Introduction

Lung cancer is the leading cause of cancer-related death worldwide. Over 2 million new cases are diagnosed each year and result in more than 1.7 million deaths [1]. The most common form is non-small cell lung cancer (NSCLC). Nearly half of patients are diagnosed at an advanced stage of disease, which leads to poor 5-year overall survival (OS). The observed 5-year OS in Europe is 13% and has not changed much in the last few decades [2]. Until this decade, chemotherapy was the standard of care and, in fact, the only systemic treatment option for advanced NSCLC. The median overall survival (mOS) of patients on chemotherapy was up to 13.4 months [3].

The development of targeted therapies redefined the treatment paradigm for patients with oncogene-driven NSCLC. All pivotal clinical trials, performed in advanced epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive NSCLC, demonstrated improved response rates and progression-free survival in patients treated with targeted therapy compared with standard chemotherapy [3]. Moreover, with the sequential use of ALK-targeted agents, median overall survival of more than 7 years has been observed in patients treated in routine clinical practice [4]. Consequently, predictive biomarker testing and targeted therapies have been introduced into standard care for patients with advanced NSCLC [5, 6]. Currently, international guidelines recommend testing for EGFR mutations, ALK and ROS1 rearrangements, and BRAF mutations for all patients with advanced non-squamous NSCLC [6]. In our country, reflex testing for particular predictive biomarkers has been adopted in accordance with European guidelines as soon as they were published. However, access to targeted therapies for NSCLC followed a slower pace, similarly to other Central and Eastern European (CEE) countries [7, 8]. This is supported by recently published data reporting a lag time of 14 months between approval of new anticancer drugs by the European Medicines Agency and a positive national reimbursement decision in Slovenia [9]. Despite significant improvements, the benefits of targeted therapies are still restricted to a small proportion of patients with advanced NSCLC who harbor targetable driver mutations.

The unmet need for effective therapies in patients with NSCLC without a targetable oncogene was hoped to be met by immuno-oncology. The immune checkpoint inhibitors (ICIs) atezolizumab, nivolumab, and pembrolizumab were first studied in second-line treatment of advanced NSCLC. Substantial improvements in mOS rates of up to 13.8 months were observed compared with up to 9.6 months achieved with docetaxel [10-13]. Even more impressive results were achieved in the first-line setting. In the pivotal trial of pembrolizumab monotherapy in a patient population with programmed death–ligand 1 (PD-L1) ≥50%, a mOS of 30 months was observed [14, 15]. To further improve treatment results, the combination of two previous first-line standards, chemotherapy and immunotherapy, was studied in unselected patient populations and further added efficacy compared with chemotherapy alone while retaining a reasonable safety profile [16]. These significant improvements are indeed coupled with new immune-related adverse events (AEs). But even though treatment-related AEs are recorded in the majority of patients, more than 60%, only approximately 15% experience severe AEs (grade 3 or 4), treatment discontinuation, or, very rarely, fatal toxicity [17].

Although immunotherapy represents a new treatment standard for advanced NSCLC, many questions still need to be answered to ensure its optimal use in everyday clinical practice [18]. It is vital to evaluate how the impressive efficacy data and favorable safety profile reported in randomized clinical trials (RCTs) translate into everyday clinical practice effectiveness. A substantial gap in outcomes between patients included in clinical trials and those treated in the real-world scenario was observed, particularly in cancer populations of older patients with comorbidities [19]. Clinical trials tend to include younger patients in good performance status (PS) with minimal comorbidity, thus making real-world data for populations of advanced NSCLC, who tend to be older and with multiple comorbidities, most interesting [20, 21]. There are many published studies on the real-world effectiveness of immunotherapy with ICIs in advanced NSCLC (Tables 1 and 2). Most of them provide reassuring data for second-line mono-immunotherapy, including also patients with poor prognostic characteristics (Table 2). However, data in the first-line setting are limited and not as reassuring, especially when compared with the pivotal trial (Table 1). Of note, real-world data published so far mainly involve patients from North America and Western Europe, similar to those included in pivotal trials. To our knowledge, no real-world data on immunotherapy outcomes in NSCLC for CEE countries, which are still facing a gap in cancer control, have been published so far [22].

Table 1. First-line immunotherapy outcomes in the pivotal RCTs, real-world studies, and present study First author, year Study design (country) Drug Patients, n Age median (range) Gender: males, n (%) PS ≥ 2, n (%) CNS metastases, n (%) Median PFS, mo Median OS, mo 1-year OS, % Reck, 2016 & 2019 [11, 12] RCT, multicentric Pem 154 64.5 (33–90) 92 (59.7) 1 (0.6) 18 (11.7) 10.3 30.0 70.3 Ksienski, 2019 [34] Observational, multicentric (Canada) Pem 141 70.0 (41–91)a 97 (51.1) a 65 (34.2) a 26 (13.7) a 3.7a 24.3 ND Velcheti, 2019 [39] Observational, multicentric (U.S.) Pem 188 72.0 (46–84) 90 (47.9) 0 23 (12.2) 6.8 19.1 60.4 Amrane, 2019 [24] Observational, multicentric (France) Pem 108 67.0 (37–87) 70 (64.8) 25 (23.1) 19 (17.6) 10.1 15.2 ND Tamiya, 2019 [32] Observational, multicentric (Japan) Pem 213 71 (39–91) 176 (82.6) 41 (19.2) ND 8.3 17.8 ND Tambo, 2020 [40] Observational, multicentric (Japan) Pem 95 72.0 (51–89) 71 (74.7) 21 (22.1) ND 6.1 NR 58.3 Current study Observational, single center (Slovenia) Pem 26 65.5 (39–78) 16 (62.0) 3 (11.0) 4 (15.0) 9.3 NR 62.0 a Reported for 190 patients, of which 49 were treated in second-line setting. Abbreviations: CNS, central nervous system; ND, no data; NR, not reached; OS, overall survival; Pem, pembrolizumab; PFS, progression-free survival; PS, performance status; RCT, randomized clinical trial. Table 2. Second-line immunotherapy outcomes in the pivotal RCTs, real-world studies, and present study First author, year Study design (country) Drug Patients, n Age, median (range), yr Gender: male, n (%) PS ≥ 2, n (%) CNS metastases, n (%) Median PFS, mo Median OS, mo 1-year OS, % Brahmer, 2015 [8] RCT, multicentric Nivo 135a 62.0 (39–85) 111 (82.0) 2 (1.5) 9 (6.6) 3.5 9.2 42.0 Borghaei, 2015 [7] RCT, multicentric Nivo 292b 61.0 (37–84) 151 (51.7) 0 34 (11.6) 2.3 12.2 51.0 Herbst, 2015 [9] RCT, multicentric Pem 344c 63.0 (56–69) 212 (61.6) 3 (0.9) 56 (16.3) 3.9 10.4 43.2 Rittmeyer, 2016 [10] RCT, multicentric Atezo 425 63.0 (33–82) 261 (61.4) 0 85 (10.0)d 2.8 13.8 55.0 Brustugun, 2016 [41] Observational, single center (Norway) Nivo 58 64.6 (32–88) 28 (48.3) 14 (24.1) 0 4.0d 11.7 50.0 Schouten, 2017 [42] Observational, multicentric (Netherlands) Nivo 248 63.0 (29–84) 136 (54.8) 40 (16.1) 56 (22.6) 2.6 10.0 ND Dudnik, 2018 [26] Observational, multicentric (Israel) Nivo 260 67.0 (41–99) 176 (67.7) 139 (53.5) 55 (21.1) 2.8 5.9 ND Manrique, 2018 [43] Observational, multicentric (Spain) Nivo 188 58.0 (45–81) 144 (76.6) 19 (10.1) 42 (22.3) 4.8 12.8 55.0 Lin, 2018 [27] Observational, single center (Taiwan) Nivo, Pem 74 62.1 (34–87) 43 (58.1) 36 (48.6) 33 (44.6) 1.8 7.9 46.0 Kobayashi, 2018 [44] Observational, multicentric (Japan) Nivo 142 67.0(34–85) 106 (74.6) 23 (16.2) 27 (19.0) 1.9 ND ND Geier, 2018 [45] Observational, multicentric (France) Nivo 259 62.0 (29–85) 187 (72.2) 15 (5.8) 53 (20.5) 2.3 11.0 47.9 Juergens, 2018 [46] Observational, multicentric (Canada) Nivo 472 66.0 (36–92) 203 (43.0) 42 (8.9) 62 (13.1) 3.5e 12.0 50.0 Fujimoto, 2018 [47] Observational, multicentric (Japan) Nivo 613 66.9 (ND) 433 (71) 141 (23) ND ND ND 54 Montana, 2018 [28] Observational, multicentric (France) Nivo 98 65.5 (42–85) 70 (71.4) 39 (39.7) ND 1.8 6.3 ND Almazan, 2019 [48] Observational, multicentric (Spain) Nivo 221 64.5 (NR) 185 (83.7) 30 (13.8) 22 (10.0) 5.3 9.7 ND Khozin, 2019 [49] Observational, multicentric (U.S.) Nivo, Pem 1,344f 69.0 (61–75) 747 (55.6) ND ND ND 8.0 39.0 Khozin, 2019 [50] Observational, multicentric (U.S.) Atezo, Nivo, Pem 5,257g 69.0 (62–76) 2,819 (53.6) ND ND 3.2 9.3 ND Ahn, 2019 [29] Observational, single centre (Korea) Nivo, Pem 155 64.0 (35–58) 113 (72.9) 34 (21.9) 61 (39.4) 3.0 10.2 ND Crino, 2019 [51] Observational, multicentric (Italy) Nivo 371a 68.0 (31–91) 298 (80.3) 22 (5.9) 37 (9.9) 4.2 7.9 39.0 El Karak, 2019 [38] Observational, (Lebanon) Nivo, Pem 110 66.0 (ND) 75 (68.2) ND 17 (15.5) 4.0 8.1 ND Grossi, 2019 [33] Observational, multicentric (Italy) Nivo 1,588b 66.0 (27–89) 1,029 (64.8) 108 (6.8) 409 (25.7) 3.0 11.3 48.0 Morita, 2020 [52] Observational, multicentric (Japan) Nivo 901h 67.0 (30–90) 651 (72.3) 157 (17.4) 201 (22.3) 2.1 14.6 54.3 Figueiredo, 2020 [31] Observational, multicentric (Portugal) Nivo 219 64.0 (37–83) 154 (70.3) 29 (13.2) ND 4.9 13.2 56.5 Weis, 2020 [53] Observational, single centre (U.S.) Atezo 43 67.2 (ND) 23 (53.5) 9 (20.9) ND 2.0 6.5 ND Nivo 81 64.3 (ND) 39 (48.2) 21 (28.4) ND 2.2 8.4 ND Martin, 2020 [37] Observational, multicentric (Argentina) Nivo 109 65.0 (56–72) 63 (57.8) 17 (15.6) ND 6.1 12.1 ND Barlesi, 2020 [30] Observational, multicentric (France) Nivo 1,420i 66.0 (35–91) 986 (69.4) 241 (17.1) 282 (19.9) 2.8 11.2 48.6 Current study Observational, single center (Slovenia) Atezo, Nivo, Pem 40 63.0 (42–77) 20 (50.0) 1 (3.0) 8 (20.0) 3.5 9.9 35.0 a Only squamous cell lung cancer. b Only nonsquamous cell lung cancer. c cohort treated with pembrolizumab 2 mg/kg. d Reported for atezolizumab and docetaxel cohort combined. e Time to treatment failure. f 227 (16.9%) patients in first line. g 1,329 (25.3%) patients in first line. h 38 (4.2%) patients in first line. i Four (0.3%) patients in first line. Abbreviations: Atezo, atezolizumab; CNS, central nervous system; ND, no data; NR, not reached; Nivo, nivolumab; OS, overall survival; Pem, pembrolizumab; PFS, progression-free survival; PS, performance status; RCT, randomized clinical trial.

Here, we report the first results of a real-world observational study evaluating treatment outcomes for patients with advanced NSCLC treated with ICI monotherapy, either in first- or second-line setting at a single academic center in a Central and Eastern European country.

Patients, Materials, and Methods Patients

The study included consecutive patients with pathologically confirmed advanced NSCLC treated with ICI monotherapy between August 2015 and November 2018 in routine clinical practice at a single academic center in Slovenia. Patients received pembrolizumab in the first-line setting if they had a PD-L1 expression ≥50%, or atezolizumab, nivolumab, or pembrolizumab in the second-line setting. PD-L1 testing was mandatory before first-line but not second-line therapy and was performed on formalin-fixed, paraffin-embedded histology samples or cytospins by using PD-L1 monoclonal antibodies (22C3 clone by DAKO, Glostrup, Denmark or SP263 clone by Ventana/Roche, Oro Valley, AZ).

Nivolumab was available within a compassionate use program already in August 2015, whereas atezolizumab and pembrolizumab were available only after granted the marketing authorization by the European Medicines Agency and national reimbursement. Pembrolizumab, both for first- and second-line, was reimbursed in August 2017, and second-line atezolizumab was reimbursed in May 2018. Included patients may have had controlled central nervous system (CNS) disease, with or without previous CNS irradiation. All patients were free of corticosteroid treatment. All included patients were routinely tested for EGFR mutations and ALK rearrangement and, after 2016, also for ROS1 rearrangements. None of the included patients had a known driver oncogene, and none had known autoimmune disease. All patients are treated and routinely followed at a single institution, where clinicians are encouraged to record and grade all AEs by Common Terminology Criteria for Adverse Events, version 4 and to evaluate the objective response rate (ORR) according to RECIST 1.1 [23, 24].

Data Collection

Data were retrieved from the hospital-based lung cancer registry, which prospectively collects comprehensive demographics, pathological and molecular characteristics, and treatment and survival data of all patients with lung cancer diagnosed and treated at the center. The hospital registry includes approximately 600 new patients with lung cancer per year, representing nearly half of all newly diagnosed patients with lung cancer in Slovenia. Patients consent to collecting data in the frame of the lung cancer registry at the time of diagnosis or start of treatment. All data were collected anonymously. For this study, progression and survival status were updated, and the data were retrieved in December 2019.

Outcome Measures and Statistical Analysis

Patient and treatment characteristics were analyzed using descriptive statistics. Treatment