Background
Nivolumab has shown a survival benefit compared with docetaxel as second‐line treatment for patients with previously treated advanced squamous non‐small cell lung cancer (NSCLC) in a ...randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program.
Patients and Methods
Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information.
Results
The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2–9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any‐grade and grade 3–4 adverse events was 29% and 6%, respectively. Treatment‐related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment‐related deaths.
Conclusion
To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real‐world setting are consistent with those obtained in clinical trials.
Implications for Practice
Nivolumab is approved in the U.S. and Europe for the treatment of advanced non‐small cell lung cancer (NSCLC) after failure of prior platinum‐based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real‐world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.
摘要
背景。一项随机 III 期试验结果表明,在晚期鳞状非小细胞肺癌 (NSCLC) 患者的二线治疗中,纳武单抗与多西紫杉醇相比具有一定的生存优势。患者和医生在常规临床实践中的经验往往与对照临床试验环境中所获得的经验有所差别。本研究介绍了在世界范围内开展的纳武单抗 NSCLC 扩大受试计划中,所选择的鳞状 NSCLC 患者意大利队列的所有数据。
患者和方法。经治的晚期鳞状 NSCLC 患者每 2 周接受 3 mg/kg 的纳武单抗治疗,疗程为 24 个月。全程进行安全监测;收集的疗效数据包括客观肿瘤反应、进展日期和生存信息。
结果。意大利队列包括 371 名至少接受过一剂纳武单抗治疗的患者。总体患者治疗结果显示,客观有效率 (ORR) 为 18%,疾病控制率 (DCR) 为 47%,中位总生存期 (OS)为 7.9 个月(95% 可信区间 6.2‐9.6)。亚组分析结果显示,先前接受过两线或以上治疗的患者,ORR、DCR 和 中位OS分别为 17%、48%和9.1 个月(n = 209),而疾病进展后接受治疗的患者的 ORR、DCR 和 中位OS 分别为 8%、40% 和 10.0个月 (n = 65)。总体患者治疗结果显示,任意级别和 3‐4 级不良事件发生率分别为 29% 和 6%。14 名患者 (5%) 因出现治疗相关的不良事件而停止治疗。无与治疗相关的死亡事件。
结论。到目前为止,本报告最为全面地介绍了当前对照临床试验环境以外的临床实践中,纳武单抗应用于晚期鳞状 NSCLC 治疗的临床经验。这些数据表明,纳武单抗在广泛的真实世界环境中,有效性和安全性与临床试验中获得的结果一致。
实践意义:纳武单抗已在美国和欧洲获批,可在患者接受铂类药物化疗失败后,用于治疗晚期非小细胞肺癌 (NSCLC)。在这支之前接受过治疗的意大利患者队列中,晚期鳞状 NSCLC 的真实世界环境治疗过程引入了纳武单抗扩大受试计划,纳武单抗的疗效和安全性与先前的纳武单抗临床试验中得出的结果一致。
A nivolumab expanded access program in advanced squamous non‐small cell lung cancer was conducted worldwide to allow patients unable to take part in nivolumab clinical trials to gain access to treatment before it became commercially available. This article presents data from a cohort of Italian patients enrolled in the program.
The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory ...approval.
Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model.
A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis.
The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab.
Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, ...non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.
This analysis evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in elderly patients with stage IIIB or IV squamous non–small-cell lung cancer (NSCLC) enrolled in the ...expanded access programme (EAP) in Italy.
Nivolumab was available on physician request. Safety data included adverse events (AEs). Efficacy data included investigator-assessed tumour response, progression date and survival information. Results were analysed for patients aged <65, 65–<75 and ≥75 years and for the overall population.
A total of 371 patients with squamous NSCLC were enrolled at 96 centres between April 2015 and September 2015; 34% (n = 126), 47% (n = 175) and 19% (n = 70) were aged <65, 65–<75 and ≥75 years, respectively. Efficacy was similar among patients aged <65, 65–<75 and ≥75 years and the overall population (objective response rates: 18%, 18%, 19% and 18%, respectively; disease control rates: 49%, 47%, 43% and 47%, respectively). Median overall survival was reduced in patients aged ≥75 years (5.8 months) versus patients aged <65; years (8.6 months), patients aged 65–<75 years (8.0 months) and the overall population (7.9 months). The incidence of grade 3–4 treatment-related AEs was low in patients aged 65, 65–<75 and ≥75 years and the overall population (3%, 9%, 3%, 6%, respectively). Discontinuation rates due to treatment-related AEs were low irrespective of age (4–5%).
These EAP results suggest that elderly patients with advanced squamous NSCLC benefit from nivolumab, with tolerability similar to that in the overall population.
•Elderly patients with squamous non–small-cell lung cancer in an Italian expanded access programme benefited from nivolumab.•Objective response rates were similar (18–19%) for ages <65, 65–<75 and ≥75 years and all ages.•Median overall survival was reduced for ages ≥75 years (5.8 months) versus all ages (8.0 months).•Safety and tolerability with nivolumab were similar irrespective of age.
The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations.
Clinical data and KRAS mutational status were analysed in ...patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events.
Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively.
Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.
Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and ...patients with EGFR-mutant nonsqamous NSCLC.
Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians’ request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab.
Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation–positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% p = 0.007), in former and current smokers than in never-smokers (21.5% versus 9.2% p = 0.0001), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% p = 0.04). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors.
The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation.
Nivolumab was the first immune checkpoint inhibitor approved for previously treated advanced non–small cell lung cancer (NSCLC). Before its introduction in the market, nivolumab was made available to ...NSCLC patients through an expanded access program (EAP). Here we present the Italian cohort of patients with non-squamous NSCLC enrolled in a worldwide nivolumab EAP, with subgroup analyses involving elderly patients, patients with central nervous system (CNS) metastases and patients receiving nivolumab beyond progression.
Pretreated patients with advanced non-squamous NSCLC received nivolumab at 3 mg/kg every 2 weeks up to 24 months. Efficacy data (investigator-assessed tumour response, progression date and survival) and safety data were collected.
1588 patients were treated across 153 Italian centres. Overall response rate and disease control rate were 18% and 44%, respectively; median overall survival (OS) was 11.3 months (95% CI: 10.2–12.4). Elderly patients (≥70 n = 522; ≥75 n = 232) achieved outcomes similar to the global study population; patients with CNS metastases (n = 409) had an OS of 8.6 months (95% CI: 6.4–10.8), and a 1-year OS rate of 43%. Nivolumab was administered beyond progression to 276 patients (26%), 57 of whom achieved subsequent disease control; the median OS of patients receiving nivolumab beyond progression was 16.2 months (95% CI: 14.0–18.4), while 1-year OS rate was 62%.
To date, this is the largest clinical experience with nivolumab in a real-world setting. Our data support its use in clinical practice for pretreated non-squamous NSCLC, including patients with older age or CNS metastases.
•The Italian expanded access program (EAP) made nivolumab available to a wide population of non–small cell lung cancer (NSCLC) patients.•The outcomes of non-squamous NSCLC patients were consistent with the pivotal trial.•Nivolumab was effective and safe in subgroups poorly represented in clinical trials.•Postprogression benefit was observed with continued administration of nivolumab.•The Italian EAP is the largest real-life clinical experience with nivolumab to date.
•Immunotherapy significantly improved the outcome of advanced NSCLC.•1959 advanced NSCLC patients received Nivolumab in the Italian expanded access program.•Activation of the immune system through ...the appearance of irAEs correlated with outcome.
The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31–65 % and 2–5 % respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy.
We collected the records of 1959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis.
Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p < 0.0001), disease control rate (DCR 60.5% vs 40.2%; p < 0.0001), median progression-free survival (mPFS 6.0 months 95% CI 4.9–7.1 vs 3.0 95% CI: 2.8–3.2, p < 0.0001) and median overall survival (mOS 16.7 months 95% CI: 13.5–19.9 vs 9.4 95% CI: 8.4–10.4, p < 0.00001) compared to patients who did not. At multivariate analysis the development of an irAE remained an independent indicator of nivolumab efficacy (HR 1.44 95% CI: 1.22–1.71 p < 0.0001).
This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome.