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PURPOSE We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non–small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738 ) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS). METHODS Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point. RESULTS Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti–PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure. CONCLUSION Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.

Background Combination of pertuzumab, trastuzumab and chemotherapy is standard of care for first-line treatment of patients with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. Most randomized studies used combination of taxanes and anti HER2 targeted treatment as 1st line treatment. The combination of vinorelbine, trastuzumab and pertuzumab has shown anti-tumor activity in a phase 2 trial. No trials have compared outcomes between vinorelbine to taxane in combination with pertuzumab and trastuzumab. Methods We retrospectively evaluated all patients with metastatic HER-2 positive breast cancer treated in two institutions between 3/2013 and 3/2018. Patients' clinical data were obtained from electronic medical records. We identified patients who were treated with vinorelbine (oral or intravenous) or a-taxane (docetaxel or paclitaxel) in combination with trastuzumab and pertuzumab as a first-line treatment. We compared progression free survival (PFS), overall survival (OS) and toxicity profiles between the two groups. Results The study included 120 patients (73 in the taxane and 47 in the vinorelbine group). There were several between-group differences: 65% of the taxane group patients were metastatic at diagnosis compared to 40% in the vinorelbine group (p=0.008), 18% of the taxane group received trastuzumab in the adjuvant setting vs. 45% in the vinorelbine group (p=0.003). More patients in the taxane group were asymptomatic (43.4% vs 23.4%, p=0.04). PFS was significantly longer in the taxane group compared to the vinorelbine group (35.4 months vs 13.9 months, p=0.0005). OS was also longer in the taxane group, but difference did not reach statistical significance (48.8 months vs 34.5 months, p=0.13). In the subgroup of patients with recurrent disease (excluding patients with de-novo metastatic disease), there was no difference for OS (32.6 vs 33.1 months for taxane and vinorelbine, respectively). Toxicity profiles differed between the groups, with more patients in the taxane group experiencing diarrhea, peripheral neuropathy and asthenia, and more patients in the vinorelbine group experiencing neutropenia. Discontinuation of chemotherapy due to toxicity was more common in the taxane group compared to the vinorelbime group. (38% vs. 17%, p=0.015). Conclusions In this retrospective analysis, first-line treatment with taxane combined with trastuzumab and pertuzumab for HER-2 positive metastatic breast cancer resulted in improved outcomes compared with the combination of vinorelbine, trastuzumab and pertuzumab. The vinorelbine arm revealed a favorable toxicity profile. Patients with recurrent disease (excluding de-novo metastatic disease) had similar outcomes with either chemotherapy. A randomized study is warranted. Citation Format: Daniel Jack Reinhorn, Irina Kuchuk, Judit Prus, Michal Sarfaty, Hadar Goldvaser, Ofer Rotem, Daniel Hendler, Dalia Zoref, Victoria Neiman, Tzipora Shohat, Olga Ulitsky, Shlomit Yust-Katz, Bella Nisenbaum, Maya Gottfried, Rinat Yerushalmi. Taxane versus vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with metastatic HER2-positive breast cancer - A retrospective two-center study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-33.

Mutació del MET; Capmatinib Mutación del MET; Capmatinib MET mutation; Capmatinib Background Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. Patients and methods Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. Results Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4–33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8–11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). Conclusions MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479). This study was funded by Novartis Pharmaceuticals Corporation.

BackgroundAfatinib is approved for first-line treatment of patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC). Here, we report findings from a combined analysis of three phase IIIb studies of afatinib in EGFR tyrosine kinase inhibitor (TKI)-naïve patients.MethodsEGFR-TKI-naïve patients withEGFRm+ NSCLC received afatinib 40 mg/day. Dose reductions were permitted for adverse events (AEs). Efficacy endpoints included progression-free survival (PFS), time to symptomatic progression (TTSP), and tumor response. Subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), presence of brain metastasis, age and common/uncommonEGFRmutations (plus other factors).Results1108 patients were treated. Median age was 61 years (range, 25–89); 19.2% had baseline brain metastases, 4.4% had ECOG PS ≥2, and 17.9% had tumors harboring uncommon mutations. Treatment-related AEs (TRAEs) were reported in 97.2%, most commonly diarrhea and rash. 41.6% had AEs leading to dose reduction. Median PFS was 13.0 months [95% confidence interval (CI): 12.0–13.8]; median TTSP was 14.8 months (95% CI: 13.9–16.1). Objective response rate (ORR) was 55.0%. Age, presence of baseline brain metastases, major (G719X, L861Q, S768I) or compound uncommon mutations had little/no effect on PFS, TTSP, or ORR, while outcomes were poorer in patients with ECOG PS 2 or exon 20 insertion/T790M mutations.ConclusionsAfatinib was tolerable with no new safety signals. Afatinib demonstrated encouraging efficacy in a broad patient population, including those with brain metastases or uncommonEGFRmutations.

The fatality of non-small-cell lung cancer (NSCLC) and the role of the cancer microenvironment in its resistance to therapy are long recognized. Accumulating data allocate a significant role for mesenchymal stem cells (MSCs) in the malignant environment. Previously, we have demonstrated that MSCs from NSCLC metastatic bone marrow (BM) niche deleteriously affected NSCLC cells. Here, we have decided to examine the effect of MSCs from the primary niche of the lung (healthy or adjacent to tumor) on NSCLC phenotype. We cultured NSCLC cell lines with healthy/NSCLC lung-MSCs conditioned media (secretome) and showed elevation in cells' MAPKs and translation initiation signals, proliferation, viability, death, and migration. We also established enhanced autophagy and epithelial to mesenchymal transition processes. Moreover, we observed that MSCs from tumor adjacent sites (pathological niche) exhibited a more profound effect than MSCs from healthy lung tissue. Our findings underscore the capacity of the lung-MSCs to modulate NSCLC phenotype. Interestingly, both tumor adjacent (pathological) and distant lung-MSCs (healthy) promoted the NSCLC's TI, proliferation, migration, and epithelial to mesenchymal transition, yet the pathological MSCs displayed a greater affect. In conclusion, by comparing the effects of normal lung-MSCs, NSCLC adjacent MSCs, and BM-MSCs, we have established that the primary and metastatic niches display opposite and critical effects that promote the cancerous systemic state. Specifically, the primary site MSCs promote the expansion of the malignant clone and its dispersion, whereas the metastatic site MSCs facilitates the cells re-seeding. We suggest that sabotaging the cross-talk between MSCs and NSCLC affords effective means to inhibit lung cancer progression and will require different targeting strategies in accordance with niche/disease stage.

The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial. The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013–2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile. The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36–0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4–1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5–1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2–0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2–0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39–1.23)] or the subgroups. Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

Objectives Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting. Materials and methods Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naive NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety. Results Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2–16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8–17.6) and 13.4 months (95 % CI: 11.8–14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6–21.8) and 15.9 months (95 % CI: 13.9–19.1) in patients with EGFR exon 19 deletions. Conclusions Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.

PURPOSE Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. METHODS Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. RESULTS Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. CONCLUSION Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.

The introduction of licensed front-line immunotherapies has heralded a new era for the treatment of non-oncogene-addicted, advanced non-small cell lung cancer (NSCLC). Yet as with all evolutions in clinical management, changes in practice can outpace the availability of the clinical evidence needed to inform subsequent therapeutic decision making. At the time of writing, there is limited available evidence on the optimum therapeutic options after progression on immunotherapy. Further research is needed to define mechanisms of immunotherapy resistance in patients with advanced NSCLC, and to understand the implications for subsequent treatment response. Pending the availability of robust clinical data and proven therapeutic options to underpin an optimized therapeutic pathway after progression on immunotherapy, attention must turn to the potential utility of currently licensed agents and any available supporting clinical data in this setting. Within this context we review the mechanistic arguments and supporting evidence for the use of anti-angiogenic agents as a means of targeting immunosuppression within the tumor microenvironment. We consider whether VEGF inhibition may help to normalize the tumor vasculature and to address immunosuppression - reinstating, and potentially enhancing, the effect of subsequent therapies. We also highlight evidence needs and signpost ongoing trials that should enable current clinical opinion in this area to be replaced by robust, evidence-based guidance.

PURPOSE Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. PATIENTS AND METHODS Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. RESULTS Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. CONCLUSION Our study demonstrates the clinical benefit of anti–programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

Background The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines. Methods A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period. Results A very high proportion of lung cancer cases are confirmed histologically/cytologically (75–100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75–100% of cases being discussed at a multidisciplinary tumor board at specialized centers. Conclusions Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges. Electronic supplementary material The online version of this article (10.1186/s12885-018-4023-4) contains supplementary material, which is available to authorized users.

Summary Background In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). Methods In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4–6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1–3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. Findings Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and −0·9 (−4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44–0·97; two-sided nominal p=0·029). Interpretation Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. Funding Merck & Co.

2565 Background: Approval of pembrolizumab for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors that have progressed on prior therapy was supported by data from KEYNOTE-158 (NCT02628067). At the data cutoff of Dec 6, 2018, the ORR was 34.3% among 233 patients (pts) with MSI-H/dMMR solid tumors enrolled in all cohorts of KEYNOTE-158, 77.6% had duration of response (DOR) ≥24 mo, median PFS was 4.1 mo, and median OS was 23.5 mo. We present results from 351 pts enrolled in KEYNOTE-158 cohort K at the data cutoff of Oct 5, 2020. Methods: Cohort K of this phase 2, open-label study enrolled adults with any previously treated advanced noncolorectal MSI-H solid tumor, measurable disease per RECIST v1.1, and ECOG PS of 0–1. MSI-H/dMMR status was assessed locally from a tumor tissue sample and defined as ≥1 of 4 MMR proteins absent by immunohistochemistry or as ≥2 allelic loci size shifts of 5 microsatellite markers by PCR. Pts received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD, unacceptable toxicity, investigator decision, or withdrawal of consent. The primary endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints were DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Efficacy was assessed in all pts who received ≥1 dose of treatment with ≥6 mo follow-up; safety was assessed in all treated pts. Results: 351 pts were enrolled in KEYNOTE-158 cohort K across multiple tumor types, including endometrial (22.5%), gastric (14.5%), small intestine (7.4%), ovarian (7.1%), cholangiocarcinoma (6.3%), and pancreatic (6.3%). 41.0% had 1 prior line of therapy; 55.6% had ≥2 prior lines. Median time from first dose to database cutoff (Oct 5, 2020) was 37.5 (range, 0.2–55.6) mo; 16.0% were continuing treatment. The ORR among the 321 eligble pts was 30.8% (CR, 27; PR, 72); median DOR was 47.5 mo (Table). Treatment-related AEs occurred in 64.7% of pts (grade 3–5, 12.0%), led to discontinuation in 6.6%, and led to death in 3 pts (myocarditis, pneumonia, and Guillain-Barre syndrome). Immune-mediated AEs and infusion reactions occurred in 20.2% of pts (grade 3–4, 4.3%) and led to death in 2 pts with no other contributing factors (myocarditis [AE start, day 26; death, day 33] and Guillain-Barre syndrome [AE start, day 22; death, day 41]). Conclusions: Pembrolizumab demonstrated a high ORR (30.8%), durable clinical benefit, and a manageable safety profile in this heavily pretreated advanced MSI-H/dMMR noncolorectal pan-tumor population. Clinical trial information: NCT02628067. [Table: see text]

e21110 Background: Immune checkpoint inhibitor (ICI) therapy represents one of the most promising cancer treatments to date. However, despite unprecedented rates of durable response, only a small proportion of patients benefits from this approach. Major efforts are therefore required to characterize treatment resistance mechanisms, as well as to identify reliable biomarkers for response. We have previously shown that in response to various types of cancer therapy, including ICIs, the host may induce pro-tumorigenic processes that can promote therapy resistance. Here we examined systemic host-response proteomic profiles in non-small cell lung cancer (NSCLC) patients, aiming to discover biomarkers for response to ICI therapy and to unravel underlying resistance mechanisms. Methods: As part of our ongoing PROPHETIC clinical trial (NCT04056247), plasma samples were obtained at baseline (T0) and early-on treatment (T1; following the first treatment) from 120 NSCLC patients receiving ICI therapy. Proteomic profiling of the plasma samples was performed using proximity-extension assay (PEA) technology; validation was carried out for a fraction of the samples using ELISA-based arrays. To identify a proteomic signature that predicts clinical outcome, machine learning algorithms were applied following a random separation of the cohort into a discovery set and a validation set. Results: A proteomic signature predictive of response to treatment was identified and validated. Bioinformatic analysis identified potential mechanisms of resistance based on differentially expressed proteins associated with pro-tumorigenic biological processes. Statistical analysis of the clinical data identified multiple novel differential clinical parameters between responders and non-responders, either at baseline or by comparing T0 to T1, which may suggest host-mediated effects. Conclusions: Our study demonstrates the potential clinical utility of analyzing the host response to ICI therapy, in particular for the discovery of novel predictive biomarkers for NSCLC patient stratification. Clinical trial information: NCT04056247.

e15579 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide and is heterogenous in its molecular features. Checkpoint inhibitors (CPIs) are approved for only about 5% of unresectable or metastatic CRC with MSI-high (MSI-H)/deficient MMR (dMMR); however, they do not benefit the majority of advanced CRC patients. Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound with demonstrated activity in cancers with RAS mutations which are found in ̃50% of CRC. This study aims to evaluate the combination of selinexor with pembrolizumab, an anti-PD-L1 CPI, in chemotherapy refractory CRC. Methods: This phase 1/2, open-label study enrolled patients with advanced/metastatic CRC with progression after prior chemotherapy (1-3 lines for KRAS wild-type (wt), 1-2 for KRAS mutant (mut)), initially into a selinexor monotherapy period to evaluate bioavailability/bioequivalence of a new selinexor formulation, followed by a combination therapy where patients were treated with selinexor 80 mg PO QW and pembrolizumab 200 mg IV every 3 weeks. Patients were assessed for anti-tumor activity, safety, and tolerability of the combination therapy. Results: Enrollment in this study has been completed, and 29 patients have received at least 1 dose of combination therapy: median age was 56 years, 19 (65.5%) male, and 15 (51.7%) have RAS mutations. Median number of lines of prior antineoplastic therapies was 2. Median duration of combination treatment is 39 days (range: 1-246 days). Seventeen patients (58.6%) discontinued therapy mostly due to progressive disease, and 18 patients are evaluable for response. Best response was stable disease in 7 patients (6 of them (85.7%) had RAS mut CRC), and progressive disease in 11 patients (8 of them (72.7%) had RAS wt CRC. Median progression free survival (PFS) is 120 days for patients with RAS mut CRC and 41 days for those with RAS wt CRC. Notably, none of the RAS mut had MSI-H/dMMR CRC while one RAS wt with SD had MSI-H/dMMR CRC. The most common treatment-emergent adverse events (total; ≥Grade 3) were nausea (72.4%; 0%), vomiting (41.4%; 0%), decreased appetite (34.5%; 0%), and fatigue (34.5%; 10.3%). Seven patients (24.1%) had at least 1 treatment-emergent serious adverse event. Conclusions: Selinexor in combination with pembrolizumab has demonstrated disease control in patients with chemotherapy refractory advanced/metastatic CRC. Greater anti-tumor activity was observed in patients with RAS mutations despite absence of MSI-H/dMMR. The therapy was well tolerated with no unanticipated adverse events observed. These results warrant further investigation of selinexor in combination with pembrolizumab in CRC, particularly in CRC with RAS mutations. Clinical trial information: NCT04256707.

The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries. A total of 130 patients were included, the majority (n=84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n=70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n=33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n=61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n=84/113) and 94% of patients (n=93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n=29/113) and at 6 months compared with 3 months in 6% of patients (n=6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n=57/124) with available CT data at 3 and/or 6 months. Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression.

BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...

Purpose In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab. Patients and Methods Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator’s choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting. Results Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively). Conclusion With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

Although studies in several cancer types suggest that metformin has antitumor activity, its effect on the outcome of targeted therapies in metastatic renal cell carcinoma (mRCC) is poorly defined. We aimed to analyze the effect of metformin use on the outcome of sunitinib treatment in diabetic patients with mRCC.We performed a retrospective study of diabetic patients with mRCC, who were treated with sunitinib in 8 centers across 2 countries. Patients were divided into metformin users and nonusers. The effect of metformin use on response rate, progression-free survival (PFS), and overall survival (OS), was tested. Furthermore, univariate and multivariate analyses of the association between clinicopathologic factors and metformin use, and outcome were performed using the entire patient cohort.Between 2004 and 2014, 108 diabetic patients with mRCC were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The groups were balanced regarding clinicopathologic factors. Clinical benefit (partial response + stable disease) in group 1 versus 2 was 96% versus 84% (P = .054). Median PFS was 15 versus 11.5 months (P = .1). Median OS was 32 versus 21 months (P = .001). In multivariate analyses of the entire patient cohort (n = 108), factors associated with PFS were active smoking and pretreatment neutrophil to lymphocyte ratio3. Factors associated with OS were metformin use (hazard ratio, 0.21; P .0001), Heng risk, active smoking, liver metastases, and pretreatment neutrophil to lymphocyte ratio 3.Metformin might improve the OS of diabetic patients with mRCC who are treated with sunitinib.

Objectives LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib+docetaxel versus placebo+docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib+docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents. Materials and methods The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication ( N =1307) and for the two main histologies: adenocarcinoma ( n =653) and squamous cell carcinoma (SCC; n =553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders. Results and conclusion The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perforations was 1.2% with nintedanib+docetaxel versus 0.2% with placebo+docetaxel. The incidence of some events was higher with nintedanib+docetaxel versus placebo+docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1–2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib+docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatment differences in the SCC subpopulation; most events were Grade 1–2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib+docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile.

e21685 Background: ALKi represent the standard 1st- and 2nd -line treatment (Tx) for ALK+ aNSCLC patients (pts). The value of ALKi in the 3rd-line setting is unclear. We retrospectively assessed the real-world impact of a 3rd -line ALKi vs. non-ALKi Tx in ALK+ aNSCLC pts. Methods: Consecutive ALK+ aNSCLC pts were identified in the working databases of 7 Israeli oncology centers; pts receiving any systemic Tx beyond 2 different ALKi were selected for the comparative analysis. Pts whose immediate next Tx line (post-2nd-ALKi) was a 3rdALKi (Group (Gr) A) were compared to pts whose immediate next Tx line (post-2nd-ALKi) was non-ALKi Tx (Gr B), in terms of overall survival (OS) and time to next Tx line (TNT). Results: 158 consecutive ALK+ aNSCLC pts diagnosed in January 2011 - March 2019 were included, median follow up from diagnosis of aNSCLC was 41 months (mo) (IQR 8-45). Median OS from aNSCLC diagnosis was 56 mo (95% CI 36-66). Post-2nd-ALKi line was a 3rd ALKi for 23 pts (Gr A) and a non-ALKi Tx for 10 pts (Gr B). 7 of Gr B (70%) received ALKi as a later line Tx. Median OS after initiation of post-2nd-ALKi Tx was 27 mo (95% CI, 7-NA) for Gr A vs. 16 mo (95% CI, 7-NA) for Gr B; p-non-significant (NS) with or without adjustment for sex, age, brain metastases. TNT on post-2nd-ALKi Tx was 6 mo (95% CI, 2-27) for Gr A vs. 2.5 mo (95% CI, 0-NA) for Gr B; p-NS. Conclusions: Following progression on a 2ndALKi, OS and TNT were numerically higher for pts receiving a 3rd ALKi, but statistically NS. Extensive exposure of pts in the non-ALKi Tx Gr to an ALKi at a later stage might have impacted these results. Further studies are required to identify patients likely to benefit from ALKi after progressing on 2 or more ALKi Tx lines. [Table: see text]

Novel therapeutic approaches that address the malignant cells in their stroma microenvironment are urgently needed in lung cancer. The stroma resident mesenchymal stem cells (MSCs) interact with cancer cells in diverse ways including microvesicles (MVs) that transfer proteins and RNA species thereby modulating recipient cells' phenotype. Previously, we have demonstrated that MSCs' secretome from the primary non-small cell lung cancer (NSCLC) niche (lung) and metastatic niche (bone marrow (BM)) demonstrate opposite effects on NSCLC cells in a translation initiation (TI) dependent manner. Here, we examined the effect of MVs secreted from BM-MSCs' or lung-MSCs (healthy, NSCLC) to NSCLC phenotype. Briefly, NSCLC cell lines treated with Lung or BM-MSCs' MVs were assayed for viability (WST-1), cell count/death (trypan), migration (scratch), TI status and MAPKs activation (immunoblotting). Corresponding to previous published trends, Lung-MSCs' MVs promoted NSCLC cells' assayed traits whereas, BM-MSCs' MVs suppressed them. Activation of MAPKs and autophagy was registered in lung-MSCs MVs treated NSCLC cell lines only. Furthermore, lung-MSCs' MVs' treated NSCLC cells demonstrated an early (5 min) activation of MAPKs and TI factors (peIF4E/peIF4GI) not evident in BM-MSCs MVs treated cells. These observations depict a role for MSCs'-MVs in NSCLC phenotype design and display distinct differences between the primary and metastatic niches that correspond to disease progression. In conclusion, the systemic nature of MVs marks them as attractive therapeutic markers/targets and we propose that identification of specific cargoes/signals that differentiate between MSCs MVs of primary and metastatic niches may introduce fresh therapeutic approaches.

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Patients presenting with advanced-stage NSCLC have poor prognosis, while metastatic spread accounts for >70 % of patient's deaths. The major advances in the treatment of lung cancer have brought only minor improvements in survival; therefore, novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Furthermore, studies indicate that translation initiation factors are over expressed in NSCLC and negatively impact its prognosis. Importantly, translation initiation is highly modulated by microenvironmental cues. Therefore, we decided to examine the effect of bone marrow MSCs (BM-MSCs) from normal donors on NSCLC cell lines with special emphasis on translation initiation mechanism in the crosstalk. We cultured NSCLC cell lines with BM-MSC conditioned media (i.e., secretome) and showed deleterious effects on the cells' proliferation, viability, death, and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression [eukaryotic translation initiation factor 4E (eIF4E) and eukaryotic translation initiation factor 4GI (eIF4GI)], their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs' secretome affected NSCLC's mitogen-activated protein kinase (MAPK) signaling pathway, downregulated the cell migration, and diminished translation initiation factors' levels. Taken together, our study demonstrates that there is direct dialogue between the BM-MSCs' secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We suggest that therapeutic approach that will sabotage this dialogue, especially in the BM microenvironment, may diminish lung cancer metastatic spread and morbidity and improve the patient's life quality.

Nintedanib is a triple angiokinase inhibitor approved with docetaxel for adenocarcinoma non-small cell lung cancer after first-line chemotherapy (FLT). In the phase III LUME-Lung 1 study, overall survival (OS) was significantly longer with nintedanib/docetaxel than with placebo/docetaxel in all adenocarcinoma patients and those with time from start of FLT (TSFLT)

INTRODUCTION: No predictive clinical or genetic markers have been identified or validated for antiangiogenic agents in lung cancer. We aimed to identify a predictive clinical marker of benefit for nintedanib, an angiokinase inhibitor, using data from two large second-line non-small cell lung cancer Phase III trials (LUME-Lung 1 ([LL1] and LUME-Lung 2).METHODS: Predictive marker identification was conducted in a multi-step process using data from both trials; a hypothesis was generated, confirmed and validated. Statistical analyses included a stepwise selection approach, a recursive partitioning method and the evaluation of HRs, including treatment-by-covariate interactions. The marker was finally validated using a prospectively defined hierarchical testing procedure and treatment-by-covariate interaction for overall survival (OS) based on LL1.RESULTS: Time since start of first-line therapy (TSFLT) was identified as the only predictive clinical marker. A cut-off of 9 months was chosen for further analysis, based on HRs and recursive partitioning. The prospectively defined final validation using OS data from LL1 established the strong relationship between TSFLT and treatment with nintedanib. Patients with adenocarcinoma with TSFLT 9 months group (median OS 17.0 vs 15.1 months, HR 0.89 [95% CI 0.66-1.19]).CONCLUSIONS: Patients with shorter TSFLT derive a greater progression-free survival and OS benefit from nintedanib. This clinical marker could be used for patient selection and further investigation is warranted regarding pathways promoting aggressive tumour growth and antiangiogenic tyrosine kinase inhibitor benefit.

Until recently, docetaxel-based chemotherapy was the only established treatment for patients with metastatic hormone refractory prostate cancer (mHRPC). In 2010 to 2011, 3 more agents were shown to be associated with a survival benefit in mHRPC, including the dendritic cell vaccine sipuleucel-T, the 17,20 lyase inhibitor abiraterone, and the taxane cabazitaxel. The improved understanding of prostate cancer biology in recent years led to the development of drugs directed against precise tumorigenesis-associated molecular pathways. Molecular pathways involved in the progression of mHRPC include the androgen receptor, angiogenesis, endothelin receptor, tyrosine kinases (SRC, MET, vascular endothelial growth factor receptor, RET), and the receptor activator of nuclear factor-kB-ligand. This review will focus on recent advances in the standard treatments paradigm, and promising new targeted agents that are being investigated, in mHRPC.

Background: The antitumor activity of the anti-PD-1 monoclonal antibody pembrolizumab in patients with advanced SCLC has been evaluated in the Phase Ib basket study KEYNOTE-028 (KN028; NCT02054806) and in the Phase II basket study KEYNOTE-158 (KN158; NCT02628067). We present outcomes for patients enrolled in KN028 and KN158 who were receiving pembrolizumab after ≥2 lines of prior therapy. Methods: Eligible patients had histologically/cytologically confirmed incurable advanced SCLC, measurable disease per RECIST 1.1, ECOG PS of 0/1, had experienced progression/failure on standard therapy, and were immunotherapy-naive; patients included in this analysis had received ≥2 lines of systemic therapy. Patients in KN028 were required to have PD-L1-positive tumors (membranous PD-L1 expression in ≥1% of tumor and associated inflammatory cells or positive staining in stroma); tumor PD-L1 expression was not required in KN158. Radiographic imaging was performed Q8W for 6 mo (KN028) or Q9W for 1 y (KN158), and Q12W thereafter. Pembrolizumab (10 mg/kg Q2W [KN028] or 200 mg Q3W [KN158]) was administered for 2 y or until disease progression or intolerable toxicity. The primary endpoint in both studies was objective response rate (ORR) assessed per RECIST 1.1. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary endpoints and estimated using the Kaplan-Meier method. For this analysis, assessment of response was by independent central review. Results: Of 131 SCLC pts included in both trials, 83 were eligible for efficacy analyses (KN158, n=64; KN028, n=19). Median age was 62 (range, 24–84) y, 64% were men, and 36% had received ≥3 lines of systemic therapy. As of the data cutoff date, median follow-up was 7.7 (range, 0.5–48.7) mo. The ORR was 19.3% (95% CI, 11.4-29.4). Two patients had a complete response and 14 had a partial response per independent central review; 14 of 16 responders were PD-L1-positive. Median DOR was not reached (range, 4.1-35.8 [ongoing] mo). 9 of 16 responders (61% per Kaplan-Meier estimate) had response lasting ≥18 mo. Median PFS was 2.0 (95% CI, 1.9-3.4) mo and median OS was 7.7 (95% CI, 5.2-10.1) mo. 12- and 24-month rates were 16.9% and 13.1% for PFS, and 34% and 21% for OS. Among all SCLC patients in KN028 and KN158 irrespective of prior therapies (N=131), 8% had a grade 3 treatment-related AE (no grade 4 treatment-related AEs). 3 patients had grade 5 treatment-related AEs (intestinal ischemia, pneumonia, encephalopathy). 21% experienced an immune-mediated AE or infusion reaction. Conclusions: Pembrolizumab demonstrated promising antitumor activity in patients with advanced SCLC who had received ≥2 lines of prior therapy. Responses were durable, with the majority of patients estimated to have a response duration of at least 18 mo. No unexpected toxicities from pembrolizumab were observed. Citation Format: Hyun Cheol Chung, Sarina A. Piha-Paul, Jose Lopez-Martin, Jan H.M. Schellens, Steven Kao, Wilson H. Miller Jr., Jean-Pierre Delord, Bo Gao, David Planchard, Maya Gottfried, Alona Zer, Shadia I. Jalal, Nicolas Penel, Janice M. Mehnert, Ignacio Matos, Jaafar Bennouna, Dong-Wan Kim, Lei Xu, Suba Krishnan, Kevin Norwood, Patrick A. Ott. Pembrolizumab after two or more lines of prior therapy in patients with advanced small-cell lung cancer (SCLC): Results from the KEYNOTE-028 and KEYNOTE-158 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT073.

BACKGROUND Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC. METHODS Records from mCRPC patients treated with ketoconazole (international multicenter database, n = 162) were reviewed retrospectively. Twenty-six patients treated post docetaxel were individually matched by clinicopathologic factors to patients treated with abiraterone (national multicenter database, n = 140). We compared the PSA response, biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. RESULTS The groups were matched by Gleason score, pre-treatment disease extent, ECOG PS, pre-treatment risk category (Keizman, Oncologist 2012). Furthermore, they were balanced regarding other known confounding risk factors. In the groups of abiraterone versus ketoconazole, PSA response was 46% versus 19% (OR 4.3, P = 0.04), median biochemical PFS 7 versus 2 months (HR 1.54, P = 0.02), median radiological PFS 8 versus 2.5 months (HR 1.8, P = 0.043), median OS 19 versus 11 months (HR 0.53, P = 0.79), and treatment interruption d/t severe adverse events 8% (n = 2) versus 31% (n = 8) (0R 0.6, P = 0.023). CONCLUSIONS In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole. Prostate 74:433–440, 2014. © 2013 Wiley Periodicals, Inc.

Background: The goal of this study was to evaluate the effi cacy of ipsilateral opposite-side aspiration, a new method to overcome resistant pneumothorax after failure of a simple aspiration. The patient position is reversed (from prone to supine or vice versa) and the aspiration repeated. Methods: Between January 1, 2010, and April 3, 2012, 129 consecutive, CT image-guided, percutaneous needle biopsies of lung nodules were performed in 127 patients (75 men, 52 women; mean age, 67.8 years; range, 26-88 years). Two patients underwent repeated biopsies. The mean lesion diameter was 38 mm (range, 8-110 mm). Core biopsy and fi ne-needle aspiration (FNA) were performed in 126 procedures; in three cases, only FNA was performed. In the cases with symptomatic minimal pneumothorax and in all patients with pneumothorax . 10 mm, immediate, simple, manual aspiration was performed. Ipsilateral opposite-side aspiration was performed when simple aspiration failed. Results: Among 129 CT image-guided biopsies, pneumothorax was detected by CT scan in 54 (42%); 51 (39%) were detected during the biopsy. Delayed pneumothorax occurred in two patients (1.55%). Manual aspiration to treat pneumothorax was performed in 27 of 129 procedures (21%). Simple aspiration was successful in 20 of these 27 cases (74%). Ipsilateral opposite-side aspiration was accomplished in the remaining seven cases (26%) and was successful in six cases (86%). Two of 129 procedures (1.55%) required chest tube placement. Conclusions: Immediate, simple, percutaneous aspiration of iatrogenic pneumothorax was successful in 74% of patients needing treatment. Our proposed new method of ipsilateral oppositeside aspiration offers a solution for patients who remain with resistant pneumothorax after simple aspiration. CHEST 2013; 144(3):947–951

One third of patients with metastatic renal cell carcinoma (RCC) suffer from bone metastases. Skeletal involvement in RCC is associated with the occurrence of skeletal-related events, and may negatively impact on the outcome of patients treated with systemic therapies. In patients with RCC and bone metastases, therapies that inhibit osteoclasts, as bisphosphonates and denosumab, are used as adjunct to systemic targeted therapies to prevent skeletal-related events. Data suggest that they may also improve the outcome of systemic targeted therapies. Herein we review the preclinical and clinical data on their use, as well as remaining open questions.

Background: In the last decade, the search for gene mutations in lung cancer has been constantly growing. EGFR, KRAS mutations and, recently, the EML4-ALK fusion can guide the selection of treatment for patients who carry a specific mutation. Methods: During 2010-2011, EML4-ALK fusion test has been performed in Israel, mostly for wild type EGFR non-squamous NSCLC patients based on fluorescent in-situ hybridization (FISH) technique to detect EML4-ALK rearrangements. Results: Between January 2010 and December 2011, 3341 patients were diagnosed with lung cancer in Israel. Of the 2997 patients with NSCLC 687 had squamous cell carcinoma and 2310 had non-squamous NSCLC. This study focused on available 125 non-squamous NSCLC cases in which analysis for EML4-ALK rearrangement was available. All were negative for EGFR mutation. Nineteen (15.2%) were found positive for the fusion, a figure 2 - 10 times higher compared with previously reported findings. The EML4-ALK fusion was significantly more prevalent in younger male patients (52.1 vs. 61.3 years, p = 0.049), in whom every additional year reduced the chance to find the fusion by 7% [CI = 0.93 (0.88 - 0.99), p = 0.03]. Conclusions: A stepwise approach based on histology and prior EGFR analysis to detect EML4-ALK fusion is highly efficient with a related increased yield of detection. We recommend testing patients with non-squamous cell lung carcinoma after ruling out an EGFR mutation. The chance to find the ALK fusion is significantly greater in younger men.

The treatment of refractory meningiomas remains a challenge for both neurosurgeons and neuro-oncologists. There have been no clinical reports of the use or effects of anti-PD-1 therapy in patients with meningioma. We describe a patient whose intracranial meningioma decreased significantly in size after treatment with nivolumab, a monoclonal antibody targeting PD-1, for a concomitant advanced lung cancer. This is the first clinical report suggesting that antibodies targeting PD-1 are effective in treating meningioma. It should encourage further research into the use of checkpoint inhibitors in meningioma.

Background: Overexpression of VEGF is implicated in the pathogenesis of both renal cell carcinoma (RCC) and age-related macular degeneration (AMD). We evaluated the association between AMD and RCC risk. Methods: We conducted a matched case–control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of RCC. For every case, four eligible controls were matched on age, sex, practice site, calendar time, and duration of follow-up. Exposure of interest was diagnosis of AMD prior to cancer diagnosis. Adjusted ORs and 95% confidence intervals (CI) for RCC were estimated using conditional logistic regression. In a secondary analysis, we evaluated the association between other retinopathies and RCC and AMD and the hypovascular pancreatic cancer. Results: The study population included 1,547 patients with RCC and 6,066 matched controls. Median follow-up time was 6 years (IQR, 3–9). AMD diagnosis was associated with a significantly increased RCC risk (OR, 1.89; 95% CI, 1.09–3.29). In contrast, there was no association between other retinopathies and RCC risk (OR, 0.8; 95% CI, 0.56–1.15). AMD was associated with a lower risk for pancreatic cancer (OR, 0.47; 95% CI, 0.35–0.64). Conclusions: Patients with AMD may be at higher risk for RCC. Providers should be aware of this potential link and consider screening for RCC within this population. Impact: Providers should be aware of the potential link between AMD and RCC. Cancer Epidemiol Biomarkers Prev; 26(5); 743–7. ©2017 AACR.

Background RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. Materials and Methods We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. Results A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. Conclusion RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.

Metastasis underlies cancer morbidity and accounts for disease progression and significant death rates generally and in non-small cell lung cancer (NSCLC) particularly. Therefore, it is critically important to understand the molecular events that regulate metastasis. Accumulating data portray a central role for protein synthesis, particularly translation initiation (TI) factors eIF4E and eIF4G in tumorigenesis and patients' survival. We have published that eIF4E/eIF4GI activities and consequently NSCLC cell migration are modulated by bone-marrow mesenchymal stem cell secretomes, suggesting a role for TI in metastasis. Here, we aimed to expand our understanding of the TI factors significance to NSCLC characteristics, particularly epithelial-to-mesenchymal transition (EMT) and migration, supportive of metastasis. In a model of NSCLC cell lines (H1299, H460), we inhibited eIF4E/eIF4GI's expressions (siRNA, ribavirin) and assessed NSCLC cell lines' migration (scratch), differentiation (EMT, immunoblotting), and expression of select microRNAs (qPCR). Initially, we determined an overexpression of several TI factors (eIF4E, eIF4GI, eIF4B, and DHX29) and their respective targets in NSCLC compared with normal lung samples (70-350%↑, P

Background: Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy. Patients and methods: Patients with relapsed/refractory disease following ≥ 1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥ 12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m2/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes. Results: Two hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n ≥ 134) or single-agent chemotherapy (n ≥ 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P ≥ 0.003) and ORR (32.1% versus 13.2%, P ≥ 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent. Conclusion: Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy. Trial registration number: NCT01085136 (clinicaltrials.gov).

Several studies have shown that more than half of cancer patients have unrecognized renal insufficiency (RI), which is a reduced glomerular filtration rate (GFR) with normal serum creatinine. The aim of this study was to determine whether unrecognized RI is associated with an increased risk for chemotherapy-associated adverse effects in breast cancer patients treated with combined doxorubicin and cyclophosphamide treatment. GFR was estimated for 95 breast cancer patients from January 2005 to August 2009 using the Cockcroft-Gault formula. Unrecognized RI was defined as GFR less than 75 ml/min/1.73 m and the patients were grouped according to their estimated GFR. Logistic regression models were used to assess the effect of GFR on clinical outcomes. In total, 49 (52%) patients experienced at least one of the following chemotherapy-associated adverse effects during the course of treatment: an episode of neutropenic fever with hospital admission, a delay in chemotherapy treatment for a medical reason, a need for dose adjustment because of toxicity of the chemotherapeutic drugs, and the need for use of granulocyte colony-stimulating factor. The incidence of these adverse effects occurred more frequently in patients with GFR less than 75 compared with patients with GFR at least 75 (64 vs. 42%, odds ratio 5.29, 95% confidence interval 2.10-13.33) and remained statistically significant after adjustment for age, BMI, and initial doses of chemotherapeutic drugs (odds ratio 3.56, 95% confidence interval 1.08-11.67). Neutropenic fever, dose delay, and dose adjustment as separate outcomes occurred more frequently in the GFR less than 75 group but lost statistical significance after adjustment. Our results demonstrate that unrecognized RI is associated with an increased risk for chemotherapy-associated adverse events in this patient population. Further prospective studies are required to determine whether a dose reduction in patients with unrecognized RI reduces adverse effects without adversely affecting the benefit of treatment.

14 Background: 30% of pts with localized PC will have a biochemical relapse post local tx. The optimal tx of these pts remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit on survival remain undefined, and it is associated with significant cumulative toxicities.Thus, evaluation of new non-toxic compounds in this pt population is warranted. P-MCP is a competitive inhibitor of galectin-3, a carbohydrate-binding protein, which is known to be involved in cancer pathogenesis. Pre-clinical and clinical data suggest that P-MCP is active in PC. We aimed to evaluate the safety and PSA dynamics of tx with P-MCP in pts with BRPC. Methods: Pts with non-castrate non-metastatic BRPC were enrolled in a prospective phase 2 study of tx with oral P-MCP, at 4.8 grams X 3/day for 6 months (mos). Pts that did not progress clinically, biochemically (PSA), and radiologically, at 6 mos, were treated for subsequent 12 mos. Sample size provided 85% power to assess a decrease in PSA progression rate from 80% (natural history) to 40% (P-MCP tx) at 6 mos. Results: The study was initiated in June 2013. 35 pts were enrolled. Median age was 74 years. Treatment of the primary tumor consisted of surgery in 11% (n = 4), radiation in 69% (n = 24), and both in 20% (n = 7). No pt had tx related grade 3/4 toxicity. One patient withdrew his consent after 1 mos. Of the 34 pts analyzed, 18% (n = 6) had grade 1 toxicity. 62% (n = 21) had a stabilization/decrease of PSA, and negative scans, at 6 mos, and entered the second 12 mos tx phase. A stabilization or improvement (increase) of PSA doubling time was noted in 79% (n = 27) of pts. Disease progression at 6 mos was noted in 38% (n = 13: PSA only 29%, n = 10; PSA and scans 9%, n = 3). Conclusions: The present study suggests a potential benefit of P-MCP tx on progression of BRPC. P-MCP tx is safe. Clinical trial information: NCT01681823.

Background: Transthoracic fine needle aspiration (FNA) is one of several methods for establishing tissue diagnosis of lung lesions. Other tissue or cell sources for diagnosis include sputum, endobronchial biopsy, washing and brushing, endobronchial FNA, transthoracic core needle biopsy, biopsy from thoracoscopy or thoracotomy. The purpose of this study was to compare the sensitivity and specificity of FNA and other diagnostic tests in diagnosing lung lesions. Materials and Methods: The population included all patients undergoing FNA for lung lesions at Meir Medical Center from 2006 through 2010. Information regarding additional tissue tests was derived from the electronic archives of the Department of Pathology, patient records and files from the Department of Oncology. Sensitivity, specificity, diagnostic accuracy, and positive and negative predictive values were calculated for each test. Results: FNA was carried out in 245 patients. Malignant tumors were diagnosed in 190 cases (78%). They included adenocarcinoma (43%), squamous cell carcinoma (15%), non-small cell carcinoma, not otherwise specified (19%), neurondocrine tumors (7%), metastases (9%) and lymphoma (3%). The specificity of FNA for lung neoplasms was 100%; sensitivity and diagnostic accuracy were 87%. Conclusions: FNA is the most sensitive procedure for establishing tissue diagnoses of lung cancer. Combination with core needle biopsy increases the sensitivity. Factors related to the lesion (nature, degenerative changes, location) and to performance of all stages of test affect the ability to establish a diagnosis.

1562 Background: Data suggests that GERD with recurrent reflux and microaspiration of stomach contents, may be associated with lung injury, inflammation, activation of proliferative signals, and eventually DNA damage and malignant transformation. Recently, a large population based cohort study found that GERD may increase the risk of lung cancer in Asians. In the present nested case control study, we aimed to evaluate the association between PPI use as a surrogate for GERD and lung cancer in a large western population. Methods: We conducted a matched case-control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of lung cancer. For every case, four eligible controls were matched on age, gender, practice site, time and duration of follow-up. Exposure of interest was PPI use prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer were estimated using conditional logistic regression. Adjustment was performed for smoking. Results: The study population included 19143 lung cancer cases and 74473 matched controls. PPI use was associated with a significantly increased lung cancer risk (adjusted OR 1.70, 95%CI 1.64-1.77, p < 0.001). In a sensitivity analyses we observed similar associations when PPI use was initiated more than one year prior to cancer diagnosis (adjusted OR 1.18, 95%CI 1.13-1.23, p < 0.001) and more than two years prior to cancer diagnosis (adjusted OR 1.15, 95%CI 1.10-1.20, p < 0.001) Conclusions: ChronicPPI use, as a surrogate for symptomatic GERD, may be associated with a higher lung cancer risk.