Durable antibody responses elicited by 1 dose of Ad26.COV2.S and substantial increase after boosting: 2 randomized clinical trials.

BACKGROUND: 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. METHODS: In randomized, double-blind, placebo-controlled, phase 1/2a and phase 2 trials, participants received single-dose Ad26.COV2.S (5 × 1010 viral particles [vp]) followed by booster doses of 5 × 1010 vp or 1.25 × 1010 vp. Neutralizing antibody levels were determined by a virus neutralization assay (VNA) approximately 8-9 months after dose 1. Binding and neutralizing antibody levels were evaluated by an enzyme-linked immunosorbent assay and pseudotyped VNA 6 months after dose 1 and 7 and 28 days after boosting. RESULTS: Data 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 × 1010 vp 2-month booster dose increased binding antibodies by 4.9- to 6.2-fold 14 days post-boost versus 28 days after initial immunization. A 6-month booster elicited a steep and robust 9-fold increase in binding antibody levels 7 days post-boost. A 5.0-fold increase in neutralizing antibodies was observed by 28 days post-boost for the Beta variant. A 1.25 × 1010 vp 6-month booster elicited a 3.6-fold increase in binding antibody levels at 7 days post-boost versus pre-boost, with a similar magnitude of post-boost responses in both age groups. CONCLUSIONS: Single-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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04436276, NCT04535453.

GILT--A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. DISCUSSION: 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.

Oral vinorelbine plus cisplatin as first-line chemotherapy in nonsquamous non-small-cell lung cancer: final results of an International randomized phase II study (NAVotrial 01).

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/m(2) and cisplatin 75 mg/m(2) on day 1 (arm A) or oral vinorelbine 80 mg/m(2) on days 1 and 8 (first cycle 60 mg/m(2)) and cisplatin 80 mg/m(2) 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.

Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer.

UNLABELLED: Chemotherapy plus trastuzumab is the standard first-line treatment for Human Epidermal Receptor 2-positive (HER2-positive) metastatic breast cancer. The aim of this international phase II trial was to determine the efficacy and safety profile of an oral chemotherapy doublet, oral vinorelbine plus capecitabine, and trastuzumab in this setting. PATIENTS AND METHODS: In this single-arm, multicenter, open-label phase II study, in the first-line metastatic setting, patients received 3-weekly cycles of oral vinorelbine at 80 mg/m(2) (first cycle dose 60 mg/m(2)) day 1 and day 8, plus capecitabine at 1000 (750 if ≥ 65 years) mg/m(2) twice daily on days 1-14, plus trastuzumab at 4 mg/kg intravenously (i.v.) on day 1 (loading dose) then 2 mg/kg i.v. weekly thereafter. Treatment was continued until progression or unacceptable toxicity. RESULTS: Fifty patients with a median age of 53.5 years were enrolled. Most (82%) had visceral involvement and 34% had more than two metastatic sites. The objective response rate (RECIST 1.0) in 44 evaluable patients was 77% [95% Confidence Interval (CI)=62-89%], including complete response in 21%. The clinical benefit rate (response or stable disease for ≥ 6 months) was 93% [95% CI=81-99%]. Median duration of response was 13.3 [95% CI=9.8-15.7] months, median progression-free survival was 12.8 [95% CI=10.8-16.9] months and median overall survival was 47.0 [95% CI=30.5-64.3] months. Median number of cycles was 10 (range 1-81). The majority of patients (72%) received more than 18 weeks and 32% more than 48 weeks of treatment. The most frequent treatment-related grade 3/4 adverse events were neutropenia (71%), hand-foot syndrome (20%) and diarrhea (16%). A low-rate of grade 2 alopecia was observed (14%). CONCLUSION: The triple combination of oral vinorelbine, capecitabine and trastuzumab is highly active in terms of response rate, progression-free survival and overall survival, with a manageable toxicity profile.

Impact of histology on survival of resected non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy: subgroup analysis of the adjuvant vinorelbine (NVB) cisplatin (CDDP) versus observation in the ANITA trial.

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.

Phase III trial comparing vinflunine with docetaxel in second-line advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy.

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/m(2) or docetaxel 75 mg/m(2) 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.

Phase II study of oral vinorelbine in combination with carboplatin followed by consolidation therapy with oral vinorelbine as single-agent in unresectable localized or metastatic non-small cell lung carcinoma.

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, 60 mg/m2 on days 1, 8 and 15 (cycle 1), dose increased to 80 mg/m2 (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 60 mg/m2, then increased at 80 mg/m2 (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.