Biphenotypic lung carcinoma with coexpression of TTF-1 and ΔNP63/P40 within most of the same individual cells: a further case confirming poor prognosis and a review of literature.

The WHO Classification of Tumors, Thoracic Tumors, 5th edition, has outlined the use of TTF-1 and ΔNP63/P40 to discriminate between adenocarcinoma and squamous cell carcinoma. In 2015, the first description of a rare non-small cell lung carcinoma featuring co-expression of glandular and squamous differentiation within most of the same individual tumor cells was reported on, with ultrastructural and molecular demonstration of such a biphenotypic differentiation. We herein describe an additional case of this rare tumor entity, which is confirmed to be an aggressive neoplasm despite potential targets of therapy.

Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report.

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

What to do after immune-checkpoint inhibitors failure in advanced non-small cell lung cancer: an expert opinion and review.

INTRODUCTION: Immune-checkpoint inhibitors (IO) have significantly improved outcomes of patients with non-oncogene-addicted non-small cell lung cancer (NSCLC), becoming the first-line agents for advanced disease. However, resistance remains a significant clinical challenge, limiting their effectiveness. AREAS COVERED: Hereby, we addressed standard and innovative therapeutic approaches for NSCLC patients experiencing progression after IO treatment, discussing the emerging resistance mechanisms and the ongoing efforts to overcome them. In order to provide a complete overview of the matter, we performed a comprehensive literature search across prominent databases, including PubMed, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library, and a research of the main ongoing studies on clinicaltrials.gov. EXPERT OPINION: The dynamics of progression to IO, especially in terms of time to treatment failure and burden of progressive disease, should guide the best subsequent management, together with patient clinical conditions. Long-responders to IO might benefit from continuation of IO beyond-progression, in combination with other treatments. Patients who experience early progression should be treated with salvage CT in case of preserved clinical conditions. Finally, patients who respond to IO for a considerable timeframe and who later present oligo-progression could be treated with a multimodal approach in order to maximize the benefit of immunotherapy.

Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity.

Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICI), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, that could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.

Liquid Biopsy for Small Cell Lung Cancer either De Novo or Transformed: Systematic Review of Different Applications and Meta-Analysis.

BACKGROUND: The potential added value of liquid biopsy (LB) is not well determined in the case of small cell lung cancer (SCLC), an aggressive tumor that can occur either de novo or from the histologic transformation of non-small cell lung cancer (NSCLC). METHODS: A systematic review of studies adopting LB in patients with SCLC have been performed to assess the clinical utility of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). RESULTS: After a screening of 728 records, 62 studies (32 evaluating CTCs, 27 ctDNA, and 3 both) met predetermined eligibility criteria. Only four studies evaluated LB in the diagnostic setting for SCLC, while its prognostic significance was evaluated in 38 studies and prominently supported by both ctDNA and CTCs. A meta-analysis of 11 studies as for CTCs enumeration showed an HR for overall survival of 2.63 (1.71-4.05), with a potential publication bias. The feasibility of tumor genomic profiling and the predictive role of LB in terms of response/resistance to chemotherapy was assessed in 11 and 24 studies, respectively, with greater consistency for those regarding ctDNA. Intriguingly, several case reports suggest that LB can indirectly capture the transition to SCLC in NSCLC treated with EGFR tyrosine kinase inhibitors. CONCLUSIONS: While dedicated trials are needed, LB holds potential clinical roles in both de novo and transformed SCLC. CtDNA analysis appears the most valuable and practicable tool for both disease monitoring and genomic profiling.

Immune checkpoint inhibitors for unresectable malignant pleural mesothelioma.

Unresectable malignant pleural mesothelioma (MPM) is an aggressive disease with a 5-year survival rate of approximately 10%. Recent data suggest that MPM is an immunologically active tumor, in which checkpoint inhibition through the blockade of the anti-cytotoxic T lymphocyte antigen-4 (-CTLA-4) or anti-programmed cell death 1 (PD-1) could play a major therapeutic role. Initially, clinical trials evaluated immune checkpoint inhibitors (ICIs) in the salvage setting after platinum-based chemotherapy with mixed results in terms of efficacy. More recently, the combination of the anti-CTLA-4 agent ipilimumab plus the anti-PD-1 agent nivolumab was tested in the front-line setting, and reported a superior survival as compared to platinum/pemetrexed. While other clinical trials ore ongoing in order to investigate ICIs for MPM, it seems now evident that we have entered a new "era" for the treatment of MPM. In the future, a few issues need to be solved with regard to the use of ICIs for MPM. Among them, there is the identification of biomarkers of sensitivity to immunotherapy that may help enrich the patient population who could benefit the most from treatment, while avoiding for some other patients the potential occurrence of immune-related side effects from therapies that are anticipated to be ineffective.

Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients Aged ≥ 75 Years With Non-small-cell Lung Cancer (NSCLC): An Italian, Multicenter, Retrospective Study.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged ≥ 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy. MATERIAL AND METHODS: Inclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age ≥ 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events. RESULTS: Eighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P = .008). No difference in survival was found between patients younger and older than 80 years. CONCLUSIONS: In the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials.

Liquid Biopsy Testing Can Improve Selection of Advanced Non-Small-Cell Lung Cancer Patients to Rechallenge with Gefitinib.

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations of the epidermal growth factor receptor (EGFR). The ICARUS trial enrolled 61 patients who were rechallenged with gefitinib at progression after second-line chemotherapy. Serum-derived circulating cell-free DNA (cfDNA) collected before the rechallenge from a cohort of 29 patients, was retrospectively analyzed for the EGFR exon 19 deletions and for the p.L858R and p.T790M single nucleotide variants (SNV). The analysis of cfDNA detected the same EGFR activating mutation reported in the tumor tissue in 20/29 patients, with a sensitivity of 69%. Moreover, a p.T790M variant was found in 14/29 patients (48.3%). The median progression-free survival (PFS) was 2.7 months for p.T790M positive patients (CI 95% 1.4-3.1 months) versus 3.5 months for the p.T790M negative patients (CI 95% 1.6-5.3 months), resulting in a statistically significant difference (Long rank test p = 0.0180). These findings confirmed the role of the p.T790M mutation in the resistance to first-generation TKIs. More importantly, our data suggest that TKI rechallenge should be guided by biomarker testing.

Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility: A Single-Institution Experience.

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value. OBJECTIVE: We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s). PATIENTS AND METHODS: From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36-86) and the median number of previous treatment lines was five (range 2-8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%). RESULTS: One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63-3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0-15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80-5.03] vs. 2.13 months [95% CI 1.77-2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17-9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33-10.80] vs. 7.18 months [95% CI 5.63-9.33], respectively, p = 0.06). CONCLUSIONS: This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment.

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.

Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer.

OBJECTIVES: Although patients with advanced non-small cell lung cancer (NSCLC) and an activating epidermal growth factor receptor (EGFR) mutation benefit from the use of EGFR-tyrosine kinase inhibitors (TKI), most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR-TKIs after a chemotherapy break, based on small or retrospective studies. MATERIALS AND METHODS: A phase II trial was conducted in patients with stage III/IV NSCLC, to assess the efficacy, safety and impact on quality of life (QoL) and disease-related symptoms of gefitinib rechallenge. Eligible patients had initially responded to first-line gefitinib and progressed after second-line chemotherapy. RESULTS: Of 61 enrolled patients, 73.8% were female, 100% had EGFR-mutated adenocarcinoma and 67.2% were never-smokers. Thirty-two (52.5%) patients obtained a clinical benefit, with 3 (4.9%) achieving a partial response and 29 (47.5%) having stable disease. Median progression-free survival was 2.8 months, overall survival 10.2 months and duration of gefitinib treatment 3.6 months. The most common all grade-adverse events were diarrhea (27.6%), nausea and/or vomiting (20.3%), rash (14.7%) and dyspnea (10.3%); no new toxicities were apparent. CONCLUSION: Findings from this study indicate that gefitinib rechallenge offers modest benefit and may be taken into consideration only for patients for whom no other treatment option exists.

Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer.

BACKGROUND: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies. METHODS: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR. RESULTS: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20-29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response. CONCLUSIONS: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.

Correlation between variation in quality of life and change in hemoglobin level after treatment with epoetin alfa 40,000 IU administered once-weekly.

INTRODUCTION: Anemia is frequently associated with cancer due to the disease itself and antineoplastic treatments. This open-label, uncontrolled, multi-center study evaluated the effects of once-weekly (qw) epoetin alfa 40,000 IU on hemoglobin (Hb) levels and quality of life (QoL) in anemic patients receiving chemotherapy for solid tumors. MATERIALS AND METHODS: A total of 522 patients with Hb level < or =12 g/dL received epoetin alfa 40,000 IU qw subcutaneously for 9-20 weeks to reach and maintain Hb range of 12-14 g/dL. QoL was assessed with the Functional Assessment of Cancer Therapy-Anemia (FACT-An [anemia sub-scale]) and Cancer Linear Analogue Scale (CLAS) at study entry, after two chemotherapy cycles, and at study end. RESULTS: Mean baseline Hb was 10.43 g/dL. Hb increases (g/dL) from baseline after 4, 8, 12 weeks and at study end were 1.07, 1.77, 1.92 and 1.71 g/dL, respectively. Response rates (Hb increase > or =1 and > or =2 g/dL during trial) were 81% and 61%, respectively. Mean increases in the FACT-An score from baseline (mean 55.4) were 3.1 after two chemotherapy cycles and 3.3 at study end; mean increases in the CLAS score from baseline (58.4 mm) were 5.9 mm after two chemotherapy cycles and 6.5 mm at study end. DISCUSSION: The greatest QoL increase was recorded when patients approached Hb level of 12 g/dL, independent of the baseline Hb level. Hb changes from baseline to trial end were related to corresponding changes in the FACT-An score. A positive correlation was also observed in patients with progressive disease. Adverse events were essentially those associated with chemotherapy. Incidence of thrombovascular events (6.7%) did not differ from the expected standard treatment in cancer patients. Epoetin alfa 40,000 IU qw increased Hb levels and improved or preserved QoL.

Treatment of metastatic neuroendocrine carcinomas based on WHO classification.

A single institution prospective trial was conducted to evaluate the efficacy of biotherapy or chemotherapy in metastatic neuroendocrine carcinomas (NECs). The choice of therapy was based on the revised histological classification criteria of the WHO in an effort to define a standardized protocol for therapy of these cancers. Patients with well-differentiated NECs (WD-NECs; n=11) received therapy with octreotide long-acting release and interferon-alpha-2b for a maximum of 1 year; cases with poorly-differentiated NECs (PD-NECs; n=8) were given combination cisplatin, L-leucovorin and 5-fluorouracil chemotherapy for a maximum of 9 cycles. Five patients (4 with WD-NECs) had carcinoid syndrome. Among the patients with WD-NECs (median follow-up 20 months, range 4-40), 4 had partial responses and 7 had stable disease. In patients with PD-NECs (median follow-up 10.5 months, range 3-30), 3 had partial response, 2 stable disease, and the disease progressed in 3 cases. The 2-year survival rate in WD-NECs and PD-NECs was 88% and 66%, respectively. Grade 3-4 side-effects were limited to 9% thrombocytopenia and 12.5% neutropenia. Both these treatment regimens had a good therapeutic index and compared favourably with those previously reported for metastatic WD-NECs and PD-NECs.

Optimising management of neutropenia and anaemia in cancer chemotherapy-advances in cytokine therapy.

Neutropenia and anaemia are serious complications of myelosuppressive chemotherapy. They have a negative impact on patient quality of life and may reduce response to treatment. Febrile neutropenia, a potentially life-threatening complication of neutropenia, frequently requires hospital admission, while fatigue and weakness from anaemia reduce patient's capacity for activity. Pegfilgrastim and darbepoetin alfa, were designed to simplify and optimise treatment for patients with cancer. Once-per-cycle pegfilgrastim is as effective as daily filgrastim with respect to duration of severe neutropenia (DSN) and may have a lower incidence of febrile neutropenia than filgrastim. Darbepoetin alfa has enhanced biological activity and a serum terminal half-life three-fold longer than that of erythropoietin (EPO), which translates into rapid and sustained correction of anaemia with less frequent dosing. These novel cytokines have the potential to simplify the management of neutropenia and anaemia with fewer injections and less disruption to patients daily lives.