Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer

PURPOSE: The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with METHODS: In this ongoing, open-label, single-arm, phase II study, patients with RESULTS: At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with CONCLUSION: For patients with treatment-naïve and previously treate

Encorafenib plus binimetinib in patients with BRAFV600-mutant non-small cell lung cancer: phase II PHAROS study design

BRAF V600 mutation; Binimetinib; EncorafenibMutació de BRAF V600; Binimetinib; EncorafenibMutación de BRAF V600; Binimetinib; EncorafenibBRAFV600 oncogenic driver mutations occur in 1–2% of non-small-cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic BRAFV600-mutant NSCLC, as first- or second-line treatment. The primary end point is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives evaluated additional efficacy end points and safety. Results from PHAROS will describe the antitumor activity/safety of encorafenib plus binimetinib in patients with metastatic BRAFV600-mutant NSCLC

Characterization and management of adverse events observed with mobocertinib (TAK-788) treatment for EGFR exon 20 insertion–positive non–small cell lung cancer

Carcinoma; Càncer de pulmó de cèl·lules no petites; Seguretat del pacientCarcinoma; Cáncer de pulmón de células no pequeñas; Seguridad del pacienteCarcinoma; Non–small cell lung cancer; Patient safetyBackground Mobocertinib has demonstrated durable clinical benefit in platinum-pretreated patients (PPP) with epidermal growth factor receptor exon 20 insertion–positive non–small cell lung cancer (NSCLC). Research design and methods Pooled safety analysis of two studies included patients with NSCLC (N = 257) treated with the recommended phase 2 dose (RP2D) of mobocertinib (160 mg once daily). We report overall safety (treatment-emergent adverse events [TEAEs]) in the RP2D population; characterization of GI and skin-related events in 114 PPP from a phase 1/2 study (NCT02716116); and clinical activity in PPP with and without dose reductions due to TEAEs. Results In the RP2D population (N = 257), the most common TEAEs were diarrhea (93%), nausea (47%), rash (38%), and vomiting (37%). In PPP (N = 114), median times to diarrhea onset and resolution were 5 and 2 days, respectively. Median times to onset and resolution of skin-related events were 9 and 78 days, respectively. Among PPP with (n = 29) or without (n = 85) dose reductions due to TEAEs, overall response rates were 21% and 31% and median durations of response were 5.7 and 17.5 months, respectively. Conclusions GI and skin-related events are common with mobocertinib; minimizing dose reductions with proactive management may improve clinical outcomes.The paper received funding from Takeda Development Center Americas Inc., Lexington, MA, USA

Suitability of Thoracic Cytology for New Therapeutic Paradigms in Non-small Cell Lung Carcinoma: High Accuracy of Tumor Subtyping and Feasibility of EGFR and KRAS Molecular Testing

Introduction:The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR and KRAS molecular testing. The aim of this study was to comprehensively review the performance of cytologic specimens for the above two goals in a high-volume clinical practice.Methods:Subtyping of primary lung carcinomas by preoperative cytology was correlated with subsequent resection diagnoses during a 1-year period (n = 192). The contribution of various clinicopathologic parameters to subtyping accuracy and utilization of immunohistochemistry (IHC) for NSCLC subtyping were analyzed. In addition, the performance of cytologic specimens submitted for EGFR/KRAS molecular testing during a 1-year period (n = 128) was reviewed.Results:Of the 192 preoperative cytology diagnoses, tumor subtype was definitive versus favored versus unclassified in 169 (88%) versus 15 (8%) versus 8 (4%) cases, respectively. Overall accuracy of cytologic tumor subtyping (concordance with histology) was 93% and accuracy of definitive diagnoses 96%. For a group of patients with ADC and SqCC (n = 165), the rate of unclassified cytologic diagnoses was 3% and overall accuracy 96%. IHC was used for subtyping of 9% of those cases, yielding 100% accuracy. The strongest predictors of difficulty in subtyping of ADC and SqCC were poor differentiation (p = 0.0004), low specimen cellularity (p = 0.019), and squamous histology (p = 0.003). Of 128 cytologic specimens submitted for molecular testing, 126 (98%) were suitable for analysis, revealing EGFR and KRAS mutations in 31 (25%) and 25 (20%) cases, respectively.Conclusions:Cytologic subtyping of NSCLC is feasible and accurate, particularly when morphologic assessment is combined with IHC. Furthermore, routine cytologic specimens can be successfully used for EGFR/KRAS mutation analysis. Our data strongly support the suitability of cytologic specimens for the new therapeutic paradigms in NSCLC

Brief Report: Safety and Antitumor Activity of Alectinib Plus Atezolizumab From a Phase 1b Study in Advanced ALK-Positive NSCLC

INTRODUCTION: Alectinib is a preferred first-line treatment option for advanced ALK-positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects. METHODS: Adults with treatment-naive, stage IIIB/IV, or recurrent ALK-positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity. RESULTS: In total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1-39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64-97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo-NE), neither was median overall survival (95% CI: 33 mo-NE). CONCLUSIONS: The combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made

Distinct Clinical Course of EGFR-Mutant Resected Lung Cancers: Results of Testing of 1118 Surgical Specimens and Effects of Adjuvant Gefitinib and Erlotinib

Background:EGFR and KRAS mutations are mutually exclusive and predict outcomes with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in patients with stage IV lung cancers. The clinical significance of these mutations in patients with resected stage I–III lung cancers is unclear.Methods:At our institution, resection specimens from patients with stage I–III lung adenocarcinomas are tested for the presence of EGFR or KRAS mutations during routine pathology analysis such that the results are available before consideration of adjuvant therapy. In a cohort of 1118 patients tested over 8 years, overall survival was analyzed using multivariate analysis to control for potential confounders, including age, sex, stage, and smoking history. The impact of adjuvant erlotinib or gefitinib was examined in an independent data set of patients exclusively with EGFR mutation, in which date of recurrence was recorded.Results:In the overall population, we identified 227 KRAS (25%) and 222 EGFR (20%) mutations. Patients with EGFR-mutant lung cancers had a lower risk of death compared with those without EGFR mutations, overall survival (OS) HR 0.51 (95% confidence interval [CI]: 0.34–0.76, p < 0.001). Patients with KRAS-mutant lung cancers had similar outcomes compared with individuals with KRAS wild-type tumors, OS HR 1.17 (95% CI: 0.87–1.57, p = 0.30). A separate data set includes only patients with EGFR-mutant lung cancers identified over 10 years (n = 286). In patients with resected lung cancers and EGFR mutation, treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, disease-free survival HR 0.43 (95% CI: 0.26–0.72, p = 0.001), and a trend toward improved OS.Conclusions:Patients with resected stage I–III lung cancers and EGFR mutation have a lower risk of death compared with patients without EGFR mutation. This may be because of treatment with EGFR TKIs. Patients with, and without KRAS mutation have similar OS. These data support reflex testing of resected lung adenocarcinomas for EGFR mutation to provide prognostic information and identify patients for enrollment on prospective clinical trials of adjuvant EGFR TKIs

Prognostic Impact of KRAS Mutation Subtypes in 677 Patients with Metastatic Lung Adenocarcinomas

BackgroundWe previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared with patients with KRAS wild-type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer.MethodsWe reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6-year time period. We evaluated the associations among KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient dataset.ResultsAmong 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p = 0.99), smoking status (p = 0.33), or when comparing specific amino acid substitutions (p = 0.20). In our dataset, patients with KRAS codon 13 mutant tumors (n = 53) had shorter overall survival compared with patients with codon 12 mutant tumors (n = 624) (1.1 versus 1.3 years, respectively; p = 0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex, and smoking status (hazard ratio: 1.52, 95% confidence interval: 1.11–2.08; p = 0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 versus 1.1 years, respectively; p = 0.41).ConclusionsAmong individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are no apparent differences in outcome based on KRAS mutation subtype

KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib

BACKGROUND: Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive. METHODS AND FINDINGS: We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug. CONCLUSION: Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer

Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non-small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended