Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer ...(NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy.
In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS).
Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%–49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18–37) and median overall survival was 22.1 months (95% CI 17.1–27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher 14/27 (51.9%; 95% CI 32%–71%), 54%, and 85%, respectively than the overall population 27/101 (26.7%; 95% CI 18.4%–36.5%), 35%, 71%. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths.
Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%.
KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).
While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) ...with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance.
BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs).
Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months interquartile range (IQR): 26.5-37.6 months and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination 15.4 months; 95% confidence interval (CI) 9.2-18.0 months and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), hazard ratio (HR) = 0.96; 95% CI 0.68-1.37. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively.
No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.
•A randomised trial comparing bevacizumab plus osimertinib versus osimertinib alone in EGFR-mutant NSCLC with T790M mutations.•The primary endpoint was investigator-assessed PFS.•No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone.•TRAEs of grade ≥3 were more common in patients on combination than osimertinib alone.
Non-small cell lung cancer (NSCLC) accounts for up to 85% of all lung cancers. The last few years have seen the development of a new staging system, diagnostic procedures such as liquid biopsy, ...treatments like immunotherapy, as well as deeper molecular knowledge; so, more options can be offered to patients with driver mutations. Groups with specific treatments account for around 25% and demonstrate significant increases in overall survival, and in some subgroups, it is important to evaluate each treatment alternative in accordance with scientific evidence, and even more so with immunotherapy. New treatments similarly mean that we must reconsider what should be done in oligometastatic disease where local treatment attains greater value.
Introduction
Many methods used to assess the effectiveness of immune checkpoint (programmed death-ligand 1 or cytotoxic T-lymphocyte-associated protein 4) inhibitors for non-small cell lung cancer ...(NSCLC) are insufficient, as the therapeutic benefit of these agents is often underestimated. Consequently, immune-related evaluation criteria have been developed to better reflect their efficacy. The aim of this consensus was to obtain the opinion of lung cancer experts on the adequacy of immune-response criteria for evaluating the efficacy of these treatments.
Methods
Through two rounds of a modified Delphi consensus, 18 Spanish lung cancer experts participated in a 15-item questionnaire regarding the use of immunotherapies for NSCLC and the assessment criteria used to evaluate their effectiveness.
Results
Consensus was achieved on 80% of the items in the questionnaire. The panelists agreed that although the Response Evaluation Criteria in Solid Tumors (RECIST) are standard for the evaluation of solid tumors, immune-related response criteria would be useful for measuring the efficacy of immunotherapy. In addition, they considered that an overall survival (OS) rate at 2–5 years is the most useful end point for assessing the benefit of immunotherapy, as clinical benefit may extend beyond the RECIST criteria-defined progression of disease.
Conclusions
Although immune-related response criteria have been developed to better evaluate the efficacy of immunotherapy, their use has not been validated and is restricted to investigational applications. However, they may prove to be a useful tool for measuring the efficacy of immunotherapy agents in NSCLC, especially the OS rate at 2–5 years.
Purpose
Both nintedanib/docetaxel and anti‐PD‐1/PD‐L1 immunotherapies have demonstrated efficacy as second‐line treatment of patients with advanced lung adenocarcinoma. This is the first report on ...the efficacy of the nintedanib/docetaxel combination following first‐line platinum‐based chemotherapy and subsequent immunotherapy in a real-world setting.
Methods/patients
From May 2014 to December 2015, 390 patients in 108 Spanish centres enrolled in the nintedanib named patient use program. Inclusion criteria were advanced lung adenocarcinoma with progressive disease following at least one line of platinum‐based doublet chemotherapy. The objective was to evaluate the efficacy of the nintedanib/docetaxel combination in patients who also received immunotherapy.
Results
Eleven patients met the inclusion criteria; with a median age of 67 years. PD‐L1 expression was positive in six patients. Median progression‐free survival (PFS) of first‐line platinum‐based chemotherapy was 3.3 months (95% CI 1.9–4.6). Second‐line immunotherapy was pembrolizumab (36.5%), atezolizumab (36.5%) or nivolumab (27%). Median PFS of second‐line immunotherapy was 2.3 months (95% CI 0–6.1). The overall response rate (ORR) to second‐line immunotherapy was 18% with a disease‐control rate (DCR) of 45%. Median PFS of nintedanib/docetaxel was 3.2 months (95% CI 1.9–4.5). Best response was partial response in four patients (36%), stable disease in five patients (46%), and progressive disease in two patients (18%), for an ORR of 36% and a DCR of 82%.
Conclusion
Our experience suggests an encouraging efficacy of nintedanib/docetaxel in patients with adenocarcinoma NSCLC pretreated with platinum‐based doublet chemotherapy and immunotherapy, reinforcing the importance of an optimal therapeutic sequence for managing advanced lung adenocarcinoma.
Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine ...adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine–cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients.
Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m2, days 1/8) and cisplatin (75 mg/m2, day 1) with gemcitabine/cisplatin/iniparib (GCI) or without gemcitabine/cisplatin (GC) iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature.
One hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% 95% confidence interval (CI) 13.0%–42.1% with GC versus 20.0% (95% CI 11.9%–30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8–5.6) months with GC and 5.7 (95% CI 4.6–6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56–1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9–17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48–1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3–4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each).
Addition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS.
ClinicalTrial.gov Identifier NCT01086254.
Cytological samples obtained by endobronchial ultrasound (EBUS) are capital for diagnosis, staging and molecular profile in non-small cell lung carcinoma (NSCLC).
To assess the success rate of ...complete, partial and individual of molecular analysis in samples obtained by EBUS-guided transbronchial needle aspiration (TBNA) and/or by oesophageal ultrasound-guided fine needle aspiration with an echobronchoscope (EUS-B-FNA) in patients with NSCLC.
Prospective study including 90 patients with non-squamous NSCLC, or non-smoking squamous. Cytological samples were classified into two groups. Group 1: PEN membrane slide and/or cell blocks for the determination of mutations of EGFR, KRAS, ERBB2 and BRAF. Group 2: silane coated slides or cell blocks for rearrangements of ALK, ROS1 and MET amplification.
The success rate was 78.6% for 4 molecular alterations (EGFR, KRAS, ALK and ROS1), and 44% for 7 determinations. The individual success rate for EGFR was 97%, KRAS 96.3%, ALK 85%, ROS1 82.3%, ERBB2 71.4%, BRAF 67.7% and MET 81.1%. There were no significant differences (p=0.489) in the number of molecular analyses (1–3 vs. 4) in group 1, depending on the types of samples (cell block vs. PEN membrane slide vs. cell block and PEN membrane slide).
In patients with NSCLC, the cytological material obtained by ultrasound-guided needle aspiration is sufficient for individual and partial molecular analysis in the vast majority of cases. Membrane slides such as cell blocks are valid samples for molecular analysis.
Abstract First line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is the standard treatment in advanced EGFR -mutant Non Small Cell Lung Cancer (NSCLC) patients, with an ...improvement in response rate, progression free survival, and quality of life compared with upfront chemotherapy. However, in the real world, EGFR mutation results often return positive once chemotherapy has been started. Different clinical strategies have been tested in this situation: reserve the EGFR TKI until tumor become resistant beyond chemotherapy, stop chemotherapy and switch to EGFR TKI, introduce the EGFR TKI as a maintenance treatment, or combined strategies such as intercalated or concurrent EGFR TKI plus chemotherapy. In this review, we aim to summarize the clinical evidence of first line treatment strategy with EGFR TKI and discuss the potential options in the sequence of treatment in EGFR -mutant patients.
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