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What is this summary about? In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non–small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). What happened in the study? Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. What were the results? Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. What do the results of the study mean? Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 ( ClinicalTrials.gov )

PURPOSE We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer. [Media: see text]

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: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non–small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P=0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P

We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs).We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older.In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation.First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival.

Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

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.

NC-6004 is a nanoparticle developed using micellar technology that can improve release of cisplatin, a standard treatment for many cancer types, and achieve selective distribution to tumors. Here, in the Phase II portion of this study, the activity, safety, tolerability, and effects on quality of life of NC-6004 in combination with gemcitabine was examined in 34 squamous non-small cell lung carcinoma (NSCLC) patients, 50 biliary tract cancer patients, and 13 bladder cancer patients. All patients received 135 mg/m2 NC-6004 on day one and 1,250 mg/m2 gemcitabine on days one and eight. The median progression-free survival was 3.9 months in NSCLC patients, 4.3 months in biliary tract cancer patients, and 6.8 months in bladder cancer patients fit for cisplatin treatment. The most frequently reported Grade 3 Treatment Emergent Adverse Events across all cohorts were nausea, anemia and neutropenia, and hyponatremia. Quality of life measures for patients who received the combined therapy were generally consistent with expectations for patients undergoing chemotherapy. Overall, combined NC-6004 and gemcitabine treatment resulted in long-lasting antitumor activity and had a favorable safety profile, suggesting that it should be investigated further as a therapy for various types of cancer.

PURPOSE Ganetespib, a highly potent heat shock protein 90 inhibitor, blocks multiple oncogenic pathways, resulting in antitumor activity. We evaluated the combination of ganetespib and docetaxel for second-line therapy of patients with advanced adenocarcinoma of the lung. PATIENTS AND METHODS In this international phase III trial, patients with stage IIIB or IV adenocarcinoma diagnosed > 6 months before study entry and 1 prior systemic therapy were randomly assigned (1:1) to ganetespib 150 mg/m2 on days 1 and 15 with docetaxel 75 mg/m2 on day 1 of a 21-day cycle or to docetaxel alone. The primary end point was overall survival (OS). RESULTS Of 677 enrolled patients, 335 were randomly assigned to ganetespib and docetaxel and 337 were assigned to docetaxel. The trial was stopped early as a result of futility at a planned interim analysis. The median OS time was 10.9 months (95% CI, 9.0 to 12.3 months) in the ganetespib and docetaxel arm compared with 10.5 months (95% CI, 8.6 to 12.2 months) in docetaxel arm (hazard ratio [HR], 1.11; 95% CI, 0.899 to 1.372; P = .329). Median progression-free survival was 4.2 months in the ganetespib and docetaxel arm and 4.3 months in the docetaxel arm (HR, 1.16; 95% CI, 0.96 to 1.403; P = .119). The addition of ganetespib did not improve outcomes compared with docetaxel alone for any secondary end point, including survival in the elevated lactate dehydrogenase or EGFR and ALK wild-type populations. The most common grade 3 or 4 adverse event in both arms was neutropenia (30.9% with ganetespib and docetaxel v 25% with docetaxel). CONCLUSION The addition of ganetespib to docetaxel did not result in improved survival for salvage therapy of patients with advanced-stage lung adenocarcinoma.

[Introduction] In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up., [Methods] Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1, [Results] After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65–0.90) and PD-L1 less than 1% (0.64; 0.51–0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1, [Conclusions] At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients., This study was supported by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.

Background To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up. Patients and methods Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs. Results With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation. Conclusions With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer., Highlights • Nivolumab + ipilimumab + two cycles of chemotherapy (chemo) significantly prolonged survival versus chemo in first-line advanced NSCLC. • At 2 years, overall survival benefits were durable with nivolumab + ipilimumab + chemo versus chemo. • Benefits of nivolumab + ipilimumab + chemo were seen across most patient subgroups, including by PD-L1 and histology. • Discontinuing nivolumab + ipilimumab + chemo due to treatment-related AEs did not negatively impact long-term benefits. • Nivolumab + ipilimumab + two cycles of chemo is an efficacious first-line treatment option for advanced non-oncogene-driven NSCLC.

Patients with relapsed/refractory acute myeloid leukaemia (AML), ineligible for intensive chemotherapy and allogeneic stem cell transplantation, have a dismal prognosis. For such cases, hypomethylating agents are a viable alternative, but with limited success. Combination chemotherapy using a hypomethylating agent plus another drug would potentially bring forward new alternatives. In the present manuscript, we present the cell and molecular background for a clinical scenario of a 44‐year‐old patient, diagnosed with high‐grade serous ovarian carcinoma, diagnosed, and treated with a synchronous AML. Once the ovarian carcinoma relapsed, maintenance treatment with olaparib was initiated. Concomitantly, the bone marrow aspirate showed 30% myeloid blasts, consistent with a relapse of the underlying haematological disease. Azacytidine 75 mg/m2 treatment was started for seven days. The patient was administered two regimens of azacytidine monotherapy, additional to the olaparib‐based maintenance therapy. After the second treatment, the patient presented with leucocytosis and 94% myeloid blasts on the bone marrow smear. Later, the patient unfortunately died. Following this clinical scenario, we reproduced in vitro the combination chemotherapy of azacytidine plus olaparib, to accurately assess the basic mechanisms of leukaemia progression, and resistance to treatment. Combination chemotherapy with drugs that theoretically target both malignancies might potentially be of use. Still, further research, both pre‐clinical and clinical, is needed to accurately assess such cases.

Cardiotoxicity is a well-recognised side effect of cancer-related therapies with a great impact on outcomes and quality of life in the cancer survivor population. The pathogenesis of chemotherapy-induced cardiotoxicity in patients with gastrointestinal cancers involves various molecular mechanisms, and the combined use of various chemotherapies augments the risk of each drug used alone. In terms of cardiotoxicity diagnosis, novel biomarkers, such as troponins, brain natriuretic peptide (BNP), myeloperoxidases and miRNAs have been recently assessed. Echocardiography is a noninvasive imaging method of choice for the primary assessment of chemotherapy-treated patients to generally evaluate the cardiovascular impact of these drugs. Novel echocardiography techniques, like three-dimensional and stress echocardiography, will improve diagnosis efficacy. Cardiac magnetic resonance (CMR) can evaluate cardiac morphology, function and wall structure. Corroborated data have shown the importance of CMR in the early evaluation of patients with gastrointestinal cancers, treated with anticancer drugs, but further studies are required to improve risk stratification in these patients. In this article, we review some important aspects concerning the cardiotoxicity of antineoplastic drugs used in gastrointestinal cancers. We also discuss the mechanism of cardiotoxicity, the role of biomarkers and the imaging methods used in its detection.

LBA9025 Background: In CheckMate 227 part 1 (NCT02477826), 1L NIVO + IPI demonstrated long-term, durable survival benefit vs platinum-doublet chemo in patients (pts) with metastatic NSCLC regardless of tumor programmed death ligand 1 (PD-L1) expression level. Here we present the longest reported follow-up (5 y) of a phase 3 trial of 1L combination immunotherapy in metastatic NSCLC. Methods: Adults with previously untreated stage IV or recurrent NSCLC, no known EGFR/ ALK alterations , and an ECOG performance status ≤ 1 were enrolled and stratified by histology. Pts with tumor PD-L1 ≥ 1% were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W), or chemo. Pts with tumor PD-L1 < 1% were randomized 1:1:1 to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Pts were treated until progression, toxicity, or ≤ 2 y for immunotherapy. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and a novel efficacy endpoint, treatment-free interval. Treatment-free interval was measured in pts who discontinued study therapy (for any reason including treatment completion) and was defined as the time from last study dose to start of subsequent systemic therapy or death, whichever occurred first. Results: Minimum follow-up was 61.3 mo (database lock, Feb 15, 2022). In pts with tumor PD-L1 ≥ 1% (N = 1189), continued long-term OS benefit was seen with NIVO + IPI vs chemo (HR, 0.77 [95% CI, 0.66–0.91]); 5-y OS rates were 24% (NIVO + IPI), 17% (NIVO), and 14% (chemo). OS benefit also continued in pts with tumor PD-L1 < 1% (N = 550) for NIVO + IPI vs chemo (HR, 0.65 [95% CI, 0.52–0.81]); 5-y OS rates were 19% (NIVO + IPI), 10% (NIVO + chemo), and 7% (chemo). Clinical benefit with NIVO + IPI vs chemo was observed across additional efficacy endpoints in the overall population and in pts alive at 5 y (table). PFS, ORR, and DOR with NIVO and NIVO + chemo will be presented. Among pts alive at 5 y in the NIVO + IPI group, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) remained treatment-free ≥ 3 y after discontinuing study therapy; median (range) duration of NIVO ± IPI therapy was 17.7 (0-25.5) mo (PD-L1 ≥ 1%) and 9.5 (0-25.1) mo (PD-L1 < 1%). No new safety signals were observed. Conclusions: With a 5-y minimum follow-up, NIVO + IPI continues to provide long-term, durable clinical benefit vs chemo in previously untreated pts with metastatic NSCLC, regardless of PD-L1 expression. NIVO + IPI led to increased 5-y survivorship; the majority of these pts were treatment-free for ≥ 3 y post-treatment discontinuation. Clinical trial information: NCT02477826. [Table: see text]

LBA9026 Background: In CheckMate 9LA (NCT03215706), 1L NIVO + IPI combined with 2 cycles of chemo was shown to provide survival benefit vs chemo alone in pts with metastatic NSCLC. Here, we report updated efficacy and safety with a 3-year minimum follow-up, as well as exploratory biomarker analyses from this study. Methods: Adults with stage IV or recurrent NSCLC, no known sensitizing EGFR/ ALK alterations, and ECOG performance status ≤ 1 were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + 2 cycles of chemo (n = 361) or 4 cycles of chemo alone (n = 358). Pts were stratified by tumor PD-L1 expression, sex, and histology. Pts with non-squamous (NSQ) NSCLC in the chemo-alone arm could receive pemetrexed maintenance. Assessments included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). For all pts with NSQ NSCLC and with tissue evaluable for mutational analysis (n = 313), the FoundationOne CDxTM assay was used to identify mutant (mut) or wild type (wt) KRAS and STK11 genes. Exploratory assessments included evaluation of OS and PFS with NIVO + IPI + chemo vs chemo by mutation status and safety. Results: At a minimum follow-up of 36.1 mo (database lock: Feb 15, 2022), pts continued to derive long-term, durable OS benefit with NIVO + IPI + chemo vs chemo (HR, 0.74 [95% CI, 0.62–0.87]); 3-y OS rates were 27% vs 19%. Clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across most subgroups, including by PD-L1 expression level (Table) or histology. In an exploratory analysis in pts evaluable for mutations including KRAS and STK11, OS appeared to be improved with NIVO + IPI + chemo vs chemo (median OS, 16.3 vs 13.1 mo). Similar trends of prolonged OS with NIVO + IPI + chemo vs chemo were also seen in pts with or without KRAS mutation (median OS, mut: 19.2 vs 13.5 mo; wt: 15.6 vs 12.7 mo) or STK11 mutation (mut: 13.8 vs 10.7 mo; wt: 17.8 vs 13.9 mo), respectively. Additional efficacy outcomes will be presented. No new safety signals were identified with extended follow-up. Conclusions: With a 3-year minimum follow-up, 1L NIVO + IPI + chemo demonstrated long-term, durable efficacy benefit vs chemo in pts with metastatic NSCLC. Survival benefit of NIVO + IPI + chemo vs chemo was observed regardless of KRAS and STK11 mutation status. Clinical trial information: NCT03215706. [Table: see text]

9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to

9000 Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. [Table: see text]

Erratum in Correction to Lancet Oncol 2021; 22: 198-211. [No authors listed] Lancet Oncol. 2021 Mar;22(3):e92. doi: 10.1016/S1470-2045(21)00082-6. PMID: 33662299 No abstract available.; International audience; Background: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit.Methods: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706.Findings: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.Interpretation: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.Funding: Bristol Myers Squibb.

Background: About 10,000 women are diagnosed with breast cancer and about 2000 women are diagnosed with ovarian cancer each year in Romania. There is an insufficient number of genetic studies in the Romanian population to identify patients at high risk of inherited breast and ovarian cancer. Methods: We evaluated 250 women of Romanian ethnicity with BC and 240 women of Romanian ethnicity with ovarian cancer for the presence of damaging germline mutations in breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively) using Next-Generation Sequencing (NGS) technology. Results: Of the 250 breast cancer patients, 47 carried a disease-predisposing BRCA mutation (30 patients (63.83%) with a BRCA1 mutation and 17 patients (36.17%) with a BRCA2 mutation). Of the 240 ovarian cancer patients, 60 carried a BRCA mutation (43 patients (72%) with a BRCA1 mutation and 17 patients (28%) with a BRCA2 mutation). In the BRCA1 gene, we identified 18 variants (4 in both patient groups (ovarian and breast cancer patients), 1 mutation variant in the BC patient group, and 13 mutation variants in the ovarian cancer patient group). In the BRCA2 gene, we identified 17 variants (1 variant in both ovarian and breast cancer patients, 6 distinct variants in BC patients, and 10 distinct variants in ovarian cancer patients). The prevailing mutation variants identified were c.3607C>T (BRCA1) (18 cases) followed by c.5266dupC (BRCA1) (17 cases) and c.9371A>T (BRCA2) (12 cases). The most prevalent mutation, BRCA1 c.3607C>T, which is less common in the Romanian population, was mainly associated with triple-negative BC and ovarian serous adenocarcinoma. Conclusion: The results of our analysis may help to establish specific variants of BRCA mutations in the Romanian population and identify individuals at high risk of hereditary breast and ovarian cancer syndrome by genetic testing.

Cardiology and oncology are two fields dedicated to the study of various types of oncological and cardiac diseases, but when they collide, a new specialty is born, i.e., cardio-oncology. Continuous research on cancer therapy has brought into the clinic novel therapeutics that have significantly improved patient survival. However, these therapies have also been associated with adverse effects that can impede the proper management of oncological patients through the necessity of drug discontinuation due to life-threatening or long-term morbidity risks. Cardiovascular toxicity from oncological therapies is the main issue that needs to be solved. Proper knowledge, interpretation, and management of new drugs are key elements for developing the best therapeutic strategies for oncological patients. Upon continuous investigations, the profile of cardiotoxicity events has been enlarged with the inclusion of myocarditis upon administration of immune checkpoint inhibitors and cardiac dysfunction in the context of cytokine release syndrome with chimeric antigen receptor T cell therapy. Affinity enhanced and chimeric antigen receptor T cells have both been associated with hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Therefore, the cardiologist must adhere to the progressing field of cancer therapy and become familiar with the adverse effects of novel drugs, and not only the ones of standard care, such as anthracycline, trastuzumab, and radiation therapy. The present review provides essential information summarized from the latest studies from cardiology, oncology, and hematology to bring together the three specialties and offers proper management options for oncological patients.

Head and neck squamous cell carcinoma (HNSCC) is among the 10 most common cancers worldwide, with increasing incidence.1 Approximately 10% of patients with HNSCC will be diagnosed with metastatic disease, and even when treated early, around half will have disease recurrence.2,3 The platinum-based doublet chemotherapy with cetuximab regimen has been the most widely-used therapy and considered standard of care (SoC) since it was proven effective in 2007 for recurrent/metastatic (R/M) HNSCC in the first-line setting.3,4 However, patients typically progress even after aggressive first-line therapy, and, until recently, the available options (e.g. cetuximab, methotrexate, and taxanes) have delivered limited survival benefits.3 Durvalumab is an immunotherapeutic agent that blocks the interaction between programmed cell death ligand 1 (PD-L1) and its receptors.5 Durvalumab demonstrated encouraging response rates and duration of response (DoR) with a manageable safety profile in patients with HNSCC.6 Although monotherapy agents that block the programmed cell death protein 1 (PD-1)/PD-L1 axis have shown clinical activity, immunotherapy combinations have the potential to improve upon monotherapy activity.7e9 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-L1/PD-1 pathways have largely non-redundant roles, suggesting that blockade of both could have additive or synergistic effects.10 Indeed, the combination of durvalumab and tremelimumab, an anti-CTLA-4 monoclonal antibody, was explored based on improved efficacy over monotherapy in other solid tumor types.7 This observation, in addition to the activity demonstrated by durvalumab in earlier R/M HNSCC studies, served as the rationale to evaluate durvalumab and tremelimumab in patients with R/M HNSCC. Several studies, including the EAGLE study, were initiated to evaluate combination immunotherapy regimens in various patient groups.11,12 The EAGLE study was the first phase III study to investigate durvalumab and tremelimumab in patients with R/M HNSCC who had progressed after platinumbased therapy. During the conduct of the EAGLE study, anti-PD-1 monoclonal antibodies were approved for use for R/M HNSCC progression following a platinum-based regimen. Treatment with these immunotherapies resulted in a median overall survival (OS) of 7.5e8.4 months.13,14 These immunotherapies are now recommended for second-line treatment as monotherapies for patients with R/M HNSCC.3,13,14 More recently, immunotherapy alone or in combination with platinum-based chemotherapy has shown improvements in OS in the first-line setting, underscoring the clinical utility of immunotherapy in HNSCC.15 Here, we report the results of the randomized phase III EAGLE trial evaluating durvalumab and durvalumab plus tremelimumab versus SoC therapies in patients with R/M HNSCC who have progressed following a platinumcontaining regimen.

BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P

Introduction Les donnees concernant l’immunotherapie chez les patients atteints d’un CBNPC avance avec un mauvais indice de performance ou d’autres comorbidites sont limitees. CheckMate 817 est un essai clinique de phase IIIb/IV multi-cohortes evaluant l’innocuite et l’efficacite de nivolumab + ipilimumab en 1re intention dans le CBNPC avance. Methodes Les patients inclus etaient naifs de traitement et presentaient un CBNPC avance. La cohorte A1 (n = 198) incluait des patients avec un ECOG PS 2 ou 0–1 avec un critere additionnel parmi lesquels des metastases cerebrales asymptomatiques non traitees, une insuffisance hepatique ou renale ou une infection par le VIH. La cohorte A (n = 391) incluait des patients avec un ECOG PS 0–1. Les patients presentant des mutations de l’EGFR ou des translocations ALK sensibles aux therapies ciblees disponibles ont ete exclues. Nivolumab 240 mg toutes les 2 semaines + ipilimumab 1 mg/kg toutes les 6 semaines ont ete administres pendant deux ans ou jusqu’a progression de la maladie ou toxicite inacceptable. Les criteres d’innocuite et d’efficacite ont ete evalues ; les analyses sur la cohorte A1 etaient exploratoires. Resultats Les patients de la cohorte A1 ont ete separes 2 sous-groupes : ECOG PS 2 (n = 139) et toutes les autres populations particulieres (APP ; n = 59). Les caracteristiques a l’inclusion etaient generalement equilibrees entre les 2 cohortes. La frequence d’evenements indesirables lies au traitement (EILT) de grade 3-4 etaient similaires entre les 2 cohortes ; dans la cohorte A1, les EILT de grade 3–4 etaient numeriquement plus eleves dans le sous-groupe APP vs le sous-groupe ECOG PS 2. Le taux de reponse objective etait de 25 % dans la cohorte A1 (ECOG PS 2, 20 % ; APS, 37 %) et 35 % dans la cohorte A. La survie sans progression (SSP) etait numeriquement plus courte dans la cohorte A1 que dans la cohorte A ; une charge mutationnelle elevee (≥ 10 mut/Mb) et une expression plus elevee du PD-L1 (≥ 1 % ou ≥ 50 %) etaient associees a une SSP numeriquement plus longue dans les deux cohortes A1 et A ( Tableau 1 ). Conclusion Le traitement en premiere ligne par nivolumab en association a l’ipilimumab fait etat d’un profil de securite similaire dans des populations particulieres de patients presentant un CBNPC avance, y compris celles avec un ECOG PS 2. Les patients dont la tumeur presentait une charge mutationelle ou une expression de PD-L1 elevee semblaient beneficier d’une meilleure efficacite.

Background Nivolumab (NIVO) + ipilimumab (IPI) combination demonstrated improved overall survival (OS) benefits vs chemotherapy as first-line treatment for advanced NSCLC in both tumor programmed death ligand 1 (PD-L1) expression ≥ 1% and Methods Patients with previously untreated stage IV or recurrent NSCLC, and no known sensitizing EGFR or ALK alterations, were eligible regardless of PD-L1 expression. Cohort A (n = 391) had ECOG performance status (PS) 0–1; cohort A1 (special populations; n = 198) had ECOG PS 2 or a specified comorbidity (asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV). Patients were treated with NIVO 240 mg Q2W + low-dose IPI 1 mg/kg Q6W for 2 years or until disease progression/unacceptable toxicity. Safety in cohort A was the primary endpoint; efficacy endpoints were secondary/exploratory; A1 safety and efficacy analyses were exploratory. Results Baseline characteristics apart from ECOG PS and comorbidities were similar between cohorts. With minimum follow-up of 21 months (A) and 14 months (A1), median OS was 17.0 months and 9.9 months, respectively. At 1 year, 60% of patients in A and 47% of patients in A1 were alive. OS by PD-L1 expression and tumor mutational burden levels will be presented. The safety profile (type and rate of treatment-related adverse events [TRAEs]) was consistent between the cohorts. The range of median time to onset of select TRAEs was similar between cohorts A (2–26 weeks) and A1 (2–21 weeks). The majority of select TRAEs have resolved (40%–100%). Conclusion Select TRAE profile of NIVO + low-dose IPI was similar between cohorts A and A1. Durable OS outcomes were observed with first-line NIVO+IPI in patients with advanced NSCLC (cohort A) and were comparable to CheckMate 227; although as expected, comorbidities and/or poor performance status impacted outcomes in cohort A1. Clinical trial identification NCT02869789. Editorial acknowledgement Writing and editorial assistance was provided by Mhairi Laird, PhD, of Caudex and funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, Takeda; Advisory / Consultancy: AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, Takeda; Research grant / Funding (institution): AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis,; Non-remunerated activity/ies: Principal Investigator for AstraZeneca, Bristol-Myers Squibb, Merck, Pierre Fabre and Roche sponsored trials (or ISR). C. Audigier-Valette: Honoraria (self): AbbVie, Pfizer; Honoraria (institution): Roche, MSD, Bristol-Myers Squibb, AstraZeneca; Advisory / Consultancy: Roche, MSD, Bristol-Myers Squibb, AstraZeneca, AbbVie, Pfizer. E. Felip: Advisory / Consultancy: AbbVie, AstraZeneca, Blue Print Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, TouchTime; Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda. T-E. Ciuleanu: Advisory / Consultancy: Astellas, Janssen, Bristol-Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Lilly, AstraZeneca, MSD, Sanofi, Novartis, Servier, AD Pharma. K. Jao: Advisory / Consultancy: AbbVie, AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Merck, Takeda, Roche; Speaker Bureau / Expert testimony: AstraZeneca/CIOSK. J-S. Aucoin: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche; Speaker Bureau / Expert testimony: AstraZeneca, Merck, Pfizer, Roche. K. Vermaelen: Honoraria (self): MSD, Roche; Honoraria (institution): Bristol-Myers Squibb; Advisory / Consultancy: MSD, Bristol-Myers Squibb, Roche; Research grant / Funding (institution): Bristol-Myers Squibb. O. Aren Frontera: Full / Part-time employment: Pfizer. N. Ready: Honoraria (self): Bristol-Myers Squibb, AstraZeneca, G1 therapeutics, Merck, Genentech, AbbVie, Bristol-Myers Squibb – unbranded speaker, Celgene – unbranded speaker; Advisory / Consultancy: Bristol-Myers Squibb, AstraZeneca, G1 therapeutics, Merck, Genentech, AbbVie; Speaker Bureau / Expert testimony: Bristol-Myers Squibb – unbranded speaker, Celgene – unbranded speaker; Research grant / Funding (self): Merck investigator-initiated trial. A. Curioni: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Roche, Pfizer, Takeda. H. Linardou: Advisory / Consultancy: Bristol-Myers Squibb, MSD, AstraZeneca, Roche; Speaker Bureau / Expert testimony: AstraZeneca. R. Pillai: Research grant / Funding (self): Bristol-Myers Squibb. S. Li: Full / Part-time employment: Bristol-Myers Squibb. A. Acevedo: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Full / Part-time employment: Bristol-Myers Squibb. L. Paz-Ares: Honoraria (self): Roche, MSD, Lilly, Novartis, Boehringer Ingelheim, AstraZeneca, Amgen, Sanofi, Pharmamar, Pfizer, Bristol-Myers Squibb, Merck, Takeda, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint; Leadership role: Altum Sequencing; Research grant / Funding (institution): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Background Immunotherapy with or without chemo has improved survival vs chemo in 1L aNSCLC. NIVO + chemo showed encouraging activity in a phase 1 study in this setting. CheckMate 227 is a multi-part, randomized, open-label, phase 3 study evaluating NIVO-based regimens vs chemo. We present final results from Part 2, which evaluated NIVO + chemo vs chemo in 1L aNSCLC. Methods Pts (N = 755) with chemo-naive, stage IV or recurrent NSCLC, ECOG PS 0–1, and no sensitizing EGFR/ALK alterations were randomized 1:1 to receive every 3 weeks NIVO 360 mg + chemo or chemo. Pts were stratified by histology (squamous [SQ] vs non-squamous [NSQ]), sex, and PD-L1 expression ( Results Baseline characteristics were generally balanced. Minimum follow-up was 19.5 mo. In pts with NSQ NSCLC, no statistically significant improvement in OS was seen with NIVO + chemo vs chemo (HR, 0.86 [95.62% CI, 0.69–1.08; P=0.1859]); median OS was 18.8 mo vs 15.6 mo; 12-mo OS rates were 67.3% vs 59.2%. HR for OS was 0.81 (95% CI, 0.67–0.97) in all randomized pts; 0.69 (95% CI, 0.50–0.97) in pts with SQ NSCLC. Progression-free survival and objective response rates favored NIVO + chemo in NSQ, SQ, and all randomized pts (table). Grade 3–4 tx-related adverse events occurred in 45% and 35% of all pts treated with NIVO + chemo and chemo, respectively.TableLBA3 Efficacy outcomes with 1L NIVO + chemo vs chemo in pts with NSQ NSCLC, SQ NSCLC, and in all randomized ptsTableNSQ NSCLCSQ NSCLCAll Randomized PtsNIVO + chemoChemoNIVO + chemoChemoNIVO + chemoChemon=270n = 273n=107n = 105n=377n = 378OSEvents, n (%)156 (57.8)164 (60.1)68 (63.6)75 (71.4)224 (59.4)239 (63.2)Median, mo18.815.618.312.018.314.7HR (95% CI)0.86 (0.69–1.08)aP = 0.18590.69 (0.50–0.97)0.81 (0.67–0.97)12-mo OS rate, %67.359.266.148.566.956.2PFSEvents, n (%)187 (69.3)200 (73.3)79 (73.8)82 (78.1)266 (70.6)282 (74.6)Median, mo8.75.87.14.48.45.5HR (95% CI)0.67 (0.55–0.82)0.51 (0.37–0.70)0.62 (0.52–0.73)12-mo PFS rate, %39.525.731.79.337.321.3Objective response rate, n (%)130 (48.1)80 (29.3)64 (59.8)34 (32.4)194 (51.5)114 (30.2)a95.62% CI Conclusion CheckMate 227 Part 2 did not meet the primary endpoint of OS for NIVO + chemo vs chemo in NSQ NSCLC. Descriptive analyses showed longer OS with NIVO + chemo in all randomized pts and SQ NSCLC. No new safety signals were observed. Clinical trial identification NCT02477826; Release date: June 23, 2015. Editorial acknowledgement Writing and editorial assistance was provided by Namiko Abe, PhD, of Caudex, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure L. Paz-Ares: Honoraria (self): Roche, MSD, Lilly, Novartis, Boehringer Ingelheim, AstraZeneca, Amgen, Sanofi, Pharmamar, Pfizer, Bristol-Myers Squibb, Merck, Takeda, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint; Leadership role: Altum Sequencing; Research grant / Funding (institution): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb; Officer / Board of Directors: Genomica. T.E. Ciuleanu: Advisory / Consultancy: Astellas, Janssen, Bristol-Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Lilly, AstraZeneca, MSD, Sanofi, Novartis, Servier, AD Pharma. A. Pluzanski: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Speaker Bureau / Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche, Takeda; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche. A. Nagrial: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; Research grant / Funding (institution): Astra Zeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche. R. Kowalyszyn: Advisory / Consultancy: Astellas, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, MSD, Novartis; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Lilly, MSD, Pfizer, Roche. C. Audigier-Valette: Honoraria (self): AbbVie, Pfizer; Honoraria (institution): Roche, MSD, Bristol-Myers Squibb, AstraZeneca; Advisory / Consultancy: Roche, MSD, Bristol-Myers Squibb, AstraZeneca, AbbVie, Pfizer. Y-L. Wu: Honoraria (self): AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, BMS, Roche; Non-remunerated activity/ies: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche. H. Borghaei: Honoraria (self): University of Pennsylvania, CAR T Program, Takeda [Data and Safety Monitoring Board]; Advisory / Consultancy: Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio, GLG; Research grant / Funding (self): Millennium, Merck/Celgene, Bristol-Myers Squibb/Lilly. M.D. Hellmann: Advisory / Consultancy: Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, Syndax, Shattuck Labs, Immunai, Nektar, Blueprint Medicines; Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb, AstraZeneca; Shareholder / Stockholder / Stock options: Shattuck Labs, Immunai. J. Brahmer: Advisory / Consultancy: Bristol-Myers Squibb, AstraZeneca, Genentech, Merck, Amgen. M. Reck: Honoraria (self): AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Ramalingam: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Loxo, Tesaro, Merck, Daichi; Advisory / Consultancy: Amgen, AbbVie, Lilly, Genentech, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Amgen, AstraZeneca, Takeda, Advaxis, Tesaro, Merck. L. Zhang: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, MSD, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Pfizer, Henrui Pharm. P. Bhagavatheeswaran: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F.E. Nathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. K.J. O'Byrne: Advisory / Consultancy: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Novartis, Teva, Janssen-Cilag, Natera; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Janssen-Cilag, Mundipharma; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim; Shareholder / Stockholder / Stock options: Carp Pharmaceuticals, Carpe Vitae Phaemaceuticals; Licensing / Royalties: Various patents issues with licensee as listed. Queensland University of Technology and Trinity College Dublin. All other authors have declared no conflicts of interest.

9016 Background: 1L NIVO + IPI was shown to provide durable long-term overall survival (OS) benefit vs chemo regardless of tumor programmed death ligand 1 (PD-L1) expression in patients (pts) with advanced NSCLC in CheckMate 227 Part 1 (NCT02477826); 3-year OS rates were 33% vs 22% in pts with PD-L1 ≥ 1% (HR, 0.79 [95% CI, 0.67–0.93]) and 34% vs 15% in pts with PD-L1 < 1% (HR, 0.64 [95% CI, 0.51–0.81]). Here we report updated results from the study with 4 years’ minimum follow-up. Methods: Adults with previously untreated stage IV / recurrent NSCLC, no known EGFR/ ALK alterations , and ECOG performance status ≤ 1 were enrolled; pts were stratified by squamous (SQ) and non-squamous (NSQ) histology. Pts with PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to receive NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO alone (240 mg Q2W), or chemo. Pts with PD-L1 < 1% (n = 550) were randomized 1:1:1 to receive NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1% was the primary endpoint. Results: With minimum follow-up of 49.4 months (database lock, Feb 18, 2021), pts were at least 2 years beyond the protocol-specified end of immunotherapy treatment. Pts with PD-L1 ≥ 1% continued to show durable benefit with NIVO + IPI vs chemo (HR, 0.76 [95% CI, 0.65–0.90]); 4-year OS rates were 29% (NIVO + IPI), 21% (NIVO), and 18% (chemo). At 4 years, 14% (NIVO + IPI), 10% (NIVO), and 4% (chemo) remained progression free. Among responders, 34%, 30%, and 7% remained in response, respectively. In an exploratory analysis in pts with PD-L1 ≥ 50%, 4-year OS rates were 37% (NIVO + IPI), 26% (NIVO), and 20% (chemo). In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 4-year OS rates were 24% (NIVO + IPI), 13% (NIVO + chemo) and 10% (chemo). At 4 years, 12% (NIVO + IPI), 7% (NIVO + chemo), and 0% (chemo) remained progression free. Among responders, 31%, 13%, and 0% remained in response, respectively. Among pts who progressed on NIVO + IPI vs chemo, 7% vs 40% (PD-L1 ≥ 1%), and 9% vs 33% (PD-L1 < 1%), received subsequent immunotherapy. Benefit with NIVO + IPI vs chemo was observed for both SQ and NSQ histology (Table). With long-term follow-up, no new safety signals were identified. Conclusions: With 4 years’ minimum follow-up, 1L NIVO + IPI continued to provide durable, long-term OS benefit vs chemo in pts with advanced NSCLC regardless of PD-L1 expression or histology. Clinical trial information: NCT02477826. [Table: see text]

9086 Background: Brain metastases (BM) frequently occur in patients (pts) with epidermal growth factor receptor mutated non-small cell lung cancer (EGFRm NSCLC) and represent a poor prognostic marker. This study aimed to describe the clinical characteristics, treatment patterns and survival outcomes in EGFRm NSCLC pts treated with 1st or 2nd generation tyrosine-kinases inhibitors (TKIs) in first-line (1L). Methods: The retrospective real-world study REFLECT (NCT04031898) collected data from 896 pts initiating 1L TKI between 1 January 2015-30 June 2018 in Europe and Israel. Descriptive statistics were used to assess demographic and clinical characteristics in subgroups of patients with and without BM. Kaplan-Meier methods were used to estimate median real world progression free survival (mPFS) and overall survival (mOS) from start of 1L. Results: Out of 896 pts, 198 (22.1%) had BM at start of 1L, 134 (15%) developed BM later (any time), and 564 (62.9%) had no sign of BM at the time of data collection. Among pts who later developed BM the median time between the start of 1L and first diagnosis of BM was 13.5 months. Median duration of follow-up was 21.5 months. Of 332 pts with BM at any time 64.2% were female, similar to the ratio in pts without BM (64.0%). At diagnosis, median age was 65 years in pts with BM vs. 70 in those who never developed BM. Of pts with BM at any time, 50.9% had exon 19 deletion, 30.4% L858R point mutation and 18.7 % uncommon EGFR mutations at baseline, compared to 56.6%, 31.7% and 11.7% in pts without BM, respectively. At data collection, 94.9% of the pts with BM at diagnosis had progressed compared to 79.8% among those with no BM. Overall, whole brain radiation was the most frequently used treatment for BM (31.0%) followed by stereotactic radiosurgery (18.1%) and targeted therapies (13.3%). T790M testing rates were highest among pts developing BM later (85.7%) and lowest among those with BM from start (66.1%). The T790M positivity rate was highest in pts developing BM later (65.7%) and lowest among those with BM from start (50.4%). More pts received osimertinib in later lines among those with BM at any time compared to those without BM (51.3% vs 43.8%). Median real world PFS and OS (95% CI) were shorter among pts with BM at baseline compared to those never developing BM: 10.2 (8.8, 11.5) vs 15.2 (13.7, 16.1) months, and 19.4 (17.1, 22.1) vs 30.3 (27.1, 33.8) months, respectively. At the time of data collection, 77.3% of pts with BM at baseline were deceased compared to 52.5% pts with no BM. Conclusions: More than one third of pts included in REFLECT had BM at any time. Uncommon EGFR variants at baseline were observed more frequently in pts with BM. mPFS and mOS were shorter in pts with BM at baseline compared to those never developing BM. These data highlight the need for improved treatment and CNS control in pts with EGFRm NSCLC. Clinical trial information: NCT04031898.

[Background] To assess the efficacy and safety of a metronomic schedule of oral vinorelbine (mVNR) in advanced non-small-cell lung cancer (NSCLC) in patients unfit for platinum-based combination chemotherapy., [Patients and methods] This was a multicenter, prospective, randomized, open-label phase II study in treatment-naive patients with TNM stage IIIB/IV NSCLC. Patients received mVNR at a fixed dose of 50 mg × 3 or standard schedule 60-80 mg/m2 weekly until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) without grade 4 toxicity (G4PFS; NCI-CTC v4). Main secondary objectives were safety, disease control rate (DCR) without grade 4 toxicity (G4DCR), DCR, PFS, overall survival (OS) and quality of life (QoL)., [Results] A total of 167 patients were included, 83 and 84 patients in the mVNR and standard arms, respectively. The median G4PFS was 4.0 months [95% confidence interval (CI): 2.6-4.3] and 2.2 months (95% CI: 1.5-2.9), hazard ration (HR) = 0.63 (95% CI: 0.45-0.88), P = 0.0068 in favor of metronomic arm; G4DCR was 45.8% and 26.8% in the mVNR and standard arms, respectively. Grade 3-4 treatment-related adverse events were less frequent in the mVNR arm (25.3% versus 54.4%) mainly owing to a reduction in all grades (15.7% versus 51.9%) and grade 3-4 neutropenia (10.8% versus 42%). PFS was 4.3 (95% CI: 3.3-5.1) and 3.9 months (95% CI: 2.8-5.2) in mVNR and standard arms, respectively. No difference in median OS was observed. QoL was comparable between arms., [Conclusions] Metronomic oral vinorelbine significantly prolonged median G4PFS in advanced NSCLC patients unfit for platinum combinations as first-line treatment. It was associated with a clear reduction in toxicity and may be considered as an important option in this challenging population., Pierre Fabre Médicament was the Sponsor of the study. The study was funded by Pierre Fabre Médicament. Conduct of the study: Pierre Fabre Médicament with the support of Clinipace clinical research organization (CRO) for the monitoring, of C-Med (CRO) for the data management and statistical analyses.

Introduction Dans l’essai CM 227 partie 1, l’association NIVO + IPI a ameliore la survie globale (OS) en 1L de traitement du CBNPC avance, independamment de l’expression de PD-L1. CM 9LA ( NCT03215706 ) est une etude randomisee de phase 3 evaluant l’association NIVO + IPI + 2 cycles CT vs CT en 1L de traitement du CBNPC avance. Methodes Les adultes atteints d’un CBNPC avance, naifs de traitement, ont ete randomises dans les groupes NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + CT (2 cycles) (n = 361) ou CT seule (4 cycles) (n = 358), stratifies selon le statut PD-L1 ( Resultats Lors d’une analyse intermediaire pre-specifiee (suivi minimum : 8,1 mois), l’OS etait prolongee significativement avec NIVO + IPI + CT vs CT (HR : 0,69, IC a 96,71 %C : 0,55–0,87 ; p = 0,0006), de meme pour la PFS et l’ORR. Avec un suivi plus long (minimum 12,7 mois), l’OS restait plus importante avec NIVO + IPI + CT vs CT : mediane 15,6 vs 10,9 mois (HR : 0,66, IC a 95 % : 0,55–0,80) ; les taux d’OS a 1 an etaient de 63 % vs 47 %. Le benefice clinique etait coherent pour tous les criteres d’efficacite parmi les differents sous-groupes cles, y compris par PD-L1 et par histologie. Des evenements indesirables de grade 3–4 lies aux traitements etaient de 47 % dans le bras NIVO + IPI + CT vs 38 % dans le bras CT. Conclusion L’OS a ete amelioree de maniere statistiquement significative avec NIVO + IPI + CT vs CT (4 cycles) en 1L de traitement du CBNPC avance. Aucun nouveau signal de securite n’a ete identifie.

9501 Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC. Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability. Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively. Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706 .

The purpose of this prospective observational study was to evaluate the diagnostic performance of multiparametric (mp) magnetic resonance imaging (MRI) for prostate cancer detection and to assess the interobserver variability, using the Prostate Imaging Reporting and Data Systems (PI-RADS).50 patients (mean age 68.42±6.58 years) with suspected prostate cancer fulfilling the inclusion criteria and without any exclusion criteria were enrolled. All patients were examined with mp-MRI protocol, as per European Society of Urogenital Radiology (ESUR) guidelines, before systematic transrectal ultrasound (TRUS)-guided biopsy. All examinations were read by three independent radiologists with 3-year experience in prostate MRI. Sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were calculated. Interobserver agreement was evaluated using Kappa Cohen coefficient of agreement.mp-MRI and histopathological results of TRUSguided biopsy showed a very good agreement in prostate cancer detection. The overall Se, Sp, PPV and NPV ranged between 93.3-96.7%, 55.0-80.0%, 76.3-87.9% and 88.2-94.1%, respectively. The Kappa Cohen coefficient of interobserver agreement was 0.643 between Readers 1 and 2, 0.664 between Readers 1 and Reader 3 and 0.568 between Readers 2 and 3.Our results showed a high Se for the detection of prostate cancer with mp-MRI and a high NPV to rule out prostate malignancy. PI-RADS version 2 provides an adequate standardization of mp-MRI, allowing a good level of interobserver agreement.

Background: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. Patients and methods: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m2 on day 1) was administered alone or with ganetespib (150 mg/m2 on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). Results: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). Conclusion: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.

To assess prognostic/predictive value of carcinoembryonic antigen (CEA), transthyretin (TRT), αenolase (NNE), β2-microglobulin (β2-micro), B-cell activating factor (BAFF) and circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) patients treated with chemotherapy with or without bevacizumab.72 histologically confirmed mCRC patients treated at Oncology Institute Cluj were included. Biomarker levels were measured through validated methods. A manual method was used for CTCs, involving hemolysis, cytospin centrifugation and immunocytochemical staining for pan-cytokeratin. Statistical endpoints were response, progression- free survival (PFS) and overall survival (OS).Initial chemotherapy was fluoropyrimidine/oxaliplatin-based in 93.1%; bevacizumab was added in 58.3% of the patients. Median PFS and OS were 16.4 and 24.4 months. Two-year OS for CRPR vs SD vs PD were 90% vs 48% vs 12%, respectively (p0.01). Two-year OS for chemo/ bevacizumab vs chemotherapy: 65% vs 42% (p=0.09). Baseline CEA ≥5 ng/ml had a negative prognostic impact on OS and PFS (p0.01). High baseline CEA was predictive of improved OS when adding bevacizumab (2-year OS chemo/bevacizumab vs chemo: 60% vs 17%, p0.01); adding bevacizumab in patients with normal CEA did not improve OS (p=0.29). Higher than cut-off values for TRT had a positive OS prognostic value (p0.01); higher levels for NNE, β2-microglobulin and BAFF had a negative impact (p0.01). Two-year OS for baseline1 CTC/ml vs ≥1 CTC/ ml was 74% vs 64% respectively (p=0.15).The evaluated biomarkers could be useful prognostic factors for survival. Baseline CEA also has predictive value, suggesting that patients with low levels do not benefit from bevacizumab. A non-statistically significant correlation was observed between the number of CTCs and outcome.

Background The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration NCT01183780.

This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose., SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody inhibiting vascular endothelial growth factor receptor-2, increased overall survival (OS) combined with docetaxel versus docetaxel alone in non-small cell lung cancer (NSCLC) in the REVEL trial. Pre-specified exploratory analysis examined efficacy and safety by histology. Materials and methods 1253 patients with NSCLC were randomized to receive ramucirumab (10 mg/kg; n = 628) plus docetaxel (75 mg/m 2 ) or placebo plus docetaxel (n = 625) after disease progression on or after platinum-based therapy, with or without bevacizumab or maintenance therapy. OS was analyzed using Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Primary quality-of-life analysis was time to deterioration (TtD) of the Lung Cancer Symptom Scale (LCSS) scores using the Kaplan-Meier method and Cox regression. Results Median OS for adenocarcinoma was 11.2 months for ramucirumab-docetaxel (n = 377) and 9.8 months for placebo-docetaxel (n = 348); HR = 0.83 (95% CI: 0.69–0.99). In squamous disease, median OS was 9.5 months for ramucirumab-docetaxel (n = 157) versus 8.2 months for placebo-docetaxel (n = 171); HR 0.88 (95% CI: 0.69–1.13). Median OS for other nonsquamous was 10.8 months for ramucirumab-docetaxel (n = 74) and 9.3 months for placebo-docetaxel (n = 78); HR = 0.86 (95% CI: 0.59–1.26). Treatment-emergent adverse events were comparable between treatment arms across histologic subgroups. TtD for LCSS scores was similar between treatment arms in the nonsquamous and squamous subgroups. Conclusion REVEL demonstrated similar favorable efficacy and manageable safety for ramucirumab-docetaxel across histologic subgroups of NSCLC.

Background Tempo-Lung trial randomly assessed the role of metronomic oral vinorelbine (OV) vs standard weekly oral vinorelbine in advanced NSCLC patients (pts) unfit to platinum doublets. Little data are available on treatment options after first-line in platinum-unfit pts. Methods Advanced NSCLC pts unfit to receive platinum doublets (Creatinine clearance G2; any medical condition impairing platinum treatment according to physician’s opinion) were randomized to arm A (metronomic): OV 50mg x3/week (wk) or arm B (standard): OV 60 mg/m²/wk cycle 1, then 80 mg/m²/wk. Primary endpoint was progression free-survival without grade 4 toxicity (PFSG4) and secondary efficacy and safety end-point, quality of life (QoL). Data on treatment after failure of first-line vinorelbine were collected. Results Intention-to-treat population included 165 (arm A 83 - arm B 82) pts. Baseline characteristics were well balanced between both arms. Mean dose intensity by cycle: 73.56 mg/m²/week (arm A), 55.85 mgm²/week (arm B). Median PFSG4 significantly differ in favor of metronomic arm [95%CI]: 4.0 [2.6-4.3] vs 2.2 [1.5-2.9] months (p = 0.0068), HR [95%CI] = 0.63 [0.45-0.88]. Overall treatment related adverse events (61.4% vs 84%): haematological toxicities (27.7% vs 55.6%), G3/4 neutropenia (11% vs 42%), febrile neutropenia (3.6% vs 6.2%) and G3/4 asthenia (4.8% vs 8.6%) were reduced with metronomic OV. It was observed that 40% of patients (subset) had second line treatment: immunotherapy, chemotherapy, protein kinase inhibitor, radiotherapy. No difference was found for changes in EORTC QoL scores. Secondary endpoints will be presented. Conclusions Metronomic OV could be a suitable option for advanced NSCLC pts unfit to receive platinum doublets. Less toxicity was observed in metronomic arm. QoL scores were similar in both arms. A subset of platinum unfit patients could receive second-line treatment mainly consisting on immunotherapy, chemotherapy. Clinical trial identification 2014-003859-61. Legal entity responsible for the study IRPF, Pierre Fabre Medicament. Funding Pierre Fabre Medicament. Disclosure A. Camerini: Speaker Bureau / Expert testimony, expert testimony: Pierre Fabre; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Pierre Fabre. A. Morabito: Speaker Bureau / Expert testimony, speaker bureau: Pfizer; Speaker Bureau / Expert testimony, speaker bureau: BMS; Speaker Bureau / Expert testimony, speaker bureau: MSD; Speaker Bureau / Expert testimony, speaker bureau: Roche; Speaker Bureau / Expert testimony, speaker bureau: AstraZeneca; Speaker Bureau / Expert testimony, speaker bureau: Boehringer Ingelheim. F. Grossi: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Honoraria (self): Eli Lilly; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Pierre Fabre; Honoraria (self): BMS; Honoraria (self): Novartis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): BMS; Research grant / Funding (self): MSD. R. Ramlau: Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Boehringer Ingelheim. T-E. Ciuleanu: Advisory / Consultancy: Astellas; Advisory / Consultancy: Janssen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: A et D Pharma; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Boehringer Ingelheim; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Ipsen. G.L. Ceresoli: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Astellas; Advisory / Consultancy: Boehringer Ingelheim. J. Bosch-Barrera: Honoraria (self): Pierre Fabre; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): BMS; Advisory / Consultancy: Boehringer Ingelheim. P. Landreau: Full / Part-time employment: Pierre Fabre. S. Gautier: Full / Part-time employment: Pierre Fabre. C. Ta Thanh Minh: Full / Part-time employment: Pierre Fabre. All other authors have declared no conflicts of interest.

Background Metronomic chemotherapy (CT) is a therapeutic strategy based on a regular, short interval, fixed-dose schedule developed to improve disease control and reduce toxicity. Metronomic oral vinorelbine (m-OV) showed promising results. The trial randomly compared single agent m-OV vs OV standard schedule as first-line treatment in advanced NSCLC patients (pts) unfit for platinum-based CT (P-CT). Methods CT naive pts with advanced NSCLC unfit for P-CT (Creatinine clearance G2; medical conditions impairing P-CT according to physician’s opinion) were 1:1 randomly allocated to arm A: m-OV 50mg x3/week (wk) or arm B: OV 60 mg/m²/wk cycle 1, then 80 mg/m²/wk. Primary objective: progression-free survival without grade 4 toxicity (G4PFS). Secondary objectives: disease control rate (DCR), PFS, overall survival (OS), safety, quality of life. Stratification factors: stage (IIIB vs IV), age ( 70 yrs) and ECOG PS (0-1 vs 2). Results Intention-to-treat (ITT) population included 165 pts: 83 pts (A) / 82 (B). Pt characteristics were well balanced (A vs B): mean age 76.1 vs 75.9 yrs; ECOG PS 0-1: 66% vs 62%; Stage IV: 87% vs 94% pts. Median relative dose intensity was 85% vs 69%. Primary endpoint was reached (A vs B) with median G4PFS [95%CI]: 4.0 [2.6-4.3] vs 2.2 [1.5-2.9] months (mo) (p = 0.0068), HR [95%CI] = 0.63 [0.45-0.88]. Secondary efficacy end-points were as follows (A vs B): DCR 63.9% vs 63.4%; median PFS 4.3 vs 3.9 mo; median OS: 7.1 vs 7.6 mo. Treatment related AEs (r-AEs) A vs B were: all grade 61.4% vs 84%; total hematological AEs: 27.7% vs 55.6%. Most common (≥ 5%) grade 3-4 r-AEs (A vs B) were: febrile neutropenia 3.6% vs 6.2%; neutropenia 11% vs 52%; asthenia 4.8% vs 8.6%. One grade 5 AE occurred in each arm (febrile neutropenia, neutropenic sepsis). Conclusions Positive results of first randomized prospective trial: m-OV significantly improved G4PFS as first-line CT in advanced unfit NSCLC pts, with reduced toxicity. Treatment efficacy was similar in both arms. m-OV is a suitable, safe option for first-line therapy of NSCLC pts unfit to P-CT. Clinical trial identification EudraCT: 2014-003859-61. Legal entity responsible for the study Institut de Recherche Pierre Fabre- Pierre Fabre Medicament. Funding Institut de Recherche Pierre Fabre- Pierre Fabre Medicament. Disclosure A. Morabito: Speaker Bureau / Expert testimony, Speaker Bureau: Pfizer; Speaker Bureau / Expert testimony, Speaker Bureau: BMS; Speaker Bureau / Expert testimony, Speaker Bureau: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Speaker Bureau: MSD; Speaker Bureau / Expert testimony, Speaker Bureau: Roche; Speaker Bureau / Expert testimony, Speaker Bureau: AstraZeneca. F. Grossi: Honoraria (self): Ely Lilly; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Pierre Fabre; Honoraria (self): BMS; Honoraria (self): Amgen; Honoraria (self): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD; Advisory / Consultancy: Ely Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Honoraria (self): Celgene. R. Ramlau: Advisory / Consultancy: Roche; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. T. Ciuleanu: Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Advisory / Consultancy, Travel / Accommodation / Expenses: A et D Pharma; Travel / Accommodation / Expenses: Ipsen. G.L. Ceresoli: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Astellas; Advisory / Consultancy: Boehringer Ingelheim. J. Bosch Barrera: Honoraria (self): Pierre Fabre; Honoraria (self): Roche; Honoraria (self): BMS; Advisory / Consultancy: Boehringer Ingelheim. P. Landreau: Full / Part-time employment: Pierre Fabre. S. Gautier: Full / Part-time employment: Pierre Fabre. C. Ta Thanh Minh: Full / Part-time employment: Pierre Fabre. A. Camerini: Speaker Bureau / Expert testimony, expert testimony: Pierre Fabre; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.