Comparative safety analysis of immunotherapy combined with chemotherapy versus monotherapy in solid tumors: a meta-analysis of randomized clinical trials

Liang

et al. 2020

Cancer

Background The addition of chemotherapy to a programmed death 1/programmed death ligand 1 (PD‐L1) inhibitor is a more effective option as a first‐line treatment for advanced non–small cell lung cancer (NSCLC). It might also inhibit an overactive immune response and thereby reduce immune‐related adverse events (irAEs). This meta‐analysis assessed the rate of irAEs with a PD‐(L)1 inhibitor plus chemotherapy (I+C) versus a PD‐(L)1 inhibitor alone (I) and evaluated the indirect relative risk (RR) of I+C versus I. Methods The protocol of this study was registered with PROSPERO (CRD42020139923). The pooled rates of irAEs at different grades were calculated by a single‐arm meta‐analysis weighted by sample size, and RRs were determined by direct meta‐analysis and indirect treatment comparison. Results Overall, I+C had a lower rate of grade 3 or higher irAEs than I (7.1% vs 10.6%; indirect RR, 0.516; 95% confidence interval [CI], 0.291‐0.916), although irAEs of any grade were similar. The rate of pneumonitis with I+C was lower than the rate with I for any grade (5.9% vs 7.1%; indirect RR, 0.217; 95% CI, 0.080‐0.588) and for grade 3 or higher. In the endocrine system, I+C was associated with a lower overall ratein comparison with I (16.1% vs 20.1%; indirect RR, 0.260; 95% CI, 0.120‐0.564), whereas irAEs of the digestive system were similar with I+C and I. In other systems, I+C decreased the rate of skin reactions, including rash, in comparison with I (10.4% vs 12.9%; indirect RR, 0.474; 95% CI, 0.299‐0.751). The rate of grade 3 or higher skin reactions (excluding rash) also decreased with I+C versus I (1.1% vs 2.0%) with an indirect RR of 0.158 (95% CI, 0.032‐0.765), whereas other included irAEs were similar. Conclusions In comparison with a PD‐(L)1 inhibitor alone, a combination with chemotherapy for the first‐line treatment of NSCLC decreased the rates of most irAEs, such as pneumonitis and endocrine and skin reactions, and the overall rate. Lay Summary In the first‐line treatment of advanced non–small cell lung cancer (NSCLC), the addition of chemotherapy to a programmed death 1/programmed death ligand 1 (PD‐(L)1) inhibitor is a more effective option. Adding chemotherapy might reduce immune‐related adverse events (irAEs). Thus, this article assesses the rate of irAEs with a PD‐(L)1 inhibitor plus chemotherapy (I+C) in comparison with a PD‐(L)1 inhibitor alone (I) and evaluates the indirect relative risk (RR) with I+C versus I. The key finding is that in comparison with a PD‐(L)1 inhibitor alone, a combination with chemotherapy for the first‐line treatment of NSCLC decreases the rates of most irAEs, such as pneumonitis and endocrine and skin reactions, and the overall rate.

Section: Introductionmentioning

confidence: 99%

Immune‐related adverse events of a PD‐L1 inhibitor plus chemotherapy versus a PD‐L1 inhibitor alone in first‐line treatment for advanced non–small cell lung cancer: A meta‐analysis of randomized control trials

Liang

et al. 2020

Cancer

“…14 Another study by Carretero-González et al, which involved 10 RCTs and 4,379 patients, revealed that the combination of immunotherapy with chemotherapy presented more grade 3/4 adverse events (RR: 1.32; 95% CI: 1.12-1.55) and discontinuations (RR: 2.31; 95% CI: 1.28-4.16). 15 Our study observed a significantly higher incidence of irEDs in patients treated with targeted+ICI compared with ICI-alone. The combination of targeted+ICI was also strongly associated with hypothyroidism using logistic regression.…”

Section: Discussionmentioning

confidence: 45%

Immune-related Endocrine Dysfunctions in Combined Modalities of Treatment: Real-world Data

Chan

Choi

et al. 2021

Preprint

Background The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) combinations using different modalities of anti-cancer treatment. Method A retrospective analysis was conducted on consecutive patients >18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a Hong Kong university hospital. Patients were reviewed for up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. Result A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) received ICIs during the study period. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo+ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted+ICI). A significantly higher proportion of patients using targeted+ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (>65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. Conclusions This large, real-world cohort demonstrates that combining ICI with targeted therapy has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is needed in older populations.

“…However, the evaluation of PD-L1 remains mandatory for the administration of single agent pembrolizumab, especially as first-line treatment for those patients who are not eligible for chemotherapy. 25 , 26 The immunohistochemical assessment of PD-L1 has been validated in histological (biopsies and surgical specimens) and cytological samples treated as FFPE materials (pellets and clots). 12 – 19 , 21 However, in 20–30% of patients, the only available diagnostic material is a cytological smear, thereby precluding PD-L1 evaluation and pembrolizumab therapy.…”

Section: Discussionmentioning

confidence: 99%

Reliability of programmed death ligand 1 (PD-L1) tumor proportion score (TPS) on cytological smears in advanced non-small cell lung cancer: a prospective validation study

Ricci¹,

Capizzi

Giunchi

et al. 2020

Ther Adv Med Oncol

Introduction: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assessment is mandatory for the single agent pembrolizumab treatment of patients with advanced non-small cell lung cancer (NSCLC). PD-L1 testing has been validated and is currently certified only on formalin-fixed paraffin-embedded materials but not on cytological smears. Unfortunately, a significant proportion of patients, having only cytological material available, cannot be tested for PD-L1 and treated with pembrolizumab. In this study, we aimed to validate PD-L1 IHC on cytological smears prospectively by comparing clone SP263 staining in 150 paired histological samples and cytological smears of NSCLC patients. Methods: We prospectively enrolled 150 consecutive advanced NSCLC patients. The clone SP263 was selected as, in a previous study of our group, it showed higher accuracy compared with clones 28-8 and 22-C3, with good cyto-histological agreement using a cut-off of 50%. For cyto-histological concordance, we calculated the kappa coefficient using two different cut-offs according to the percentage of PD-L1 positive neoplastic cells (<1%, 1–49% and ⩾50%; <50%, ⩾50%). Results: The overall agreement between histological samples and cytological smears was moderate (kappa = 0.537). However, when the cyto-histological concordance was calculated using the cut-off of 50%, the agreement was good (kappa = 0.740). With the same cut-off, and assuming as gold-standard the results on formalin-fixed paraffin-embedded materials, PD-L1 evaluation on smears showed specificity and negative predictive values of 98.1% and 93.9%, respectively. Conclusion: Cytological smears can be used in routine clinical practice for PD-L1 assessment with a cut-off of 50%, expanding the potential pool of NSCLC patients as candidates for first-line single agent pembrolizumab therapy.