Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer.

BACKGROUND: KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C-mutated pancreatic cancer are unknown. METHODS: We conducted a single-group, phase 1-2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C-mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed. RESULTS: The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation. CONCLUSIONS: Sotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C-mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.).

Modern era systemic therapies: Expanding concepts of cure in early and locally advanced non-small cell lung cancer.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.

Circulating tumor cells detected in follow-up predict survival outcomes in tri-modality management of advanced non-metastatic esophageal cancer: a secondary analysis of the QUINTETT randomized trial.

BACKGROUND: Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. METHODS: We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. RESULTS: CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;p=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p<0.001). CONCLUSION: The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.

Atomic Partitioning of the MPn (n = 2, 3, 4) Dynamic Electron Correlation Energy by the Interacting Quantum Atoms Method: A Fast and Accurate Electrostatic Potential Integral Approach.

Recently, the quantum topological energy partitioning method called interacting quantum atoms (IQA) has been extended to MPn (n = 2, 3, 4) wave functions. This enables the extraction of chemical insight related to dynamic electron correlation. The large computational expense of the IQA-MPn approach is compensated by the advantages that IQA offers compared to older nontopological energy decomposition schemes. This expense is problematic in the construction of a machine learning training set to create kriging models for topological atoms. However, the algorithm presented here markedly accelerates the calculation of atomically partitioned electron correlation energies. Then again, the algorithm cannot calculate pairwise interatomic energies because it applies analytical integrals over whole space (rather than over atomic volumes). However, these pairwise energies are not needed in the quantum topological force field FFLUX, which only uses the energy of an atom interacting with all remaining atoms of the system that it is part of. Thus, it is now feasible to generate accurate and sizeable training sets at MPn level of theory. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc.

Cancer: Towards a general theory of the target: All successful cancer therapies, actual or potential, are reducible to either (or both) of two fundamental strategies.

General theories (GT) are reductionist explications of apparently independent facts. Here, in reviewing the literature, I develop a GT to simplify the cluttered landscape of cancer therapy targets by revealing they cluster parsimoniously according to only a few underlying principles. The first principle is that targets can be only exploited by either or both of two fundamentally different approaches: causality-inhibition, and 'acausal' recognition of some marker or signature. Nonetheless, each approach must achieve both of two separate goals, efficacy (reduction in cancer burden) and selectivity (sparing of normal cells); if the mechanisms are known, this provides a definition of rational treatment. The second principle is target fragmentation, whereby the target may perform up to three categoric functions (cytoreduction, modulation, cytoprotection), potentially mediated by physically different target molecules, even on different cell types, or circulating freely. This GT remains incomplete until the minimal requirements for cure, or alternatively, proof that cure is impossible, become predictable.

Cancer adaptations: Atavism, de novo selection, or something in between?

From an evolutionary perspective, both atavism and somatic evolution/convergent evolution theories can account for the consistent occurrence, and astounding attributes of cancers: being able to evolve from a single cell to a complex organized system, and malignant transformations showing significant similarities across organs, individuals, and species. Here, we first provide an overview of these two hypotheses, including the possibility of them not being mutually exclusive, but rather potentially representing the two extremes of a continuum in which the diversity of cancers can emerge. In reviewing the current literature, we also discuss the criteria that should be applied to discriminate between the two competing theories and to determine their relevant contributions to oncogenesis and cancer progression. Finally, we deliberate on the potential applications of this conceptual framework in developing novel treatment strategies.

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype.

Cancer cells exhibit a wide range of metabolic phenotypes, ranging from strict aerobic glycolysis to increased mitochondrial respiration. The cause and utility of this metabolic variation is poorly understood. Given that cancer cells experience heavy selection within their microenvironment, survival requires metabolic adaptation to both extracellular and intracellular conditions. Herein, we suggest that reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype. Intracellular ROS levels can be modified by an assortment of critical parameters including oxygenation, glucose availability and growth factors. ROS act as integrators of environmental information as well as downstream effectors of signaling pathways. Maintaining ROS within a narrow range allows malignant cells to enhance growth and invasion while limiting their apoptotic susceptibility. Cancer cells actively modify their metabolism to optimize intracellular ROS levels and thereby improve survival. Furthermore, we highlight distinct metabolic phenotypes in response to oxidative stress and their tumorigenic drivers.

Synergistic Antiproliferative Activity of the RAD51 Inhibitor IBR2 with Inhibitors of Receptor Tyrosine Kinases and Microtubule Protein.

Although cancer cell genetic instability contributes to characteristics that mediate tumorigenicity, it also contributes to the tumor-selective toxicity of some chemotherapy drugs. This synthetic lethality can be enhanced by inhibitors of DNA repair. To exploit this potential Achilles heel, we tested the ability of a RAD51 inhibitor to potentiate the cytotoxicity of chemotherapy drugs. 2-(Benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) inhibits RAD51-mediated DNA double-strand break repair but also enhances cytotoxicity of the Bcr-Abl inhibitor imatinib. The potential for synergy between IBR2 and more drugs was examined in vitro across a spectrum of cancer cell lines from various tissues. Cells were exposed to IBR2 simultaneously with inhibitors of receptor tyrosine kinases, DNA-damaging agents, or microtubule disruptors. IBR2, at concentrations that inhibited proliferation between 0% and 75%, enhanced toxicity by up to 80% of imatinib and regorafenib (targets RAF and kit); epidermal growth factor receptor inhibitors erlotinib, gefitinib, afatinib, and osimertinib; and vincristine, an inhibitor of microtubule function. However, IBR2 antagonized the action of olaparib, cisplatin, melphalan, and irinotecan. A vincristine-resistant squamous cell line was not cross resistant to imatinib, but IBR2 and another RAD51 inhibitor (B02) enhanced imatinib toxicity in this cell line, its HN-5a parent, and the colon cancer line HT-29 by up to 60% and much better than verapamil, a P-glycoprotein inhibitor (P < 0.05). Given the disparate agents the functions of which are enhanced by IBR2, the mechanisms of enhancement may be multimodal. Whether RAD51 is common to these mechanisms remains to be elucidated, but it provides the potential for selectivity to tumor cells.

Using the Relative Energy Gradient Method with Interacting Quantum Atoms to Determine the Reaction Mechanism and Catalytic Effects in the Peptide Hydrolysis in HIV-1 Protease.

The reaction mechanism in an active site is of the utmost importance when trying to understand the role that an enzyme plays in biological processes. In a recently published paper [Theor. Chem. Acc. 2017, 136, 86], we formalised the Relative Energy Gradient (REG) method for automating an Interacting Quantum Atoms (IQA) analysis. Here, the REG method is utilised to determine the mechanism of peptide hydrolysis in the aspartic active site of the enzyme HIV-1 Protease. Using the REG method along with the IQA approach we determine the mechanism of peptide hydrolysis without employing any arbitrary parameters and with remarkable ease (albeit at large computational cost: the system contains 133 atoms, which means that there are 17 689 individual IQA terms to be calculated). When REG and IQA work together it is possible to determine a reaction mechanism at atomistic resolution from data directly derived from quantum calculations, without arbitrary parameters. Moreover, the mechanism determined by this novel method gives concrete insight into how the active site residues catalyse peptide hydrolysis.

Decomposition of Møller-Plesset Energies within the Quantum Theory of Atoms-in-Molecules.

We discuss two main approaches to decompose the Møller-Plesset perturbation theory molecular energies into atomic contributions within the interacting quantum atoms (IQA) formalism, as implemented in the programs Morphy and AIMAll. For this purpose, the so-called intraatomic energies (also known as self-energies) of a representative set of 55 small molecules are compared with each other. The origin of the possible discrepancies between both approaches is analyzed, and linear models linking the two approaches are proposed for each atom type.

The Transferability of Topologically Partitioned Electron Correlation Energies in Water Clusters.

The electronic effects that govern the cohesion of water clusters are complex, demanding the inclusion of N-body, Coulomb, exchange and correlation effects. Here we present a much needed quantitative study of the effect of correlation (and hence dispersion) energy on the stabilization of water clusters. For this purpose we used a topological energy partitioning method called Interacting Quantum Atoms (IQA) to partition water clusters into topological atoms, based on a MP2/6-31G(d,p) wave function, and modified versions of GAUSSIAN09 and the Quantum Chemical Topology (QCT) program MORFI. Most of the cohesion in the water clusters provided by electron correlation comes from intramolecular energy stabilization. Hydrogen bond-related interactions tend to largely cancel each other. Electron correlation energies are transferable in almost all instances within 1 kcal mol-1 . This observed transferability is very important to the further development of the QCT force field FFLUX, especially to the future modelling of liquid water.

Phase II trial of capecitabine plus erlotinib versus capecitabine alone in patients with advanced colorectal cancer.

Aim & methods: Capecitabine monotherapy as palliation for advanced colorectal cancer (CRC) is generally well tolerated. Adding erlotinib, an EGFR-tyrosine kinase inhibitor, might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone (Arm 1) or capecitabine with erlotinib (Arm 2). RESULTS: Median time-to-progression (TTP) in Arm 1 was 7.9 months versus 9.2 in Arm 2. In KRAS-wild type (WT) patients TTP was 8.4 and 11.7 months in Arms 1 and 2, respectively. In KRAS-mutated patients TTP was 7.4 and 1.9 months in Arms 1 and 2, respectively (p = 0.023). Arm 2 KRAS-WT patients, left-sided primaries, had an overall survival of 16.0 versus 12.1 months in right-sided primaries. CONCLUSION: Adding erlotinib to capecitabine increased TTP by 3.2 months in KRAS-WT patients. This study suggests that erlotinib harms patients with KRAS-mutated advanced CRC while it may provide benefit to those with KRAS-WT CRC. Further study of EGFR-tyrosine kinase inhibitors in patients with left-sided KRAS-WT CRC is warranted.

Targeting cancer's weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model.

In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation.

Functional lung avoidance for individualized radiotherapy (FLAIR): study protocol for a randomized, double-blind clinical trial.

BACKGROUND: Although radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial. METHODS/DESIGN: Eligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre-treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy-lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival. DISCUSSION: This randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02002052.

Accurate prediction of adsorption energies on graphene, using a dispersion-corrected semiempirical method including solvation.

The accurate prediction of the adsorption energies of unsaturated molecules on graphene in the presence of water is essential for the design of molecules that can modify its properties and that can aid its processability. We here show that a semiempirical MO method corrected for dispersive interactions (PM6-DH2) can predict the adsorption energies of unsaturated hydrocarbons and the effect of substitution on these values to an accuracy comparable to DFT values and in good agreement with the experiment. The adsorption energies of TCNE, TCNQ, and a number of sulfonated pyrenes are also predicted, along with the effect of hydration using the COSMO model.

Cancer: a de-repression of a default survival program common to all cells?: a life-history perspective on the nature of cancer.

Cancer viewed as a programmed, evolutionarily conserved life-form, rather than just a random series of disease-causing mutations, answers the rarely asked question of what the cancer cell is for, provides meaning for its otherwise mysterious suite of attributes, and encourages a different type of thinking about treatment. The broad but consistent spectrum of traits, well-recognized in all aggressive cancers, group naturally into three categories: taxonomy ("phylogenation"), atavism ("re-primitivization") and robustness ("adaptive resilience"). The parsimonious explanation is not convergent evolution, but the release of an highly conserved survival program, honed by the exigencies of the Pre-Cambrian, to which the cancer cell seems better adapted; and which is recreated within, and at great cost to, its host. Central to this program is the Warburg Effect, whose malign influence permeates well beyond aerobic glycolysis to include biomass interconversion and genomic heuristics. Warburg-type metabolism and genomic instability are targets whose therapeutic disablement is a major priority.

Assessment of serum tumor markers CEA, CA-125, and CA19-9 as adjuncts in non-small cell lung cancer management.

Conventional tumor markers may serve as adjuncts in non-small cell lung cancer (NSCLC) management. This study analyzed whether three tumor markers (CEA, CA19-9, and CA-125) held associations with radiographic and clinical outcomes in NSCLC. It constituted a single-center study of NSCLC patients treated with systemic therapy at the London Regional Cancer Program. Serum tumor markers were analyzed for differences in radiographic responses (RECIST v1.1 or iRECIST), associations with clinical characteristics, and all-cause mortality. A total of 533 NSCLC patients were screened, of which 165 met inclusion criteria. A subset of 92 patients had paired tumor markers and radiographic scans. From the latter population, median (IQR) fold-change from nadir to progression was 2.13 (IQR 1.24-3.02; p < 0.001) for CEA, 1.46 (IQR 1.13-2.18; p < 0.001) for CA19-9, and 1.53 (IQR 0.96-2.12; p < 0.001) for CA-125. Median (IQR) fold-change from baseline to radiographic response was 0.50 (IQR 0.27, 0.95; p < 0.001) for CEA, 1.08 (IQR 0.74, 1.61; p = 0.99) for CA19-9, and 0.47 (IQR 0.18, 1.26; p = 0.008) for CA-125. In conclusion, tumor markers are positioned to be used as adjunct tools in clinical decision making, especially for their associations with radiographic response (CEA/CA-125) or progression (CEA/CA-125/CA-19-9).

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.

Real-World Safety and Effectiveness of a Bevacizumab Biosimilar (ABP 215) in Metastatic Colorectal Cancer Patients in Canada.

BACKGROUND: ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS: Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS: A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION: The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.