Targeting KRAS in pancreatic adenocarcinoma:Progress in demystifying the holy grail

Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an important role in cancer cell proliferation,differentiation,metabolism,and survival,making it an essential mutation for targeted therapy.Despite extensive efforts in studying this oncogene,there has been little success in finding a drug to target this pathway,labelling it for decades as“undruggable”.In this article we summarize some of the efforts made to target the KRAS pathway in PC,discuss the challenges,and shed light on promising clinical trials.

Genomic diversity of colorectal cancer: Changing landscape and emerging targets

Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers(CRC) where patients undergo treatment with a curative intent. Despite these efforts, a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes, as CRC remains one of the leading causes of cancer-related deaths in the world. The development of next generation sequencing and collaborative multiinstitutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC. This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease. Additionally, the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes, largely due to better selection of personalized therapies based on an individual's tumor genomic makeup. The benefit of various treatments is often limited, where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance. These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies, assessing the role of immunotherapy and prospective, dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC.

A Single Institutional Experience with Panitumumab in Metastatic Colorectal Cancer

Introduction: Panitumumab is an EGFR inhibitor approved for use in metastatic refractory colorectal cancer. It is unclear whether patients who have progressed on cetuximab may benefit from subsequent panitumumab therapy. This retrospective analysis was conducted to describe the experience at The Ohio State University with panitumumab including in patients who have progressed on cetuximab. Methods: Patients who received at least 1 dose of panitumumab between September 2006 and December 2011 were identified using the hospital’s pharmacy database. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 was used to assess responses and Kaplan-Meier curves were used to estimate progression-free survival (PFS) and overall survival (OS). Results: Eighty-seven patients (median age 61 years) were identified. Sixty-seven percent of patients had tumors with wild-type KRAS, 3.4% had tumors with mutated KRAS and the KRAS status was unknown in 29.9%. Twenty-four percent of the patients had an ECOG performance status of 2 or above and 59.8% of patients had received ≥ 2 prior lines of chemotherapy. Thirty-two percent of patients received single-agent panitumumab while 68% received it in combination with chemotherapy. Of the patients with KRAS wild-type tumors, 10 (17.2%) had objective responses (3 complete, 7 partial) and 26 (44.8%) had stable disease. Median PFS and OS were 5.0 and 9.0 months. The presence of a rash, improved ECOG performance status and coadministration with either irinotecan or FOLFIRI, led to a significantly better OS in univariate analysis. Among patients who had clinical benefit with cetuximab, 71% had subsequent clinical benefit with panitumumab therapy. Conclusions: In our single institution analysis of patients who received panitumumab, the number of prior lines of therapy did not significantly affect OS, suggesting that panitumumab retains its efficacy in the 2nd and 3rd line setting. Additionally, panitumumab can benefit patients who previously had clinical benefit with cetuximab.

Advances in KRAS mutation inhibition in metastatic colorectal cancer

KRAS is the most frequently mutated oncogene in human malignancies,observed in approximately two in five colorectal cancers(CRC).KRAS mutations were historically considered“undruggable”ten years ago and associated with resistance to EGFR targeted therapy.The success of finding allele-specific covalent KRASG12C inhibitors recently has made markedly breakthrough in KRAS targeted therapy,and has accelerated the discovery of agents targeting other KRAS mutants,such as G12D and G12V.Evidence in preclinical and clinical settings has proved excellent efficacy of several inhibitors in KRAS mutant CRC.Sotorasib and Adagrasib are currently changing the treatment paradigm for patients with metastatic CRC harboring KRASG12C mutation.The phenomenon that KRASG12C inhibition shows inferior efficacy in patients with CRC compared with non-small cell lung cancer has been observed in clinic due to drug resistance,and combination strategies to overcome the resistance are now being investigated in clinical trials.Here,we review the development of KRAS targeted treatment in CRC,mechanisms of resistance and potential combination strategies to improve efficacy.

Perspectives on immunotherapy utilization for hepatobiliary cancers in the United States

Strategies involving immunotherapy and targeted therapies are emerging in the last years as valuable options for patients with hepatobiliary cancer(HBC)including hepatocellular carcinoma(HCC),gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICC),and extrahepatic cholangiocarcinoma(ECC).

Editorial comment on:“Systemic treatment of hepatocellular carcinoma:an EASL position paper”

Hepatocellular carcinoma is the most common cancer of the liver and worldwide,the sixth most common cancer and the third most common cause of cancer related deaths(1).The management and treatment of this disease requires a multi-disciplinary approach,which is observed in the staging and classification.In 1999,the development of the Barcelona Clinic Liver Cancer(BCLC)classification system helped to guide the appropriate treatments based on stage.While patients with stage A disease would be candidates for locoregional treatment including surgical resection,liver transplantation or liver directed therapy,treatment in patients with intermediate(B)or advanced(C)stage disease would be palliative,where the recommendation would for systemic therapy.