•Immune checkpoint inhibitors (ICIs) have shifted the therapeutic approach to NSCLC•Reproducible biomarkers of ICI benefit represent an unmet and urgent need•Circulating descriptors of cancer-host ...immune interaction were explored here•sPD-L1, CD8+PD-1+ and NK cells enclosed a highly prognostic immune effector score•Blood-based multiparametric models might non-invasively predict ICI response
Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC).
Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response.
High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1high, CD8+PD-1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable IeffS characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes. A remarkable impact of IeffS-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001).
Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.
•Liquid biopsy alone could underestimate coexistence of resistance mechanisms.•T790M plasma levels should be taken into account for clinical decisions.•Low EGFR-T790M/activating mutation ratio may ...suggest tissue re-biopsy.•p53 and Rb1 expression on diagnostic biopsy may predict SCLC transformation.
EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed.
All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR).
We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy.
Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.
The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and ...predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1-3 gene polymorphisms on outcomes of patients was examined.
Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 (C8092A, C118T), XPD (Lys751Gln), XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay.
Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate (P=0.004), progression-free survival (P=0.023) and overall survival (P=0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role (P=0.036).
This study confirms the prognostic role of ERCC1 expression and XRCC1 (Arg399Gln) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy.
Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent ...therapeutic implications.
This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed.
Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively.
Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.
Background
In most cases, T790M
EGFR
-positive NSCLC patients receiving osimertinib developed “non-drugable” progression, as the patients with common
EGFR
-sensitizing mutations were treated with ...first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression.
Methods
We conducted a study on “post-progression” (pp) outcomes of T790M
EGFR
-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), “switched therapies” or best supportive care only (BSC).
Results
144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression 19 (20.9%) of them with adjunctive LATs and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively HR 0.57 (95% CI 0.35–0.92),
p
= 0.0239 and 11.3 months vs 7.8 months, respectively HR 0.57 (95% CI 0.33–0.98),
p
= 0.0446. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively HR 0.90 (95% CI 0.68–1.18),
p
= 0.4560, while median ppOS was 20.2 months and 9.9 months, respectively HR 0.73 (95% CI 0.52–1.03),
p
= 0.0748. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs).
Conclusion
Our study confirmed that in clinical practice, in case of “non-druggable” disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.
Purpose
Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome ...benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received.
Patients
We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions.
Results
After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 CI 95% 7.9–11.2 and 11.1 months CI 95% 9.2–13.8, respectively, while TTF were 10.2 CI 95% 8.5–12.6 and 11.9 months CI 95% 9.7–17.4, respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months CI 95% 24.3–33.7 in PFS and 30.4 months CI 95% 24.7–34.9 in TTF. The median OS from the diagnosis of advanced disease was 39 months CI 95% 31.8–54.5. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS 57 months (CI 95% 42.0–73.8) compared to those that did not receive crizotinib 38 months (CI 95% 18.6–NR) and those who performed only crizotinib as target agent 15 months (CI 95% 11.3–34.0) (
P
< 0.0001).
Conclusion
The sequential administration of crizotinib and a new generation ALKis provided a remarkable clinical benefit in this real-life population, being an interesting option to consider in selected patients.
Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting ...80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted.
The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan–Meier method.
Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with ‘major’ uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer ‘minor’ mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy.
The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon–common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
•Largest dataset of NSCLC with uncommon EGFR alterations treated with osimertinib.•Best outcomes with compound uncommon–common EGFR mutations and with G719X, L861X, or S768I.•Heterogeneous activity with rarer mutations; no response with alterations at E709 residue.•Confirmed activity in the central nervous system, with intracranial ORR of 58%.•Amplification of EGFR or MET, TP53 mutations, and EGFR E709K are putative mechanisms of resistance.
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