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Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.Janssen ResearchDevelopment.

Ad26.COV2.S is a well-tolerated and effective vaccine against COVID-19. We evaluated durability of anti-SARS-CoV-2 antibodies elicited by single-dose Ad26.COV2.S and the impact of boosting.In randomized, double-blind, placebo-controlled, phase 1/2a and phase 2 trials, participants received single-dose Ad26.COV2.S (5 × 10Data were analyzed from phase 1/2a participants enrolled from 22 July-18 December 2020 (Cohort 1a, 18-55 years [y], N = 25; Cohort 2a, 18-55y, N = 17; Cohort 3, ≥65y, N = 22), and phase 2 participants from 14 to 22 September 2020 (18-55y and ≥ 65y, N = 73). Single-dose Ad26.COV2.S elicited stable neutralizing antibodies for at least 8-9 months and stable binding antibodies for at least 6 months, irrespective of age. A 5 × 10Single-dose Ad26.COV2.S elicited durable antibody responses for at least 8 months and elicited immune memory. Booster-elicited binding and neutralizing antibody responses were rapid and robust, even with a quarter vaccine dose, and stronger with a longer interval since primary vaccination.ClinicalTrials.gov Identifier: NCT04436276, NCT04535453.

Concurrent chemoradiotherapy (CRT) is considered standard for inoperable stage III non-small cell lung cancer (NSCLC). Consolidation chemotherapy (CC) following CRT is intended to further improve outcomes, yet studies have shown discordant results. This phase III study assessed CRT followed by best supportive care (BSC) or consolidation with oral vinorelbine and cisplatin.Patients received two cycles of oral vinorelbine (50 mg/m(2) days 1, 8 and 15) + cisplatin (20 mg/m(2) days 1-4) q4w + radiotherapy (RT; 66 Gy). Patients with at least stable disease (SD) were randomised to either two cycles oral vinorelbine (60-80 mg/m(2) days 1 and 8) + cisplatin (80 mg/m(2) day 1) q3w + BSC or BSC alone. Primary endpoint was progression-free survival (PFS).A total of 279 patients were enrolled for CRT and 201 patients were randomised to CC or BSC. Both CRT and CC were well tolerated, with limited radiation-mediated grade 3/4 toxicities (CRT/CC/BSC: oesophagitis-related events 12.9 %/3.1 %/0 %; grade 3 pneumonitis 0 %/0 %/2 %) and chemotherapy-mediated grade 3/4 toxicities (CRT/CC: neutropenia 11.2 %/22.1 %; leukopenia 18.3 %/26.7 %; grade 3 nausea 5.0 %/2.3 %, grade 3 vomiting 3.2 %/3.5 %). Median PFS from randomisation was 6.4 (5.0-8.7) and 5.5 (3.8-7.4) months in the CC and BSC arms (hazard ratio, HR = 0.93 [0.69-1.26]; p = 0.63), respectively; median overall survival (OS) 20.8 (13.5-25.3) and 18.5 (13.6-24.7) months, respectively.Consolidation chemotherapy after concurrent CRT did not prolong PFS or OS. Concurrent RT with oral vinorelbine and cisplatin demonstrated a favourable safety profile and represents a suitable treatment regimen for inoperable stage III NSCLC.

Background The combination of oral vinorelbine plus cisplatin has been studied in numerous trials as first-line treatment of patients with non–small cell lung cancer (NSCLC) regardless of histologic subtype. NAVoTrial 01 is the first study that explores this combination specifically in nonsquamous (NS) NSCLC by assessing the feasibility of this doublet (ratio 1:2) in an investigational approach. A reference arm with pemetrexed plus cisplatin was included. Maintenance therapy with single-agent therapy after 4 cycles of combination therapy was included in the study schedules because it reflected a trend in first-line treatment of NSCLC. Patients and Methods Stage IIIB/IV untreated/relapsed patients with NS NSCLC received a 3-week cycle of pemetrexed 500 mg/m² and cisplatin 75 mg/m² on day 1 (arm A) or oral vinorelbine 80 mg/m² on days 1 and 8 (first cycle 60 mg/m²) and cisplatin 80 mg/m² on day 1 (arm B). After 4 cycles, patients without disease progression received single-agent maintenance treatment with pemetrexed or oral vinorelbine. Results Overall, 153 patients were randomized (arm A/arm B: 51/102). Disease control rate (%) for arm A was 76.5 (95% confidence interval [CI], 62.5-87.2) and for arm B it was 75.0 (95% CI, 65.3-83.1), Response rates for arm A were 31.4% (95% CI, 19.1-45.9) and for arm B were 24.0% (95% CI, 16.0-33.6). Median progression-free survival for arm A was 4.3 months (95% CI, 3.8-5.6) and for arm B it was 4.2 months (95% CI, 3.6-4.7). Median survival for arm A was 10.8 months (95% CI, 7.0-16.4) and for arm B it was 10.2 months (95% CI, 7.8-11.9). Main grade 3/4 hematologic toxicities were neutropenia 18.3% (arm A) and 44.0% (arm B), whereas febrile neutropenia was reported in 2% of patients in each arm. Conclusion Oral vinorelbine and cisplatin had an efficacy in line with that achieved with a standard treatment such as pemetrexed and cisplatin, coupled with an acceptable safety profile.

Summary Background Data issued from the survival outcome in the ANITA trial are reported according to histology in observation (n = 433) and adjuvant chemotherapy arms (n = 407). Methods In the ANITA trial, patients with resected stage IB, stage II and stage IIIA NSCLC were randomly assigned to vinorelbine plus cisplatin or to observation. In this retrospective analysis, Kaplan–Meier plots and life tables were used to describe survival within each treatment arm and each histological subgroup: observation adenocarcinoma, observation non-adenocarcinoma, chemotherapy adenocarcinoma, chemotherapy non-adenocarcinoma. Results In the observation arm, adenocarcinoma appears to be a poor prognostic factor in patients with resected NSCLC with a median survival of 37.3 months and 45.5 months for non-adenocarcinoma. In the treatment arm, adenocarcinoma may be a predictive factor of efficacy for adjuvant chemotherapy with a larger benefit from adjuvant vinorelbine-cisplatin chemotherapy, even though other histological subtypes also benefit from this treatment. The absolute benefit on survival at 5-years of chemotherapy was 13.9% in adenocarcinoma and 5.8% in non-adenocarcinoma. Conclusion Efficacy of vinorelbine-cisplatin in adjuvant setting is independent from histology. The poor outcome of adenocarcinoma found in the observation arm was reversed by the positive impact of chemotherapy, possibly due to a higher chemosensitivity of this subtype.

Purpose To compare vinflunine (VFL) to docetaxel in patients with stage IIIB/IV non–small-cell lung cancer (NSCLC) who have experienced treatment failure with first-line platinum-based chemotherapy. Patients and Methods Randomized, multicenter, phase III study, 551 patients received either vinflunine 320 mg/m2 or docetaxel 75 mg/m2 every 21 days until disease progression or serious toxicity. The primary end point was progression-free survival (PFS). The noninferiority analysis was based on a 10% difference (types I/II error rates: 5%/20%). Secondary end points included response rate (ORR), response duration, overall survival (OS), clinical benefit, quality of life (QOL), and safety. Results Median PFS was 2.3 months for each arm (HR, 1.004; 95% CI, 0.841 to 1.199). ORR, stable disease, median OS, were 4.4% versus 5.5%, 36.0% versus 39.6%, 6.7 versus 7.2 months (HR, 0.973; 95% CI, 0.805 to 1.176), respectively. No significant difference in patient benefit and QOL (Functional Assessment of Cancer Therapy-Lung). No unexpected adverse events were observed. Grade higher than 0 (vinflunine v docetaxel) anemia (82.1% v 79.8%), neutropenia (49.3 v 39.02%), thrombocytopenia (30.6% v 14.3%), febrile neutropenia (3.3% v 4.7%), constipation (39.2% v 11.7%), fatigue (36.6% v 33.9%), injection site reaction (31.9% v 0.7%), nausea (26.7% v 23.7%), vomiting (23.8% v 14.2%), alopecia (19.8% v 35.4%), stomatis (19.4% v 12.4%), abdominal pain (20.1% v 3.6%), myalgia (14.7% v 6.6%), peripheral neuropathy (10.7% v 15.0%), arthralgia (7.0% v 7.7%), diarrhea (6.2% v 12.4%), edema (1.5% v 5.4%), and nail disorders (1.1% v 5;1%) were observed. Conclusion This noninferiority phase III study showed similar efficacy end points for vinflunine and docetaxel. Despite higher rates of some adverse effects (anemia, abdominal pain, constipation, fatigue) the overall toxicity profile of vinflunine was manageable. Therefore, VFL may be another option in the second-line treatment of patients with advanced NSCLC.

Introduction This phase II study assessed the efficacy and safety of oral vinorelbine given weekly in combination with carboplatin (CBDCA) AUC 5 once every 3 weeks for four cycles in chemonaive patients with advanced non-small cell lung carcinoma (NSCLC), followed by consolidation therapy with single-agent oral vinorelbine in non-progressive patients. Methods Chemonaive advanced NSCLC patients received four cycles of combination therapy with CBDCA AUC 5 day 1 and oral vinorelbine, 60mg/m 2 on days 1, 8 and 15 (cycle 1), dose increased to 80mg/m 2 (cycles 2–4) in absence of grades 3–4 neutropenia (NCI-CTCv2). Consolidation therapy with oral vinorelbine was continued (cycle 5) at same dosage; if dose was decreased during combination therapy, it was given at 60mg/m 2 , then increased at 80mg/m 2 (cycle 6) in absence of grades 3–4 neutropenia until PD, toxicity or patient's refusal. Results A total of 57 patients were registered and 56 patients were treated (ITT population), median age was 61 years (37–71). Objective response evaluated by RECIST was 17.9% (95% confidence interval, CI [8.9–30.4]) and disease control (CR, PR, NC) 73.2% (95% CI [59.7–84.2]), median progression-free survival 4.3 months (95% CI [3.1–5.1]) with median overall survival 9.7 months (95% CI [7.7–11.9]) and 1-year survival 37.1% (95% CI [24.4, 49.9]). Grades 3–4 neutropenia occurred in 67.9% of patients during combination and 20% during consolidation; febrile neutropenia occurred in 4 patients (7.1%) during combination therapy. Non-hematological toxicities occurred primarily during combination (grade 3 nausea and grade 3 vomiting in 7.1% of patients). Conclusions The combination of oral vinorelbine given weekly in 3-week cycles in combination with carboplatin followed by consolidation therapy with oral vinorelbine as a single-agent was able to achieve efficacy results in line with other doublets including carboplatin in terms of response as well as survival. This regimen reported a good profile of tolerability in the treatment of advanced NSCLC, allowing that this combination can be easily proposed for the palliative care of NSCLC patients where the advantages of carboplatin over cisplatin are still appreciated.

8043 Background: NVBo+P is considered as a standard treatment in M or LA NSCLC. The recent approval of Pem+P as front line chemotherapy (CT) for non SCC demonstrates that today, histology could become a “new guidance” to treat patients (pts). The importance of histological types was highlighted in a phase III trial (Scagliotti. JCO 2008). Moreover, the higher chemosensitivity of non SCC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). In GLOB 3 study, NVBo+P also showed better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan. Ann Oncol. 2009). This trial was set up to assess the efficacy of NVBo+P (Arm A) and Pem+P (Arm B) for pts with Non SCC histological type, evaluated in terms of Disease Control Rate (DCR) (SD+PR+CR). Methods: Pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² + P 75 mg/m² D1 (Arm B). After 4 cycles of combination, pts with DCR received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to stage (IIIB - IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre. Results: From 11/09 to 02/11, 153 pts were randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively. Conclusions: Even if the current results should be confirmed in a phase III study, the choice of a platinum-based doublet with oral vinorelbine as front-line chemotherapy could be a useful alternative in non SCC. Clinical trial information: 2009-012001-19.

7001 Background: Concurrent chemo-radiotherapy (CT-RT) is considered as a standard in st III NSCLC. Published trials with C after CT-RT show encouraging but discordant results. This ph III was set up to assess C in st III NSCLC. Methods: Patients (pts) received NVBo 50 mg/m² D1, D8, D15 + P 20 mg/m² D1-D4 q4w / 2 cycles (cy) + RT (66 Gy / 33 Fr). C for OR+SD pts: NVBo 60-80 mg/m² D1D8 + P 80 mg/m² D1 q3w / 2 cy + BSC (Arm A) or BSC (Arm B). PFS was the primary endpoint. Results: From 07/05 to 05/09, 279 pts received CT/RT and 201 pts (72%) were randomised to receive CT+BSC or BSC as C. Toxicity (tox) G3-4 (% pt) CT-RT/ C (Arm A/B): anaemia 3.2/3.5/1.1; thrombopenia 2.5/1.2/0.6; neutropenia (N) 11.2/11.7/5.7; febrile N 1.4/1.0/0; nausea (G3) 5.0/4.7/2.9; vomiting (G3) 3.9/3.5/2.0; anorexia 3.6/1.2/3.0; dysphagia 1.8/2.3/1.0; fatigue 3.3/ 2.3/1.0; pneumonia/ pneumonitis 2.6/0/2.0; CT-RT pain 2.2; CT-RT oesophagitis 8.6; 3 toxic deaths. Conclusions: In this ph III, NVBo+P+RT reports a high level of efficacy (OR 60.7%; DCR 86.0%) and low tox. The DCR is significantly improved in pts who received C with NVBo+ P in eval pts (p=0.0084). Lung tox was not enhanced by using NVBo+P as C. However no survival advantage for C was achieved. [Table: see text]