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.

Supplementary Figure 1. "Phase 2-Eligible" Population. Supplementary Figure 2. ALKA-372-001 and STARTRK-1 Dosing Regimens.

DOC- 25K, Supplementary Tables 1-6

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.

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.

Abstract 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.

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.

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.

This study was conducted in the setting of advanced Non-small-cell lung cancer in older patients. It is a multicenter retrospective analysis on very old persons that explores the efficacy and the safety of anti-programmed cell death protein 1 therapy. Older patients seem to tolerate immunotherapy as well as younger patients with comparable efficacy. This is a relevant message for everyday clinical practice. 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. (C) 2020 Elsevier Inc. All rights reserved.

Background: Lombardy region, Italy, has one of world's largest coronavirus disease 19 (COVID-19) outbreak with over 80,000 cases Here, we report the incidence of SARS-CoV-2 infection in patients with active cancer at the Division of Oncology, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, a comprehensive cancer institution in the capital of Lombardy, Milano Patients and Methods: From April 15th to May 15th, 2020, SARS-CoV-2 testing has been performed in patients with active cancer by paired real time-PCR in nasopharyngeal swab (NPS) (Elitech, Torino, IT) and chemiluminescent immunoassays for detection of antiviral IgG in blood (Abbot, Sligo, IR or Diasorin, Saluggia, IT) Active cancer was defined as a solid tumor requiring anticancer treatment or supportive care Tested patients were either outpatients with at least one suggestive symptom of COVID-19 assessed by telephone triage per local guidelines, or inpatients routinely tested at hospital admission, irrespective of symptoms Additionally, patients with COVID-19 requiring hospitalization at Niguarda Hospital during the study period have been tested and results pooled for evaluating concordance of NPS with serology Results: 118 patients were tested by NSP, and paired serology is available at the moment for 63 (53 4%) In the outpatient setting, 517 underwent telephone triage and 58 reported at least one symptom (11 2%) Of these, 3/29 and 3/14 (10 3 and 21 4%) tested positive on NSP and serology, respectively In the cohort of inpatients, tested regardless of symptoms, 2/82 and 4/42 (2 4 and 9 5%) tested positive on NSP and serology, respectively Finally, among oncology physicians, 2/34 and 2/34 (5 9%) tested positive on NSP and serology, respectively 7 additional hospitalized patients displaying COVID-19 disease have been tested Overall, the accuracy between NSP and serology was 82 5% and concordance was 0 415 (Cohen's k) In 5 cases, serology was positive and NSP negative, whereas the opposite was found in 6 Recruitment and testing are still ongoing at the moment of abstract submission and complete results will be presented Conclusions: In our series of patients with active cancer during a peak period of the pandemic in Lombardy, 11% of outpatients displayed COVID-19 associated symptoms and 10% had positive NSP Among inpatients tested regardless of symptoms, 2 4% had positive NSP The accuracy between NSP and serology was 82 5%

Epidermal growth factor receptor (EGFR) gene mutations are strong oncogenic drivers in a subset of non–small-cell lung cancer (NSCLC). Their inhibition with specific tyrosine kinase inhibitors (TKIs) represents a successful example of precision medicine. Nevertheless, disease progression almost invariably occurs after 9-14 months of treatment with either gefitinib, erlotinib, or afatinib (firstand second-generation TKIs) and after 19 months with osimertinib (a thirdgeneration TKI) because of the development of acquired therapeutic resistance.

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.

AbstractEntrectinib, 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

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.

Background: SQUIRE showed a significant improvement in survival with the addition of N to GC in pts with stage IV sq-NSCLC. In SQUIRE pts with EGFR-expressing tumours, we present efficacy data, and detail adverse events (AEs) by study phase (chemotherapy [Chemo] and continuation [Cont]).Methods: Pts with pathologically confirmed stage IV sq-NSCLC were randomised 1:1 to GC (G = 1250 mg/m2 iv, days [d]1 + 8; C = 75 mg/m2 iv, d1) plus N (800 mg iv, d1 + 8) (GC + N arm) or GC alone (GC arm) every 21d for ≤6 cycles (Chemo). GC + N pts with no progression continued on N alone until progressive disease or intolerable toxicity (Cont). SQUIRE included mandatory tissue collection. EGFR protein expression was assessed by IHC in a central lab (Dako EGFR PharmDx kit). Exploratory analyses were prespecified for pts with EGFR-expressing (EGFR > 0) and non-expressing tumours.Results: 982 pts (89.8% of intention-to-treat [ITT] population) had evaluable IHC assay results; 935/982 (95.2%) had EGFR > 0; baseline characteristics were balanced between GC + N and GC arms. In EGFR > 0 patients, hazard ratios (GC + N vs GC) for OS and PFS were 0.79 (95% CI 0.69–0.92, p = 0.002) and 0.84 (95% CI 0.72–0.97, p = 0.018). Treatment-emergent AEs of special interest (AESI) by study phase are shown in the table. Grade ≥3 AESI with GC + N with a >4% increase over GC (Chemo phase) were hypomagnesaemia (9.4% vs 0.9%) and skin rash (4.6% vs 0.4%). The frequency of AESI was lower in the Cont phase.Table: A05AESI grouped by medical concept, selected for treatment relevance (% patients)Chemo PhaseCont PhaseGC + N (n = 456)GC (n = 468)N (n = 242)Any gradeGrade ≥3Any gradeGrade ≥3Any gradeGrade ≥3Neutropenia43.624.644.026.90.40.4Febrile neutropenia0.70.71.71.50.80.4Anaemia39.39.945.310.713.21.2Thrombocytopenia22.110.525.610.91.20Fatigue39.77.541.77.19.50.8Hypomagnesaemia30.79.415.40.915.32.1Hypomagnesaemia (lab data)aAll treated patients with ≥1 lab assessment at baseline and post-baseline.81.419.171.26.173.07.0Skin rash76.34.610.30.425.64.1Hypersensitivity/infusion-related reaction1.80.42.1000Conjunctivitis5.902.605.00.4Interstitial lung disease (pneumonitis)0.70.20.90.60.40.4Arterial thromboembolic events4.63.13.81.92.11.7Venous thromboembolic events9.24.85.32.62.51.7a All treated patients with ≥1 lab assessment at baseline and post-baseline. Open table in a new tab Background: SQUIRE showed a significant improvement in survival with the addition of N to GC in pts with stage IV sq-NSCLC. In SQUIRE pts with EGFR-expressing tumours, we present efficacy data, and detail adverse events (AEs) by study phase (chemotherapy [Chemo] and continuation [Cont]). Methods: Pts with pathologically confirmed stage IV sq-NSCLC were randomised 1:1 to GC (G = 1250 mg/m2 iv, days [d]1 + 8; C = 75 mg/m2 iv, d1) plus N (800 mg iv, d1 + 8) (GC + N arm) or GC alone (GC arm) every 21d for ≤6 cycles (Chemo). GC + N pts with no progression continued on N alone until progressive disease or intolerable toxicity (Cont). SQUIRE included mandatory tissue collection. EGFR protein expression was assessed by IHC in a central lab (Dako EGFR PharmDx kit). Exploratory analyses were prespecified for pts with EGFR-expressing (EGFR > 0) and non-expressing tumours. Results: 982 pts (89.8% of intention-to-treat [ITT] population) had evaluable IHC assay results; 935/982 (95.2%) had EGFR > 0; baseline characteristics were balanced between GC + N and GC arms. In EGFR > 0 patients, hazard ratios (GC + N vs GC) for OS and PFS were 0.79 (95% CI 0.69–0.92, p = 0.002) and 0.84 (95% CI 0.72–0.97, p = 0.018). Treatment-emergent AEs of special interest (AESI) by study phase are shown in the table. Grade ≥3 AESI with GC + N with a >4% increase over GC (Chemo phase) were hypomagnesaemia (9.4% vs 0.9%) and skin rash (4.6% vs 0.4%). The frequency of AESI was lower in the Cont phase.

ObjectivesAlthough 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 methodsA 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.ResultsOf 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.ConclusionFindings 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.

The phase 3 DECISION trial (NCT00895674) met its primary endpoint of progression-free survival for patients with RAI-rDTC and showed a significant PFS prolongation in favor of sorafenib (SOR) vs placebo (PBO) (HR 0.587; p < 0.0001). Overall survival (OS) was immature at the time of primary analysis in Aug 2012. We report OS results from 9- and 36-months follow up with exploratory crossover adjustment analyses. Patients were randomized to SOR or PBO. PBO patients were allowed to receive SOR open-label (OL) upon progression. OS data were analyzed using 2 adjustment methods for crossover: iterative parameter estimation (IPE) and rank preserving structural failure time (RPSFT). For all analyses CIs were calculated with the Cox model and with bootstrapping to include additional variance originating from the crossover adjustment. A total of 417 patients were randomized (207 SOR; 210 PBO). After progression, 158 of 210 patients (75%) crossed over to SOR. Hazard ratios (HRs) and 95% confidence intervals (CI) at the 3 data cutoffs are shown in the table. Although not significant, a consistent separation of the KM curves in favor of SOR was seen. OS crossover adjustment results showed larger treatment effects than ITT (ITT: 0.80-0.88; IPE : 0.70-0.80; RPSFT: 0.61-0.77). Due to the increasing effect of SOR in PBO patients over time, the separation between the 2 KM curves became smaller. Although significance was not reached in ITT, a trend in OS prolongation favoring SOR was observed consistently over successive time points. OS crossover adjustment results suggest that the true OS treatment effect may be larger than seen in the ITT analysis. The IPE method appears to produce more stable adjusted HRs across the 3 time points than RPSFT. These results should be considered as exploratory.Tabled 1Database cutoffHR (Cox model 95% CI) (bootstrapping 95% CI )ITT*IPERPSFT2012 Aug0.80 (0.54–1.19) (0.53, 1.18)0.70 (0.47–1.04) (0.40, 1.38)0.61 (0.40–0.94) (0.18, 2.16)2013 May0.88 (0.63–1.24) (0.63, 1.25)0.79 (0.57–1.11) (0.46, 1.61)0.69 (0.49–0.99) (0.33, 1.65)2015 Jul0.92 (0.71–1.21) (0.71, 1.21)0.80 (0.61–1.05) (0.48, 1.71)0.77 (0.58–1.02) (0.42, 1.79)*Unadjusted for treatment switch Open table in a new tab

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.

The DECISION trial established that sorafenib prolonged progression-free survival (PFS) compared to placebo in patients with progressive RAI-rDTC (Lancet 2014). Here we sought to identify prognostic and predictive factors correlated with treatment outcomes.

BACKGROUND:Malignant peritoneal mesothelioma (MPM) is a rare disease characterized by a difficult diagnosis, different types of presentation, variable course and poor prognosis.MATERIALS AND METHODS:Eighty-one patients with MPM observed in 14 Italian oncology institutions from 1982 to 2007 have been examined with the aim of delineating the history of MPM.RESULTS:Presentation symptoms were ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting in various associations. Computed tomography scan and echotomography signs were ascites, abdominal mass and peritoneal thickening. Peritoneal fluid cytology (61 cases) was positive for mesothelioma in 31 and for malignancy, not mesothelioma, in 13. Laparoscopy was carried out in 40 cases and laparotomy in 36. Thrombocytosis was present in 59 cases. Associated tumors diagnosed during the lifetime were colorectal cancer in two cases and cheek carcinoma, thyroid carcinoma, tongue carcinoma, bladder carcinoma and testicular seminoma. Thirty patients were treated with surgery and 45 with chemotherapy. The median survival time from diagnosis is 13 months. Ascites, fever and vomiting were significative variables at presentation; only vomiting holds significance in a multivariate analysis.CONCLUSIONS:MPM is a disease with various types of presentation, frequently associated with thrombocytosis, sometimes with other tumors. Survival and diagnosis time can differ in various types of MPM. Prognosis is poor.