaths without effective measures could be taken. Thus, prevention, early recognition and prompt intervention are of great importance in management of these severe cases. Firstly, clinicians should evaluate the base-line status of patients and recognize possible risk factors that may contribute to the development of treatment-related adverse effects. Besides, patients and their family members should be educated to identify early symptoms so that prompt intervention could be taken. Meanwhile, during the course of treatment, regular examinations and closely monitor of patients were vital. Nevertheless, if IRAEs already developed, measures should be taken to control them without delay. For grades 1–2 AEs, discontinuation of therapeutic drugs may not be necessary. However, for grades 3–4 AEs, discontinuation of drugs is necessary, temporarily or even permanent. Besides, corticosteroid may be needed from time to time and it must be used rationally.

As well described by Naidoo, patients exposed to corticosteroids for IRAE become immunocompromised, as a consequence in cases of recurrence of respiratory event it become crucial to carefully ruled out some bacterial or fungal infections such as aspergillosis (36).

Finally, we found in the present metanalysis progression of disease as a side effect of treatment with an incidence of 1.0% (95% CI, 0–2.9%). Recently, Champiat et al. reported tumor hyperprogression related to anti-PD1 or anti-PDL1 treatments, defined as a doubling of the tumor growth rate. We believe that a homogenization of the term “hyperprogressive disease” is to be considered in future studies to compare this deleterious and rare side effect across studies (37).

There were some limitations in our study. Firstly, most included trials were open-label, which may lead to selection bias of patients. In addition, data in some abstracts were ambiguous and were not the final results. Moreover, patients included were those highly selective in clinical trials and may not reflect the condition in real world.

Conclusions

Immune related adverse effects can on occasion be life-threatening even though usually rare. This metanalysis demonstrated that incidence of pneumonitis in NSCLC treated with PD-1 and PD-L1 inhibitor therapy was significantly higher than that with chemotherapy. Further metanalysis should be conducted to deeply investigate the incidence of other rare and potentially unrecognized life-threatening IRAEs.

Acknowledgements

Funding: This work was supported by grants from the National Natural Science Foundation of China (grant number: 81401903, 81572937 and 81572273); the Natural Science Foundation of Jiangsu province (grant number: BL2013026, BK20140736 and BK20161386); Program of Nanjing Science and Technology of Nanjing Science and Technology Committee (grant number: 201605059); and Jiangsu Provincial Medical Youth Talent (grant number: QNRC2016125).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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