Simple Summary: Retrospective analyses suggest that men treated with immune-checkpoint inhibitor (ICI) monotherapy for non-small cell lung cancer (NSCLC) have better outcomes than women. However, female patients have more favorable responses when chemotherapy (CHT) is given together with ICI. We aimed to explore the clinical impact of such sex differences in two cohorts, receiving ICI monotherapy or ICI-CHT combination, respectively. We found no significant difference in outcomes between men and women treated with either therapeutic regimen. However, known predictive factors for ICI response such as the expression of programmed-death ligand 1 (PD-L1) on tumor cells or patient performance status had significant implications for men rather than for women. Our results warrant increased research efforts to clarify sex-specific differences in anti-tumor immune response mechanisms and in the efficacy of ICI therapies, especially in women. Men with non-small cell lung cancer (NSCLC) have a more favorable response to immune-checkpoint inhibitor (ICI) monotherapy, while women especially benefit from ICI-chemotherapy (CHT) combinations. To elucidate such sex differences in clinical practice, we retrospectively analyzed two cohorts treated with either ICI monotherapy (n = 228) or ICI-CHT combination treatment (n = 80) for advanced NSCLC. Kaplan–Meier analyses were used to calculate progression-free (PFS) and overall survival (OS), influencing variables were evaluated using Cox-regression analyses. No significant sex differences for PFS/OS could be detected in either cohort. Men receiving ICI monotherapy had a statistically significant independent impact on PFS by Eastern Cooperative Oncology Group performance status (ECOG) ≥2 (hazard ratio (HR) 1.90, 95% confidence interval (CI): 1.10–3.29, p = 0.021), higher C-reactive protein (CRP; HR 1.06, 95%CI: 1.00–1.11, p = 0.037) and negative programmed death-ligand 1 (PD-L1) status (HR 2.04, 95%CI: 1.32–3.15, p = 0.001), and on OS by CRP (HR 1.09, 95%CI: 1.03–1.14, p = 0.002). In men on ICI-CHT combinations, multivariate analyses (MVA) revealed squamous histology (HR 4.00, 95%CI: 1.41–11.2, p = 0.009) significant for PFS; and ECOG ≥ 2 (HR 5.58, 95%CI: 1.88–16.5, p = 0.002) and CRP (HR 1.19, 95%CI: 1.06–1.32, p = 0.002) for OS. Among women undergoing ICI monotherapy, no variable proved significant for PFS, while ECOG ≥ 2 had a significant interaction with OS (HR 1.90, 95%CI 1.04–3.46, p = 0.037). Women treated with ICI-CHT had significant MVA findings for CRP with both PFS (HR 1.09, 95%CI: 1.02–1.16, p = 0.007) and OS (HR 1.11, 95%CI: 1.03–1.19, p = 0.004). Although men and women responded similarly to both ICI mono- and ICI-CHT treatment, predictors of response differed by sex.
Keywords: immunotherapy; immune-checkpoint inhibitor; response prediction; men and women; pembrolizumab; nivolumab; atezolizumab; ECOG; CRP; chemo-immunotherapy
Cancer immunotherapy using immune-checkpoint inhibitors (ICI) directed against programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) has revolutionized lung cancer treatment [[
Early phase-3 ICI monotherapy studies in NSCLC, with the exception of the OAK study for atezolizumab, showed a numerical prognostic benefit favoring men in subgroup analyses [[
Our study group has evaluated various biomarkers for lung cancer immunotherapy in real-life cohorts, where women repeatedly had more favorable hazard ratios for progression-free survival (PFS) and overall survival (OS) as compared to men [[
The bi-centric ICI monotherapy cohort consisted of 228 retrospectively evaluated consecutive patients with advanced NSCLC that had received at least one cycle of either nivolumab, pembrolizumab or atezolizumab at the lung cancer unit of Kepler University Hospital Linz or at the Medical Oncology unit of Paracelsus Medical University Salzburg between May 2015 and December 2019. The ICI-CHT cohort comprised 80 consecutive patients treated with platinum-based doublet CHT combined with pembrolizumab or atezolizumab (plus bevacizumab) at Kepler University Hospital Linz between June 2018 and December 2019. The patient registry as well as the present evaluation have been approved by the ethics committee of the federal state of Upper-Austria (EK Nr. 1139/2019).
Patients were retrospectively followed from ICI therapy initiation on to death or censored at the date of last verified contact. Disease progression was retrospectively defined by imaging and death, as well as by reviewing the relevant medical records. Therapy could be applied beyond disease progression in selected cases of considerable clinical benefit. In addition, in stage IV patients with PD-L1 expression <50% and contraindications to CHT, first-line ICI treatment could be initiated upon tumor-board decision. Therapy line was defined as treatment for non-curable (e.g., stage IV [[
Chemo-immunotherapy was applied according to the respective phase 3 studies, using carboplatin/pemetrexed/pembrolizumab for non-squamous and carboplatin/paclitaxel/pembrolizumab for squamous-cell carcinomas [[
Radiological response to ICI monotherapy was routinely assessed by a chest- and upper abdomen CT scan using iodinated contrast medium every 10 to 12 weeks, equaling four cycles of nivolumab or three cycles of pembrolizumab or atezolizumab. In the ICI-CHT cohort, equivalent re-staging was performed after every two cycles of combination therapy. Re-staging could be preponed due to suspected disease progression and imaging modalities such as
All statistical analyses were accomplished using R (R: A Language and Environment for Statistical Computing; Version 4.1.1). Sex-specific differences in baseline characteristics were tested for statistical significance using a two-samples t-test or the Mann-Whitney-U-test for non-normally distributed variables; categorical variables were tested using the Chi–Square–Test. Kaplan–Meier-analyses were used to calculate PFS and OS in all patients as well as according to sex. Results were expressed as median in months (95% confidence interval (CI)) unless otherwise specified. The Kaplan–Meier curves were compared statistically using the log rank test, whereas a p-value < 0.05 was regarded statistically significant. Uni- and multivariate models for predictive factors of PFS and OS in the ICI monotherapy and ICI-CHT cohort in all patients and according to sex were accomplished using Cox-regression analyses. Variables included in these models were age (years), sex (only in the models for all patients), smoking status (< vs. ≥5 pack years), histological subtype (adeno- vs. squamous-cell carcinoma), palliative therapy line (1,2 vs. ≥3; only in the models for ICI monotherapy), Eastern Cooperative Oncology Group performance status (ECOG; 0.1 vs. ≥2) and presence of a targetable genetic tumor alteration (anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase ROS (ROS-1)). We also included C-reactive protein and absolute lymphocyte count, assessed using a Cobas
Baseline patient and tumor characteristics of the ICI monotherapy and ICI-CHT combination cohort for all patients and separately for men and women are shown in Table 1.
Kaplan–Meier analyses (Figure 1) showed no significant sex difference, neither in the ICI monotherapy cohort (PFS: men 3M (3–5), women 3M (3–6), p = 0.273; OS: men 10M (8–14), women 10M (6–14), p = 0.592), nor in the CHT-ICI cohort (PFS: men 6M (5–10), women 5M (3-/), p = 0.780; OS: men 15M (10-NA), OS women: 10M (7-NA), p = 0.399), respectively.
Uni- and multivariate predictors of PFS and OS for both therapy cohorts are presented in Table 2.
In the ICI monotherapy cohort, multivariate analyses showed ECOG and PD-L1 status as significant predictors of PFS, while OS was significantly influenced by ECOG and CRP. Chemo-immunotherapy-treated patients displayed a significant multivariate influence of ECOG, CRP and PD-L1 on PFS and of ECOG, presence of a targetable genetic tumor alteration and CRP on OS. Sex did not play a significant role in these analyses; neither alone, nor in combination with any other variable evaluated.
Uni- and multivariate analyses for PFS and OS according to sex are shown in Table 3 and Table 4.
Among women treated with ICI monotherapy, no significant predictor of PFS could be identified, while ECOG was significant for OS. Female patients in the ICI-CHT cohort showed a significant interaction of both PFS and OS with CRP. Men in the ICI monotherapy cohort had a significant impact of ECOG, CRP and PD-L1 status on PFS and of CRP on OS. Among male patients in the ICI-CHT cohort, squamous histology predicted reduced PFS, while ECOG and CRP proved significant for OS.
Our data suggest that sex did not significantly influence outcomes in the reported cohorts of patients having received PD-1/PD-L1 directed ICI therapy either alone or in combination with platinum-based doublet CHT.
In the ICI monotherapy setting, multivariate models revealed ECOG and PD-L1 status as the main variables for PFS, while ECOG and CRP were most relevant for OS. Similarly, in the ICI-CHT combination cohort, ECOG, CRP and PD-L1 were the main determinants of PFS, and ECOG, presence of a targetable genetic alteration and CRP of OS. These findings largely resemble the current state of knowledge on predictive biomarkers for prediction of response to ICI therapy: Despite several years of biomarker research, PD-L1 expression, performance status and presence of a targetable genetic alteration as in EGFR or ALK are still the most common biomarkers routinely applied in daily clinical practice, knowing that their predictive power is limited [[
Evidence from several metanalyses suggests that men have more favorable responses to ICI monotherapies, while women have a comparably larger benefit on ICI-CHT combinations [[
Imbalances in baseline patient characteristics may have influenced these findings: Both treatment cohorts included considerably more men than women probably mainly due to the higher incidence of lung cancer among men [[
Besides these mentioned sex differences on the demographic level, more profound variations in the pathophysiological mechanisms of anticancer immune response and tumor immune evasion contribute to the sex-specific response to ICI therapy [[
If tumor antigenicity however can be enhanced, e.g., by the application of CHT, women may derive a larger benefit from their stronger immune responses and enhanced immune cell infiltration into the tumor [[
Naturally, our study and its results are limited by its retrospective, registry-based design. Still, it reflects two cohorts of patients treated in daily clinical practice at tertiary lung cancer centers and thus allows an insight into real life data that may unearth findings not evident in clinical trial settings. Although we regard the overall sample size of the ICI monotherapy cohort rather substantial, the ICI-CHT cohort as well as several subgroups in subsequent analyses were comparably small, which confines the significance of the statistical tests reported as well as the comparability between the two therapy cohorts. In addition, reflecting the current demographics of NSCLC incidence, more men than women were included in both reported cohorts, which may limit their comparability. However, the simulation of a numerically balanced sex ratio in both therapy cohorts as described in supplementary analysis one (Supplementary Analysis S1) did not substantially alter PFS and OS outcomes.
We conclude that although there was no evident sex difference in outcomes with either mono- or chemo-immunotherapy for advanced NSCLC, prognostic factors differed between men and women. These variations may be explained by sex-specific variations in host antitumor immune response and ICI therapy effects, as well as by differences in demographic and socioeconomic factors such as smoking, comorbidities, and prevalence of targetable genetic tumor alterations. Our finding that known prognostic factors currently used in clinical practice seem to apply to male rather than to female patients urgently warrants further research in that field, specifically for women.
Graph: Figure 1 Kaplan–Meier curves for progression-free and overall survival in the mono- (a,b) and chemo-immunotherapy cohort (c,d) according to sex. Results are presented as months (95% confidence interval). CI = confidence interval, NA = not applicable.
Table 1 Baseline patient and tumor characteristics for all patients and according to sex in the mono- and chemo-immunotherapy cohort. Results are presented as absolute number and percent within the respective group unless otherwise specified. p values are for comparison between men and women.
Mono-Immunotherapy Chemo-Immunotherapy All ( Male ( Female ( All ( Male ( Female ( Mean age (years; SE) 67.4 (0.71) 68.9 (1.0) 65.1 (1.0) 0.003 62.9 (1.1) 63.2 (1.3) 62.5 (1.8) 0.623 Age categories ( 0.030 0.636 <60 years 47 (20.6) 21 (15.4) 26 (28.2) 28 (35.0) 16 (34.0) 12 (36.4) 60–69 years 80 (35.1) 45 (33.1) 35 (38.0) 34 (42.5) 20 (42.6) 14 (42.4) 70–79 years 78 (34.2) 53 (39.0) 25 (27.2) 17 (21.3) 11 (23.4) 6 (18.2) 80+ years 23 (10.1) 17 (12.5) 6 (6.5) 1 (1.3) 0 (0.0) 1 (3.0) ECOG ( 0.167 0.104 0.1 172 (75.4) 107 (78.7) 65 (70.7) 68 (86.1) 38 (80.9) 30 (93.8) ≥2 56 (24.6) 29 (21.3) 27 (29.4) 11 (13.9) 9 (19.2) 2 (6.2) Mean pack years (SE) 45.1 (2.1) 50.9 (2.9) 36.5 (2.9) <0.001 40.9 (3.0) 44.3 (3.7) 36.1 (4.8) 0.067 ICI substance ( 0.897 NA Nivolumab 90 (39.5) 52 (38.2) 38 (41.3) - - - Pembrolizumab 105 (46.1) 64 (47.1) 41 (44.6) 77 (96.3) 45 (95.7) 32 (97) Atezolizumab 33 (14.5) 20 (14.7) 13 (14.1) 3 (3.8) 2 (4.3) 1 (3) Therapy line ( 0.629 NA 1,2 136 (59.7) 110 (80.9) 72 (78.3) 77 (96.3) 45 (95.7) 32 (97) ≥3 92 (40.3) 26 (21.7) 20 (21.7) 3 (3.8) 2 (4.3) 1 (3) Median number of ICI-CHT cycles (IQR) - - - - 4 (2) 4 (2) 4 (2) 0.962 Median number of ICI-monotherapy cycles (IQR) 4 (5) 4 (5) 4 (7) 0.343 3 (5.3) 3 (4) 2 (7) 0.761 Histological subtype ( 0.005 0.409 Adenocarcinoma 140 (62.2) 74 (54.8) 66 (73.3) 61 (77.2) 34 (73.9) 27 (81.8) Squamous-cell carcinoma 85 (37.8) 61 (45.2) 24 (26.7) 18 (22.8) 12 (26.1) 6 (18.2) PD-L1 positive ( 137 (68.8) 84 (70.6) 53 (66.3) 0.517 41 (54.7) 23 (53.5) 18 (56.3) 0.812 PD-L1 expression ( 0.820 0.277 n.a. 29 (12.7) 18 (13.2) 11 (12) 5 (6.3) 4 (8.5) 1 (3) <1% 67 (29.4) 38 (27.9) 29 (31.5) 34 (42.5) 20 42.6) 14 (42.4) 1–49% 71 (31.1) 44 (32.4) 27 (29.3) 26 (32.5) 17 (36.2) 9 (27.3) ≥50% 61 (26.8) 36 (26.5) 25 (27.2) 15 (18.6) 6 (12.8) 9 (27.3) Targetable genetic alteration ( 18 (7.9) 6 (4.4) 12 (13.0) 0.018 6 (7.5) 2 (4.3) 4 (12.1) 0.189 Mean lymphocyte count (G/L; SE) 1.4 (0.1) 1.4 (0.1) 1.4 (0.1) 0.388 1.3 (0.1) 1.3 (0.1) 1.2 (0.1) 0.973 Mean C-reactive protein (mg/dL; SE) 3.5 (0.3) 3.5 (0.4) 3.4 (0.5) 0.261 3.1 (0.6) 2.6 (0.6) 3.7 (1.2) 0.788
Table 2 Uni- and multivariate analyses for progression-free- and overall survival for all patients in the mono-immunotherapy and chemo-immunotherapy cohort. Results are presented as hazard ratio (95% confidence interval), with a ratio >1 signifying an increased risk of progression/death or death, respectively.
Univariate Multivariate Univariate Multivariate HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Mono-immunotherapy ( Progression-free survival Overall survival Age (years) 0.99 (0.98–1.00) 0.543 0.99 (0.98–1.00) 0.753 Female vs. male 0.86 (0.65–1.15) 0.312 0.91 (0.66–1.25) 0.551 ECOG (≥2 vs. 0.1) 1.51 (1.09–2.10) 0.014 1.56 (1.08–2.26) 0.017 1.89 (1.31–2.74) <0.001 1.78 (1.17–2.72) 0.008 Therapy line (≥3 vs. 1,2) 1.50 (1.08–2.10) 0.002 1.45 (1.02–2.07) 0.040 Targetable genetic alteration (yes vs. no) 1.64 (0.99–2.70) 0.060 1.87 (1.11–3.15) 0.020 Lymphocyte count (G/L) 0.98 (0.85–1.13) 0.783 0.87 (0.72–1.06) 0.871 Squamous-cell vs. adenocarcinoma 0.99 (0.74–1.32) 0.917 1.18 (0.86–1.62) 0.314 Pack years (≥5 vs. <5) 0.93 (0.60–1.44) 0.731 1.03 (0.63–1.68) 0.917 CRP (mg/dL) 1.05 (1.01–1.08) 0.005 1.08 (1.05–1.12) <0.001 1.06 (1.02–1.10) 0.003 PD-L1 status (neg. vs. ≥1%) 1.56 (1.13–2.14) 0.006 1.51 (1.09–2.08) 0.013 1.22 (0.86–1.73) 0.268 1.21 (0.85–1.72) 0.303 Age (years) 1.00 (0.97–1.03) 0.884 1.01 (0.97–1.05) 0.691 Female vs. male 1.09 (0.64–1.87) 0.747 1.32 (0.67–2.63) 0.423 ECOG (≥2 vs. 0.1) 2.27 (1.13–4.56) 0.027 2.27 (1.07–4.80) 0.032 3.48 (1.59–7.63) 0.002 3.76 (1.50–9.42) 0.005 Targetable genetic alteration (yes vs. no) 2.02 (0.85–4.78) 0.110 1.96 (0.75–5.10) 0.171 2.85 (1.03–7.86) 0.043 Lymphocyte count (G/L) 1.08 (0.76–1.53) 0.688 0.84 (0.50–1.41) 0.500 Squamous-cell vs. adenocarcinoma 1.55 (0.83–2.91) 0.171 1.59 (0.71–3.57) 0.265 Pack years (≥5 vs. <5) 0.53 (0.27–1.07) 0.075 0.69 (0.26–1.79) 0.685 CRP (mg/dL) 1.11 (1.06–1.18) <0.001 1.11 (1.06–1.17) <0.001 1.16 (1.10–1.22) <0.001 1.13 (1.07–1.19) <0.001 PD-L1 status (neg. vs. ≥1%) 1.48 (0.86–2.54) 0.155 1.76 (1.00–3.08) 0.049 1.43 (0.71–2.91) 0.319 1.57 (0.77–3.23) 0.219
Table 3 Uni- and multivariate analyses for progression-free survival in the mono- and chemo-immunotherapy cohort according to sex. Results are presented as hazard ratio (95% confidence interval), with a ratio >1 signifying an increased risk of progression/death.
Progression-Free Survival Univariate Multivariate Univariate Multivariate HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Mono-immunotherapy ( Male Female Age (years) 0.99 (0.98–1.01) 0.860 0.99 (0.97–1.02) 0.351 ECOG (≥2 vs. 0.1) 2.19 (1.39–3.45) <0.001 1.90 (1.10–3.29) 0.021 1.16 (0.71–1.88) 0.553 1.27 (0.74–2.19) 0.384 Therapy line (≥3 vs. 1,2) 1.34 (0.86–2.10) 0.194 1.69 (1.01–2.52) 0.044 Targetable genetic alteration (yes vs. no) 2.20 (0.88–5.46) 0.091 1.56 (0.83–2.92) 0.165 Lymphocyte count (G/L) 1.03 (0.90–1.17) 0.660 0.83 (0.62–1.12) 0.228 Squamous-cell vs. adenocarcinoma 0.99 (0.69–1.43) 0.954 0.92 (0.57–1.51) 0.752 Pack years (≥5 vs. <5) 0.97 (0.45–2.09) 0.940 0.86 (0.49–1.50) 0.592 CRP (mg/dL) 1.09 (1.04–1.13) <0.001 1.06 (1.00–1.11) 0.037 1.01 (0.96–1.07) 0.696 PD-L1 status (neg. vs. ≥1%) 1.93 (1.26–2.95) 0.002 2.04 (1.32–3.15) 0.001 1.29 (0.79–2.10) 0.316 1.26 (0.78–2.07) 0.344 Age (years) 1.01 (0.97–1.04) 0.717 0.99 (0.96–1.04) 0.936 ECOG (≥2 vs. 0.1) 2.30 (1.02–5.23) 0.046 1.75 (0.72–4.26) 0.217 6.06 (1.28–28.7) 0.023 5.18 (0.91–29.5) 0.064 Targetable genetic alteration (yes vs. no) 1.33 (0.32–5.61) 0.700 2.24 (0.74–6.84) 0.155 Lymphocyte count (G/L) 0.97 (0.64–1.48) 0.896 1.60 (0.67–3.78) 0.288 Squamous-cell vs. adenocarcinoma 2.68 (1.17–6.12) 0.019 4.00 (1.41–11.2) 0.009 1.04 (0.35–3.10) 0.938 Pack years (≥5 vs. <5) 0.75 (0.29–1.96) 0.556 0.42 (0.15–1.19) 0.101 CRP (mg/dL) 1.14 (1.04–1.25) 0.004 1.10 (1.04–1.17) 0.001 1.09 (1.02–1.16) 0.007 PD-L1 status (neg. vs. ≥1%) 1.45 (0.72–2.93) 0.297 1.45 (0.70–3.03) 0.321 1.62 (0.68–3.85) 0.274 1.59 (0.65–3.93) 0.311
Table 4 Uni- and multivariate analyses for overall survival in the mono- and chemo-immunotherapy cohort according to sex. Results are presented as hazard ratio (95% confidence interval), with a ratio >1 signifying an increased risk of death.
Overall Survival Univariate Multivariate Univariate Multivariate HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Mono-immunotherapy ( Male Female Age (years) 1.00 (0.98–1.02) 0.783 0.99 (0.97–1.01) 0.345 ECOG (≥2 vs. 0.1) 2.44 (1.44–4.12) <0.001 1.78 (0.97–3.39) 0.063 1.64 (0.96–2.81) 0.072 1.90 (1.04–3.46) 0.037 Therapy line (≥3 vs. 1,2) 1.30 (0.81–2.09) 0.273 1.63 (0.94–2.80) 0.090 Targetable genetic alteration (yes vs. no) 1.97 (0.79–4.92) 0.145 1.87 (0.97–3.62) 0.060 Lymphocyte count (G/L) 0.95 (0.78–1.14) 0.567 0.73 (0.51–1.04) 0.726 Squamous-cell vs. adenocarcinoma 1.11 (0.74–1.66) 0.624 1.25 (0.74–2.10) 0.601 Pack years (≥5 vs. <5) 0.83 (0.36–1.91) 0.666 1.10 (0.59–2.07) 0.764 CRP (mg/dL) 1.11 (1.07–1.16) <0.001 1.09 (1.03–1.14) 0.002 1.05 (0.99–1.10) 0.084 PD-L1 status (neg. vs. ≥1%) 1.32 (0.83–2.09) 0.245 1.35 (0.84–2.16) 0.216 1.09 (0.64–1.88) 0.747 1.10 (0.64–1.90) 0.738 Age (years) 1.02 (0.96–1.07) 0.535 0.99 (0.95–1.05) 0.956 ECOG (≥2 vs. 0.1) 4.89 (1.83–13.1) 0.002 5.58 (1.88–16.5) 0.002 3.74 (0.45–31.4) 0.225 1.26 (0.09–16.4) 0.860 Targetable genetic alteration (yes vs. no) 1.09 (0.14–8.30) 0.934 2.16 (0.67–6.68) 0.201 Lymphocyte count (G/L) 0.62 (0.31–1.26) 0.187 1.63 (0.61–4.35) 0.329 Squamous-cell vs. adenocarcinoma 1.93 (0.65–5.71) 0.237 1.23 (0.35–4.37) 0.751 Pack years (≥5 vs. <5) 0.90 (0.21–3.96) 0.886 0.48 (0.13–1.80) 0.277 CRP (mg/dL) 1.18 (1.08–1.70) <0.001 1.19 (1.06–1.32) 0.002 1.13 (1.06–1.20) <0.001 1.11 (1.03–1.19) 0.004 PD-L1 status (neg. vs. ≥1%) 1.27 (0.48–3.34) 0.634 2.78 (0.91–8.46) 0.072 1.78 (0.62–5.09) 0.282 1.39 (0.47–4.13) 0.553
Conceptualization, D.L., A.B., F.H., G.R., A.H., R.W., E.B., B.K., R.G. and B.L.; Data curation, D.L., A.B., F.H., G.R., E.B. and B.K.; Formal analysis, D.L., A.B., F.H., G.R., A.H. and B.K.; Investigation, D.L., A.B., F.H., G.R., A.H., R.W., E.B., B.K., R.G. and B.L.; Methodology, D.L., F.H., G.R., A.H., R.W., E.B., B.K., R.G. and B.L.; Project administration, D.L., F.H., G.R., R.W., R.G. and B.L.; Resources, D.L., A.B., F.H., G.R., E.B., B.K., R.G. and B.L.; Software, D.L., A.B. and B.K.; Supervision, D.L., G.R., R.W., E.B., R.G. and B.L.; Validation, D.L., F.H., G.R., A.H., R.W., E.B., R.G. and B.L.; Visualization, D.L., A.B., F.H., G.R., A.H., B.K. and R.G.; Writing—original draft, D.L. and A.B.; Writing—review & editing, D.L., A.B., F.H., G.R., A.H., R.W., E.B., B.K., R.G. and B.L. All authors have read and agreed to the published version of the manuscript.
This research received no external funding.
This study was approved by the local ethics committees of Upper-Austria (EK Nr. 1139/2019). It was conducted in an entirely retrospective fashion, without an experimental approach or additional patient contact. Only patient data assessed in clinical routine were analyzed. Patient data were collected in an anonymized fashion and securely electronically stored in a way, that only the authors had access to the data.
The need for patients' written informed consent was waived according to the institutional ethics committee's regulations for non-interventional retrospective studies.
According to the terms imposed by the ethics committee, the full datasets analyzed during the current study cannot be made publicly available, as they contain possibly identifiable patient data. Upon reasonable request to the authors and if approved as an amendment by the responsible local ethics committee, selected anonymized data can however be shared.
D.L. has served as consultant/advisor to Roche and Merck Sharp & Dohme and received travel/accommodation funding from Roche and Merck Sharp & Dohme. F.H. has received travel/accommodation funding from Bristol-Myers Squibb, Roche and Merck Sharp & Dohme. G.R. has served as consultant/advisor to Roche, has received speakers' honoraria from Bristol-Myers Squibb and Roche and has received travel/accommodation and research funding from Roche. A.H. has received travel/accommodation funding from Roche. R.W. has received speakers' honoraria and travel/accommodation funding from and served as consultant/advisor to Roche, Merck Sharp & Dohme and Bristol-Myers Squibb. E.B. has received speakers' honoraria from and served as consultant/advisor to Roche, Merck Sharp & Dohme, and Bristol-Myers Squibb; he has received travel/accommodation funding from Roche and Merck Sharp & Dohme. R.G. has received speakers' honoraria and research funding from Roche, Merck Sharp & Dohme and Bristol-Myers Squibb, he has served as consultant/advisor to Roche and Bristol-Myers Squibb and has received travel/accommodation funding from Roche. B.L. has received speakers' honoraria from and has served as consultant/advisor to Roche, Merck Sharp & Dohme and Bristol-Myers Squibb. A.B. and B.K. declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. That is relevant to the content of this article.
Supported by Johannes Kepler Open Access Publishing Fund.
The following supporting information can be downloaded at: https://
By David Lang; Anna Brauner; Florian Huemer; Gabriel Rinnerthaler; Andreas Horner; Romana Wass; Elmar Brehm; Bernhard Kaiser; Richard Greil and Bernd Lamprecht
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