Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study.

BACKGROUND: No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC. METHODS: Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m(2) on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825. FINDINGS: Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group). INTERPRETATION: Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC. FUNDING: AstraZeneca.

STK11/LKB1 alterations worsen the poor prognosis of KRAS mutated early-stage non-squamous non-small cell lung carcinoma, results based on the phase 2 IFCT TASTE trial.

BACKGROUND: STK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC). PATIENTS AND METHODS: Surgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated. RESULTS: Among 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1-3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2-4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5-10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6-5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS. CONCLUSION: This analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.

Capmatinib efficacy for METex14 non-small cell lung cancer patients: Results of the IFCT-2104 CAPMATU study.

BACKGROUND: Capmatinib is a selective MET inhibitor with demonstrated efficacy in a phase II study of non-small cell lung cancer (NSCLC) patients harboring METex14 mutations. However, the real-world outcomes of capmatinib are largely unknown. From June 2019, the French Early Access Program (EAP) provided capmatinib to METex14 NSCLC patients who were ineligible for or for whom first-line standard therapies had failed. METHODS: IFCT-2104 CAPMATU was a multicenter study that included all METex14 NSCLC patients who received capmatinib as part of the EAP until August 2021. The primary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). RESULTS: A total of 146 patients were included. The median age was 74.9 years, 56.6 % were never-smokers, and 32.4 % had brain metastases. The median TTF, median PFS and median OS from capmatinib initiation were 5.1 months (95 % CI 4.2-6.0), 4.8 months (95 % CI 4.0-6.0) and 10.4 months (95 % CI 8.3-13.2), respectively. Evaluation of the best response to capmatinib was available for 134 patients and resulted in an ORR of 55.3 % (95 % CI 46.8 %-63.6 %). The median PFS was 7.7 months for treatment-naïve patients and 6.0 and 4.1 months for patients who had received one or 2 + prior lines of treatment, respectively. For patients with brain metastases, the median PFS was 3.0 months. Capmatinib had a known and manageable safety profile, with grade 3 to 4 adverse events, mostly peripheral edema (8.2 %), occurring in 17.8 % of patients. CONCLUSION: In this large real-world study of METex14 NSCLC patients, the efficacy of capmatinib was confirmed, with a manageable safety profile, even in patients with brain metastases and in those who received several lines of treatment. This study reinforces the key role of capmatinib for these patients.

[Interest of focal radiotherapy in case of oligoprogression under immunotherapy in the treatment of metastatic non-small cell lung cancer]. / Oligroprogression sous nivolumab du cancer bronchique non à petites cellules métastatiques traitées par radiothérapie.

INTRODUCTION: The prognosis of metastatic non-small cell lung cancer (NSCLC) has been improved by the use of immune checkpoint inhibitors (ICI). Unfortunately, in some cases, cancer cells will develop resistance mechanisms. In case of progression in a limited number of lesions (oligoprogression), focal treatment with radiotherapy is proposed while continuing the ICI therapy. METHODS: A cohort of 37 patients with metastatic NSCLC treated with nivolumab (anti-PD-1) in second or subsequent line and who received focal radiotherapy for oligoprogression with continuation of nivolumab was compared with a control cohort of 87 patients no oligoprogressor treated par immunotherapy. RESULTS: After a median follow-up of 37 months [18; 62], the median progression free survival (PFS) in the radiotherapy-treated cohort was 15.04 versus 5.04 months in the control cohort, with a statistically significant difference (P=0.048). The median PFS following focal radiotherapy in the oligoprogressor group was 7.5 months. In univariate analysis, the presence of lung metastasis was associated with increased PFS, in contrast to the presence of brain metastases, which were associated with decreased PFS in the radiotherapy group. The median overall survival was not reached in both groups, with no significant difference between the two cohorts. CONCLUSION: The combination of focal radiotherapy in case of oligoprogression and continued treatment with nivolumab in the treatment of metastatic NSCLC in the second or subsequent line of treatment seems to be with an increase in PFS.

Telomere Status of Advanced Non-Small-Cell Lung Cancer Offers a Novel Promising Prognostic and Predictive Biomarker.

Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment.

Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO).

BACKGROUND: The IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC). METHODS: In a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131). RESULTS: Forty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8-41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3-5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity. CONCLUSIONS: Neoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.

Efficacy of Dabrafenib Plus Trametinib Combination in Patients with BRAF V600E-Mutant NSCLC in Real-World Setting: GFPC 01-2019.

Dabrafenib plus trametinib combination is approved in Europe for BRAF V600E-mutant metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to assess efficacy and safety of this combination in a real-world setting. This retrospective multicentric study included 40 patients with advanced NSCLC harboring BRAF V600E mutation and receiving dabrafenib plus trametinib. The median progression-free survival (PFS) and overall survival (OS) were 17.5 (95% CI 7.1-23.0) months and 25.5 (95% CI 16.6-not reached) months in the entire cohort, respectively. For the 9 patients with first-line treatment, median PFS was 16.8 (95% CI 6.1-23.2) months and median OS was 21.8 (95% CI 1.0-not reached) months; for the 31 patients with second-line or more treatments, median PFS and OS were 16.8 (95% CI 6.1-23.2) months and 25.5 (95% CI 16.6-not reached) months, respectively. Adverse events led to permanent discontinuation in 7 (18%) patients, treatment interruption in 8 (20%) and dose reduction in 12 (30%). In conclusion, these results suggest that efficacy and safety of dabrafenib plus trametinib combination in patients with BRAF V600E metastatic NSCLC are comparable in a real-world setting and in clinical trials for both previously untreated and treated patients.

Encephalitis related to immunotherapy for lung cancer: Analysis of a multicenter cohort.

INTRODUCTION: Using immune-checkpoint inhibitors (ICIs) to manage cancer is associated with various immune-related adverse events. Central and/or peripheral neurological disorders are rare and potentially serious. We analyzed the characteristics of non-small-cell lung cancer (NSCLC) patients who developed immune-related encephalitis under anti-programmed-death protein-1 or its ligand (PD-1/PD-L1). METHODS: Clinical, biological and radiological characteristics of ICI-treated NSCLC patients with immune-related encephalitis, from 6 centers, were evaluated retrospectively. RESULTS: The 6 centers included 9 patients: all men, all smokers, median (range) age 67 (48-77) years, 78% adenocarcinomas, first- or second-line ICI for 5 and 4 patients, respectively. Two patients had non-active cerebral metastases at ICI onset. A median of 5 (1-22) ICI infusions preceded neurological symptoms, the most frequent being confusion (78%), fever (45%) and cerebellar ataxia (33%). CSF analyses revealed a median white blood cell count of 22/mm3 (1-210/mm3), with hyperlymphocytosis in 8 patients and high protein levels in all. All bacteriological and virological analyses were negative. Cerebral MRI was considered normal for 5 patients; 4 patients had FLAIR hypersignals consistent with brain parenchyma inflammation. Three patients required intensive care. All patients received corticosteroids (different doses), a median of 8.5 (6-18) days post-onset. Corticosteroids achieved rapid symptom regression without sequelae in 8 patients. The last patient, with the longest time until corticosteroid introduction, died. ICIs were never restarted in any patient. CONCLUSION: Immune encephalitis, a rare but serious complication of anti-PD-1/PD-L1 therapy, carries a good prognosis when managed with early corticosteroids.

Combined treatment modalities in Pancoast tumor: results of a monocentric retrospective study.

BACKGROUND: A retrospective monocentric study of consecutive patients with superior sulcus tumor non-small cell lung cancer (SS-NSCLC), treated by induction concurrent chemoradiotherapy (CRT), article management. METHODS: From 1994 to 2005, 36 patients (15 T3, 21 T4 tumors, including N2-N3 node involvement) received induction CRT with cisplatin/vinorelbine/fluorouracil combined with 44 Gy radiotherapy (5 daily 2 Gy fractions/week). After CRT completion, RECIST evaluation and operability were assessed. In resectable patients, surgery was performed one month after CRT. Patients with unresectable disease followed CRT up to 66 Gy. The median of follow-up period was 38.6 months [2-206]. RESULTS: Induction CRT was completed for 94.4% with 71% radiological objective response (OR). Sixteen patients (44%) underwent surgical resection, and pathologic complete resection was performed in 93.8%. There were 7 patients (44%) with pathologic complete response. The median disease-free survival (DFS) time was 12.9 months with DFS rates at 1 and 2 years 53.6% and 39.1% respectively. The median overall survival (OS) was 46.4 months. The OS rates at 2 and 5 years were 68.8% and 37.5% respectively with no difference between T3 and T4 tumors. In unresectable disease, the median DFS time was 8.1 months. The DFS rate at 1 year was 25.2%. The median OS was 9.1 months. The OS rates at 1 and 2 years were 45% and 16.9% respectively. Recurrences were found in 72% of patients. Brain metastasis was the most common site of recurrence. Prognostic factors for OS were the response to induction treatment, the possibility of surgery, and pathologic complete response. CONCLUSIONS: This trimodality treatment regimen confers a survival outcome in agreement with previous studies. Patients with pretreatment N3 lymph node should be included in trimodality treatment.

Immunohistochemistry evaluation of biomarker expression in non-small cell lung cancer (Pharmacogenoscan study).

OBJECTIVES: Platinum-based chemotherapy regimens are the standard treatment of non-small cell lung cancer (NSCLC). In this study, our objective was to identify tumor tissue protein biomarkers that might predict a benefit from these treatments. MATERIALS AND METHODS: The Pharmacogenoscan study prospectively included consecutive chemotherapy-naive NSCLC patients at any stage between 2005 and 2010 at six hospitals in the Rhône-Alpes-Auvergne region of France. Of the 537 patients in the full analysis set, 460 had a complete histological diagnosis. We used the tumor tissue samples for an immunohistochemical evaluation of eight biomarkers: ERCC1, BRCA1, p53, p27kip1, class III ß-tubulin (TUBB3), Bax, Fas, and FasL. We looked for associations between these biomarkers and the disease control rate (DCR) after 2/3 cycles of platinum-based chemotherapy, progression-free survival (PFS), and overall survival (OS). RESULTS: A tissue sample adequate for testing at least one biomarker was available for 289 patients. We found no significant association between biomarker expression levels and clinical or pathological variables; TUBB3 showed a trend toward higher expression in adenocarcinomas (P=0.005). For none of the biomarkers were significant associations found between expression level and DCR, PFS, or OS. TUBB3-negative and FasL-negative tumors showed associations of borderline significance with higher DCR. CONCLUSION: In a large cohort of patients with predominantly advanced or metastatic NSCLC, none of eight tested immunohistochemical biomarkers predicted the chemotherapy response or survival. Our data indicate limited usefulness of protein biomarkers in metastatic NSCLC and a need for further research based on molecular signatures of greater complexity.

Organizing pneumonia after rituximab therapy: Two cases.

Rituximab, a chimeric monoclonal antibody against CD20, very rarely causes lung toxicity. Clinical presentations include lung infiltrates, alveolar hemorrhage, and adult respiratory distress syndrome. Three cases of organizing pneumoinia (formerly called bronchiolitis obliterans with organizing pneumonia or BOOP) have been reported. In our experience, organizing pneumonia occurred in 2 of 25 patients treated with rituximab, for RA and Castleman's disease, respectively. Because organizing pneumonia may be asymptomatic, as illustrated by one of our cases, we recommend obtaining a chest radiograph routinely before rituximab re-treatment.