Transient disappearance of RAS mutant clones in plasma: A counterintuitive clinical use of EGFR inhibitors in RAS mutant metastatic colorectal cancer

Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more recently reported in some patients with primary RAS mutant cancers, supporting for the first time an unexpected negative selection of RAS mutations during the clonal evolution of mCRC. To date, the extent of conversion to RAS wild type disease at the time of progression has not been clarified yet. As a proof of concept, we prospectively enrolled mCRC patients progressing under anti-VEGF based treatments. Idylla™system was used to screen RAS mutations in plasma and the wild type status of RAS was further confirmed through IT-PGM (Ion Torrent Personal Genome Machine) sequencing. RAS was found mutant in 55% of cases, retaining the same plasma mutation as in the primary tumor at diagnosis, while it was found wild-type in 45%. Four patients testing negative for RAS mutations in plasma at the time of progression of disease (PD) were considered eligible for treatment with EGFR inhibitors and treated accordingly, achieving a clinical benefit. We here propose a hypothetical algorithm that accounts for the transient disappearance of RAS mutant clones over time, which might extend the continuum of care of mutant RAS colorectal cancer patients through the delivery of a further line of therapy

Surgical and survival outcomes with perioperative or neoadjuvant immune-checkpoint inhibitors combined with platinum-based chemotherapy in resectable NSCLC: A systematic review and meta-analysis of randomised clinical trials

: The use of neoadjuvant or perioperative anti-PD(L)1 was recently tested in multiple clinical trials. We performed a systematic review and meta-analysis of randomised trials comparing neoadjuvant or perioperative chemoimmunotherapy to neoadjuvant chemotherapy in resectable NSCLC. Nine reports from 6 studies were included. Receipt of surgery was more frequent in the experimental arm (odds ratio, OR 1.39) as was pCR (OR 7.60). EFS was improved in the experimental arm (hazard ratio, HR 0.55) regardless of stage, histology, PD-L1 expression (PD-L1 negative, HR 0.74) and smoking exposure (never smokers, HR 0.67), as was OS (HR 0.67). Grade > = 3 treatment-related adverse events were more frequent in the experimental arm (OR 1.22). The experimental treatment improved surgical outcomes, pCR rates, EFS and OS in stage II-IIIB, EGFR/ALK negative resectable NSCLC; confirmatory evidence is warranted for stage IIIB tumours and with higher maturity of the OS endpoint

ALK Traslocated Pulmonary Sarcomatoid Carcinoma

Abstract Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a heterogeneous group of primitive lung cancer representing from 0.3% to 3% of all primary lung malignancies. Most patients with PSC consist of elderly, smoking men with a large, peripheral mass with welldefined margins. Case Report: We report a case of carcinosarcoma with ALK translocation in a 43 years old woman with a good response to therapy with Alectinib and a Progression Free survival (PFS) of 15 months. She underwent Total body CT scan that showed bone, liver and spleen metastasis. Histological sample was obtained with bronchoscopy, showing carcinosarcoma. Molecular analysis performed on tumor tissue showed an 80% immunochemistry ALK positivity and a negativity for EGFR, ROS 1 with a tumor proportion score (TPS) of programmed death ligand (PDL-1) of 20%. After one cycle of platinum-based doublet chemotherapy, interrupted for hematological toxicity, she was treated with Alectinib. We obtained a complete radiological response (CR) in extrapulmonary sites of disease but a SUV increased level was present in right upper lobe lesion (RUL). After few months she received Stereotactic Body Radiation Therapy (SBRT) in RUL showing a partial response. Discussion: PSC are a mixture of carcinoma and sarcoma containing differentiated sarcomatous elements. Generally, they are considered chemo resistant. In the last years, there has been development of targeted and immunotherapy in lung cancer but the role of these drugs in PCS is still unknown. Lots of studies are evaluating the role of MET amplification, PDL1 overexpression, EGFR mutation, ALK translocation. Conclusion: ALK rearrangement is a rare finding in PSC. This article shows the importance to test patients in order to find driver mutation even in rare and poor prognosis histological features of lung cancer. Keywords: Sarcomatoid carcinoma (SC); lung; ALK, ALectini

Prolactin as a Potential Early Predictive Factor in Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab

BACKGROUND/AIMS: Prolactin (PRL) is a peptide hormone and several studies have demonstrated its role as a cytokine in human T cell-mediated immunity. We are unaware if PRL is a positive or negative immunomodulator, but its effects on the regulation of T cells could inhibit the antitumor activity elicited by nivolumab (NIVO). We aimed to assess whether the occurrence of hyperprolactinemia in metastatic non-small cell lung cancer (mNSCLC) patients treated with NIVO is associated with poor clinical outcomes. METHODS: We evaluated 26 mNSCLC patients treated with NIVO. Blood samples were collected in every patient to evaluate PRL basal levels before starting the therapy with NIVO and before each following administration of NIVO. All patients underwent a conventional CT to investigate the effect of therapy according to Immune-related Response Evaluation Criteria in Solid Tumors (IrRECIST). RESULTS: Twenty patients (77%) developed hyperprolactinemia during the treatment, whereas 6 patients (23%) had stable levels of PRL during the therapy (p = 0.001). A total of 95% of the 20 patients with hyperprolactinemia had progressive disease (PD), according to CT results, whereas only 2 patients (33%) out of 6 with stable PRL levels had PD (p = 0.004). CONCLUSIONS: Hyperprolactinemia in mNSCLC patients treated with NIVO could potentially represent a negative early predictive factor for poor clinical outcomes, thus anticipating PD shown by CT sca

Evaluation of efficacy of ALK inhibitors according to body mass index in ALK rearranged NSCLC patients—A retrospective observational study

No evidence exists as to whether body mass index (BMI) impairs clinical outcomes from ALK inhibitors (ALKi) in patients with ALK-rearranged non-small cell lung cancer (NSCLC). Retrospective data of patients affected by metastatic ALK-rearranged NSCLC treated with ALKi were collected. We divided patients into “low- BMI” (≤25 kg/m2) and “high- BMI” (>25 kg/m2) categories and correlated them with overall survival (OS) and progression-free survival (PFS). We included 40 patients treated with ALKi. We observed a 3-year OS of 81.5% in high-BMI vs. 49.6% in low-BMI categories (p = 0.049); the 3-year first-line PFS was superior in high-BMI vs. low-BMI patients (47% vs. 19%, p = 0.019). As expected, patients treated with Alectinib had a 55.6% 3-year PFS vs. 7.1% for others treated with ALKi (p = 0.025). High-BMI was associated with a 100% 3-year PFS rate vs. 25.4% in low-BMI Alectinib patients (p = 0.03). BMI was independently correlated with first-line PFS and OS at multivariate analysis with PS (HR 0.39, CI 95% 0.16–0.96, p = 0.042; HR 0.18, CI 95% 0.05–0.61, p = 0.006). High-BMI was associated with higher efficacy in ALK-rearranged patients. These results are particularly exciting for Alectinib and could be correlated to mechanisms that should be investigated in subsequent prospective studies

TK inhibitor pazopanib primes DCs by downregulation of the β-catenin pathway

Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of thematuration markers HLA-DR, CD40 and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/b-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4þ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherap

Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors

(1) Background. The onset of a drug-drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN(R) (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0-2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN(R). (3) Results. Ninety-two patients, median age of 68.5 years (range 43-89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02; HR 0.281, 95% CI 0.096-0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC

Italian Nivolumab Expanded Access Program in Nonsquamous Non-Small Cell Lung Cancer Patients: Results in Never-Smokers and EGFR-Mutant Patients

Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC