Immune checkpoint inhibitors (ICIs), either alone or combined with chemotherapy, represent the cornerstone of the treatment of advanced non-small cell lung cancer (NSCLC) without targetable gene ...alterations. Programmed death ligand-1 expression currently represents the only available biomarker to predict response to ICI, although its reliability is debated. However, most patients still do not derive benefit from immunotherapy, making the identification of further predictive biomarkers extremely needed. Serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) and Kelch-like ECH-associated protein 1 (KEAP1) mutations occur in 25–30% and 11–27% of advanced NSCLC, respectively. Several studies associated their presence with poor outcomes in patients treated with ICI. However, more recent evidence showed poor outcomes among NSCLC with STK11/LKB1 and/or KEAP1 mutations regardless of the treatment received. We reviewed the literature to provide a comprehensive, timely and structured overview of the role of STK11/LKB1 and KEAP1 mutations in NSCLC. Although conflicting outcomes have been reported by studies evaluating their impact in KRAS wild-type patients or regardless of KRAS mutation, the correlation between STK11/LKB1 and KEAP1 mutations and poor outcomes with ICI appears to be consistent in presence of concurrent KRAS mutations. The main limitations of most studies are represented by the inclusion of other gene mutations (e.g. TP53) together with STK11 and KEAP1 mutations as a group and by the lack of comparison arms including patients who received other treatments (e.g. chemotherapy). Studies evaluating the impact of STK11 and KEAP1 mutations on the outcomes with ICI and other therapies showed a similar effect regardless of the treatment received, suggesting a prognostic, rather than predictive, value.
•STK11 and KEAP1 mutations were described as predictors of poor outcomes with ICI.•Poor outcomes are consistent among patients with concurrent KRAS mutation.•Less consistency exists if STK11 and KEAP1 are not associated with KRAS mutation.•Studies evaluating outcomes with ICI and other treatments showed a similar effect.•STK11 and KEAP1 mutations might be prognostic, not predictive, factors in NSCLC.
•Immune checkpoint blockade (ICB) has shown unprecedented results in NSCLC.•Immune profiles predictive of ICB efficacy have not been entirely assessed.•Tissue and circulating immune cells were ...analyzed in nivolumab treated NSCLC.•The pool size of circulating NK and CD8+ cells positively impacts on ICB response.•Cytometric assay of immune effector cells may define patients who benefit from ICB.
A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters.
Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3ζ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes.
KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.
The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.
BackgroundBone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We ...hypothesized that BoM may influence sensitivity to immunotherapy.MethodsPretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM.ResultsCohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p < 0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p < 0.0001; Cohort B: 2.7 versus 5.2 months, p < 0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p < 0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78).ConclusionsBoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy.
The impact of baseline versus intercurrent steroids on the efficacy of upfront chemotherapy plus pembrolizumab (CT-ICI) for advanced non-small cell lung cancer (NSCLC) patients is unclear. We ...conducted a retrospective study on metastatic NSCLC patients treated with upfront CT-ICI at our institution between March 2020 and December 2021. The use of steroids was considered as the administration of at least 10 mg of prednisone equivalent. Of 101 patients, 36 (35.6%) received steroid therapy at baseline, and 18 (17.8%) started steroids on treatment. Overall, median progression-free survival (mPFS) was 6.5 months (95% CI, 5.9−8.9) and median overall survival (mOS) was 18.2 months (95% CI, 8.9-NR). Patients taking baseline steroids had significantly shorter survival than those not taking them and those assuming intercurrent steroids (mPFS 5.0 vs. 9.2 vs. 7.3 months, p < 0.001; mOS 7.0 months vs. not reached, p < 0.001). Baseline steroids were significantly associated with poorer survival outcomes in the multivariate model (OS HR 2.94, p = 0.02; PFS HR 3.84, p > 0.001). Conversely, intercurrent prescription did not reach a significant value regardless of other pivotal variables included in the model. Baseline steroid administration was associated with a detrimental effect on survival outcomes in NSCLC patients treated with CT-ICI. The role of intercurrent steroid administration should be further explored in larger studies.
Treatment with inhibition of programmed cell death 1 (PD-1) or its ligand (PD-L1) improves survival in advanced non-small-cell lung cancer (NSCLC). Nevertheless, only a subset of patients benefit ...from treatment and biomarkers of response to immunotherapy are lacking. Expression of PD-L1 on tumor cells is the primary clinically-available predictive factor of response to immune checkpoint inhibitors, and its relevance in cancer immunotherapy has fostered several studies to better characterize the mechanisms that regulate PD-L1 expression. However, the factors associated with PD-L1 expression are still not well understood. Genomic alterations that activate KRAS, EGFR, and ALK, as well as the loss of PTEN, have been associated with increased PD-L1 expression. In addition, PD-L1 expression is reported to be increased by amplification of CD274, and decreased by STK11 deficiency. Furthermore, PD-L1 expression can be modulated by either tumor extrinsic or intrinsic factors. Among extrinsic factors, the most prominent one is interferon-γ release by immune cells, while there are several tumor intrinsic factors such as activation of the mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Myc pathways that can increase PD-L1 expression. A deeper understanding of PD-L1 expression regulation is crucial for improving strategies that exploit inhibition of this immune checkpoint in the clinic, especially in NSCLC where it is central in the therapeutic algorithm. We reviewed current preclinical and clinical data about PD-L1 expression regulation in NSCLC.
Highlights • Squamous lung cancers have been regarded as tumors without targetable molecular alterations. • FGF/FGFR pathway deregulation is increasingly recognized across different tumors. • ...FGF/FGFR pathway is one of the most promising druggable target in squamous lung cancers. • FGFR amplifications, mutations, translocations are the most frequent mechanisms of activation. • mAbs, ligand traps, TKIs directed versus FGF/FGFR are in development in lung tumor.
Background
The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer ...(NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting.
Objective
We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC.
Patients and methods
We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO–UMC system, a standardized probabilistic algorithm.
Results
Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizotinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as
highly probable
and 69.5% as
probable
. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%).
Conclusion
Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs.
•Currently, only FFPE samples are acceptable for the IHC assessment of PD-L1 in NSCLC.•Cytological smears are the only available material for a subset of patients.•IHC for PD-L1 in cytological smears ...of NSCLC is feasible using the >50% cut-off.•PD-L1 IHC on cytological smears expands the pool of NSCLC candidate to immunotherapy.
Introduction The assessment of PD-L1 expression by immunohistochemistry is mandatory for the administration as first-line therapy of the anti PD-1 check-point inhibitor Pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC). Currently, only formalin-fixed paraffin-embedded samples are acceptable for PD-L1 immunostaining with the anti-PD-L1 antibodies 22-C3 and SP263. We investigated retrospectively the accuracy of the anti PD-L1 antibodies 22-C3, 28-28, SP263 in 50 paired histological samples and cytological smears of NSCLC patients.
Results The accuracy of the three antibodies for the detection of PD-L1 in histological samples was higher for the antibody SP263 (AUC/ROC = 1) compared to the clones 28-8 (AUC/ROC =,991) and 22-C3 (AUC/ROC =,942). The overall concordance between histological samples and cytological smears using the SP263 clone was moderate (kappa = 0,364). However when the cyto-histological concordance was calculated using just the <50% vs ≥50% cut-off the agreement (kappa = 0.626) was good. The accuracy of the antibody SP263 in cytological smears was good (AUC/ROC =,921). A fluorescent in situ hybridization analysis on 10 histological cases positive for PD-L1 at immunohistochemistry showed amplification of the CD274 gene only in one case.
Conclusions Immunocytochemical staining for PD-L1 in diagnostic cytological smears of NSCLC is feasible and applicable at least using the >50% cancer cell cut-off. The three antibodies SP263, 22-C3 and 28-8 are all suitable for the diagnostic detection of PD-L1 on tissue sections with a superiority of the SP263 clone. The implementation of PD-L1 immunocytochemistry on cytological smears will likely expand the pool of NSCLC patients candidate to first-line immunotherapy.
Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was ...also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC.
In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS).
Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months).
Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met.
Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.
Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. ...The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-γ is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-γ may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion.
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