Targeting KRAS Oncogene for Patients With Colorectal Cancer: A New Step Toward Precision Medicine.

KRAS mutations are common driver oncogenes associated with the development of several solid tumors. KRAS oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of KRAS oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.

Neoadjuvant Immune Checkpoint Inhibitor Therapy for Patients With Microsatellite Instability-High Colorectal Cancer: Shedding Light on the Future.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm of mismatch repair-deficient/microsatellite instability-high (MMMR-D/MSI-H) colorectal cancer (CRC). Unique molecular features of MMR-D/MSI-H CRC with frameshift alterations, which result in mutation-associated neoantigen (MANA) generation, create an ideal molecular framework for MANA-driven T-cell priming and antitumor immunity. These biologic characteristics of MMR-D/MSI-H CRC resulted in rapid drug development with ICIs for patients with MMR-D/MSI-H CRC. Observed deep and durable responses with the use of ICIs in advanced-stage disease have stimulated the development of clinical trials with ICIs for patients with early-stage MMR-D/MSI-H CRC. Most recently, neoadjuvant dostarlimab monotherapy for nonoperative management of MMR-D/MSI-H rectal cancer and neoadjuvant NICHE trial with nivolumab and ipilimumab for MMR-D/MSI-H colon cancer resulted in groundbreaking results. Although nonoperative management of patients with MMR-D/MSI-H rectal cancer with ICIs will potentially define our current therapeutic approach, therapeutic goals of neoadjuvant ICI therapy for patients with MMR-D/MSI-H colon cancer may differ given that nonoperative management has not been well established for colon cancer. Herein, we overview recent advancements in ICI-based therapies for patients with early-stage MMR-D/MSI-H colon and rectal cancer and elaborate on the future treatment paradigm of this unique subgroup of CRC.

A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).

BACKGROUND: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). METHODS: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1. RESULTS: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. CONCLUSION: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

Study of Prothrombotic Changes in Metabolic Syndrome.

The metabolic syndrome is a complex disorder of various metabolic risk factors in a single individual having central obesity and commonly associated with diabetes and cardiovascular diseases. The aim of our study was to study the relationship between coagulation abnormalities and metabolic syndrome. We performed a prospective cross-sectional study in a tertiary care hospital. A total of fifty cases of metabolic syndrome and fifty age & sex matched controls were selected. These two groups were investigated for Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), Fibrinogen levels, Plasminogen Activator Inhibitor 1(PAI1) levels and Factor VIII levels. In cases with metabolic syndrome, significantly increased levels of Fibrinogen, Factor VIII and Plasminogen Activator Inhibitor1 (PAI1) were observed. PT & APTT were shorter in cases with metabolic syndrome. The coagulation parameters studied, correlated significantly with the components of metabolic syndrome. Metabolic syndrome is a hypercoagulable state and further studies are required for further evaluation of the consequences of this hypercoagulable state. There is a need for clinical trials evaluating prophylactic anticoagulation for prevention of venous thrombosis in patients with metabolic syndrome.

The evolving management of metastatic triple negative breast cancer.

Advanced triple negative breast cancer (TNBC) is an incurable disease classified by its lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Due to its lack of therapeutic targets, it has historically been treated with single agent chemotherapy, with combination cytotoxic therapy typically reserved for patients with high disease burdens, symptomatic disease, and/or impending visceral crisis. Recent molecular analyses have revealed that this clinical group of TNBCs is in fact quite biologically heterogeneous, with multiple TNBC subtypes defined by distinct biology and clinical behavior. Building on this biology, 2 targeted strategies are now approved for selected patients with advanced TNBC: the poly (ADP-ribose) polymerase inhibitors for advanced TNBC with a germline mutation in BRCA1/2, and the combination of the programmed death ligand 1-specific antibody atezolizumab with nab-paclitaxel for advanced TNBC that expresses programmed death ligand 1 on immune cells within the tumor. These targeted agents tend to be associated with a more favorable side effect profile and longer disease control than standard chemotherapy. A number of other targeted therapies have shown promise in early clinical trials, and several are now in definitive phase 3 testing for advanced TNBC. These include the antiapoptotic kinase inhibitors ipatisertib and capivasertib, and the antibody-drug conjugate sacituzumab govitecan-hziy. Approved biomarker-driven treatment options for this disease are thus likely to expand in the near-term. Here we review current treatment options and emerging targeted therapies for advanced TNBC. For patients who do not meet criteria for approved targeted therapies, participation in clinical trials evaluating precision medicines with candidate predictive biomarkers in advanced TNBC should be encouraged.