Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials.

A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer.

PURPOSE: We conducted a phase I study to evaluate the maximum tolerated dose (MTD), safety, and efficacy of trametinib in combination with TAS-102 in patients with chemotherapy-refractory KRAS-mutant, wild-type PIK3CA/PTEN metastatic colorectal cancer (mCRC). METHODS: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with chemorefractory mCRC without priorTAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. Primary endpoint was evaluation of MTD. RESULTS: 25 eligible patients were enrolled in this study. During the dose de-escalation phase, no dose-limiting toxicities (DLT) were observed at the full doses of trametinib/TAS-102 and the MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1 to5 and days 8 to12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was two months (95% confidence interval [CI] 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%). CONCLUSIONS: Trametinib in combination with TAS-102 demonstrated a manageable safety profile. However, this combination did not achieve meaningful clinical benefit in patients with RAS-mutated PIK3CA and PTEN wild-type refractory mCRC. CLINICAL TRIAL INFORMATION: NCT03317119.

Therapeutic Advances and Challenges in the Management of HER2-Positive Gastroesophageal Cancers.

Gastroesophageal cancer is one of the most common cancers in the world, with a high rate of mortality. While there has been significant progress over the past decade, particularly with the addition of anti-HER2 therapies to platinum-based chemotherapy agents in the advanced setting, the prognosis remains poor and the treatment options for this disease entity remain limited. In this review, we discuss the current therapeutic landscape for HER2-positive gastroesphageal cancer and the seminal clinical trials that have shaped our approach to this disease entity. In addition, we highlight some of the challenges to the understanding and management of this disease, specifically discussing the breadth of molecular diversity and intratumoral heterogeneity of HER2 expression that impact the clinical efficacy and prognosis. Furthermore, we discuss the potential role of next-generation sequencing (NGS) and circulating-tumor DNA (ctDNA) as complementary tools to immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) to guiding clinical decision making. Finally, we highlight promising clinical trials of new treatment regimens that will likely reshape the therapeutic approach to this disease entity.

Locally advanced anal small cell carcinoma with durable complete response to chemoradiation followed by consolidation chemotherapy: case report and literature review.

Extrapulmonary small cell carcinoma (EPSCC) is a rare and aggressive clinical entity that can involve a variety of anatomic locations, including the gastrointestinal tract. Involvement of the gastrointestinal tract is associated with a particularly poor prognosis with patients often presenting with widespread dissemination on initial clinical presentation or rapidly progressing to systemic disease from locoregional involvement. Primary small cell carcinoma of the anal canal is extremely rare, with limited published case reports in the literature. As a result, management of this disease is not well defined, and outcomes are poor with high rates of disease relapse. We report a patient with locally advanced anal small cell carcinoma after presenting with irregular bowel movements, changes in stool caliber, and rectal bleeding for two months and achieved a durable complete response to concurrent chemoradiation with cisplatin and etoposide followed by consolidation chemotherapy and discuss our current understanding of this disease. Specifically, we review the epidemiology, risk factors, clinical course, the treatment strategies over the past two decades, and prognosis for EPSCC. Finally, we conclude our discussion by reviewing the rationale of our treatment regimen and the potential role and benefit of consolidation therapy in the management of this rare and aggressive disease.

MAP2K1 Mutations in Advanced Colorectal Cancer Predict Poor Response to Anti-EGFR Therapy and to Vertical Targeting of MAPK Pathway.

BACKGROUND: MAP2K1 mutations, otherwise known as MEK mutations, are rare oncogenic alterations that have been implicated in MAPK pathway activation. The impact of MAP2K1 mutations in colorectal cancer on EGFR antibody response has not been characterized. PATIENTS AND METHODS: Antitumor activity was assessed in mouse xenograft models with SW48 cell lines harboring MAP2K1 mutation, and protein expression of the RAS signaling pathway was studied by Western blot analysis. We retrospectively identified patients with MAP2K1-mutated metastatic colorectal cancer patients treated at City of Hope Comprehensive Cancer Center between 2015 and 2020 using next-generation sequencing. Patients' tumor characteristics, treatment response, and outcome are described. Additional patients with the MAP2K1 mutation were identified from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center oncogenomic databases. RESULTS: Antitumor activity in mouse xenograft models demonstrated efficacy with combination therapy with EGFR and MEK inhibition with either BRAF or ERK inhibitors. Five patients treated at City of Hope between 2015 and 2020 harbored a MAP2K1 mutation at a frequency of 1%. APC and TP53 were common coalterations. All disease was RAS and BRAF wild type, except 1 case that harbored a concurrent KRAS mutation. Four RAS/BRAF wild-type MAP2K1-mutated patients was treated with anti-EGFR, anti-EGFR + MEK and BRAF inhibitors, and anti-EGFR + ERK inhibitors. All 4 patients experienced disease progression. CONCLUSION: MAP2K1 mutation in colorectal cancer is associated with poor response to EGFR inhibition. EGFR inhibition with or without MEK, BRAF, or ERK inhibitors did not result in any clinical benefit in our limited experience.

Fulminant Disseminated Intravascular Coagulation as Initial Presentation of BRAF-Mutated Melanoma.

Acute disseminated intravascular coagulation (DIC) is a pathological process involving dysfunction of the coagulation cascade. In this case report, we discuss a 33-year-old woman with BRAF V600E-mutated metastatic melanoma who presented in fulminant DIC with concurrent hemorrhagic and thrombotic manifestations and discuss the patient's brief response to combination therapy. In our discussion, we highlight the current understanding of DIC and also identify opportunities for future research to elucidate the genetic aberrations in melanoma that may result in treatment resistance to combination therapy.

Checkpoint inhibition in advanced gastroesophageal cancer: clinical trial data, molecular subtyping, predictive biomarkers, and the potential of combination therapies.

The development of checkpoint inhibitors has redefined the treatment paradigm for advanced gastroesophageal cancer. While recent developments have improved clinical outcomes, the prognosis for the disease remains meager. In this review, we discuss the rationale and detail the results from recent phase I-III trials supporting the activity of PD-1 inhibitors. Specifically, we highlight the seminal clinical trials leading to the FDA approval of pembrolizumab for advanced gastroesophageal cancer. Finally, we review the current understanding and future considerations of molecular subtyping and predictive biomarkers to help guide therapy and the promise of combination therapy to further improve the efficacy of checkpoint inhibitors.

Refining the management of resectable esophagogastric cancer: FLOT4, CRITICS, OE05, MAGIC-B and the promise of molecular classification.

The multidisciplinary management of locoregional esophagogastric cancers (GCs) has evolved significantly over the past two decades. While perioperative chemotherapy, adjuvant chemotherapy, and postoperative chemotherapy with chemoradiation (CRT) have demonstrated improved survival when compared to surgery alone, there is no universal standard for resectable gastroesophageal cancer. Current global management patterns vary by geographic region, partly related to phase III data originating from each global region. Herein we detail the landmark phase III trials that support the various multimodality treatment paradigms in resectable GC, with particular focus on findings from more recent phase III gastroesophageal cancer trials including FLOT4, MAGIC-B, OE05, and CRITICS. We highlight important ongoing and future approaches including the potential of molecular subtyping, predictive biomarkers, and immunotherapy as avenues to further improve outcomes in resectable gastroesophageal cancer.

Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single-agent checkpoint blockade.

Immune checkpoint inhibitors have demonstrated broad single-agent antitumor activity and a favorable safety profile that render them attractive agents to combine with other systemic anticancer therapies. Pancreatic cancer has been fairly resistant to monotherapy blockade of programmed cell death protein 1 receptor, programmed death ligand 1, and cytotoxic T-lymphocyte associated protein 4. However, there is a growing body of preclinical evidence to support the rational combination of checkpoint inhibitors and various systemic therapies in pancreatic cancer. Furthermore, early clinical evidence has begun to support the feasibility and efficacy of checkpoint inhibitor-based combination therapy in advanced pancreatic cancer. Despite accumulating preclinical and clinical data, there remains several questions as to the optimal dosing and timing of administration of respective agents, toxicity of combination strategies, and mechanisms by which immune resistance to single-agent checkpoint blockade are overcome. Further development of biomarkers is also important in the advancement of combination systemic therapies incorporating checkpoint blockade in pancreatic cancer. Results from an impressive number of ongoing prospective clinical trials are eagerly anticipated and will seek to validate the viability of combination immuno-oncology strategies in pancreatic cancer.

Moving Beyond Conventional Clinical Trial End Points in Treatment-refractory Metastatic Colorectal Cancer: A Composite Quality-of-life and Symptom Control End Point.

PURPOSE: This review highlights the evidence supporting symptom control and quality-of-life (QOL) measures as predictors of survival in treatment-refractory metastatic colorectal cancer (mCRC) and describes a composite symptom control and QOL end point recently reported in a Phase III trial that may serve as a more reasonable end point of efficacy in this population. METHODS: A literature search was conducted using MEDLINE to identify clinical studies (including case series and observational, retrospective, and prospective studies) that reported the predictive value of QOL measures for survival in mCRC. The search was limited by the following key words: quality of life, survival, and colorectal cancer. We then performed a second search limited to studies of randomized and Phase III design in mCRC to identify studies that used QOL assessments as their primary end points. A manual search was also performed to include additional studies of potential relevance. FINDINGS: There is increasing evidence to support that symptom control and QOL measures are predictors of survival in treatment-refractory mCRC and can serve as an alternative but equally as important end point to survival in this population. A recent large, randomized Phase III trial using a composite primary end point of lean body mass, pain, anorexia, and fatigue reported the feasibility in evaluating benefit in mCRC beyond conventional clinical trial end points. IMPLICATIONS: Future studies in treatment-refractory mCRC may be better served by evaluating improvement in symptom control and QOL, which may otherwise serve as the best predictor of survival in last-line treatment settings.