Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial.

Objectives: To assess the efficacy and safety of sotorasib in patients with brain metastases using data from the phase 3 CodeBreaK 200 study, which evaluated sotorasib in adults with pretreated advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).

Materials And Methods: Patients with KRAS G12C-mutated NSCLC who progressed after platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1:1 to sotorasib or docetaxel. An exploratory post-hoc analysis evaluated central nervous system (CNS) progression-free survival (PFS) and time to CNS progression in patients with treated and stable brain metastases at baseline.

Should Radiation Dose Be Personalized in Patients With Localized NSCLC and Actionable Genetic Alterations? Insight From a Multicenter Real-World Study.

Objectives: Radiation therapy (RT) is central to the management of unresectable stage I to III NSCLC. However, the impact of actionable genetic driver alterations (AGAs) on locoregional control (LRC) from RT remains uncertain. A retrospective, multicenter real-world study was undertaken to determine if common AGAs impact LRC after RT.

Molecular determinants of sotorasib clinical efficacy in KRAS-mutated non-small-cell lung cancer.

Molecular determinants of KRAS(G12C)inhibitor efficacy in KRAS-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRAS-mutated NSCLC co-mutational subsets and transcriptional subtypes.

Emerging Role of Targeted Therapies Combined With Radiotherapy in Inoperable Stages I to III NSCLC: A Review From the IASLC ART Subcommittee.

Precision oncology has transformed the management of NSCLC by tailoring treatment to the specific genetic alterations driving oncogenesis. Targeted therapies, such as tyrosine kinase inhibitors, have been found to dramatically improve survival in patients with advanced-stage NSCLC. However, treatment options remain limited for patients with early or locally advanced stage (I-III) NSCLC harboring driver mutations, when the disease is not resectable, or the patient is unsuitable for surgery due to poor fitness or comorbidities.

Prevalence and breakdown of driver mutations in a large UK non-small cell lung cancer cohort.

Kirsten rat sarcoma viral oncogene () is a frequently mutated oncogene in lung cancer, now amenable to targeted therapy with allele-specific G12C inhibitors. Non-small cell lung cancer (NSCLC) driver mutations show geographical variability and therefore the mutation breakdown, co-occurring oncogenic mutation rate and associated PD-L1 expression were studied in a large UK cohort. We interrogated archival clinical next-generation sequencing (NGS) data over 5 years.

First-line osimertinib compared to earlier generation TKIs in advanced EGFR-mutant NSCLC: A real-world survival analysis.

Objectives: This study aimed to compare the overall survival (OS) of patients with advanced EGFR-mutant NSCLC treated with first-line osimertinib versus earlier-generation EGFR tyrosine kinase inhibitors (TKIs) in a real-world setting. Secondary endpoint included OS in patients with uncommon EGFR mutations. Exploratory aim focused on the impact of TKIs sequencing strategies.

Phase II Study to Determine the Antitumor Activity and Safety of Simlukafusp Alfa (FAP-IL2v) Combined with Atezolizumab in Esophageal Cancer.

Purpose: In this study, we report the results from the esophageal squamous cell carcinoma (SCC) cohort of a phase II, noncomparative, basket study evaluating the antitumor activity and safety of fibroblast activation protein-IL2 variant (FAP-IL2v) plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721).

Patients And Methods: Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 to 1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor-naïve. Patients received FAP-IL2v 10 mg plus atezolizumab 1,200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks and then every 2 weeks plus atezolizumab 840 mg intravenously every 2 weeks.

The evolution of non-small cell lung cancer metastases in TRACERx.

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS mutation: a randomised, open-label, phase 3 trial.

Background: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRAS. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRAS mutation who had been previously treated with other anticancer drugs.

Methods: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries.

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion.

Introduction: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete.

Methods: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers.

More to the RAS Story: KRAS Inhibition, Resistance Mechanisms, and Moving Beyond KRAS.

Despite the discovery of oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as , , and . The discoveries that (1) malignant oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward -driven cancers. Although the development of allele-selective KRAS inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers.

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma.

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRAS, the most common mutation, is found in ~13% of patients.

EPAC-lung: European pooled analysis of the prognostic value of circulating tumour cells in small cell lung cancer.

Background: Circulating tumour cell (CTC) number is an independent prognostic factor in patients with small cell lung cancer (SCLC) but there is no consensus on the CTC threshold for prognostic significance. We undertook a pooled analysis of individual patient data to clinically validate CTC enumeration and threshold for prognostication.

Methods: Four European cancer centres, experienced in CellSearch CTC enumeration for SCLC provided pseudo anonymised data for patients who had undergone pre-treatment CTC count.

Direct Ras G12C inhibitors: crossing the rubicon.

Despite its status as the most commonly mutated oncogene in cancer, Ras has long been considered 'undruggable'. In 2019, we will see the first clinical trial results for direct mutant Ras inhibitors, a result of persistent cross-disciplinary research that has been informed by a number of previous clinical and biological failures.

Effectiveness of dabrafenib in the treatment of patients with BRAF V600-mutated metastatic melanoma in a Named Patient Program.

Given the approval of dabrafenib in patients with BRAF-mutant metastatic melanoma, a better understanding of treatment patterns and clinical outcomes with dabrafenib in a clinical setting is warranted. We performed a retrospective chart review of patients who received dabrafenib in a compassionate use setting through the Named Patient Program (DESCRIBE I study) during December 2010-August 2013 in Europe, New Zealand and Australia. Of the 331 Named Patient Program patients included, the majority (95.

KRAS-mutant non-small cell lung cancer: Converging small molecules and immune checkpoint inhibition.

KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches, an efficacy associated in particular with TP53 co-mutation. In this review we detail reasons for previous failures in KRAS-mutant NSCLC, evidence to suggest that KRAS mutation is a genetic marker of benefit from immune checkpoint inhibition, and emerging direct inhibitors of K-Ras which will soon be combined with immunotherapy during clinical development.

Somatic cancer genetics in the UK: real-world data from phase I of the Cancer Research UK Stratified Medicine Programme.

Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context.

Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013.

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting.

Background: We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer.

Methods: In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses.

Circulating Tumor Cells with Aberrant Copy Number Predict Progression-Free Survival during Crizotinib Treatment in -Rearranged Non-Small Cell Lung Cancer Patients.

The duration and magnitude of clinical response are unpredictable in -rearranged non-small cell lung cancer (NSCLC) patients treated with crizotinib, although all patients invariably develop resistance. Here, we evaluated whether circulating tumor cells (CTC) with aberrant -FISH patterns [-rearrangement, -copy number gain (-CNG)] monitored on crizotinib could predict progression-free survival (PFS) in a cohort of -rearranged patients. Thirty-nine -rearranged NSCLC patients treated with crizotinib as first ALK inhibitor were recruited prospectively.