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Non–small cell lung cancer; Brain metastases; Somatic mutations Càncer de pulmó de cèl·lules no petites; Metàstasis cerebrals; Mutacions somàtiques Cáncer de pulmón de células no pequeñas; Metástasis cerebrales; Mutaciones somáticas Introduction In the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses. Methods Adults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC. Results With a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals. Conclusions With a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC. This study was supported by Bristol Myers Squibb (Princeton, NJ).

Background Precision medicine in oncology aims to identify the most beneficial interventions based on a patient’s individual features and disease. However, disparities exist when providing cancer care to patients based on an individual’s sex. Objective To discuss how sex differences impact the epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment, with a focus on data from Spain. Results Genetic and environmental factors (social or economic inequalities, power imbalances, and discrimination) that contribute to these differences adversely affect cancer patient health outcomes. Increased health professional awareness of sex differences is essential to the success of translational research and clinical oncological care. Conclusions The Sociedad Española de Oncología Médica created a Task Force group to raise oncologists’ awareness and to implement measures to address sex differences in cancer patient management in Spain. This is a necessary and fundamental step towards optimizing precision medicine that will benefit all individuals equally and equitably.

Avelumab; Cetuximab; Non–small cell lung cancer Avelumab; Cetuximab; Càncer de pulmó de cèl·lules no petites Avelumab; Cetuximab; Cáncer de pulmón de células no pequeñas Introduction We present the results of a phase 2a trial of first-line avelumab (anti–programmed death-ligand 1 antibody) plus cetuximab (anti–EGFR antibody) in patients with advanced squamous NSCLC. Methods Patients with recurrent or metastatic squamous NSCLC received avelumab 800 mg (d 1 and 8), cetuximab 250 mg/m2 (d 1) and 500 mg/m2 (d 8), cisplatin 75 mg/m2 (d 1), and gemcitabine 1250 mg/m2 (d 1 and 8) for four 3-week cycles, followed by avelumab 800 mg and cetuximab 500 mg/m2 every 2 weeks. The primary end point was the best overall response; the secondary end points were progression-free survival, duration of response, overall survival, and safety. Efficacy analyses were reported from an updated data cutoff. Results A total of 43 patients were enrolled. The median follow-up was 6.6 months for the primary analyses and 9.2 months for the efficacy analyses. In the efficacy analyses, 15 patients had a confirmed partial response (objective response rate, 34.9% [95% confidence interval: 21.0%–50.9%]), and the median duration of response was 7.1 months (95% confidence interval: 4.2–12.5 mo). The median progression-free survival and overall survival were 6.1 months and 10.0 months, respectively. In the safety analyses (primary analysis), 38 patients (88.4%) had a treatment-related adverse event, of whom 24 (55.8%) had a grade 3 or higher treatment-related adverse event. Conclusions The combination of avelumab + cetuximab and chemotherapy showed antitumor activity and tolerable safety; however, the ORR was not improved compared with those reported for current standards of care (NCT03717155). This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany, and Pfizer. Employees of the sponsor are coauthors of this manuscript and contributed to the design, execution, interpretation of the analyses, writing the report, and the decision to submit the article for publication, along with other coauthors. We thank the patients and their families, the investigators, co-investigators, and study teams at each participating center and the healthcare business of Merck KGaA, Darmstadt, Germany. Medical writing support was provided by Abhijith Thippeswamy of ClinicalThinking and funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer.

This open-label Phase II study conducted prior to routine EGFR mutation testing, assessed whether acquired resistance to erlotinib in NSCLC patients with a given MET protein expression level enriched for EGFRmt could be overcome by emibetuzumab, an antibody against MET. Although some responses were seen, the trial did not meet its primary endpoint. Introduction: The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. Patient and Methods: Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (>= 10% of cells expressing MET at >= 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in >= 60% of cells >= 2+ (MET > 60%). Results: One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET >= 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). Conclusion: Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit. (C) 2022 Elsevier Inc. All rights reserved.

Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/mIn this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/mBetween Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group).Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control.PharmaMar.

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si lo hubiere, y los autores pertenecientes a la UAM, At present, we did not find any articles that studied seroprevalence and its persistence several months later in lung cancer patients in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with coronavirus disease 2019 (COVID-19) go on to develop antibodies (Abs) against viral proteins. However, it is not known how long these Abs last nor whether cancer treatments could affect the duration of immune response. Methods: This prospective, longitudinal, multicenter serological study in the setting of SARS-CoV-2 infection was carried out in 50 Spanish hospitals. Eligibility criterion was the diagnosis of any lung cancer. The determination of anti-SARS-CoV-2 IgG Abs was performed by qualitative immuno-enzymatic assay using enzyme-linked immunosorbent assay (ELISA) kit from NovaLisa whose Abs target the recombinant antigen N of the nucleocapsid of SARS-CoV-2. The first Ab determination was performed between April 21 and June 3, 2020. The second Ab determination was performed in all previously seropositive patients, between September 10 and November 20, 2020. Study objectives were to prospectively determine seroprevalence in unselected lung cancer patients during the first wave of the pandemic; the persistence of immunity; protection or lack thereof against reinfection; and the influence of treatments on maintenance or loss of immunity. Results: Of 1,500 patients, 128 were seropositive, overall prevalence of 8.5% seropositivity [95% confidence interval (CI): 7.2–10.1%]. Seventy-five percent were in active cancer treatment. Forty-seven point seven percent of IgG positive participants had experienced a symptomatic illness suspected of being infected with SARS-CoV-2 (95% CI: 38.8–56.6%). A second determination was performed on average 4.5 months later [interquartile range (IQR), 4.0–5.0 months] and obtained for 104 of the initially seropositive patients (81%), it could not be obtained in 24 patients, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% of patients. The severity of the infection, the need for hospitalization (P=0.032) and the presence of symptoms at diagnosis (P=0.02) were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Abs loss. Conclusions: Immunity against SARS-CoV-2 does not appear to be compromised by treatment and persists beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population, This study was supported by Roche Pharma and the European Union Horizon 2020 Research and Innovation Program under grant agreement No. 875160 CLARIFY project

RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first-line platinum-based therapy. Here, we present results from RESILIENT part 1. This open-label, single-arm, safety run-in evaluation with dose-exploration and dose-expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0-73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40-65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45-4.24) months and 8.08 (5.16-9.82) months, respectively. Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum-based therapy. Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes. The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum-based therapy. No new safety concerns were reported. The most common moderate-to-severe side effects were diarrhea (20% of patients) and neutropenia (16%). Tumors responded to treatment in 44% of patients. Average survival was 8.08 months, and time to disease progression was 3.98 months. Liposomal irinotecan trials are ongoing.

Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC.Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/mA total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia.Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days.gov Identifier. NCT03098030.

Background: Molecular response based on ctDNA dynamics may be predictive of benefit from immunotherapy in NSCLC, complementing radiologic disease assessment and potentially enabling early clinical decision-making, but data in SCLC are lacking. The phase 2, multi-arm, signal-searching BALTIC study (NCT02937818) assessed novel treatment combinations in platinum-refractory/resistant ES-SCLC; we report efficacy, safety, and exploratory ctDNA and PD-L1 analyses from pts who received D + T in Arm A. Methods: Eligible pts had ES-SCLC, progressive disease (PD) during or within 90 days of completing 1L platinum-based CT, WHO PS 0-1, and life expectancy ≥8 weeks. In Arm A, pts received D 1500 mg + T 75 mg q4w for 4 cycles, followed by maintenance D 1500 mg q4w until PD. The primary endpoint was ORR (investigator assessment, RECIST v1.1). Secondary endpoints included DCR, PFS, OS, and safety and tolerability. Prespecified exploratory analyses included assessment of baseline/on-treatment ctDNA levels measured by maximum variant allele frequency (MaxVAF), and PD-L1 expression on tumor cells (TC) and immune cells (IC) (VENTANA PD-L1 [SP263] Assay). Results: 41 pts received treatment with D + T (median age 63 years; 76% male; 76% PS 1). At the data cut-off (DCO; Jun 22, 2020), median treatment duration was 12 weeks, with 3 pts ongoing D treatment (these pts had received ≥38, ≥21, and ≥19 doses of D, respectively, at DCO). Confirmed ORR was 7.3% (95% CI 1.54‒19.92; 3 partial responses [PR]). DCR at 12 weeks was 27%. 21 pts (51%) were PD-L1 evaluable. Of 12 pts with PD-L1 expression (TC or IC) ≥1%, 3 (25%) had a best response of PR or stable disease, compared with 1 (11%) of 9 pts with PD-L1 (TC or IC) Conclusions: Although limited antitumor activity was observed in refractory/resistant ES-SCLC in BALTIC, association of lower baseline ctDNA levels (MaxVAF) with longer OS may reflect the prognostic effect of disease burden. Association of on-treatment reduction in ctDNA level with longer OS suggests potential use of ctDNA as a surrogate of treatment response in ES-SCLC. Further analyses in larger datasets and in a randomized setting are warranted. Citation Format: Niels Reinmuth, Oscar Juan-Vidal, Zsolt Horváth, Dariusz Kowalski, Anna Kryzhanivska, Eszter Csánky, Gabriella Gálffy, Maciej Bryl, David Vicente, Ihor Vynnychenko, Zsolt Pápai-Székely, Jon Armstrong, Tapashi Dalvi, Yashaswi Shrestha, Mingchao Xie, Haiyi Jiang, Igor Bondarenko. Durvalumab (D) plus tremelimumab (T) in platinum-refractory/resistant extensive-stage small cell lung cancer (ES-SCLC): Efficacy, safety and ctDNA dynamics from Arm A of the phase 2 BALTIC study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT533.

TPS9152 Background: Gal-3 is a protein that binds specifically to N-acetylglucosamine-expressing carbohydrates, which are upregulated on key tumorigenic cell surface proteins. Gal-3 is widely over-expressed in the tumor microenvironment and is generally linked to poor outcomes. Gal-3 regulates immune cell function of T cells and macrophages, and promotes neovascularization and fibrosis [Peng Cancer Res 2008; Markowska J Biol Chem 2011; Kouo Cancer Immunol Res 2015]. Gal-3 sequesters interferon gamma, reduces T-cell influx, and contributes to tumor cell evasion of the immune system via LAG-3 activation [Chen PNAS 2009; Gordon-Alonso Nat Commun 2017]. Gal-3 has been identified as a marker of resistance to checkpoint inhibitors (CPIs); patients with stage IV NSCLC with high Gal-3 levels (> 70% Gal-3 immunohistochemical staining) have been shown to be resistant to the CPI pembrolizumab [Capalbo Int J Mol Sci 2019]. Animal data indicate synergy between CPI therapy and Gal-3 inhibition [Vuong Cancer Res 2019; Zhang FEBS Open Bio 2021]. Thus, inhibiting Gal-3 together with CPI-based immunotherapy may enhance tumor-specific immune responses, and overcome CPI resistance. Methods: GALLANT-1 (NCT05240131) is a 3-part, placebo-controlled phase Ib/IIa trial that will investigate safety and efficacy of GB1211 (a Gal-3 inhibitor) + atezo vs placebo + atezo in patients with advanced NSCLC. Part A will include 8–12 patients and study safety and tolerability of 200 mg and 400 mg GB1211 twice-daily + atezo (open-label). Primary endpoint is number of adverse events (AEs) after 12 weeks’ treatment and will determine the dosage for Part B. Part B will include 75–94 patients, and is a randomized, double-blind study of GB1211 + atezo or placebo + atezo. Primary endpoints are safety (number of AEs) and efficacy (percentage change from baseline in the sum of longest diameter of target lesions after 12 weeks’ treatment). Part C is an expansion study including patients from Parts A and B, with safety and efficacy assessments. Eligibility criteria: advanced or metastatic stage IIIB or IV NSCLC adenocarcinoma; measurable disease per RECIST v1.1; expression of programmed death ligand-1 on ≥50% of tumor cells; eligible for 1200 mg atezo every 3 weeks. Exclusion criteria: symptomatic, untreated, or actively progressing central nervous system metastases; prior systemic chemotherapy for treatment of recurrent advanced or metastatic disease, except if part of neoadjuvant/adjuvant therapy; prior treatment with immune CPIs and/or GB1211; presence of EGFR mutation and ALK, ROS1, and RET alterations; treatment with antineoplastic or systemic immunotherapeutic agents prior to first GB1211 dose; severe infectious disease < 4 weeks prior to first GB1211 dose; active hepatitis B or C, HIV, or COVID-19. The study is being initiated; updated enrollment status will be presented at the meeting. Clinical trial information: NCT05240131.

TPS8600 Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by early metastasis and a high recurrence rate with currently available treatment options. Although SCLC is generally sensitive to initial chemotherapy, responses are not durable and most patients eventually relapse. Prognosis is poorer in the relapsed/refractory (R/R) setting and currently available treatment options, including checkpoint inhibitors, are associated with a median overall survival of 2-9 months (Chauhan 2020; Trigo 2020; Chung 2020). Approximately 15% of patients have a TP53 wild-type ( TP53WT) gene. In patients with extensive-stage SCLC, TP53WT is paradoxically associated with an inferior response to chemotherapy (Dowlati 2016). Thus, the presence of TP53WT may help identify a small subset of patients with an even greater unmet need. Murine double minute 2 (MDM2) is the key negative regulator of the tumor suppressor protein, p53, which can induce apoptosis of malignant cells by shifting the balance between prosurvival and proapoptotic BCL-2 family members. In SCLC cell lines, MDM2 inhibition restored p53 function leading to downregulation of prosurvival Bcl-2 and Mcl-1 proteins, and upregulation of the proapoptotic Bim protein, thereby inducing cancer cell death (Yu 2019). Navtemadlin (KRT-232) is a potent, selective, orally available MDM2 inhibitor that restores p53 function to drive apoptosis of TP53WT malignancies. Treatment with navtemadlin may be an effective strategy for patients with TP53WT SCLC. Methods: The open-label, multicenter Phase 2 KRT-232-112 study (NCT05027867) is evaluating navtemadlin in TP53WT patients with R/R SCLC. Eligibility criteria include age ≥18 years, ECOG performance status ≤2, presence of measurable disease and demonstrated radiographic progression after ≥1 prior platinum-containing therapy with no curative therapy available. Patients must have received a checkpoint inhibitor if available and not contraindicated. Patients with symptomatic or uncontrolled central nervous system metastases or those with prior MDM2 inhibitor treatment will be excluded. In part 1 of the study, approximately 20 patients will be randomly assigned to receive oral navtemadlin once daily in 21-day cycles at 240 mg 7 days (D) on/14D off (Arm A) or 180 mg 7D on/14D off (Arm B) until disease progression or unacceptable toxicity. In part 2, an additional 18 patients will be enrolled in each arm selected for expansion. The primary endpoint is objective response rate per RECIST v1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, and safety. This trial is ongoing and will enroll patients at approximately 40 global sites. Clinical trial information: NCT05027867.

9010 Background: Atezolizumab plus chemotherapy was safe and yielded promising clinical outcome as frontline therapy for patients (pts) with advanced NSCLC with untreated brain metastases (BM) in the ATEZO-BRAIN study (NCT03526900). Methods: A multicenter single-arm phase II trial with a Bayesian design for evaluating the safety and efficacy of atezolizumab plus carboplatin with pemetrexed every 3 weeks for 4-6 cycles, followed by maintenance with pemetrexed plus atezolizumab in pts with stage IV non-squamous NSCLC without EGFR or ALK genetic alterations and untreated BM. Pts not presented neurologic symptoms at baseline; but anticonvulsants and dexamethasone (DXM) ≤ 4mg qd were allowed. Co-primary endpoints were safety and investigator-assessed progression-free survival (PFS) at 12 weeks according to RANO-BM and RECIST v1.1 for brain and systemic disease, respectively. Here we present the final data and an exploratory analysis based on PD-L1 expression and corticosteroid treatment at baseline. Results: Out of 40 pts included in the study, 22 (55%) were receiving DXM at baseline and 20 (50%) had positive expression of PD-L1. Sixteen (40%) pts had confirmed intracranial response based on RANO-BM (12 PR, 4 CR) and 19 (47.5%) pts achieved systemic response (all PR). Only 4 pts had discordant responses between the body and the brain. No differences were observed in the overall systemic and intracranial response rate according to the PD-L1 expression or the use of corticosteroids at baseline. As of December 31, 2021 (median follow-up, 20 months), the updated median (95% CI) systemic PFS was 8.9 (6.7 to 13.8) and intracranial PFS was 6.9 (4.7 to 11.9). Median (95% CI) OS was 13.6 (9.72 to not reached) and estimated 2-year OS rate (95% CI) was 30.5% (18.4 to 50.4). Median (95%CI) OS was longer for PD-L1 positive pts (16.2; 10.3 to not reached) compared to PD-L1 negative pts (10.7; 7.6 to not reached) but differences were not statistically significant due to the limited statistical power (HR = 0.99; 95% CI 0.35 to 2.12). No significant differences in OS were observed between pts receiving or not baseline DXM treatment. Treatment was well tolerated and no grade 5 toxicities were observed. Conclusions: In this updated analysis, treatment with atezolizumab plus carboplatin and pemetrexed yields a promising 2-year OS rate and intracranial response rate in patients with untreated BM from NSCLC, regardless of treatment with corticosteroids at baseline and PD-L1 expression. Clinical trial information: NCT03526900.

Plasma samples from 72 EGFR‐mutant advanced NSCLC patients, collected upon progression to first‐line TKI, were analyzed by seven methodologies (two NGS‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods). Our study demonstrates a good to excellent agreement between methodologies and supports the use of liquid biopsies for therapy decision‐making., Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next‐generation sequencing (NGS)‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods were compared using 72 plasma samples, from EGFR‐mutant non‐small‐cell lung cancer (NSCLC) patients progressing on a first‐line tyrosine kinase inhibitor (TKI). NGS platforms as well as high‐sensitivity PCR‐based methodologies showed excellent agreement for EGFR‐sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false‐positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.

Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [

Background This randomized phase 2 trial compared the efficacy and safety of second‐line nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) with or without the addition of CC‐486 (an oral formulation of 5‐azacytidine) in patients with advanced‐stage, nonsquamous non‐small cell lung cancer. Methods Patients were randomized to receive either nab‐paclitaxel 100 mg/m2 on days 8 and 15 plus CC‐486 200 mg daily on days 1 to 14 or single‐agent nab‐paclitaxel 100 mg/m2 on days 1 and 8, with both regimens administered every 21 days until tumor progression or unacceptable toxicity. The primary endpoint was progression‐free survival. Secondary endpoints included the overall response rate, the disease control rate, and overall survival. Results Between January 2015 and August 2016, 161 patients were randomized (81 to the combination arm and 80 to the single‐agent nab‐paclitaxel arm). There was no benefit from the addition of CC‐486 to nab‐paclitaxel. The median progression‐free survival was 3.2 months for the combination and 4.2 months for single‐agent nab‐paclitaxel (hazard ratio, 1.3; 95% confidence interval, 0.9‐1.9). The median overall survival was 8.1 months in the combination arm and 17 months in the single‐agent nab‐paclitaxel arms (hazard ratio, 1.7; 95% confidence interval, 1.08‐2.57). Grade 3 or greater treatment‐related, emergent adverse events were reported by 40.5% of patients in the combination arm and by 31.6% of those in the single‐agent nab‐paclitaxel arm. Conclusions Single‐agent nab‐paclitaxel was associated with promising outcomes and a tolerable safety profile as second‐line treatment for patients with advanced‐stage, nonsquamous non‐small cell lung cancer. There was no benefit from the addition of CC‐486 to nab‐paclitaxel.

8562 Background: Nal-IRI is investigated as monotherapy in patients with SCLC who progressed on or after platinum regimen. The RESILIENT study is a Part 1 study of a Phase 2/3 trial to assess safety, tolerability, and efficacy of Irinotecan Liposome Injection in patients with SCLC. Methods: Nal-IRI is evaluated in patients ≥18 yrs with advanced SCLC with an ECOG performance status ≤1 and adequate organ function; prior exposure to immunotherapy is allowed. Safety and tolerability at dose levels of 85 mg/m2 and 70 mg/m2 are the primary endpoints, with assessment of exploratory efficacy signal. Results: At 24 Dec 2018 safety cutoff 12 patients in Part 1 received ≥1 dose of nal-IRI (Cohort 1 [C-1] at 85 mg/m2 dose n=4; Cohort 2 [C-2] at 70 mg/m2 dose n=8; median age 60.0 yrs; range 49–73 yrs). Three patients experienced ≥1 DLT (Cohort 1 n=3/4; Cohort 2 n=0/8). Most frequent treatment-emergent adverse events (TEAE) were gastrointestinal (GI) disorders (any grade): diarrhea (91.7%), nausea (58.3%), vomiting (41.7%), decreased appetite (58%), abdominal pain (33%) manageable by antidiarrheal regimen and antiemetics; as well as fatigue (50%) and asthenia (37.5%). Overall, hematologic toxicity was neutropenia (any grade) at 16.7% and anemia (any grade) at 16.7%. At 11 Dec 2018 efficacy cutoff the best objective response was partial response (PR) at 33.3% in 4/12 patients (C-1 n=1/4; C-2 n=3/8), median time to response was 6 wks. Overall disease control rate (DCR) was 58.3%; progressive disease (PD) was observed in 2 patients (16.7%), and 3 patients were non-evaluable (25%). Conclusions: Initial assessment suggests that nal-IRI at 70 mg/m2 dose given bi-weekly is well-tolerated and has promising antitumor activity in patients with SCLC who progressed on or after platinum regimen. Part 1 dose expansion is ongoing. Clinical trial information: NCTN03088813. [Table: see text]

TPS9123 Background: Preclinical studies have demonstrated that cetuximab plus chemotherapy results in immunogenic cell death and an increase in CD8+ T cells in the tumor microenvironment. Avelumab (an anti–PD-L1 antibody) has previously shown antitumor activity in NSCLC. We hypothesize that the combination of cetuximab with platinum-based chemotherapy and avelumab may have synergistic antitumor activity. Methods: This phase IIa, single-arm, multicenter study is investigating the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in patients with advanced squamous NSCLC who are treatment naive in the advanced setting (NCT03717155). Eligibility criteria include histologically confirmed stage IV, metastatic or recurrent NSCLC with squamous histology, with no prior systemic therapy for metastatic NSCLC, no prior therapy with any antibody/drug targeting T-cell coregulatory proteins, and ECOG PS of 0 to 1. Patients with a tumor harboring an activating EGFR mutation or ALK rearrangement are excluded. Patients will receive doublet chemotherapy (cisplatin 75 mg/m2 on day 1, gemcitabine 1250 mg/m2 on days 1 and 8), cetuximab on days 1 (250 mg/m2) and 8 (500 mg/m2), and avelumab 800 mg on days 1 and 8 for a total of four 3-week cycles. Thereafter, avelumab (800 mg) and cetuximab (500 mg/m2) will be administered as maintenance treatment Q2W until disease progression, unacceptable toxicity, or withdrawal. Enrollment in a safety run-in, which will evaluate the safety and tolerability of avelumab in combination with cetuximab plus gemcitabine and cisplatin, is planned for the first 6 patients. Enrollment began on October 30, 2018. Study enrollment will continue until approximately 40 evaluable patients have been recruited. The primary endpoint is confirmed best overall response per RECIST 1.1 by investigator assessment. Secondary endpoints include safety (NCI CTCAE v5.0) and tolerability of the combination, duration of response, survival, and tumor biomarkers. The study is ongoing at sites in Hungary and Spain. Clinical trial information: NCT03717155.

Resumen Objetivo Conocer la prevalencia de disfagia en mayores institucionalizados y la efectividad de un metodo clinico para su deteccion. Metodologia Estudio longitudinal prospectivo en una muestra aleatoria de residentes mayores. Se realizo una valoracion de la deglucion por un metodo clinico estandarizado con diferentes volumenes y viscosidades (MECVV). Tras la valoracion se aplicaron cuidados especificos y se realizo un seguimiento. Resultados Se estudiaron 40 residentes. La prevalencia de disfagia no conocida fue del 42,5%, pasando tras la valoracion por el MECVV de un 22,5% a un 65% (p = 0,012). La disfagia detectada por el MECVV se relaciono con el riesgo nutricional, medido por el Mini Nutritional Assessment (MNA) (p = 0,007) y la presencia de demencia (p = 0,028). Conclusiones El diagnostico de disfagia en esta muestra de ancianos institucionalizados aumenta cuando se aplica un metodo clinico para su deteccion, alcanzando una prevalencia elevada y similar a otros estudios.

9101Background: Approximately 20 % of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. In this study, we have anal...

e21028Background: U-EGFRm in exons 18-21 account for 12-15% of overall EGFR mutations in non-small cell lung cancer (NSCLC). Afatinib has shown activity against some u-EGFRm, especially G719X, L861...

e21089Background: OM-NSCLC represents a distinct prognostic group within stage IV lung cancer. Prognostic factors influencing outcome in these patients are not well-known. Methods: We analyzed 84 O...

9070Background: MET signaling represents one mechanism of resistance to EGFR inhibition in EGFR mutant (mt) NSCLC. Emibetuzumab (LY2875358, LY) is a humanized IgG4 monoclonal bivalent MET antibody ...

To determine the prevalence of dysphagia in a population of institutionalised elderly people, and the effectiveness of a clinical method for its detection.A prospective study was conducted on a random sample of elderly residents. A clinical evaluation along with an assessment with different volumes and viscosities (MECVV) were used. Specific care and follow up was arranged following this assessment.Forty residents were studied. The prevalence of unrecognised dysphagia was 42.5%. Following assessment by the MECVV, the prevalence rose from 22.5% to 65% (P=.012). Dysphagia detected by MECVV was related to nutritional risk, as measured by the Mini-Nutritional Assessment (MNA) (P=.007), and to the diagnosis of dementia (P=.028).The diagnosis of dysphagia in this sample of institutionalised elderly people increases when applying a clinical method for detection, reaching a prevalence similar to other studies.

e17545 Background: CDDP+NVBO as induction and concomitant regimen with RT has shown good efficacy outcomes and safety profile (Krzakowski, J Thor Oncol. 2008). The objective of this study was to evaluate the effectiveness and toxicities of the combination of CDDP and NVBO given at full doses concomitantly with RT in LA-NSCLC. Methods: Between February 2010 and May 2011, 26 chemo-naive patients (p) with histologically confirmed stage IIIA/IIIB unresectable LA NSCLC were treated. Treatment consisted of 4 cycles (cy) of NVBO 60 mg/m2 on days 1 and 8 and CDDP 80 mg/m2 every 3 weeks plus RT 66 Gy starting on day 1, cy 2. A standard Fleming two stage design is being used. The sample size is calculated with a power of 90% and a two-sided type 1 error allowance of 5%. Stage 1 included 25 pts, with subsequent expansion to a total of 45. Results: Patient’s characteristics were: Median age, 59 years (range 48-71); males, 92%; smokers, 60%; adenocarcinoma, 28% / squamous, 64%; stage IIIA, 54% / IIIB, 46%. 21 p completed the 4 cy treatment as per protocol. We analyzed 92 cy. Hematological toxicities (% cy): grade (g) 3/4 neutropenia, 42.3%; g3 anemia, 3.3%; g3 thrombocytopenia, 2.2%; febrile neutropenia, 1 p. Non-hematological toxicities (% cy): g3 oesophagitis, 6.5%; g4 diarrhea, 1.1%. 21 p were evaluable for response. 1 CR (4.8%), 17 PR (81%) and 1 SD (4.5%) were reported. ORR 85.8%. Survival analysis has not been performed due to short follow-up. Conclusions: The findings of this interim analysis confirm the previously reported outcomes of efficacy and safety with NVBO plus CDDP when administered concurrently with RT in stage IIIA/IIIB p. The trial has met the criteria for continuation into stage 2.

e15144 Background: IV NVB plus hydrocortisone (HC) compared with HC alone resulted in improved clinical benefit, progression-free survival (PFS) and PSA response rate in HRPC. The oral formulation of NVB avoids the side effects associated with the IV injection, may reduce administration and toxicity-related costs and is easy to administer. Due to these advantages, single agent NVBO treatment could be considered as an optimal option for patients (p) with HRPC previously treated with a taxane or as first-line treatment when a taxane is not indicated. We retrospectively evaluated efficacy and toxicity or NVBO administered as single agent as first or second-line chemotherapy of metastatic HRPC. Methods: Retrospectively data was collected from p with metastatic HRPC treated with NVBO 80 mg/m2 on days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the 1st cycle (cy), plus prednisone 10 mg/day. Patients had received either a taxane as 1st-line treatment or had a documented contraindication to receiving docetaxel. 1 cy was equivalent to a 3-week period. Results: Data on 67 p treated in 13 Spanish centres were included. Median age 73 years (range 54-86). ECOG PS 0, 16.4%; 1, 56.7%; 2, 11.9%. Median PSA 88.9 ng/mL. Prior chemotherapy, 58.2%. Median number of cy was 4 (range 1-6). 56.9% of p could escalate NVBO to 80 mg/m2. 265 cy were performed, 9.1% were delayed and 2.3% had a dose reduction. Grade 3-4 events were infrequent and mainly hematological: neutropenia (6% of p), anemia (4.5%), pain (3%), infection (1.5%), asthenia (3%), respiratory (1.5%), cystitis (1.5%), rectal bleeding (1.5%), febrile syndrome (1.5%), renal (1.5%). No febrile neutropenia was reported. PSA response rate 16.1%, PSA stable was reported in 41.9%. 39 p were evaluable for measurable disease; among them, PR 17.9%, SD 48.7%. Median follow-up, 7.1 months. Median overall survival, 11 months [95% CI: 7.3-14.7]. Median PFS, 2.9 months [95% CI: 2.2-3.6]. Conclusions: NVBO is a safe and active regimen in previous chemotherapy treated HRPC. For those p who cannot receive a taxane as first-line therapy, NVBO can also be considered as an effective first-line treatment.

4587 Background: The effect of pemetrexed in MUC is not well characterized. Vinflunine is the standar second-line in MUC with adjusted benefits and no more drugs have been aproved. SOGUG reports a systematic review of MUC patient series with high activity of P in monotherapy. Methods: Patients with locally advanced urothelial carcinoma and/or MUC whom received P 500 mg/m(2) every 21 days with folic acid and vitamin B12 supplementation, were elected. These patients received P in second, third or fourth-line of chemotherapy. Results: 44 patients have been reported (39males), median age 62 [41-82]. Of all 44 patients; 21, 22, and 1 patients received P as second-line, third and fourth-line respectively. A median of 4 courses were administered [1-12] and disease control (SD+PR+CR) was achieved in 19 patients for an overall control rate of 43.2%. Four groups with significant differences in PFS (p=.033) were established (1.bone-metastasis, 2.visceral-metastasis, 3. nodal-visceral-metastasis and 4.nodal-metastasis). OS was significant between 2nd and 4th group (p=.036) . Mean PFS and OS were 125days [17-606] and 219days [17-1168] respectively for all 44 patients. Mean PFS and OS of 8 patients with bone metastasis were 75 days and 134 days. Mean PFS and OS of 10 patients with visceral metastasis were 65 days and 144 days. Mean PFS and OS of 8 patiens with nodal+visceral metastasis were 154 and 228 days. Mean PFS and OS of 18 patients with nodal metastasis were 166 days and 299 days. Conclusions: Our longer and multicenter follow-up shows that single agent P in monotherapy as second, third and fourth line in MUC is associated with high activity and long-time survival specially in metastatic nodal MUC. These results suggest that P as monotherapy requires to be further studied, more patients are being collected.