ABSTRACT
BACKGROUND AND AIM: A better understanding of resistance to checkpoint inhibitors is essential to define subsequent treatments in advanced non-small cell lung cancer. By characterizing clinical and radiological features of progression after anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1), we aimed to define therapeutic strategies in patients with initial durable clinical benefit. PATIENTS AND METHODS: This monocentric, retrospective study included patients who presented progressive disease (PD) according to RECIST 1.1 criteria after anti-PD-1/PD-L1 monotherapy. Patients were classified into two groups, "primary resistance" and "Progressive Disease (PD) after Durable Clinical Benefit (DCB)", according to the Society of Immunotherapy of Cancer classification. We compared the post-progression survival (PPS) of both groups and analyzed the patterns of progression. An exploratory analysis was performed using the tumor growth rate (TGR) to assess the global growth kinetics of cancer and the persistent benefit of immunotherapy beyond PD after DCB. RESULTS: A total of 148 patients were included; 105 of them presented "primary resistance" and 43 "PD after DCB". The median PPS was 5.2 months (95% CI: 2.6-6.5) for primary resistance (p < 0.0001) vs. 21.3 months (95% CI: 18.5-36.3) for "PD after DCB", and the multivariable hazard ratio was 0.14 (95% CI: 0.07-0.30). The oligoprogression pattern was frequent in the "PD after DCB" group (76.7%) and occurred mostly in pre-existing lesions (72.1%). TGR deceleration suggested a persistent benefit of PD-1/PD-L1 blockade in 44.2% of cases. CONCLUSIONS: PD after DCB is an independent factor of longer post-progression survival with specific patterns that prompt to contemplate loco-regional treatments. TGR is a promising tool to assess the residual benefit of immunotherapy and justify the continuation of immunotherapy in addition to radiotherapy or surgery.
ABSTRACT
The development of immune checkpoint inhibitors (ICIs) constitutes a major therapeutic advance in the treatment of a number of malignancies [...].
ABSTRACT
INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.
Subject(s)
Adenocarcinoma , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Female , Humans , Male , Middle Aged , Adenocarcinoma/pathology , Carcinoma, Non-Small-Cell Lung/pathology , In Situ Hybridization, Fluorescence , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Treatment OutcomeABSTRACT
Immune checkpoint inhibitors represent a major therapeutic advance in non-small-cell lung cancer with several approved anti-programmed death-1 and anti-programmed death-L1 immunotherapies. A majority of patients however, will not respond to immune checkpoint inhibitors and display primary resistance while a subset of initially responsive patients will present secondary resistance. Thus, there is a crucial need for biomarkers to enable better prediction and diagnosis, and to overcome such resistance. Along with improvement in the understanding of immune escape, new biomarkers are being developed, including large scale proteomic, genomic and transcriptomic approaches in tumor and blood samples. We review the novel biomarkers that have been investigated in non-small-cell lung cancer and discuss how they can rationalize therapeutic strategies.
ABSTRACT
Physiological aging causes qualitative or quantitative immune system decline, also called immunosenescence. Older people with cancer are often ineligible for chemotherapy. The new immunotherapies (with PD1, PDL1 and CTLA4 checkpoint inhibitors) have proven their effectiveness in many tumor types regardless of age and are often better tolerated than chemotherapy. In the older population, the subgroup data from the different pivotal studies show fairly reassuring efficacy and safety data, despite the frequent lack of power given the small population included. There remains, however, some doubt that age may be a risk factor for hyperprogression. Studies focusing on older subjects and dedicated meta-analysis seem necessary to obtain more accurate data.
