Clinical and Translational Oncology (2021) 23:882–891 https://doi.org/10.1007/s12094-020-02482-9 RESEARCH ARTICLE Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies M. Sotelo1 · T. Alonso‑Gordoa2 · P. Gajate2 · E. Gallardo3 · R. Morales‑Barrera4 · J. L. Pérez‑Gracia5 · J. Puente6 · P. Sánchez7 · D. Castellano8 · I. Durán1,9 Received: 5 June 2020 / Accepted: 18 August 2020 / Published online: 8 September 2020 © The Author(s) 2020 Abstract Background The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. Materials and methods We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. Results Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemo- therapy arm [46/57 (81%) vs 44/74 (59%)]. Conclusion Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab. Keywords Atezolizumab · Metastatic urothelial cancer · Duration of response · Spain 5 * I. Durán University Clinic of Navarra, Pamplona, Spain ignacioduranmartinez@gmail.com 6 Medical Oncology Department, Hospital Clínico San Carlos, 1 Instituto de Investigación Sanitaria del Hospital Clínico San Marqués de Valdecilla University Hospital, Edificio Sur. Carlos (IdISSC), CIBERONC, Madrid, Spain Despacho 277, Avda Valdecilla s/n, 39005 Santander, Spain 7 2 Medical Department, Roche Farma S.A., Madrid, Spain Ramon y Cajal University Hospital, Madrid, Spain 8 3 Doce de Octubre University Hospital, Madrid, Spain Parc Taulí Hospital Universitari, Institut d’Investigació 9 i Innovació Parc Taulí I3PT, Universitat Autònoma de Instituto de Investigación Marqués de Valdecilla (IDIVAL), Barcelona, Sabadell, Spain Santander, Spain 4 Vall d’Hebron University Hospital, Barcelona, Spain 13 Vol:.(1234567890) Clinical and Translational Oncology (2021) 23:882–891 883 Introduction 1 (PD-L1) in the tumour microenvironment [11–13]. Back in 2014, an expansion cohort of about seventy patients Urothelial cancer (UC) is a frequent disease globally with with heavily pretreated advanced UC was treated with an over 549,000 new diagnoses worldwide in 2018 [1]. The anti-PD-L1 antibody (i.e. atezolizumab) as part of a multi- incidence and mortality of UC differ across countries due tumour phase I study. Beyond positive safety data, unprec- to differences in risk factors, diagnostic practices and edented activity was reported with ORR in the range of accessibility of therapies. In Spain, the incidence of this 40–50% in patients whose tumours highly expressed tumour is particularly high, ranking fifth altogether and PD-L1-positive tumour-infiltrating immune cells [14]. rising up to the fourth most frequent malignancy among These results led to considering testing this compound in males. In 2020, more than 22,000 diagnoses of UC are advanced UC patients beyond platinum progression and, expected in our country representing a relevant medical due to the favourable toxicity profile, this drug appeared challenge [2]. Around 70% of UC diagnoses are in early as an option for cisplatin-unfit patients. Hence, two sepa- stages (non-muscle-invasive disease) where prognosis rate trials (IMvigor 210 and IMvigor 211) were launched after appropriate treatment remains overall favourable and tested atezolizumab in different populations. IMvigor with a 5 year overall survival (OS) exceeding 90%. Nev- 210 was a phase 2 study with two single-arm cohorts ertheless, 25% of patients present with disease invading where patients either treatment naïve unfit for cisplatin the Muscularis propria or beyond (muscle-invasive UC) (cohort 1) or with progression beyond first-line chemo- and despite optimal management, roughly 40–50% will therapy (cohort 2) received atezolizumab with the ORR relapse, presenting metastatic disease not amenable for as the primary endpoint. The positive results of these two surgical treatment. Additionally, about 5% of the new diag- cohorts moved atezolizumab development forward and led noses present with advanced disease at diagnosis. Meta- to drug approval and the incorporation of this compound static UC harbours a poor prognosis with a 5 year OS that in treatment algorithms [15, 16]. Across drug develop- historically does not exceed 10–15% [3, 4]. Chemotherapy ment, the expression of PD-L1 appeared as a potential regimens based on cisplatin have become the most utilized positive predictor of response to immunotherapy. Atezoli- ones in this setting. The cisplatin–gemcitabine (CG) com- zumab was subsequently tested in a randomized phase 3 bination provides objective response rates (ORR) in the study (IMvigor 211) that compared chemotherapy vs. range of 50% with 12% of complete responses (CR) and a atezolizumab in patients with advanced UC and progres- median OS of around 15 months [5]. Despite these prom- sion beyond platinum-based chemotherapy. The primary ising results, two facts have historically limited progress endpoint of OS was tested hierarchically in pre-specified in advanced UC therapeutics. First, about 50% of patients populations according to the PD-L1 expression assuming with metastatic disease are considered unfit to receive cis- greater benefit to atezolizumab in patients with higher platin according to predefined criteria (the Galsky’s crite- PD-L1 expression. Nevertheless, there were no differences ria). These patients can only receive alternative regimens, regarding OS according to this design and PD-L1 expres- such as carboplatin, or other regimes with inferior out- sion behaved as a prognostic rather than predictive factor, comes to cisplatin [6, 7]. Second, nearly all patients with favouring also the chemotherapy arm. Yet, atezolizumab metastatic disease, regardless of their response to first-line showed longer DoR, was better tolerated and was superior treatment, will end up progressing and the classic chemo- to chemotherapy in landmark analyses [17, 18]. therapy agents explored in the second line have historically We report data from an individual-level pooled analysis provided scarce benefit with an ORR of less than 10%, of the subset of Spanish patients in the IMvigor210 cohort 2 a short duration of response (DoR) and a median OS of and IMvigor211 studies to explore whether their outcomes about 7 months [8]. Therefore, defining a better treatment differed from overall results or not. for cisplatin-unfit patients and improving poor outcomes in the second-line setting are unmet needs. In this context, a different approach to treat UC has been developed considering specific features of this Materials and methods tumour [9]. One distinctive characteristic of UC is the high rate of somatic mutations observed that may poten- We analyzed the efficacy and safety of atezolizumab in tially increase the capacity of the host immune system Spanish patients that were recruited in the cohort 2 of the to distinguish UC cells as foreign. This would eventually IMvigor 210 and IMvigor 211 studies. Patients of both stud- lead to proper tumour cell identification and elimination ies were aged ≥ 18 years with advanced or metastatic urothe- [10]. Nevertheless, UC cells might escape immune surveil- lial carcinoma whose disease had progressed after previous lance through the expression of programmed death-ligand platinum-based chemotherapy Baseline characteristics are presented in Table 1. 13 884 Clinical and Translational Oncology (2021) 23:882–891 Table 1  Baseline characteristics ITT popula- IC0/1 popula- IC2/3 popula- Atezolizumab (n = 74) Chemotherapy (n = 57) tion (n = 131) tion (n = 98) tion (n = 33) Age Median (years; range) 66 (41–85) 67.5 (41–85) 64.0 (4–83) 68.0 (41–85) 66.0 (47–84) ≥ 80 years 8 (6.1%) 6 (6.1%) 2 (6.1%) 7 (9.5%) 1 (1.8%) Sex Female 23 (17.6%) 18 (18.4%) 5 (15.2%) 13 (17.6%) 10 (17.5%) Male 108 (82.4%) 80 (81.6%) 28 (84.8%) 61 (82.4%) 47 (82.5%) Tobacco use Current 21 (16.0%) 17 (17.3%) 4 (12.1%) 14 (18.9%) 7 (12.3%) Former 26 (19.8%) 20 (20.4%) 6 (18.2%) 20 (27.0%) 6 (10.5%) Never 84 (64.1%) 61 (62.2%) 23 (69.7%) 40 (54.1%) 44 (77.2%) Primary tumour site Renal pelvis 12 (9.2%) 9 (9.2%) 3 (9.1%) 4 (5.4%) 8 (14.0%) Ureter 17 (13.0%) 12 (12.2%) 5 (15.2%) 12 (16.2%) 5 (8.8%) Bladder 100 (76.3%) 75 (76.5%) 25 (75.8%) 56 (75.7%) 44 (77.2%) Urethra/Other 2 (1.5%) 2 (2.0%) 0 (0.0%) 2 (2.7%) 0 Metastatic disease 108 (82.4%) 82 (83.7%) 26 (78.8%) 64 (86.5%) 44 (77.2%) Site of metastases Visceral 96 (73.3%) 73 (74.5%) 23 (69.7%) 59 (79.7%) 37 (64.9%) Liver 32 (24.4%) 24 (24.5%) 8 (24.2%) 19 (25.7%) 13 (22.8%) ECOG performance status 0 53 (40.5%) 40 (40.8%) 13 (39.4%) 34 (45.9%) 19 (33.3%) 1 78 (59.5%) 58 (59.2%) 20 (60.6%) 40 (54.1%) 38 (66.6%) Serum haemoglobin < 10 g/dl 14 (10.7%) 13 (13.3%) 1 (3.0%) 8 (10.8%) 6 (10.5%) Number of risk factors 0 40 (30.5%) 30 (30.6%) 10 (30.3%) 25 (33.8%) 15 (26.3%) 1 64 (48.9%) 46 (46.9%) 18 (54.5%) 34 (45.9%) 30 (52.6%) 2 21 (16.0%) 17 (17.3%) 4 (12.1%) 12 (16.2%) 9 (15.8%) 3 6 (4.6%) 5 (5.1%) 1 (3.0%) 3 (4.1%) 3 (5.3) Previous cystectomy 62 (47.3%) 45 (45.9%) 17 (51.5%) 30 (40.5%) 32 (56.1%) Time from previous chemotherapy < 3 months 43 (32.8%) 35 (35.7%) 8 (24.2%) 26 (35.1%) 17 (29.8%) Number of previous systemic regimens in the metastatic setting 0 43 (35.1%) 29 (29.6%) 14 (42.4%) 20 (27.0%) 23 (40.4%) 11 59 (45.0%) 48 (49.0%) 11 (33.3%) 34 (45.9%) 25 (43.9%) 2 23 (17.6%) 17 (17.3%) 6 (18.2%) 14 (18.9%) 15 (26.3%) ≥3 6 (4.6%) 4 (4.1%) 2 (6.1%) 6 (8.1%) 0 Previous systemic regimen setting Metastatic 88 (67.2%) 69 (70.4%) 19 (57.6%) 54 (73.0%) 34 (59.6%) Neoadjuvant or adjuvant chemotherapy with 42 (32.1%) 28 (28.6%) 14 (44.4%) 19 (25.7%) 23 (40.4%) progression within ≤ 12 months Other 1 (0.8%) 1 (1.0%) 0 1 (1.4%) 0 Data are median (range), n (%), or n/N (%), unless otherwise specified Once data from both studies were combined, we modified ITT population (all the subjects with their described the ORR, DoR, PFS and OS, of patients who response assessed) and according to the PD-L1 expres- received atezolizumab (from both IMvigor210 and 211 sion (Ventana PD-L1 SP142 assay) on tumour-infiltrating studies) or chemotherapy (from IMvigor211), in the immune cells (IC0/1 if < 5% of tumour-infiltrating immune 13 Clinical and Translational Oncology (2021) 23:882–891 885 expressed PD-L1 or IC2/3 if ≥ 5% expressed PD-L1). patients who responded, the DoR clearly favored the atezoli- Safety outcomes were described in the ITT (all the rand- zumab arm. Median DoR was not reached for atezolizumab omized subjects). vs 6.4 months for chemotherapy being these differences sta- Patients received atezolizumab 1200 mg or chemother- tistically significant (HR 0.24, 95% CI 0.07–0.66; p = 0.005) apy (vinflunine 320 mg/m2, paclitaxel 175 mg/m2 or doc- (Fig. 1). Moreover, remarkable differences were observed in etaxel 75 mg/m2 based on the physician’s choice), intrave- indicators of long-term benefit. Among those patients who nously every 3 weeks until unacceptable toxicity, RECIST presented either a partial or complete response (12 and 17 v1.1 progression, or informed consent withdrawal. patients in atezolizumab and chemotherapy, respectively), the 6-month survival rates were quite different in favor of the immunotherapy group. Thus, 91.7% of atezolizumab treated Results responders were alive at 6 months versus 64.5% of patients who received chemotherapy. This trend was maintained Our sample comprised 21 (6.6%) patients out of the 315 overtime and when analyzing the long-term efficacy, the dif- recruited in the cohort 2 of the IMvigor 210 study plus ferences between the two treatment arms were even larger. 110 (11.8%) out of the 931 subjects in the IMvigor 211 Hence, the 12 month survival rates were 66.7% and 19.9% study. These 131 patients treated in Spanish centers were for immunotherapy and chemotherapy patients, respectively. assigned to either atezolizumab (n = 74; 56.5%) or chemo- Although the median progression-free survival (PFS) was therapy (n = 57; 43.5%) and made up the intention-to-treat 5.3 months (95% CI 3.7–6.7) in the chemotherapy arm com- (ITT) population. However, the response was missing in 4 pared to 2.1 months (95% CI 2.0–2.5) in the atezolizumab patients, and therefore the resulting 127 patients made up the arm (p = 0.043), 12-month PFS rates were not significantly modified ITT (mITT) population for efficacy outcomes, 74 different (p = 0.0574), 12.2% (95% CI 5.0–22.8) for chemo- (58.3%) on atezolizumab and 53 (41.7%) on chemotherapy therapy and 9.1% (95% CI 3.4–18.4) for atezolizumab. (67.9% vinflunine and 32.1% taxanes). Median OS was numerically superior in the atezolizumab Analysis of the efficacy data revealed no statistically sig- group compared to the chemotherapy group, (9.2 months; nificant differences across arms in ORR with 12 (20.3%) 95% CI 6.5–11.7 vs 7.7 months; 95% CI 5.3–10.8) albeit not responses out of the 59 evaluable patients in the atezoli- reaching statistical significance (Fig. 2). However, patients zumab arm compared with 17 (37.0%) out of the 46 patients in the atezolizumab group did have fewer events than in the in the chemotherapy arm (p = 0.059). Nonetheless, in those chemotherapy group, (66.2% vs 84.9%; p = 0.018) Table 2. Fig. 1  Duration of response in the mITT population. HR 0.24, 95% CI 0.07–0.66; p = 0.005 13 886 Clinical and Translational Oncology (2021) 23:882–891 Fig. 2  Overall survival in the mITT population. HR 0.86, 95% CI 0.57–1.29; p = 0.462 Interestingly, when the efficacy analysis was performed Discussion stratifying patients according to the PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvi- For more than three decades, no progress has been made in ronment, our analyses did not find any significant difference advanced UC therapeutics [8]. Yet, the recent incorpora- either in ORR, DoR, PFS or OS regardless of the IC group tion of immunotherapy with the arrival to the clinic of the in patients treated with either atezolizumab or chemotherapy check-point inhibitors has reshaped the treatment scenario, (Table 2). and both atezolizumab (an anti-PD-L1) and pembrolizumab The safety analysis revealed that any-grade treatment- (an anti-PD-1) have become standard options for patients related adverse events occurred in 44/74 (59%) atezolizumab with advanced UC with either progression beyond first-line patients vs. 46/57 (81%) chemotherapy patients. Grade 3–4 chemotherapy or treatment naïve and unfit to receive cis- adverse events were documented in 6 (8%) patients given platin [19]. Immunotherapy has demonstrated substantial atezolizumab vs. 28 (49%) given chemotherapy (Fig. 3). benefit in this patient population and a better toxicity profile Among patients on chemotherapy, grade 3–4 AEs occurred across different trials [15, 16, 20, 21]. Nevertheless, there in 57.5% of patients allocated to vinflunine and in 29% of are still unanswered questions about the real impact and patients assigned to taxanes. whether clinical or biological factors might help us predict The most frequent adverse events (those who affected to the efficacy of this innovative treatment strategy or not [22]. at least 10% of patients) were asthenia, pruritus and diar- Sub-analyses of certain populations in this context could rhoea in patients treated with atezolizumab. For patients on unveil details relevant for a better understanding of the activ- chemotherapy, the commonest adverse events were asthenia, ity and safety and could help explain unexpected results or neutropenia, constipation, alopecia, abdominal pain, anae- even pose new questions that might deserve to be answered. mia, nausea, diarrhoea, mucositis, decreased appetite and A pooled analysis of the Spanish patients in two relevant vomiting. The most common grade 3–4 adverse events in trials of atezolizumab in advanced UC patients is presented the chemotherapy group were neutropenia (28%), asthenia here. When analyzing efficacy, ORR showed no statisti- (12%), constipation (9%), anaemia (7%) and abdominal pain cally significant differences between the immunotherapy (5%). A detailed list of treatment-related AEis by frequency and the chemotherapy arms as previously reported in other and severity is presented in Table 3. atezolizumab studies, such as IMvigor 211, where ORR was 13 Clinical and Translational Oncology (2021) 23:882–891 887 Table 2  Efficacy outcomes PD-L1 score mITT IC0/1 IC2/3 Atezolizumab Chemotherapy Atezolizumab Chemotherapy Atezolizumab Chemotherapy (n = 74) (n = 53) (n = 54) (n = 41) (n = 20) (n = 12) Overall ­survivala Patients with 49 (66.2%) 45 (84.9%) 37 (68.5%) 36 (87.8%) 12 (60.0%) 9 (75.0%) event (%) Median (months; 9.2 (6.5–11.7) 7.7 (5.3–10.8) 9.2 (6.5–11.7) 6.4 (4.1–8.6) 10.9 (2.4–12.4) 12.0 (4.2–13.6) 95% CI) 6 month overall 65.9% (53.8–75.5) 61.7% (47.1–73.3) 68.4% (54.2–79.0) 56.1% (39.7–69.6) 59.2% (34.7–77.2) 81.8% (44.7–95.1) survival rate (95% CI) 12 month overall 24.4% (13.1–37.6) 26.2% (14.8–39.1) 22.3% (10.5–36.9) 21.8% (10.4–35.9) 37.6% (15.2–60.1) 41.6% (13.1–68.4) survival rate (95% CI) Progression-free ­survivalb Patients with 67 (90.5%) 49 (92.5%) 51 (94.4%) 39 (95.1%) 16 (80.0%) 10 (83.3%) event (%) Median (months; 2.1 (2.0–2.5) 5.3 (3.7–6.7) 2.1 (2.0–2.5) 4.2 (2.2–7.7) 2.2 (1.8–4.2) 5.3 (3.4–10.4) 95% CI) 12 month PFS 9.1% (3.4–18.4) 12.2% (5.0–22.8) 6.9% (2.0–16.1) 10.4% (3.3–22.1) 20.0% (6.2–39.3) 18.2% (2.9–44.2) rate (95% CI) Objective response rate No. of evaluable 59 46 43 34 16 12 patients No. of patients 12 (20.3%; 17 (37.0%; 7 (16.3%; 12 (35.3%; 5 (31.3%; 5 (41.7%; with response 11.0–32.8) 23.2–53.5) 6.8–30.7) 19.7–53.5) 11.0–58.7) 15.2–72.3) (%; 95% CI) Best overall response Complete 3 (4.1%) 3 (5.7%) 1 (1.9%) 2 (4.9%) 2 (10.0%) 1 (8.3%) response Partial response 9 (12.2%) 14 (26.4%) 6 (11.1%) 10 (24.4%) 3 (15.0%) 4 (33.3%) Stable disease 14 (18.9%) 18 (34.0%) 11 (20.4%) 11 (26.8%) 3 (15.0%) 7 (58.3%) Progressive 33 (44.6%) 11 (20.8%) 25 (46.3%) 11 (26.8%) 8 (40.0%) 0 disease Missing or 15 (20.3%) 7 (13.2%) 11 (20.4%) 7 (17.1%) 4 (20.0%) 0 unevaluable Duration of ­responsec Patients with 4 (33%) 15 (88%) 3 (42.9%) 11 (91.7%) 1 (20.0%) 4 (80.0%) event (%) Median (months; NE (6.7-NE) 6.4 (2.3–8.3) NE (6.7-NE) 6.3 (2.2–10.3) NA (2.1-NE) 7.0 (2.1-NE) 95% CI) 6 month survival 91.7% (53.9–98.8) 64.7% (37.7–82.3) 100% (NE-NE) 66.7% (33.7–86.0) 80.0% (20.4–96.9) 60.0% (12.6–88.2) rate (%; 95% CI) 12 month sur- 66.7% (33.7–86.0) 19.9% (3.3–34.3) 57.1% (17.2–83.5) 20.0% (3.3–46.9) 80.0% (20.4–96.9) 20% (0.8–58.2) vival rate (%; 95% CI) a Death b Progressive disease or death c Response stop or death 13 888 Clinical and Translational Oncology (2021) 23:882–891 limitations that has jeopardized progress of UC therapeutics has been the short duration of the responses presented to cytotoxic treatment. Despite relatively high ORR to chemo- therapy in first line, virtually all responders will eventually relapse (most of the times early) and historical treatment options provided little or no benefit in this setting [25]. The results of our analysis illustrate remarkable differences in survival in the responders according to their treatment arm. Those patients who responded to atezolizumab presented a survival benefit at the 6 and 12 month landmarks. In the latter, around three times, more patients were alive in the atezolizumab responders compared to those who responded Fig. 3  Safety in the ITT population. Proportion of patients with to chemotherapy. This behaviour appears common across adverse events. Data are percentages of patients presenting with AEs different checkpoint inhibitors and different tumour types and is becoming one of the hallmarks of immunotherapy almost identical in both study arms [16]. Outcomes were [26]. slightly different with pembrolizumab when compared with Lastly, our analysis comes to confirm the benefit of ate- chemotherapy in the Keynote-045 study where it achieved zolizumab in terms of safety when compared with cytotox- superior ORR (21.1% vs 11.4%; p = 0.001). Whether these ics. As we already saw in IMvigor 211, the adverse-event results could be related to less use of vinflunine over taxanes profile of atezolizumab was also favourable compared with in the Keynote-045 trial remains unanswered [21]. Another chemotherapy in the Spanish population. parameter of efficacy, such as OS, showed also no statisti- The proportion of patients with any AE was lower in the cally significant differences between treatment groups in our atezolizumab treated patients as well as the severity of these analysis. Yet, the reported numerical values are consistent events when compared with those who received chemother- with the recently reported from real-world data studies of apy. This confirms a distinctive common characteristic to atezolizumab and the pivotal study of pembrolizumab [21, most immunotherapy studies, the benefit of this treatment 23]. strategy in terms of safety, which results are particularly Furthermore, regarding the analysis of the predictive relevant in a patient population that normally present comor- value of PD-L1 staining, no significant differences in OS bidities. Despite the valuable information provided by these were observed when patients were stratified according to this analyses, some limitations must be acknowledged, mainly biomarker. A trend towards PD-L1 expression as a favour- the exploratory nature and the relatively low sample size able prognostic factor was observed. Hence, those patients despite combining two groups from two different studies. IC2/3 presented a better survival in both groups and actually, Once more, as in the IMvigor 211 trial, PD-L1 expression OS was superior in this subgroup for the chemotherapy arm does not seem to discriminate patients who might benefit although not reaching statistical significance. This adds to from atezolizumab. Looking for biomarkers must be man- other reports that suggest that PD-L1 staining is a prognostic datory to identify patients with advanced urothelial cancer factor rather than predictive and could justify the lack of who might benefit from this immune checkpoint inhibitor. substantial differences in efficacy in these patient’s popula- In summary, this pooled analysis of the Spanish popula- tions. Regarding PFS, the results obtained in this pooled tion included in the IMvigor210 cohort 2 and 211 trials cor- analysis in favour of chemotherapy are overall consistent roborates the major hallmarks of immunotherapy. Despite with most previous trials comparing cytotoxics with immu- not identifying statistically significant differences in ORR notherapy in different tumour types although PFS value as and OS and a worse PFS when compared with chemother- a surrogate marker of activity is questioned in this context apy, atezolizumab demonstrated an unprecedented long-term [24]. Probably the most striking results of this work have to benefit in those patients who responded to immunotherapy do with the long-term benefit observed in the responders in with a very favourable safety profile. Identifying potential the immunotherapy group. For decades, one of the major predictive factors of response remains a critical unmet need. 13 Clinical and Translational Oncology (2021) 23:882–891 889 Table 3  Treatment-related Atezolizumab Chemotherapy adverse events (n = 74) (n = 57) Most common treatment-related adverse events of any grade All 44 (59%) 46 (81%) Asthenia 22 (30%) 28 (49%) Pruritus 10 (14%) 1 (2%) Diarrhoea 9 (12%) 8 (14%) Decreased appetite 7 (10%) 7 (12%) Rash 6 (8%) 2 (3%) Arthralgia 4 (5%) 5 (9%) Decreased neutrophil count 0 22 (39%) Constipation 2 (3%) 21 (37%) Alopecia 0 12 (21%) Anemia 0 10 (18%) Nausea 3 (4%) 10 (18%) Mucosal inflammation 1 (1%) 8 (14%) Vomiting 2 (3%) 7 (12%) Abdominal pain 0 7 (12%) Nail dystrophy 1 (1%) 5 (9%) Decreased platelet count 0 5 (9%) Dizziness 0 4 (7%) Febrile neutropenia 0 3 (5%) Increased lacrimation 0 3 (5%) Myalgia 0 3 (5%) Paraesthesia 0 3 (5%) Pyrexia 1 (1%) 3 (5%) Grade 3 or 4 treatment-related adverse events All 6 (8%) 28 (49%) Asthenia 3 (4%) 7 (12%) Ulcerative colitis 1 (1%) 0 Haematuria 1 (1%) 0 Intestinal obstruction 2 (3%) 2 (4%) Constipation 0 5 (9%) Decreased neutrophil count 0 16 (28%) Anaemia 0 4 (7%) Diaorrhea 0 1 (2%) Abdominal pain 0 3 (5%) Febrile neutropenia 0 3 (5%) Peripheral neuropathy 0 1 (2%) Phlebitis 0 1 (2%) Sepsis 0 1 (2%) Stomatitis 0 1 (2%) Intestinal subocclusion 0 1 (2%) General physical health deterioration 0 1 (2%) Adverse events of all grades reported in at least 5% of patients in either group. All grade 3 or 4 are listed in both groups 13 890 Clinical and Translational Oncology (2021) 23:882–891 Acknowledgements The authors acknowledge the contribution of all Squibb, Seattle Genetics, Pharmacyclics, Janssen and Novartis; re- patients, centers and PIs participating in this study: Dr. Castellano– search funding from Roche/Genentech, AstraZeneca. Hospital Universitario 12 de Octubre, Dr. Pérez Gracia–Clínica Univer- sitaria de Navarra, Dr. Alonso and Dr. Gajate–Hospital Ramón y Cajal, Ethical approval All procedures performed in studies involving human Dr. Pérez Valderrama and Dr. Durán Martínez–Hospital Universitario participants were in accordance with the ethical standards of the institu- Virgen del Rocío, Dr. García del Muro–Institut Catala d Oncologia tional reserach committee and with the 1964 Helsinki declarartion and Hospital Duran i Reynals, Dr. Arranz–Hospital General Universitario its later ammendments or comparable ethical standards. Gregorio Marañón, Dr. Morales–Hospital Universitari Vall d’Hebron, Dr. Gallardo–Corporacio Sanitaria Parc Tauli, Dr. Puente–Hospi- Informed consent Informed consent was obtained from all individual tal Universitario Clínico San Carlos, Dr. Mellado–Hospital Clinic participants included in the study. i Provincial, Dr. Mellado–Hospital de la Santa Creu i Sant Pau, Dr. Lainez–Hospital de Navarra, Dr. Mendez–Hospital Universitario Reina Consent to participate Patients already gave their consent to partici- Sofia, Dr. Montesa–Hospital Clínico Universitario Virgen de la Vic- pate in the corresponding trials. toria, Dr. Caballero–Hospital General Universitario de Valencia, Dr. García–Complejo Hospitalario Universitario de Santiago (CHUS), Consent for publication All authors have consented to submission of Dr. González Del Alba–Hospital Universitario Son Espases, Dr. Bor- this article for publication. rega–Hospital San Pedro de Alcántara, Dr. Chirivella–Hospital Clínico Universitario de Valencia. The authors are grateful to Syntax for Sci- Availability of data and material “Qualified researchers may request ence, S.L. for their technical assistance in the analysis, writing and access to individual patient level data through the clinical study data submission of this manuscript. request platform (https​://vivli​.org/). Further details on Roche’s criteria for eligible studies are available here. (https:​ //vivli.​ org/member​ s/ourme​ Author contributions Introduction and discussion M.S. and I.D. All mbers/​ ). For further details on Roche’s Global Policy on the Sharing of authors have participated in this analysis, but especially in revising it Clinical Information and how to request access to related clinical study critically and all authors have approved the final article. documents, see here. (https​://www.roche​.com/resea​rch_and_devel​ opmen​t/who_we_are_how_we_work/clini​cal_trial​s/our_commi​tment​ _to_data_shari​ng.htm).” Funding This study was funded by Roche Farma, Spain. Compliance with ethical standards Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long Conflict of interest Teresa Alonso Gordoa has received honoraria for as you give appropriate credit to the original author(s) and the source, consultancy/advisory or speaker from Ipsen, Pfizer, Roche/Genentech, provide a link to the Creative Commons licence, and indicate if changes Sanofi, Bayer, Astellas, Janssen-Cilag, Merck Sharp & Dohme, Bris- were made. The images or other third party material in this article are tol-Myers Squibb and Eisai. Pablo Gajate has received honoraria for included in the article’s Creative Commons licence, unless indicated participation in advisory boards from Roche; as a speaker from Pfizer, otherwise in a credit line to the material. If material is not included in Bristol-Myers Squibb and Roche/Genentech; and travel expenses from the article’s Creative Commons licence and your intended use is not Pfizer and Roche/Genentech. Enrique Gallardo has received honoraria permitted by statutory regulation or exceeds the permitted use, you will for Consultant or Advisory Role: Sanofi, Janssen, Astellas, Pfizer, Bay- need to obtain permission directly from the copyright holder. To view a er, Roche, Ipsen, Novartis, Eisai, EUSA Pharma, BMS, AstraZeneca, copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. Merck, Rovi, Daiichi Sankyo, Techdow. 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