Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy.

The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2-3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9-20.6); whereas 44/77 (57.1%) patients with grade 0-1 ST exhibited mOS of 8.2 months (CI 95%, 5.5-10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29-0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4-5.7) in patients with grade 2-3 ST, compared to patients with grade 0-1 ST with mPFS of 3.4 months (CI 95%, 2.7-4.1; HR, 0.49; CI 95%, 0.3-0.8; p = 0.004). Grade 2-3 ST (HR, 0.51; CI 95%, 0.29-0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27-0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27-0.9; p = 0.023), whereas there was a trend towards ST grade 2-3 (HR, 0.54; CI 95%, 0.29-1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.

Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With RAS Wild-type Metastatic Colorectal Cancer: The Phase 2 Single-Arm Clinical CAVE Trial.

IMPORTANCE: Rechallenge therapy with anti-epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC) after initial response to anti-EGFR-based first-line treatment. The association of treatment with cetuximab plus avelumab with overall survival (OS) may be worthy of investigation in this setting. OBJECTIVE: To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab. DESIGN, SETTING, AND PARTICIPANTS: This single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients with RAS WT mCRC had a complete or partial response to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy. Baseline circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R mutation analysis was done. INTERVENTIONS: Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m2 and, subsequently, 250 mg/m2 weekly) until disease progression or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: Seventy-seven patients were enrolled (42 men, 35 women; median age, 63 years); 71 had microsatellite stable tumors (MSS), 3 microsatellite instability-high tumors (MSI-H), 3 unknown. The study met the primary end point, with median OS (mOS) of 11.6 months (95% CI, 8.4-14.8 months). Median PFS (mPFS) was 3.6 months (95% CI, 3.2-4.1 months). Common grade-3 adverse events were cutaneous eruption, 11 (14%), and diarrhea, 3 (4%). For 67 of 77 (87%) patients, baseline analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R variations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients with RAS/BRAF WT ctDNA had mOS of 17.3 months (95% CI, 12.5-22.0 months) compared with 10.4 months (95% CI, 7.2-13.6 months) in patients with mutated ctDNA (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90; P = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) in RAS/BRAF WT patients compared with 3.0 months (95% CI, 2.6-3.5 months) in patients with mutated ctDNA (HR, 0.42; 95% CI, 0.23-0.75; P = .004). CONCLUSIONS AND RELEVANCE: The findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in RAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04561336.

Valorization of Olive Mill Wastewater by Membrane Processes to Recover Natural Antioxidant Compounds for Cosmeceutical and Nutraceutical Applications or Functional Foods.

Olive oil boasts numerous health benefits due to the high content of the monounsaturated fatty acid (MUFA) and functional bioactives including tocopherols, carotenoids, phospholipids, and polyphenolics with multiple biological activities. Polyphenolic components present antioxidant properties by scavenging free radicals and eliminating metabolic byproducts of metabolism. The objective of this research project was to recover the biologically active components rich in polyphenols, which include treatment of olive oil mills wastewater, and, at the same time, to remove the pollutant waste component resulting from the olive oil manufacturing processes. With specific focus on using technologies based on the application of ultra and nanofiltration membranes, the polyphenols fraction was extracted after an initial flocculation step. The nano-filtration permeate showed a reduction of about 95% of the organic load. The polyphenols recovery after two filtration steps was about 65% w/v. The nanofiltration retentate, dried using the spray dryer technique, was tested for cell viability after oxidative stress induction on human keratinocytes model in vitro and an improved cell reparation in the presence of this polyphenolic compound was demonstrated in scratch assays assisted through time lapse video-microscopy. The polyphenols recovered from these treatments may be suitable ingredients in cosmeceuticals and possibly nutraceutical preparations or functional foods.

Selumetinib for the treatment of non-small cell lung cancer.

INTRODUCTION: KRAS is the most frequently mutated oncogene in NSCLC, occurring in around a third of patients. However, this largest genomically defined subgroup of lung cancer patients seem to remain 'undruggable', with any effective targeted therapy approved at the moment. The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supportive of KRAS testing in clinical practice of NSCLC therapy. Areas covered: A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone. Disappointing data emerged from the next phase III trial in which the addition of selumetinib to docetaxel in patients with advanced KRAS mutant lung cancer did not improve survival or show clinical benefit. Expert opinion: Promising strategies against this common mutation are under evaluation in clinical trials. Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumor agents, by simultaneous inhibition of the RAS-RAF-MEK-MAPK pathway. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors.

Developments in pharmacotherapy for treating metastatic non-small cell lung cancer.

INTRODUCTION: Most patients with non-small cell lung (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, have advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available. Areas covered: The main state-of-the-art synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for NSCLC treatment, are reviewed and discussed from phase III randomized practice-changing trials onwards. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken. Expert opinion: The survival of NSCLC patients is increasing, regardless of the presence or not of a specific target, due to the availability of new generation drugs. The continuous deep knowledge of the mechanisms of NSCLC development and the constant research into new drugs should lead to the discovery of new potential targets and the synthesis of corresponding inhibitors to improve the outcomes of each subgroup of patients in order to control the disease in a constantly growing percentage of patients.

The Role of the Antiangiogenetic Ramucirumab in the Treatment of Advanced Non Small Cell Lung Cancer.

Angiogenesis is one of the most important phenomena sustaining tumor development and metastatization, including for non small cell lung cancer (NSCLC). A dominant role in angiogenesis is played by the vascular endothelial growth factor (VEGF) and its signaling pathway. Ramucirumab, is a fully human immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of the VEGF receptor-2 (VEGFR-2) with high specificity and affinity blocking the interaction of VEGFR-2 and VEGF ligands, thus inhibiting their signaling pathways and the consequential endothelial proliferation and migration. A recent phase III randomized trial named REVEL, demonstrated the efficacy of ramucirumab in combination with docetaxel as second line treatment of advanced NSCLC, leading to its FDA and EMA approval in this clinical setting. In the REVEL trial advanced NSCLC patients whose disease had progressed after first line platinum-based chemotherapy, were administered ramucirumab plus docetaxel or placebo plus docetaxel. More than 1,250 patients were treated and patients randomized to the treatment with ramucirumab plus docetaxel showed a significant longer median overall survival compared to those randomized to chemotherapy only. Ramucirumab is the first antiangiogenetic agent approved in the treatment both of squamous and non squamous NSCLC. In fact, it is not associated with increased risk of respiratory bleeding in the squamous histology, and also has demonstrated efficacy in both histology types. The role of ramucirumab, already cleared in the second-line treatment of advanced NSCLC, needs to be clarified further and is currently being explored also in the first-line treatment of advanced NSCLC.

The safety of second-line treatment options for non-small cell lung cancer.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) patients after first-line therapy ultimately suffer progression. At this time, many patients still have a good performance status and can be considered for further active treatment. Two chemotherapeutic agents, docetaxel and pemetrexed (only in non-squamous histology), and the biological drug anti-epidermal growth factor receptor (EGFR) erlotinib, were approved for clinical use in the second-line treatment of NSCLC patients. In the last few years further new second-line therapies have become available in the clinical practice. Areas covered: This review will discuss the adverse events of the pivotal trials ledding to the approval of second-line therapies for the treatment of not oncogene-addicted NSCLC patients. Expert opinion: In recent years, new second-line options for NSCLC are: the anti-EGFR, afatinib (only in squamous NSCLC); the anti-angiogenics, nintedanib (only in lung adenocarcinoma) and ramucirumab, in combination with docetaxel; the immunotherapeutics, nivolumab, pembrolizumab, and atezolizumab. In the second-line approach, the main endpoint of treatment should always be survival, but with great respect for symptoms palliation and preserving patients' quality of life. Therefore, differing toxicity profiles of the available therapeutic options are often a deciding factor in second-line setting for NSCLC.

Complete response to capecitabine in a frail, elderly patient with metastatic colorectal cancer: A case report.

The clinical management of frail, elderly patients affected by colorectal cancer (CRC) remains a subject of debate. The present study reports the case of an elderly man with metastatic CRC (mCRC) who was successfully treated with capecitabine. The patient survived for 29 months, thus highlighting its potential activity in terms of obtaining a complete response and high efficacy. A 77-year-old man presented with adenocarcinoma of the rectum with multiple and synchronous liver metastases, in addition to several comorbidities. The patient received single-agent capecitabine chemotherapy (825 mg/mq twice a day) on days 1-14 of a 21-day cycle. Following 12 cycles of well-tolerated therapy, a computed tomography scan revealed a complete response with no evidence of liver metastases. An overall survival of 29 months was documented, and the patient eventually succumbed to a diabetes-related complication. In compromised patients with mCRC, reduced-dose capecitabine is an excellent therapeutic option due to its positive safety profile, activity and efficacy.

Pharmacotherapeutic options for treating adverse effects of Cisplatin chemotherapy.

INTRODUCTION: Cisplatin is widely used in the treatment of several tumors such as lung, ovarian and testicular cancer with different degrees of effectiveness, and its use is burdened by some side effects. AREAS COVERED: This review includes the most important cisplatin side effects such as neurotoxicity, nephrotoxicity, ototoxicity, nausea and vomiting. They can affect patient's quality of life and lead to treatment interruptions with effectiveness reduction. EXPERT OPINION: Specific mechanisms of cisplatin-induced DNA damage and production of reactive oxygen species are the main ones responsible of toxicity. Several clinical approaches have been developed to reduce or prevent these effects with very promising results. The greatest potential for clinical practice is for amifostine, vitamin E, silymarin and NK-1 receptor antagonists.

The role of pembrolizumab in the treatment of advanced non-small cell lung cancer.

Lung cancer is the leading cause of death cancer related worldwide. The standard therapies have unmet medical needs both due to the limited activity and relevant toxicity of platinum-based chemotherapy and to the low frequency of specific alterations required to use targeted therapies. Immune checkpoint inhibition due to restoring the immune system's capacity to eradicate tumors is undergoing in extensive investigation in non-small cell lung cancer (NSCLC) as a new treatment approach. Programmed cell death protein-1 (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1) have recently led to significantly and durable improvements in the clinical outcome of several kind of tumors including lung cancer. Pembrolizumab, approved by the U.S. FDA for the treatment of advanced NSCLC progressed after other therapies and with expression of PD-L1, has demonstrated durable response and prolonged overall survival (OS) especially in patients with high PD-L1 expression. Further investigation are needed to improve treatment outcomes through combination of immunotherapy or combined with other targeted therapies.

Overcoming Resistance to EGFR Inhibitors in NSCLC.

BACKGROUND: The clarification of several molecular pathways underlying the tumorigenesis has led to the development of several targeted drugs that have substantially improved the treatment of Non-Small-Cell Lung Cancer (NSCLC). The Epidermal Growth Factor Receptor (EGFR) is the target of several Tyrosine-Kinase Inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. EGFR-TKIs markedly improve progression-free survival of patients with advanced NSCLC with EGFR mutations compared with chemotherapy. METHODS: We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. RESULTS: Although first- and second-generation agents offer in target population (with EGFR mutations) a substantial improvement of outcomes compared with standard chemotherapy, unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms. Novel- (third) generation EGFR inhibitors have a selective mechanism of action and are currently in advanced clinical development, producing encouraging results in patients with acquired resistance to previous generation agents. CONCLUSION: The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC, and third-generation EGFR inhibitors are the most promising approach to the issue.

Optimal drugs for second-line treatment of patients with small-cell lung cancer.

INTRODUCTION: Despite the high response rate to chemotherapy, there have been few advances in the treatment of small-cell lung cancer (SCLC) in the last decades. The state-of-the-art second-line therapy and future research developments in relapsed SCLC are reviewed. AREAS COVERED: There are no optimal drugs for second-line treatment of recurrent SCLC but only agents registered for this use. Topotecan remains the standard-of-care for the treatment of second-line platinum-sensitive SCLC patients worldwide, while amrubicin is another option, but registered only in Japan. To date, no targeted agents reporting interesting results in second-line SCLC treatment are available. The next-generation DNA sequencing should discover somatic gene alterations and their roles in SCLC to help in selecting patients who could benefit from a targeted agent. Two immunotherapeutics, ipilimumab and nivolumab, have shown promising preliminary results and are being investigated in ongoing trials. EXPERT OPINION: Second-line treatment is not an option for most SCLC patients. Given the evidence up to now, the potentials for immuno-oncology in SCLC are high. The hope is that these expectations are met, and that all drugs being developed will offer new and improved treatment options for SCLC patients.

Endocrinopathies induced by immune-checkpoint inhibitors in advanced non-small cell lung cancer.

The advent of immunotherapy has recently expanded the therapeutic options in advanced non-small cell lung cancer (NSCLC). In these patients, the recent efficacy demonstration of antibodies against immune checkpoints: the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1), has led to approval of nivolumab and pembrolizumab (anti-PD-1) in the treatment of advanced NSCLC. The mechanism of action of checkpoint inhibitors explains the development of autoimmune diseases as a side-effect of these medications. Among these, a spectrum of endocrine disorders has been also reported. This manuscript focuses particularly on endocrine disorders induced by immuno-checkpoint inhibitors employed in NSCLC, in order to suggest the strategies for their diagnosis and effective management.

Current status of targeted therapies in advanced gastric cancer.

INTRODUCTION: In metastatic gastric cancer, chemotherapy is the standard treatment because it prolongs survival when compared to best supportive care alone. However, even after the use of more effective regimens, the overall survival remains disappointing, justifying the need for new treatment options. AREAS COVERED: Areas covered in this review include the most common molecular pathways, which have provided novel targets in gastric cancer therapy. These therapeutic strategies include EGFR inhibitors, anti-angiogenic agents, cell cycle inhibitors and apoptosis promoters. EXPERT OPINION: Several mAbs and kinase inhibitors, especially those targeting EGFR and VEGF/VEGFR, have already demonstrated promising activity in gastric cancer. The Phase III ToGA trial reported an increase in overall survival for patients with human EGF receptor (HER)2-positive gastric cancer treated with chemotherapy and trastuzumab compared to chemotherapy alone. This means that accurate HER2 testing in gastric cancer is necessary. Final data of ongoing trials with novel agents will be critical to further progress with this cancer.