Italian Cohort of Nivolumab Expanded Access Program in Squamous Non‐Small Cell Lung Cancer: Results from a Real‐World Population

Abstract

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.

Abstract

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?

Introduction

Squamous non‐small cell lung cancer (NSCLC) comprises almost 30% of all NSCLC cases [1]. Relatively few treatment options are available for advanced stages of this disease once progression occurs after first‐line systemic therapy. Docetaxel has been the standard of care for many years, despite providing limited clinical benefit [2]. Discrete genetic alterations are rarely observed in squamous NSCLC, and molecularly targeted agents are not indicated in squamous NSCLC [3].

Nivolumab is a fully human programmed death 1 (PD‐1) immune checkpoint inhibitor antibody that was shown to provide a long‐term survival benefit in patients with previously treated advanced squamous NSCLC in the randomized phase III trial CheckMate 017, which compared nivolumab with docetaxel in patients after failure of first‐line platinum‐based chemotherapy [4]. Median overall survival (OS) was 9.2 months in the nivolumab group compared with 6.0 months in the docetaxel group, and a 41% reduction in the risk of death was observed with nivolumab treatment (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44–0.79; p < .001). This OS benefit was sustained with longer follow‐up: 2‐year OS rates were 23% with nivolumab and 8% with docetaxel [5]. Nivolumab has also been shown to provide similar benefit in patients with previously treated advanced nonsquamous NSCLC in the randomized phase III trial CheckMate 057 [6]. On the basis of these results, nivolumab was approved in the U.S. and the European Union for locally advanced/metastatic NSCLC with disease progression after prior platinum‐based chemotherapy.

A nivolumab expanded access program (EAP) in advanced squamous NSCLC was conducted worldwide to allow patients who were unable to take part in local nivolumab clinical trials to gain access to treatment before it became commercially available. The experience of patients and physicians in routine clinical practice is often different from that in a controlled clinical trial setting. EAPs, with their comparatively broad entry criteria, more closely mimic the real‐world setting and provide opportunities to evaluate common treatment scenarios. Here, we present comprehensive data from the entire Italian cohort of patients with squamous NSCLC enrolled in the nivolumab NSCLC EAP.

Materials and Methods

Patients

Eligible patients were aged 18 years or older with histologically or cytologically confirmed stage IIIB or IV squamous NSCLC. All patients had disease progression or recurrence during or after one or more prior systemic treatments for advanced or metastatic disease; patients who developed recurrent disease within 6 months of completing platinum‐based adjuvant, neoadjuvant, or definitive chemoradiation therapy for locally advanced disease were also eligible. Patients with treated central nervous system (CNS) metastases that had been stable for ≥2 weeks were eligible, provided that they did not require corticosteroids or were on a stable or decreasing dose of no more than 10 mg prednisone daily (or equivalent). Other key inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status ≤2; completion of prior chemotherapy, tyrosine kinase inhibitors, tumor vaccine, cytokines, or palliative radiotherapy ≥2 weeks before starting nivolumab, with resolution of all adverse events to baseline or stabilization; adequate organ function; and life expectancy ≥6 weeks. Patients were excluded if they had active, known, or suspected autoimmune disease, with the exception of type 1 diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring hormone replacement therapy, or psoriasis not requiring systemic treatment. Other exclusion criteria included carcinomatous meningitis, prior therapy with any drug specifically targeting T‐cell costimulation or checkpoint pathways, symptomatic interstitial lung disease, and eligibility for another clinical study with nivolumab. All patients provided written, informed consent to their participation in the study.

Study Design and Treatment

Nivolumab was made available upon physician request through the EAP. The EAP guidelines were approved at each participating center, and participating physicians had to comply with generally accepted good clinical practice and ethical standards.

All patients received nivolumab 3 mg/kg administered intravenously every 2 weeks for up to 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent. No reduction in nivolumab dose was allowed, but treatment was delayed in the event of toxicity. Patients could continue nivolumab treatment beyond progression if they were deriving investigator‐assessed clinical benefit in the absence of rapid disease progression, provided that they were also tolerating the study drug, they had stable performance status, and that such treatment would not delay any intervention to prevent serious complications of disease progression.

Assessments

Safety was monitored throughout the program by continuous assessment of adverse events, physical examination, ECOG performance status, hematology and clinical chemistry tests, and thyroid function tests, according to local regulations and standard of care. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, and their causal relationship to treatment was determined by the investigators.

Although there were no prespecified endpoints for this EAP, investigators were encouraged to make every effort to document objective disease progression always according to RECIST criteria. In situations of doubtful responses, the cases were discussed with the principal investigator of the trial who revised retrospectively all the instrumental records according to RECIST criteria. Efficacy data collected included investigator‐assessed objective tumor response, date of progression, and survival information. In addition to the overall population, efficacy and safety data were collected for the following subgroups: patients who had received two or more prior lines of therapy and patients treated with nivolumab beyond initial disease progression.

Statistical Analysis

The population for both efficacy and safety analyses included all patients who received at least one dose of nivolumab. Objective response rate (ORR), disease control rate (DCR, defined as the combined rates of complete response, partial response, and stable disease), progression‐free survival (PFS), and OS were evaluated. Progression‐free survival and OS were estimated using the Kaplan‐Meier method, and 95% CIs were derived using the asymptotic variance Greenwood method. Progression‐free survival was calculated as the time from the start of nivolumab treatment until evidence of progressive disease or death, whichever occurred first. A Cox regression model was used to explore the association between patient characteristics and OS; HRs and their 95% CIs were reported.

Results

Patients and Treatment

Between April 2015 and September 2015, 371 patients were enrolled in the EAP at 96 centers in Italy and received at least one dose of nivolumab. Most patients were male (80%), and the majority were former smokers (61%; Table 1). Twenty‐two patients (6%) had an ECOG performance status of 2, 70 (19%) were 75 years of age or older, and 37 (10%) had CNS metastases. More than half of the population was heavily pretreated: 209 patients (56%) had received at least two lines of prior systemic therapy.

Patients received a median of six doses of nivolumab (range, 1–22) and had a median follow‐up of 7.1 months (range, 0.1–16.4). Patients in the subgroup that had received two or more prior lines of therapy were treated with a median of eight doses of nivolumab (range, 1–24) and had a median follow‐up of 7.1 months (range, 0.1–24.5.4). Sixty‐five patients (18%) were treated beyond disease progression and received a median of ten doses of nivolumab (range, 4–29), with a median follow‐up of 9.1 months (range, 2.1–16.4). At the time of analysis, 281 patients (76%) had discontinued treatment in the overall population, mostly because of progressive disease (n = 167; 59%) or death (n = 68; 24%; Table 2); 90 patients (24%) remained on treatment.

Efficacy

In the overall population, the ORR was 18%, including four complete responses (1%) and 63 partial responses (17%); an additional 108 patients had stable disease, giving a DCR of 47% (Table 3). The 1‐year OS rate was 39% and median OS was 7.9 months (95% CI 6.2–9.6; Fig. 1A), whereas the 1‐year PFS rate was 27% and median PFS was 4.2 months (95% CI 3.4–5.0; Fig. 1B). Multivariate analysis showed that OS was adversely affected by the presence of liver and bone metastases and by ECOG performance status above zero (Table 4). However, the presence of stable, asymptomatic CNS metastases had no measurable impact on OS.

In patients who had received two or more prior lines of therapy, the ORR was 17%, which included all four complete responses seen in the overall population, and the DCR was 48% (Table 3). The 1‐year OS rate in this subgroup was 42%, and median OS was 9.1 months (95% CI 6.1–12.1; Fig. 1A); 1‐year and median PFS were, respectively, 28% and 4.2 months (95% CI 2.8–5.6; Fig. 1B). In particular, patients who received nivolumab in the second line had a median OS of 7.2 months (95% CI 5.6–8.7) with a 1‐year OS rate of 34.8% and a 18‐month OS rate of 21.8%.

Twenty‐six of the 65 patients treated beyond progression derived unconventional benefit from the extended treatment, with subsequent tumor reduction or lesion stabilization. Twenty‐three (88.5%) of these patients were male, 25 (96.1%) had an ECOG performance status of 0–1; 20 (76.9%) were current or previous smokers. Two of them (7.7%) had brain metastasis, nine (34.6%) had bone metastasis, and four (15.4%) had liver metastasis. Overall, this subgroup had an ORR of 8% (all partial responses) and DCR of 40% (Table 3). Median OS was 10.0 months (95% CI 7.6–12.4), and 1‐year OS was 42% (Fig. 1A).

Safety

Of the 371 patients in the overall population, 109 (29%) had adverse events considered to be treatment related, which were grade 3–4 in 21 patients (6%; Table 5). The most common treatment‐related adverse events of any grade were rash (8%), fatigue/asthenia (6%), diarrhea (5%), and pain (5%). Grade 3–4 treatment‐related adverse events occurring in more than one patient comprised diarrhea and increased transaminases (n = 4 each; 1%); pain and rash (n = 3 each; 1%); and fatigue/asthenia (n = 2; 1%). Three patients had treatment‐related pneumonitis, including one case of grade 3–4 pneumonitis, which resolved. Overall, 281 patients (76%) discontinued nivolumab treatment (Table 2). In 26 patients (9%), discontinuation was due to adverse events: these were treatment‐related in 14 patients (5%) and included pneumonitis (n = 3); diarrhea, hepatotoxicity, and skin toxicity (n = 2 each); and bilateral exophthalmos, dyspnea, headache, paralytic ileus, and psoriasis (n = 1 each).

In the subgroup that had received two or more prior lines of therapy, treatment‐related grade 3–4 adverse events were reported in 12 patients (6%) and included most commonly transaminase increase (n = 3; 1%), diarrhea (n = 2; 1%), fatigue/asthenia (n = 2; 1%), and pulmonary toxicity (n = 4; 1%). In total, 152 patients from of this subgroup (73%) discontinued treatment, 11 (7%) because of adverse events. Five patients (3%) experienced treatment‐related adverse events leading to discontinuation, comprising headache, pneumonitis, hepatic toxicity, bilateral exophthalmos, and dyspnea.

Two patients (3%) treated beyond progression had treatment‐related grade 3–4 adverse events (both diarrhea). Forty‐nine patients (75%) in this subgroup discontinued treatment; two patients (4%) did so because of adverse events, but in neither case were these considered treatment‐related.

Treatment‐related adverse events of immune etiology (select adverse events) were managed using protocol‐defined toxicity management algorithms. There were no treatment‐related deaths.

Discussion

This report details the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside a controlled clinical trial setting to date. Our population (n = 371) included 56% of patients treated with two or more previous systemic regimens, 6% of patients with ECOG performance status 2, 19% of patients aged 75 years or older, and 10% of patients with CNS metastases. Despite the poor prognosis of this population, we observed a median OS of 7.9 months, an ORR of 18%, and a DCR of 47% with the caveat that a few cases were discussed retrospectively for response and PFS with the principal investigator in presence of doubtful data. As expected, we found that poorer prognostic factors, such as the presence of liver and bone metastases and ECOG performance status above zero, adversely affected OS in multivariate analysis, confirming the validity of the data in this study. Our finding that CNS metastases had no measurable impact on OS may have been influenced by the small number of affected patients (n = 37) and by the exclusion of patients with symptomatic CNS metastases per the program's eligibility criteria. Nivolumab was well tolerated in this Italian cohort, with only 5% of patients discontinuing therapy because of treatment‐related adverse events. Most adverse events were mild to moderate, and the proportion of patients who had grade 3–4 treatment‐related adverse events was low (6%).

The efficacy of nivolumab in this real‐world setting largely mirrored that observed in the nivolumab arm of the phase III CheckMate 017 trial in patients with advanced squamous NSCLC (median OS, 9.2 months; ORR, 20%; DCR, 49%) [4]. The safety profile of nivolumab in the Italian cohort was also consistent with that in CheckMate 017 (7% of patients with grade 3–4 events and 3% with treatment‐related events leading to discontinuation). In addition, the results achieved with nivolumab were similar to those seen in randomized trials with other anti‐PD‐1 or anti‐programmed death ligand 1 therapies [7, 8].

In this EAP, efficacy and safety results obtained both in patients who received nivolumab after two or more prior lines of therapy and in those treated beyond progression (noting the small number of patients in this subgroup) appeared similar to the results of the overall population of the study. Measurement of disease progression by RECIST version 1.1 may not fully capture patient benefit from immunotherapies, and some immunotherapy studies including this EAP have therefore explored continuation of therapy beyond progression if patients demonstrate ongoing clinical benefit [9]. In this Italian cohort, some patients treated beyond progression achieved sustained reductions or stabilization of tumor burden with manageable toxicity. Clinical benefit from continuing nivolumab at disease progression has been reported previously in patients with NSCLC [4], as well as other tumor types [9, 10].

Evaluation of PD‐L1 expression was not planned in this trial given that there is no evidence that it is an effective predictive biomarker in squamous cell carcinoma in second‐line setting and beyond, as demonstrated in the CheckMate 017 trial [5].

Conclusion

Acknowledging the inherent limitations of a study of this type, data from this cohort of Italian patients with previously treated advanced squamous NSCLC suggest that the efficacy and safety profiles of nivolumab in a broad, real‐world setting are consistent with those obtained in clinical trials [4]. Nivolumab provided clinical activity coupled with a manageable safety profile in patients treated with at least two lines of prior therapy and in those treated beyond progression, and further investigation may be warranted in these populations. Taken together, these results suggest that nivolumab can provide a much needed addition to the currently limited treatment options for patients with advanced squamous NSCLC.

Acknowledgments

We thank the patients and their families who made this EAP possible, as well as the clinical study teams who were involved in this program (see supplemental online Appendix for a complete list of investigators in Italy). This work was funded by Bristol‐Myers Squibb. Professional medical writing and editorial assistance was provided by Wendy Sacks, Ph.D., and Emilia Raskiewicz of StemScientific, funded by Bristol‐Myers Squibb.

Author Contributions

Conception/design: Lucio Crinò, Paolo Bidoli, Angelo Delmonte, Francesco Grossi, Filippo De Marinis, Andrea Ardizzoni, Fabiana Vitiello, Giuseppe Lo Russo, Hector Soto Parra, Enrico Cortesi, Federico Cappuzzo, Luana Calabrò, Marcello Tiseo, Daniele Turci, Teresa Gamucci, Paola Antonelli, Alessandro Morabito, Antonio Chella, Diana Giannarelli, Domenico Galetta

Provision of study material or patients: Lucio Crinò, Paolo Bidoli, Angelo Delmonte, Francesco Grossi, Filippo De Marinis, Andrea Ardizzoni, Fabiana Vitiello, Giuseppe Lo Russo, Hector Soto Parra, Enrico Cortesi, Federico Cappuzzo, Luana Calabrò, Marcello Tiseo, Daniele Turci, Teresa Gamucci, Paola Antonelli, Alessandro Morabito, Antonio Chella, Diana Giannarelli, Domenico Galetta

Collection and/or assembly of data: Lucio Crinò, Paolo Bidoli, Angelo Delmonte, Francesco Grossi, Filippo De Marinis, Andrea Ardizzoni, Fabiana Vitiello, Giuseppe Lo Russo, Hector Soto Parra, Enrico Cortesi, Federico Cappuzzo, Luana Calabrò, Marcello Tiseo, Daniele Turci, Teresa Gamucci, Paola Antonelli, Alessandro Morabito, Antonio Chella, Diana Giannarelli, Domenico Galetta

Data analysis and interpretation: Lucio Crinò, Paolo Bidoli, Angelo Delmonte, Francesco Grossi, Filippo De Marinis, Andrea Ardizzoni, Fabiana Vitiello, Giuseppe Lo Russo, Hector Soto Parra, Enrico Cortesi, Federico Cappuzzo, Luana Calabrò, Marcello Tiseo, Daniele Turci, Teresa Gamucci, Paola Antonelli, Alessandro Morabito, Antonio Chella, Diana Giannarelli, Domenico Galetta

Manuscript writing: Lucio Crinò, Paolo Bidoli, Angelo Delmonte, Francesco Grossi, Filippo De Marinis, Andrea Ardizzoni, Fabiana Vitiello, Giuseppe Lo Russo, Hector Soto Parra, Enrico Cortesi, Federico Cappuzzo, Luana Calabrò, Marcello Tiseo, Daniele Turci, Teresa Gamucci, Paola Antonelli, Alessandro Morabito, Antonio Chella, Diana Giannarelli, Domenico Galetta

Final approval of manuscript: Lucio Crinò, Paolo Bidoli, Angelo Delmonte, Francesco Grossi, Filippo De Marinis, Andrea Ardizzoni, Fabiana Vitiello, Giuseppe Lo Russo, Hector Soto Parra, Enrico Cortesi, Federico Cappuzzo, Luana Calabrò, Marcello Tiseo, Daniele Turci, Teresa Gamucci, Paola Antonelli, Alessandro Morabito, Antonio Chella, Diana Giannarelli, Domenico Galetta

Disclosures

Paolo Bidoli: Eli Lilly & Co., Boehringer (C/A); Francesco Grossi: Bristol‐Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Pierre Fabre (SAB); Andrea Ardizzoni: Bristol‐Myers Squibb, Celgene (RF), Bristol‐Myers Squibb, Merck Sharp & Dohme, Boehringer, Pfizer (H); Bristol‐Myers Squibb, Celgene, Merck Sharp & Dohme, Boehringer (SAB); Federico Cappuzzo: Bristol‐Myers Squibb, Roche, Pfizer, AstraZeneca (C/A). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

References

Author notes