Immunotherapy is becoming a standard of care for many cancers. Immune-checkpoint inhibitors (ICI) can generate immune-related adverse events. Interstitial lung disease (ILD) has been identified as a ...rare but potentially severe event.Between December 2015 and April 2016, we conducted a retrospective study in centres experienced in ICI use. We report the main features of ICI–ILD with a focus on clinical presentation, radiological patterns and therapeutic strategies.We identified 64 (3.5%) out of 1826 cancer patients with ICI–ILD. Patients mainly received programmed cell death-1 inhibitors. ILD usually occurred in males, and former or current smokers, with a median age of 59 years. We observed 65.6% grade 2/3 severity, 9.4% grade 4 severity and 9.4% fatal ILD. The median (range) time from initiation of immunotherapy to ILD was 2.3 (0.2−27.4) months. Onset tended to occur earlier in lung cancer versus melanoma: median 2.1 and 5.2 months, respectively (p=0.02). Ground-glass opacities (81.3%) were the predominant lesions, followed by consolidations (53.1%). Organising pneumonia (23.4%) and hypersensitivity pneumonitis (15.6%) were the most common patterns. Overall survival at 6 months was 58.1% (95% CI 37.7–73.8%).ICI–ILD often occurs early and displays suggestive radiological features. As there is no clearly identified risk factor, oncologists need to diagnose and adequately treat this adverse event.
Summary Background Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous ...non-small-cell lung cancer (NSCLC). The SAiL ( MO19390 ) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice. Methods Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB–IV); an Eastern Cooperative Oncology Group performance status of 0–2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7·5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov , number NCT00451906. Findings At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade ≥3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients 1%). Bevacizumab was temporarily interrupted after 28 (2%) of 1347 bleeding events and 72 (7%) of 1025 hypertension events, and permanently discontinued after 110 (8%) bleeding events and 40 (4%) hypertension events. No new safety signals were reported. Interpretation Our results confirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC. Funding F Hoffmann-La Roche Ltd.
HER2 mutations are identified in approximately 2%of non-small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC.
We ...retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments.
HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti-human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate DCR, 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively.
This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.
Summary Background Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients ...older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. Methods In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70–89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0–2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. Findings 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30·3 months (range 8·6–45·2). Median overall survival was 10·3 months for doublet chemotherapy and 6·2 months for monotherapy (hazard ratio 0·64, 95% CI 0·52–0·78; p<0·0001); 1-year survival was 44·5% (95% CI 37·9–50·9) and 25·4% (19·9–31·3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 48·4% vs 28 12·4%; asthenia 23 10·3% vs 13 5·8%). Interpretation Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. Funding Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.
Alectinib demonstrated clinical efficacy and an acceptable safety profile in two phase II studies (NP28761 and NP28673). Here we report the pooled efficacy and safety data after 15 and 18 months more ...follow-up than in the respective primary analyses.
Enrolled patients had ALK receptor tyrosine kinase gene (ALK)-positive NSCLC and had progressed while taking, or could not tolerate, crizotinib. Patients received oral alectinib, 600 mg twice daily. The primary end point in both studies was objective response rate assessed by an independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included disease control rate, duration of response, progression-free survival, overall survival, and safety.
The pooled data set included 225 patients (n = 138 in NP28673 and n = 87 in NP28761). The response-evaluable population included 189 patients (84% n = 122 in NP28673 and n = 67 in NP28761). In the response-evaluable population, objective response rate as assessed by the IRC was 51.3% (95% confidence interval CI: 44.0–58.6 all PRs), the disease control rate was 78.8% (95% CI: 72.3–84.4), and the median duration of response was 14.9 months (95% CI: 11.1–20.4) after 58% of events. Median progression-free survival as assessed by the IRC was 8.3 months (95% CI: 7.0–11.3) and median overall survival was 26.0 months (95% CI: 21.4–not estimable). Grade 3 or higher adverse events (AEs) occurred in 40% of patients, 6% of patients had treatment withdrawn on account of AEs, and 33% had AEs leading to dose interruptions/modification.
This pooled data analysis confirmed the robust systemic efficacy of alectinib in ALK-positive NSCLC with a durable response rate. Alectinib also had an acceptable safety profile with a longer duration of follow-up.
We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy (RT) and chemotherapy (CT) in unresectable stage III non-small-cell lung ...cancer (NSCLC).
Patients were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction CT with cisplatin (120 mg/m2) on days 1, 29, and 57, and vinorelbine (30 mg/m2/wk) from day 1 to day 78, followed by thoracic RT at a dose of 66 Gy in 33 fractions (2 Gy per fraction and 5 fractions per week). In the concurrent arm, the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d (days 1 to 5 and days 29 to 33); patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127.
Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P = .24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%).
Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.
Brigatinib is a next-generation ALK inhibitor (ALKi) that shows efficacy in ALK inhibitor naïve and post-crizotinib ALK+ advanced NSCLCs (aNSCLCs). The efficacy of brigatinib was retrospectively ...assessed in patients with aNSCLCs included in the brigatinib French Early-Access Program (1 August 2016−21 January 2019). The primary endpoint was investigator-assessed progression-free survival (invPFS) and the primary analysis was updated in 2021 with a longer follow-up, focused on post-brigatinib lorlatinib efficacy. Sixty-six centers included 183 patients: median age 60 ± 12.7 years; 78.3% never/former smokers; median of 3 ± 1 previous lines and 2 ± 0.5 ALKis; 37.1% ECOG PS 2 and 55.6% >3 metastatic sites. The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4−42.4). InvPFS was 7.4 months (95% CI 5.9−9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8−9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6−27.6). The median DOT and OS from brigatinib initiation tend to decrease with the number of ALK inhibitors used in previous lines of therapy. Based on the data collected, 92 (50.3%) patients received ≥1 agent(s) post-brigatinib and 68 (73.9%) of them received lorlatinib, with 51 (75%) immediately receiving it post-brigatinib, 12 (17.6%) receiving it after one and 5 (7.4%) after ≥2 subsequent treatments. The median follow-up was 29.9 (95% CI 25.7−33.1) months. Lorlatinib mDOT was 5.3 (95% CI 3.6−7.6) months with a median OS from lorlatinib initiation of 14.1 (95% CI 10.3−19.2) months. The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients and provide new data on the activity of lorlatinib after brigatinib.
Stereotactic body radiation therapy (SBRT) for early-stage lung cancer can be achieved with several methods: respiratory gating, body frame, or real-time target and motion tracking. Two target ...tracking methods are currently available with the CyberKnife® System: the first one, fiducial tracking, requires the use of radio-opaque markers implanted near or inside the tumor, while the other, Xsight® Lung Tracking System, (XLTS) is fiducial-free. With XLTS, targeting is synchronized directly with target motion, which occurs due to respiration. While the former method (fiducial tracking) is well documented, the clinical relevance of the latter (tracking without fiducials) has never been well described to this date.
A study was performed at our department for each patient treated for lung cancer with CyberKnife using XLTS. Selection criteria were: primary or recurring T1 or T2 stage non-small-cell lung cancer (NSCLC) with 15-60 mm tumor size. Initial staging included CT-Scan and FDG-PET.
Fifty-one patients not amenable to surgery were treated with XLTS. Median follow-up was 15 months (range, 5-30 months). Median tumor size was 24 mm (range, 15-60 mm). Median total dose was 60 Gy (36-60 Gy) in three fractions. Actuarial overall survival was 85.5% (95% CI = 74.5-96%) at 1 year and 79.4% (95% CI = 64-94.8%) at 2 years. Actuarial local control rate was 92% (95% CI = 84-99%) at one 1 year and 86% (95% CI = 75-97%) at 2 years.
Local control and overall survival rates were similar to previous reports that used fiducials for tumor tracking. Toxicity was lower than most studies since tumor tracking did not require fiducial implantion. This fiducial-free method for respiratory motion tracking is a valid option for the most fragile patients.
Background
In Europe, few data regarding the characteristics of
EGFR
exon 20 insertion (20ins) mutations in non-small cell lung cancer (NSCLC) are available.
Objective
Using a large real-world ...cohort, we assessed the incidence, characteristics, and outcomes of patients with non-squamous (nsq) NSCLC harboring
EGFR
exon 20ins.
Patients and Methods
The Epidemio-Strategy and Medical Economics advanced and metastatic lung cancer data platform including advanced/metastatic nsqNSCLC patients from January 2015 was analyzed (cut-off date: June 30, 2020). Characteristics, epidermal growth factor receptor (
EGFR
) mutation and other mutations, treatment patterns, and clinical outcomes were assessed for patients harboring
EGFR
exon 20ins, common
EGFR
mutations, other
EGFR
mutations, and wild-type
EGFR
. Survival parameters were estimated by the Kaplan-Meier method in these four groups.
Results
Out of 9435 nsqNSCLC patients tested for
EGFR
, 1549 (16.4%) had a mutation, including 61 with
EGFR
exon 20ins (3.9% of all mutated
EGFR
). These 61 patients had a mean age of 63.6 years, were mostly female (68.9%) and non-smokers (55.7%), with de novo stage IV disease (73.8%) and performance status 0–1 (76.9%). Almost all patients (95.1%) with exon 20ins received systemic therapy (median, three lines). First-line systemic treatments consisted mainly of combination chemotherapy (70.7%), single-agent EGFR tyrosine kinase inhibitors (10.3%), and single-agent immunotherapy (5.2%). After a median follow-up of 25.0 (95% confidence interval CI 22.3–32.4) months, the median real-world overall survival was 24.3 (19.1–32.6) months in patients with exon 20ins compared to 35.4 (95% CI 32.6–37.5) in patients with common
EGFR
mutation (
n
= 1049) (
p
= 0.049) and 19.6 (95% CI 18.6–20.5) in patients with wild-type
EGFR
(
n
= 7866) (
p
= 0.2).
Conclusions
This large national study in nsqNSCLC patients confirms that
EGFR
exon 20ins is a rare condition (0.6%). The prognosis associated with exon 20ins appears to be in line with that of wild-type
EGFR
, but worse than common
EGFR
mutations, highlighting the need for advancements for this rare population.
Occupational exposure constitutes a common risk factor for lung cancer. We observed molecular alterations in 73% of never-smokers, 35% of men and 8% of women were exposed to at least one occupational ...carcinogen. We report herein associations between molecular patterns and occupational exposure.BioCAST was a cohort study of lung cancer in never-smokers that reported risk factor exposure and molecular patterns. Occupational exposure was assessed
a validated 71-item questionnaire. Patients were categorised into groups that were unexposed and exposed to polycyclic aromatic hydrocarbons (PAH), asbestos, silica, diesel exhaust fumes (DEF), chrome and paints. Test results were recorded for
and
mutations, and
alterations.Overall, 313 out of 384 patients included in BioCAST were analysed. Asbestos-exposed patients displayed a significantly lower rate of
mutations (20%
44%, p=0.033), and a higher rate of
mutations (18%
4%, p=0.084).
alterations were not associated with any occupational carcinogens. The DEF-exposed patients were diagnosed with a
mutation in 25% of all cases. Chrome-exposed patients exhibited enhanced
and
mutation frequency.Given its minimal effects in the subgroups, we conclude that occupational exposure slightly affects the molecular pattern of lung cancers in never-smokers. In particular, asbestos-exposed patients have a lower chance of
mutations.
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