Lung cancer is the most common cause of cancer-related death worldwide, owing to its metastatic spread at the time of diagnosis. As a result, chemotherapy is the standard of care for the majority of patients. In recent years, the role of chemotherapy has expanded to include maintenance therapy and approved second-and third-line treatments. Nonetheless, traditional chemotherapy has modestly improved outcomes in patients with advanced non-small-cell lung cancer (NSCLC). Research efforts have been redirected toward the integration of molecularly-targeted agents into a treatment algorithm with unprecedented survival rates in selected patients. This article will provide an update on the multiple systemic regimens available to treat NSCLC, and discuss emerging molecular-based therapies.

With advances in technology and bioinformatics, we are now positioned to view and manage cancer through an evolutionary lens. This perspective is critical as our appreciation for the role of tumor heterogeneity, tumor immune compartment, and tumor microenvironment on cancer pathogenesis and evolution grows. Here, we explore recent knowledge on the evolutionary basis of cancer pathogenesis and progression, viewing tumors as multilineage, multicomponent organisms whose growth is regulated by subcomponent fitness relationships. We propose reconsidering some current tenets of the cancer management paradigm in order to take better advantage of crucial fitness relationships to improve outcomes of patients with cancer. SIGNIFICANCE: Tumor and tumor immune compartment and microenvironment heterogeneity, and their evolution, are critical disease features that affect treatment response. The impact and interplay of these components during treatment are viable targets to improve clinical response. In this article, we consider how tumor cells, the tumor immune compartment and microenvironment, and epigenetic factors interact and also evolve during treatment. We evaluate the convergence of these factors and suggest innovative treatment concepts that leverage evolutionary relationships to limit tumor growth and drug resistance.

Evaluations of resistance mechanisms to targeted treatments in non-small-cell lung cancer (NSCLC) are necessary for development of improved treatment after disease progression and to help delay progression of disease. Populations of cells that survive after initial treatment form the basis of resistance via outgrowth of resistant clones or activation of alternative signaling pathways. In this report we describe a clinical trial approach in which patients with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), C-ros-1 proto-oncogene (ROS1), and hepatocyte growth factor receptor (MET) exon 14 alterations and early stage (IA-IIIA) NSCLC will be treated with induction EGFR tyrosine kinase inhibitor (TKI) or crizotinib, a TKI that inhibits ALK, ROS1, and MET. We will evaluate resected tumor samples for pathologic response to induction therapy, overall response rate, and disease-free survival. Additionally, we will assess patients for early evidence of resistance to targeted therapy in terms of activation of alternative signaling pathways and for identification of resistance clones in remnant cell populations.

Background: Paraneoplastic leukemoid reaction (PLR) is a well-described entity in which the white blood cell count expands to greater than 50,000/mm3 in association with malignancy. It is thought to occur in approximately 10-15% of cancers. Notably, PLR is known to be predictive of a poor prognosis. Recent work has demonstrated that there may be a relationship between PLR activated by intratumoral production of granulocyte colony-simulating factor (G-CSF), the RAS/RAF/MEK pathway and tumorogenesis. Specifically, activation of the RAS/RAF/MEK pathway is thought to regulate G-CSF production, which in turn, mediates expansion and mobilization of cells that produce factors that promote tumor metastasis. Methods/results: In this report we demonstrate the PLR response to treatment in a patient with non-small cell lung cancer. Additionally, we demonstrate elevated G-CSF in the patient[U+05F3]s serum 507. pg/ml (0-39.1. pg/ml) and positive staining by immunohistochemistry of G-CSF in the patient[U+05F3]s tumor tissue. Finally, we describe a possible pathway by which this promotes tumor spread. Conclusion: Though G-CSF has been traditionally viewed as a prognostic marker, here we provide evidence that it may be a valuable marker to investigate for treatment response at a cellular level.

Background

Unsuccessful KRAS-specific treatment approaches in non-small-cell lung cancer (NSCLC) might reflect underlying disease heterogeneity. We sought to define clinical "syndromes" within advanced KRAS mutant NSCLC to improve future clinical trials and create a clinical framework for future molecular development.

Patients and methods

To test a series of a priori hypotheses regarding KRAS-mutant NSCLC clinical syndromes, we conducted a multi-institutional retrospective medical record review. Survival probabilities were estimated using the Kaplan-Meier model. Between-group differences were assessed using the log-rank test. Multivariate Cox regression analyses and Wilcoxon rank sum testing were used to assess progression-free survival and overall survival (OS) differences.

Results

Among 218 patients with advanced KRAS-mutant NSCLC, OS and progression-free survival with first-line chemotherapy did not differ by intrathoracic versus extrathoracic spread, smoking intensity, or the specific KRAS mutation. Metastatic disease at diagnosis resulted in significantly worse OS than recurrent, unresectable disease (median OS, 14.6 vs. 40.9 months; P = .001). Among the patients with metastatic disease at diagnosis, nonscalp, soft tissue metastases (syndrome X; 6% of cases; 95% confidence interval [CI], 2.5%-10.1%) signified a poor prognosis (median OS, 7.5 vs. 15.9 months for the controls; P = .021). The response to first-line chemotherapy (syndrome Y; 41% of cases; 95% CI, 32.3%-50.6%) signified a good prognosis (median OS, 26.7 vs. 11.9 months; P = .002). The overlap between these 2 syndromes was minimal (2 of 111). Multivariate analysis confirmed these observations. The hazard ratio for death for syndromes X and Y was 2.64 (95% CI, 1.13-6.14) and 0.45 (95% CI, 0.28-0.76), respectively.

Conclusion

Chemotherapy-responsive disease and nonscalp, soft tissue spread might represent distinct clinical syndromes within KRAS-mutant NSCLC. The molecular biology underlying this heterogeneity warrants future studies.

Background

Current guidelines recommend that patients with peripheral arterial disease (PAD) cease smoking and be treated with aspirin, statin medications, and angiotensin-converting enzyme (ACE) inhibitors. The combined effects of multiple guideline-recommended therapies in patients with symptomatic PAD have not been well characterized.

Methods and results

We analyzed a comprehensive database of all patients with claudication or critical limb ischemia (CLI) who underwent diagnostic or interventional lower-extremity angiography between June 1, 2006 and May 1, 2013 at a multidisciplinary vascular center. Baseline demographics, clinical data, and long-term outcomes were obtained. Inverse probability of treatment propensity weighting was used to determine the 3-year risk of major adverse cardiovascular or cerebrovascular events (MACE; myocardial infarction, stroke, or death) and major adverse limb events (MALE; major amputation, thrombolysis, or surgical bypass). Among 739 patients with PAD, 325 (44%) had claudication and 414 (56%) had CLI. Guideline-recommended therapies at baseline included use of aspirin in 651 (88%), statin medications in 496 (67%), ACE inhibitors in 445 (60%), and smoking abstention in 528 (71%) patients. A total of 237 (32%) patients met all four guideline-recommended therapies. After adjustment for baseline covariates, patients adhering to all four guideline-recommended therapies had decreased MACE (hazard ratio [HR], 0.64; 95% CI, 0.45 to 0.89; P=0.009), MALE (HR, 0.55; 95% CI, 0.37 to 0.83; P=0.005), and mortality (HR, 0.56; 95% CI, 0.38 to 0.82; P=0.003), compared to patients receiving less than four of the recommended therapies.

Conclusions

In patients with claudication or CLI, combination treatment with four guideline-recommended therapies is associated with significant reductions in MACE, MALE, and mortality.

Purpose

MET dysregulation is an oncogenic driver in non-small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor (EGFR)-mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance.

Methods

A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR-mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination.

Results

The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%.

Conclusion

Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. METHODS: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. RESULTS: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). CONCLUSIONS: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

Introduction

Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.

Methods

We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.

Results

A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.

Conclusions

In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAF^V600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRAS^G12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.