Abstract Objectives ROS1 proto-oncogene translocations define a new molecular subgroup in non-small cell lung cancers (NSCLC) and are associated with a response to the MET/ALK inhibitor, crizotinib. ...These rearrangements are described in 0.9–1.7% NSCLC, in wild-type EGFR, KRAS and ALK (“triple negative”) lung adenocarcinomas. Rapid and efficient identification of these alterations is thus becoming increasingly important. Materials and methods In this study, 121 triple negative lung adenocarcinomas were screened by both IHC with the ROS1 D4D6 antibody, and FISH using two commercially available ROS1 break-apart probes. To address a possible cross-reactivity of the ROS1 antibody with other protein kinase receptors, we screened 80 additional cases with known EGFR , KRAS , PI3KCA , BRAF , HER2 mutations or ALK -rearrangement. Results We diagnosed 9 ROS1-rearranged adenocarcinomas, with both a positive FISH result (51–87% rearranged nuclei) and a positive IHC staining (2+/3+ cytoplasmic staining). Only one of the ROS1 -positive FISH cases was characterized by a classical split pattern, the others showed a variant pattern, most commonly involving a loss of the 5′ telomeric probe. Considering a positivity threshold of 2+ stained cells, the sensitivity of the ROS1 D4D6 antibody compared to FISH was 100% and the specificity 96.9%, as two HER2 -mutated tumors were positive with D4D6 antibody, without any translocation in FISH. All the ROS1-positive cases were at an advanced stage, arising in never or light smokers. They were mainly solid cribriform and acinar adenocarcinomas, with signet ring cells noted in 5 cases, and calcifications in 3 cases. One positive case was an invasive mucinous carcinoma. Conclusion Our results show that a screening algorithm based on an IHC detection of ROS1 fusion proteins, confirmed if positive or doubtful by a ROS1 break-apart FISH assay, is pertinent in advanced “triple negative” lung adenocarcinomas, since the prevalence of ROS1-positive cases in this selected population reaches 7.4% in our series.
Durvalumab is a humanized monoclonal antibody targeting programmed cell death ligand‐1 (PD‐L1), leading to an antitumor activity, used as consolidation therapy in patients with locally advanced ...unresectable non‐small cell lung cancer (NSCLC). Several immune‐related adverse events (irAEs) have previously been described in patients following treatment with immune checkpoint inhibitors (ICIs). To the best of our knowledge, we report the first case of immunotherapy‐induced fully reversible bronchiolitis and bronchiectasis, despite the fact that its pathophysiological mechanism has been previously considered to be irreversible.
Here we report a case of durvalumab‐induced lesions of bronchiolitis and fully reversible bronchiectasis. This immune‐related adverse event has not previously been described.
Background:
The role and timing of whole or stereotaxic brain radiotherapy (BR) in patients with advanced non-small cell lung cancer (aNSCLC) and asymptomatic brain metastases (aBMs) are not well ...established. This study investigates whether deferring BR until cerebral progression was superior to upfront BR for patients with aNSCLC and aBM.
Methods:
This open-label, multicenter, phase III trial, randomized (1:1) aNSCLC patients with aBMs to receive upfront BR and chemotherapy: platin–pemetrexed and bevacizumab in eligible patients, followed by maintenance pemetrexed with or without bevacizumab, BR arm, or the same chemotherapy with BR only at cerebral progression, chemotherapy (ChT) arm. Primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), global, extra-cerebral and cerebral objective response rate (ORR), toxicity, and quality of life ClinicalTrials.gov identifier: NCT02162537.
Results:
The trial was stopped early because of slow recruitment. Among 95 included patients, 91 were randomized in 24 centers: 45 to BR and 46 to ChT arms (age: 60 ± 8.1, men: 79%, PS 0/1: 51.7%/48.3%; adenocarcinomas: 92.2%, extra-cerebral metastases: 57.8%, without differences between arms.) Significantly more patients in the BR-arm received BR compare with those in the ChT arm (87% versus 20%; p < 0.001); there were no significant differences between BR and ChT arms for median PFS: 4.7, 95% confidence interval (CI):3.4–7.5 versus 4.8, 95% CI: 2.4–6.5 months, for median OS: 8.5, 95% CI:.6–11.1 versus 8.3, 95% CI:4.5–11.5 months, cerebral and extra-cerebral ORR (27% versus 13%, p = 0.064, and 30% versus 41%, p = 0.245, respectively). The ChT arm had more grade 3/4 neutropenia than the BR arm (13% versus 6%, p = 0.045); others toxicities were comparable.
Conclusion:
The significant BR rate difference between the two arms suggests that upfront BR is not mandatory in aNSCLC with aBM but this trial failed to show that deferring BR for aBM is superior in terms of PFS from upfront BR.
Background
Immune checkpoint inhibitors (ICIs) have been approved as second‐line therapy for advanced non–small cell lung cancers (NSCLCs) progressing after platinum‐based chemotherapy. However, some ...patients' disease progressed rapidly and sometimes exhibited explosive tumor progression. This descriptive, prospective study aimed to assess the characteristics of nonresponders with rapid progression (RP), defined as progression‐free survival (PFS) ≤2 or 2‐4 months under ICIs.
Methods
This analysis included all consecutive ICI‐treated (second‐or‐more line) patients with RP ≤4 months from 1 September 2016 to 31 August 2017 and compared the clinical characteristics, treatments, and outcomes (overall survival OS; responses; PFS, according to treatment line) of NSCLCs that progressed after ≤2 vs 2‐4 months on ICIs.
Results
Comparisons of the 224 (70.2%) patients with ≤2‐month and 95 (29.8%) with 2‐ to 4‐month RP revealed the former had less frequent nonsmokers and ECOG PS = 0, more frequent stage IV disease and higher neutrophil/lymphocyte ratio. Their respective ICI PFS rates were: 1.6 95% CI: 0.1‐2 and 2.7 2.0‐4.2 months, with 16.5% and 11.6% having partial responses to first‐ and second‐line therapies post‐ICI chemotherapy. Their respective median OS rates were 6.0 and 9.0 months (P ≤ .009). Multivariate analysis retained only PFS of the first‐line therapy pre‐ICI and neutrophil/lymphocyte ratio at ICI onset as being significantly associated with ≤2‐month RP.
Conclusion
In the real‐life setting, NSCLC RP on ICI remains a challenge. New descriptive and analytic studies are needed to identify factors predictive of RP.
Immune checkpoint inhibitors (ICIs) have been approved as second‐line therapy for advanced non–small cell lung cancers (NSCLCs) progressing after platinum‐based chemotherapy. However, some patients' disease progressed before 2 or 4 months—without any response—and sometimes exhibited explosive tumoral progression. This descriptive prospective study aimed to assess the management and clinical outcomes of nonresponders with rapid progression, defined as progression‐free survival ≤2 or 2‐4 months under ICI.
Immune-checkpoint inhibitor (ICI) efficacy in patients with NSCLC harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF-, HER2-, ...MET-, and RET-NSCLC in a real-world setting.
In this retrospective, multicenter study in ICI-treated BRAF-, HER2-, MET- or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS).
There were 107 patients with NSCLC (mean age, 65.5 y) included from 21 centers: 37% were never-smokers, 54% were men, and 93% had adenocarcinoma. Among them, 44 had BRAF mutation (V600: 26), 23 had HER2 mutation, 30 had MET mutation, and nine had RET translocation. Programmed cell death ligand 1 (PD-L1) status was known for 70 patients and was greater than or equal to 1% in 34 patients. Before ICI, patients had received a median of one treatment line. Median duration of response, PFS, and OS were 15.4 (95% confidence interval CI: 12.6–not reached NR) months, 4.7 (95% CI: 2.3–7.4) months, and 16.2 (95% CI: 12.0–24.0) months, respectively, for the entire cohort. The response rates for BRAF-V600, BRAF–non-V600, HER2, MET, and RET-altered NSCLC were 26%, 35%, 27%, 36%, and 38%, respectively. For patients who were PD-L1 negative and those who were PD-L1 positive, PFS was 3.0 (95% CI: 1.2–NR) and 4.3 (95% CI: 2.1–8.5) months, respectively, and OS was 11.7 (95% CI: 4.1–NR) and 35.8 (95% CI: 9.0–35.2) months, respectively. Toxicities were reported in 28 patients (26%), including 11 patients (10%) with a grade greater than or equal to three.
In this real-world setting, ICI efficacy against patients with BRAF-, HER2-, MET-, or RET-NSCLC seemed close to that observed in unselected patients with NSCLC. Large prospective studies on these subsets of patients are needed.
Comprehensive geriatric assessment (CGA) is recommended to assess the vulnerability of elderly patients, but its integration in cancer treatment decision making has never been prospectively ...evaluated. Here, in elderly patients with advanced non-small-cell lung cancer (NSCLC), we compared a standard strategy of chemotherapy allocation on the basis of performance status (PS) and age with an experimental strategy on the basis of CGA.
In a multicenter, open-label, phase III trial, elderly patients ≥ 70 years old with a PS of 0 to 2 and stage IV NSCLC were randomly assigned between chemotherapy allocation on the basis of PS and age (standard arm: carboplatin-based doublet if PS ≤ 1 and age ≤ 75 years; docetaxel if PS = 2 or age > 75 years) and treatment allocation on the basis of CGA (CGA arm: carboplatin-based doublet for fit patients, docetaxel for vulnerable patients, and best supportive care for frail patients). The primary end point was treatment failure free survival (TFFS). Secondary end points were overall survival (OS), progression-free survival, tolerability, and quality of life.
Four hundred ninety-four patients were randomly assigned (standard arm, n = 251; CGA arm, n = 243). Median age was 77 years. In the standard and CGA arms, 35.1% and 45.7% of patients received a carboplatin-based doublet, 64.9% and 31.3% received docetaxel, and 0% and 23.0% received best supportive care, respectively. In the standard and CGA arms, median TFFS times were 3.2 and 3.1 months, respectively (hazard ratio, 0.91; 95% CI, 0.76 to 1.1), and median OS times were 6.4 and 6.1 months, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.1). Patients in the CGA arm, compared with standard arm patients, experienced significantly less all grade toxicity (85.6% v 93.4%, respectively P = .015) and fewer treatment failures as a result of toxicity (4.8% v 11.8%, respectively; P = .007).
In elderly patients with advanced NSCLC, treatment allocation on the basis of CGA failed to improve the TFFS or OS but slightly reduced treatment toxicity.
Objective
Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune‐related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been ...excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer.
Methods
A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response.
Results
The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty‐four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression‐free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression‐free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation.
Conclusion
Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.
Background
The optimal treatment duration of ICIs for patients with advanced NSCLC remains uncertain. In phase 3 clinical trials, treatment continued for 2 years or until disease progression with ...similar long-term survival rates. Real-life data are missing.
Patients and methods
This academic multicentric retrospective study aims at analyzing the characteristics of patients who discontinued treatment after at least 18 months of ICI monotherapy, in the setting of controlled disease.
Results
Of the 1127 patients treated with immunotherapy in the given period in six centers, 107 patients had their tumor controlled after at least 18 months of treatment and 54 (50%) of them had discontinued ICI. The median duration of treatment was 26 months. Treatment was stopped due to prescriber choice or toxicity in 46% and 22% of cases, respectively. After a median follow-up of 21 months from ICI discontinuation (95% CI 15.0–26.1 months), 18 (33%) patients experienced tumor progression after a median time of 10.0 months (range 2–33). From discontinuation, 12-month overall survival (OS) and progression-free survival (PFS) were 90% (95% CI 77.7–95.7) and 71% (95% CI 56.8–81.5), respectively; 24-month OS and PFS were 84% (95% CI 68.7–92.2) and 63% (95% CI 46.1–76.2), respectively. Duration of disease control after ICI discontinuation was correlated with tumor response at treatment discontinuation: PFS rate at 12 months was 76% after complete response (CR n = 11) or partial response (PR
n
= 37) and 22% after only stable disease (SD n = 6) as best response,
p
-value = 0.0002. PFS rate at 12 months was 80% for CR and/or complete metabolic response with 18F-FDG PET/CT (CMR) and 65% for others. Fourteen patients out of the 18 relapse patients received a subsequent treatment: seven with ICI rechallenge (best response 14% PR and 86% SD) and five with localized therapy with 60% CR.
Conclusions
This real-life study provides new insight into long-term outcomes of patients with advanced NSCLC treated with ICI for at least 18 months before treatment discontinuation in the absence of PD. Tumor response and CMR with FDG PET just before therapy discontinuation may be a predictive factor of prolonged disease control upon discontinuation. These results call for caution in discontinuing treatment in patients with stable disease as the best response.
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