Development of a Novel Predictive-Prognostic Scoring Index for Immune Checkpoint Inhibitors in Advanced Non-small Cell Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of patients with driver mutation absent advanced non-small cell lung cancer (NSCLC). The present study aimed to develop a reliable, reproducible, and practical scoring system to prognosticate and predict response to ICI response in patients with advanced NSCLC. PATIENTS AND METHODS: All patients who were diagnosed as having unresectable/advanced stage NSCLC and were treated with at least one cycle of ICIs at the Medical Oncology Departments of Dr. Burhan Nalbantoglu State Hospital (Nicosia, Cyprus) and Near East University Hospital (Nicosia, Cyprus) were included in the study. The association between variables and OS was evaluated using a Cox proportional hazards regression model. Variables with a P-value less than 0.05 in the univariate analysis were included in the multivariate model. A prognostic scoring system was developed.  Survival estimates were calculated using the Kaplan-Meier method. The value of the Concordance index (C-index) and the area under the curve (AUC) was used to evaluate the discriminative ability of scoring systems. RESULTS: One hundred fifty consecutive patients with unresectable/metastatic NSCLC who received PD-1 inhibitors between March 2017 and November 2022 were included. In the multivariate Cox regression model, serum lactate dehydrogenase (LDH), C-reactive protein (CRP) levels, and Eastern Cooperative Oncology Group Performance Status (ECOG PS) were significantly associated with OS. We generated a new score using CRP ³1.0 mg/dL, ECOG PS ³2, and LDH level >ULN. Relative weight was based on the HRs of multivariate analyses (CRP ³1.0 mg/dL 2 points, ECOG PS ³2 2.5 points, and LDH level >ULN 1.5 points). The cohort was divided into three risk groups based on the sum of factors present: 0-2.5 (good risk), 3.5-4.5 (intermediate risk), or 6 (poor risk). The median OS was 18.9, 7.4, and 2.9 months for good, intermediate, and poor risk categories, respectively (log-rank test, p<0.001). The Harrell C-index of CEL to predict OS and PFS was 0.73 and 0.69, respectively, indicating significant predictability. The AUC of the scoring index for predicting the responses was 0.765 (95% CI: 0.685-0.845). CONCLUSION: The CEL score is a promising prognostic and predictive index consisting of serum CRP levels (C), ECOG PS (E), and serum LDH levels (L). This represents another step forward in the treatment of patients with advanced NSCLC.

Real-World Data of Combined Immunochemotherapy in Patients With Nonsquamous Advanced NSCLC. A Single-Center Retrospective Study.

Introduction: On the basis of the landmark trial KEYNOTE-189 (KN-189), pembrolizumab plus chemotherapy has become the standard-of-care first-line treatment for patients with advanced nonsquamous NSCLC without oncogenic driver alterations.KN-189 included a selected patient population and lacks external validity. In clinical practice, many patients do not meet the inclusion criteria of KN-189, although they are treated accordingly. It is unknown whether these patients benefit equally as the trial population. Methods: We retrospectively analyzed all patients with advanced nonsquamous NSCLC without targetable oncogenic alterations who received the KN-189 treatment regimen between April 2018 and May 2021 at the University Hospital Basel, Switzerland. Patients were grouped into those who retrospectively met the inclusion criteria of KN-189 (group A) and those who did not (group B). Outcome parameters included progression-free survival (PFS), overall survival (OS), and objective response rate. Multivariate subgroup analyses were performed. Results: We identified 75 patients, including 29 patients in group A and 46 patients in group B. Median PFS was 9.2 and 4.6 months in group A and B, respectively (p = 0.12). Median OS was 16.5 and 6.5 months in group A and B, respectively (p = 0.11). Objective response rate was 59% in group A and 33% in group B (p = 0.03). Eastern Cooperative Oncology Group performance status greater than or equal to 2 and active infections were significantly associated with shorter PFS and OS. Conclusions: We report real-world data for patients treated according to the KN-189 regimen with inferior outcomes in patients who did not meet the KN-189 inclusion criteria. Better treatment options for this vulnerable patient population are needed.

Clinical Potential of Circulating Cell-Free DNA (cfDNA) for Longitudinally Monitoring Clinical Outcomes in the First-Line Setting of Non-Small-Cell Lung Cancer (NSCLC): A Real-World Prospective Study.

BACKGROUND: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. METHODS: From February 2020 to May 2022, treatment-naïve patients with advanced NSCLC were consecutively enrolled at the Medical Oncology Unit of the Paolo Giaccone University Hospital, Palermo (Italy). We quantified cfDNA in terms of ng/µL using a QubitTM dsDNA HS Assay Kit. The agreement between the cfDNA and radiologic response was evaluated from baseline (T0) to the radiologic evaluation (T1). RESULTS: A total of 315 liquid biopsy samples were collected from 63 patients at baseline, with a total of 235 paired plasma samples from 47 patients at disease re-evaluation. A fair concordance was observed between early and durable radiographic and cfDNA response (Cohen's kappa coefficient = 0.001); 11 and 18 patients receiving TKI (Pearson's chi-squared test = 4.278; Cohen's kappa coefficient = 0.039) and IO treatments (Pearson's chi-squared test = 7.481; Cohen's kappa coefficient = 0.006) showed a significant and durable association between cfDNA dynamics and the first radiologic evaluation, whereas among the 18 patients undergoing CT, no significant correlation was observed (Pearson's chi-squared test = 0.720; Cohen's kappa coefficient = 0.396). The ECOG-PS 2 patients presented with the mean baseline cfDNA levels 2.6-fold higher than those with ECOG-PS 0-1 (1.71 vs. 0.65 ng/µL; p = 0.105). CONCLUSIONS: Our real-world study demonstrates that quantitative changes in cfDNA values correlated with responses to therapy and relapse of disease in treatment-naïve patients with advanced NSCLC undergoing TKI- and IO-based treatments.

Current state of knowledge on immunotherapy in ECOG PS 2 patients. A systematic review.

BACKGROUND: Patients with Eastern Cooperative Oncology Group Performance Status 2 (ECOG PS 2) are not included in most randomized clinical trials and registry studies. Nevertheless, immune checkpoint inhibitors are registered in the USA and Europe regardless of the performance status. Evidence regarding the effectiveness and safety of such treatment in this cohort is sparse. METHODS: Using PubMed (to July 2020), the relevant literature on the effect of ECOG PS 2 on the efficacy and safety of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) with ECOG PS 2 was searched. RESULTS: A database search conducted using an international repository (PubMed) identified 191 records. Additional 3 records were identified through other sources. After pre-selection, 92 records were excluded, and 102 full-text articles were assessed for eligibility. With further exclusion of articles not meeting the inclusion criteria, 44 studies were entered into the qualitative synthesis. CONCLUSIONS: Immunotherapy seems to be justified in PS 2 patients with NSCLC. This method of treatment has been proven to be safe and tolerable. However, outcomes in this population remain suboptimal and the impact of immunotherapy in this cohort is less dramatic. Multiple scales evaluating many factors beyond PS scores have been suggested to help stratify the PS 2 to reinforce the chance of achieving better treatment outcomes. Randomized trials are needed to determine the benefits of immune checkpoint inhibitors (ICIs) for patients with poor ECOG PS.

First-line immunotherapy in non-small cell lung cancer patients with poor performance status: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become the standard of care for the first-line treatment of advanced non-small cell lung cancer patients (NSCLC), either as single agents or combined with chemotherapy. The evidence sustaining their role for poor performance status (ECOG PS ≥2) patients is limited. METHODS: We search PubMed and the proceedings of international oncology meetings to perform a systematic review to assess the outcomes poor PS NSCLC patients who received ICIs as first-line treatment. A meta-analysis included retrospective studies focusing on pembrolizumab monotherapy in PD-L1 ≥50% NSCLC. We reported the global objective response rate (ORR), disease control rate (DCR) and landmark progression-free and overall survival (PFS and OS, respectively) in ECOG PS ≥2 and 0-1 patients, respectively. RESULTS: Forty-one studies were included in the systematic review. Thirty-two retrospective studies focused on pembrolizumab monotherapy in PD-L1 ≥50% cases. In total, 1,030 out of 5,357 (19%) of patients across 30 studies presented with a PS ≥2 at pembrolizumab initiation. In 18 studies with detailed clinical information, worse outcomes in poor PS compared to good PS patients were documented. The meta-analysis revealed that ORR and DCR within the PS ≥2 patient population were 30.9% and 41.5% respectively (55.2% and 71.5% in PS 0-1 patients). The rates of PFS (at 3, 6, 12 and 18 months) and OS (at 6, 12, 18 and 24 months) were approximately double in the good PS compared to the poor PS group of patients. In the three prospective trials where of ICIs in PS 2 populations, the diverse strictness in PS definition likely contributed to the differential outcomes observed. Six retrospective studies dealt with chemo-immunotherapy combinations. CONCLUSIONS: Still with limited prospective evidence sustaining the role of immunotherapy in previously untreated NSCLC with poor PS, 19% of patients in retrospective series dealing with pembrolizumab in PD-L1 ≥50% tumors had an ECOG PS ≥2. Clinical effort encompassing the definition of poor PS, of the factors conditioning it, and the development of dedicated treatment strategies is required to improve the outcomes in this patient population.

First-line pembrolizumab in advanced non-small cell lung cancer patients with poor performance status.

BACKGROUND: Pembrolizumab is the first-line standard of care for advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumour proportion score (TPS) ≥ 50%. Eastern Cooperative Oncology Group performance status (PS) 2 patients may receive pembrolizumab, despite the absence of sustaining evidence. PATIENTS AND METHODS: GOIRC-2018-01 is a multicentre, retrospective, observational study. PS 2 NSCLC patients with a PD-L1 TPS ≥50% receiving first-line pembrolizumab from June 2017 to December 2018 at 21 Italian institutions were included. Clinical-pathological characteristics were correlated with disease response and survival outcomes; adverse events were recorded. The primary objective was 6-months progression-free rate (6-months PFR). RESULTS: One hundred fifty-three patients (median age 70 years) were enrolled. At a median follow-up of 18.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.4 (95% confidence interval, 95% CI, 1.6-2.5) and 3.0 months (95% CI 2.4-3.5), respectively. 6-months PFR was 27% (95% CI 21-35%). Patients with a PS 2 determined by comorbidities (n = 41) had significantly better outcomes compared with disease burden-induced PS 2 (n = 112). Indeed, 6-months PFR was 49% versus 19%, median PFS 5.6 versus 1.8 months and OS 11.8 versus 2.8 months, respectively. Additional potential prognostic factors (radiotherapy, antibiotics, steroids received before pembrolizumab) correlated with clinical outcomes. The determinant of PS 2 resulted the only factor independently impacting on both PFS and OS. No toxicity issues emerged. CONCLUSIONS: Outcomes of PS 2 NSCLC patients with PD-L1 TPS ≥50% receiving first-line pembrolizumab were globally dismal but strongly dependent on the reason conditioning the poor PS itself.

A Review of Recent Advances in the Treatment of Elderly and Poor Performance NSCLC.

Until recently, chemotherapy has remained the mainstay of treatment for the majority of patients with advanced non-small cell lung cancer (NSCLC). Excellent responses have been observed with immune-checkpoint inhibitors, and targeted treatments for those tumours with actionable mutations, resulting in a paradigm shift in the treatment approach for these patients. Elderly patients and those with poor performance status (PS), such as Eastern Cooperative Oncology Group (ECOG) 2, have historically been excluded from clinical trials due to poor outcomes. There is therefore a lack of data to define the optimal treatment strategy for these patients. Due to improved tolerability of novel therapies, inclusion of these patients in clinical trials has increased, and sub-group analyses have identified many treatments demonstrating potential activity. Here, we summarise key recent advances in the treatment of NSCLC, specifically evaluating their efficacy and tolerability in these patient cohorts.

Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced Non-Small Cell Lung Cancer without epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations - Still a daily challenge.

Cytotoxic chemotherapy remains the core treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) with tumours that do not have actionable molecular alterations, such as epidermal growth factor receptor (EGFR)-sensitising mutations, anaplastic lymphoma kinase (ALK) translocations or ROS1 translocations. Age and performance status (PS) are two pivotal factors to guide treatment decisions regarding the use of chemotherapy in lung cancer patients. Lung cancer is predominantly a disease of the elderly, with more than two-thirds of patients aged ≥65 years, the current definition of 'elderly'. The prevalence of poor PS, as estimated by patients themselves, can be as high as 50%. Both the elderly and PS2 patients are underrepresented in clinical trials. Therefore, optimising treatment strategy for the subgroup of elderly or PS2 patients with advanced NSCLC remains challenging as a result of a paucity of clinical trial data. The current review focusses on the elderly or PS2 patients without actionable oncogenic drivers and attempts to summarise current available data on recent treatments trials including angiogenesis inhibitors and immune-checkpoint inhibitors.