Real-world evidence for immune checkpoint inhibitors in extensive-stage small cell lung cancer

Since their introduction into the treatment algorithm across several malignancies, immune checkpoint inhibitors (ICIs) have considerably improved patient life expectancy.

Accounting for about 15% of all lung cancer, small cell lung cancer (SCLC) remains one of the most aggressive cancers with a markedly high proliferative rate and poor prognosis. Among SCLC, extensive-stage SCLC (ES-SCLC) represents approximately two-thirds of all cases (1). Chemotherapy alone remained, for decades, the mainstay of treatment for lung cancer reaching a therapeutic plateau in terms of survival and response rate (2,3). Platinum plus etoposide has represented the gold standard treatment for ES-SCLC with a median overall survival (OS) of 9–10 months and a progression-free survival (PFS) of 5–6 months (4). Recently, the approval of ICIs has opened novel therapeutic horizons and established a new standard-of-care for patients affected by ES-SCLC (5). As demonstrated in the Impower 133 trial, atezolizumab, a humanized monoclonal antibody to programmed death-ligand 1 (PD-L1), plus chemotherapy has resulted in a significantly longer PFS [5.2 vs. 4.3 months; P=0.02; hazard ratio (HR), 0.77; 95% confidence interval (CI): 0.62–0.96] as well as OS (12.3 vs. 10.3 months; P=0.007; HR, 0.70; 95% CI: 0.54–0.91) in patients affected by ES-SCLC (6). Likewise, chemotherapy plus durvalumab, another PD-L1 antibody, has also shown favourable outcomes in terms of OS when compared with chemotherapy alone in treatment-naïve ES-SCLC (7). Conversely, neither pembrolizumab nor nivolumab with or without ipilimumab have reached significant endpoints in terms of OS in the KEYNOTE-604 and CheckMate 451 trials, respectively (8,9). Accordingly, European Society for Medical Oncology (ESMO) has approved atezolizumab or durvalumab in association with platinum plus etoposide as first line therapy in ES-SCLC, when ICIs are not contraindicated (10).

Results from randomized controlled trials (RCTs) have to be considered complementary to real-world evidence. In parallel with RCTs, significant improved OS of first line immunotherapy in ES-SCLC in real-world setting has been shown by Sagie et al. Interestingly, chemoimmunotherapy was associated with longer survival in patients with both Eastern Cooperative Oncology Group (ECOG) performance status 0–1 and 2–3 when compared to chemotherapy alone, although not significantly in patients with performance status 2–3 (11). Conversely, in another real-world retrospective investigation in patients with ES-SCLC a shorter median OS (mOS) among patients with ECOG performance status of 2 in comparison to those with good ECOG at 0 to 1 of atezolizumab plus platinum-etoposide chemotherapy has been reported (12). Clinicians must remain aware of the possibility of conflicting outcomes in real world as compared to RCTs.

Fujimoto and co-authors have conducted a multicenter, prospective, hospital-based cohort study in patients with ES-SCLC receiving carboplatin and etoposide with atezolizumab as first-line treatment focusing on the potential interference, in clinical practice, of trial eligibility criteria on outcomes (13). Two hundred and seven patients have been included and categorized as trial-eligible or trial-ineligible according to inclusion and exclusion criteria of aforementioned trials, respectively (6,7). Authors established two criteria. Whilst in Criterion 1, patients with asymptomatic untreated brain metastasis were considered eligible for the trials, in Criterion 2 these patients were considered ineligible. Trial-ineligible patients were 91 (44%) or 75 (36%), depending on whether asymptomatic brain metastases were considered or not as criteria for ineligibility, respectively. The majority of patients [184 (89%)] had good performance status [0–1]. In overall population, the median PFS of the combination therapy group was 4.9 months (95% CI: 4.6–5.4) and the median OS was 14.7 months (95% CI: 12.6–16.2). Moreover, 6-month PFS probability was 38.8% (95% CI: 32.4–45.7%) whilst the 12-month OS probability was 60.8% (95% CI: 53.9–67.3%). The disease control rate, by Fujimoto investigation, was 93% in trial eligible patients in comparison to 77% (P=0.002) or 80% (P=0.007) considering asymptomatic brain metastasis as inclusion criteria or not. Significant difference has been reported for median PFS (5.1 vs. 4.7 months, HR, 0.72; 95% CI: 0.53–0.97; P=0.03) between trial eligible and trial ineligible patients, respectively, considering asymptomatic brain metastasis not as exclusion criteria.

Adverse events have been reported more frequently amongst trial-ineligible patients, although this data is not significant. Febrile neutropenia was the most common overall hematologic adverse effect (13%).

Difficulties occur in the management of older SCLC patients as RCTs mainly include subjects with age ranging between 18 and 64 years (14). Immunosenescence, greater burden of comorbidities, altered gut microbiome as well as poorer performance status are some of the potential factors impacting on response (15,16). Data on ICIs efficacy in SCLC older patients are not consistent from RCT and mainly refers to Real World Evidence.

In a study published in 2019, Schild et al. reported that survival of order patients (≥80 years) affected by SCLC is associated with cancer stage, performance status as well as treatment option (17).

With regard to ICIs combined to chemotherapy, Fujimoto et al. reported a significantly better OS among SCLC patients under 75 years old versus older patients (HR, 0.66; 95% CI: 0.45–0.97; P=0.03) (18).

Data from RCT on ICIs are available in older patients with non-small cell lung cancer (NSCLC). IPSOS study (NCT03191786) as well as the eNERGY study (NCT03351361), two phase III trials evaluating first-line immunotherapy in NSCLC older patients (>70 years) have been published. Specifically, in the IPSOS study including 453 NSCLC platinum ineligible patients aged >70 years, atezolizumab significantly improved OS vs. chemotherapy (stratified HR, 0.78; 95% CI: 0.63, 0.97; P=0.028), with a median follow-up of 41.0 months (19). Despite no statistically significant benefit in OS being observed in the entire population, the eNERGY study, comparing the combination of nivolumab and ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) versus carboplatin-based doublet chemotherapy in first-line treatment of performance status (PS) 2 or elderly (≥70 years) NSCLC patients, has also demonstrated a significant benefit of ICIs compared to computed tomography (CT) for older patients with PS 0-1, with median OS of 22.6 months (95% CI: 18.1–36) vs. 11.8 months (95% CI: 8.9–20.5) (P=0.02) (20,21).

The relevant pathology and clinical differences existing between SCLC and NSCLC imply that data obtained from the aforementioned trials may not be applicable to SCLC patients. Additional real-world studies as well as RCTs are required.

In regard to safety profile, older patients appear to experience more serious immune related adverse effects (irAEs) which may be due to reduced functional reserve, age-associated comorbidities, and polypharmacy (15,16,22).

Of interest, however, is a pooled analysis of four RCTs with single-agent ICI by Food and Drug Administration (FDA) that showed grade 3 or 4 treatment-related adverse events with programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) blocking antibodies were less frequent in NSCLC patients ≥75 years (23%) compared to patients >65 years (49%) and <65 years (47%) revealing a safer toxicity profile for ICIs when compared to standard chemotherapy, especially in older patients (23).

A limitation of the Fujimoto study is represented by the small size population when stratified for ineligibility criteria, suggesting the need for further studies to identify the impact of each criterion on outcomes in SCLC patients. Evidence also from other ethnicities is required.

By limiting the immune-escape phenomenon and hampering cancer progression, ICIs have undoubtedly produced advantages for patients affected by ES-SCLC although it is important to consider clinical practice evidence when interpreting results emerging from RCTs.

Acknowledgments

Funding: None.

Footnote

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