Research ArticleClinical Studies

Italian Cohort of the Nivolumab EAP in Squamous NSCLC: Efficacy and Safety in Patients With CNS Metastases

DIEGO CORTINOVIS, RITA CHIARI, ANNAMARIA CATINO, FRANCESCO GROSSI, FILIPPO DE MARINIS, FRANCESCA SPERANDI, FRANCOVITO PIANTEDOSI, MILENA VITALI, HECTOR J. SOTO PARRA, MARIA RITA MIGLIORINO, CARLO TONDINI, DAVIDE TASSINARI, ANTONIO FRASSOLDATI, FRANCESCO VERDERAME, ANTONIO PAZZOLA, FRANCESCO COGNETTI, GENNARO PALMIOTTI, PAOLO MARCHETTI, ARMANDO SANTORO, DIANA GIANNARELLI, FRANCESCA COLONESE and ANGELO DELMONTE
Anticancer Research August 2019, 39 (8) 4265-4271; DOI: https://doi.org/10.21873/anticanres.13590

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Abstract

Background/Aim: Brain metastases are an additional challenge in patients with non-small-cell lung cancer (NSCLC) because most chemotherapy agents cannot cross the blood–brain barrier. Nivolumab has demonstrated efficacy in patients with advanced squamous NSCLC, but because patients with central nervous system (CNS) metastases are typically excluded from registration trials, ‘field-practice’ data are needed. Patients and Methods: Patients in the Italian cohort of the Expanded Access Program (EAP) who had CNS metastases at baseline were analyzed. Results: Thirty-seven patients with CNS metastases received a median of six doses of nivolumab. Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months. Conclusion: The safety and efficacy of nivolumab in patients with CNS metastases appear to be similar to those seen in the overall EAP cohort in Italy.

Squamous non-small-cell lung cancer (NSCLC) is a distinct clinical and pathological subtype of NSCLC, characterized by a high mutation rate and substantial genomic complexity, which may contribute to its poor prognosis (1). Recently, the treatment paradigm for NSCLC has changed with the introduction of immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab and durvalumab) that block the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway and restore the antitumor immune response (2-7).

Nivolumab, a fully human PD1 antibody, has been approved in the USA and the European Union for the treatment of patients with locally advanced or metastatic NSCLC whose disease progresses during or after platinum-based chemotherapy (8, 9). Median overall survival (OS) was significantly longer with nivolumab compared to docetaxel in patients who were previously treated for advanced squamous NSCLC in CheckMate 017 [9.2 vs. 6.0 months; hazard ratio for death=0.59; 95% confidence interval (CI)=0.44-0.79; p<0.001] (3), with 2-year OS rates of 23% with nivolumab and 8% with docetaxel (10, 11). Comparable results were obtained in CheckMate 057 (4).

The expanded access program (EAP) for nivolumab in advanced NSCLC allowed patients from several countries who were unable to participate in local nivolumab clinical trials to obtain treatment with nivolumab before it became commercially available. Patients with central nervous system (CNS) metastases are commonly excluded from trials. CNS metastases are an adverse prognostic factor, in part because most cytotoxic chemotherapy agents do not readily cross the blood–brain barrier (12). An analysis of preliminary data from the entire Italian cohort of patients with squamous NSCLC enrolled in the nivolumab NSCLC EAP was recently reported (13). Here, we present preliminary data for a subset of these patients who had CNS metastases.

Patients and Methods

Patients. Eligibility criteria for the EAP were: age ≥ 18 years; histologically or cytologically confirmed stage IIIB or IV squamous NSCLC; disease progression or disease recurrence during or after ≥1 prior systemic treatments for advanced or metastatic disease; recurrent disease within 6 months after completion of platinum-based chemoradiation for locally advanced disease; Eastern Cooperative Oncology Group (ECOG) performance status ≤2; prior chemotherapy, tyrosine kinase inhibitor treatment, immunotherapy or palliative radiotherapy completed ≥2 weeks before initiation of nivolumab; resolution or stabilization of all adverse events (AEs) prior to baseline; adequate organ function; life expectancy ≥6 weeks; treated metastatic CNS lesions without neurological symptoms related to those lesions for ≥2 weeks before enrolment and no need of corticosteroids or on a stable or a decreasing dose ≤10 mg of prednisone daily (or equivalent).

Exclusion criteria were: autoimmune disease (except type 1 diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring hormone replacement therapy or psoriasis not requiring systemic treatment); HIV infection; carcinomatous meningitis; symptomatic interstitial lung disease; prior therapy with any drug specifically targeting T-cell co-stimulation or checkpoint pathways, or eligibility for another clinical study with nivolumab. All patients provided written, informed consent.

Study design and treatment. Physicians requested nivolumab through the EAP and complied with good clinical practice and ethical standards. The EAP guidelines were approved by the Institutional Review Board at each participating center. Patients received i.v. nivolumab 3 mg/kg/2 weeks for up to 24 months or until disease progression, unacceptable toxicity, or consent withdrawal. Dose reduction was not allowed, but delayed treatment was permitted in the event of toxicity.

Assessments. There were no pre-specified study endpoints. Safety evaluation: AEs record, physical examination, ECOG performance status, haematology and clinical chemistry tests, and thyroid function tests according to local regulations and standards of care. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (14), and their causal relationship to treatment was determined by the investigators. Efficacy: investigator-assessed objective tumor response, date of disease progression (time from the first drug administration to disease progression or death from any cause), and survival.

View this table:
Table I.

Patient demographic and baseline characteristics.

Statistical analysis. Patients included in the safety and efficacy analyses received at least one dose of nivolumab. Objective response rate (ORR), disease control rate [DCR; the combined rates of complete response (CR), partial response, and stable disease], progression-free survival (PFS), and OS were evaluated. Median PFS and OS were estimated using the Kaplan–Meier method, with 95%CIs derived using the asymptotic variance Greenwood method. PFS was calculated as the time between the first nivolumab cycle and evidence of progressive disease (PD) or death.

Results

Patients and treatment. A total of 371 patients (Table I) were enrolled in the EAP between April and September 2015 at 96 centers in Italy and received at least 1 (median=6, range=1-22) dose of nivolumab. Median follow-up was 7.1 months (range=0.1-16.4 months).

Figure 1.
Figure 1.

Kaplan–Meier estimates of overall survival (OS; A) and progression-free survival (PFS; B). CNS: Central nervous system; EAP: expanded access program.

CNS metastases were diagnosed in 37/371 (10%) (Table I). In this subgroup, 22% had received corticosteroids and 57% had received prior radiotherapy. Median number of nivolumab doses was 6 (range=1-18), median follow-up 5.5 months (range=0.7-15 months). Six (16%) and two (5%) patients received concomitant corticosteroids and radiotherapy, respectively, during the EAP for the control of symptoms related to CNS metastases.

At the time of the analysis, nivolumab had been discontinued in 281 patients (76%) in the overall population, primarily because of PD [n=167 (59%)] or death [n=68 (24%)]. Among patients with CNS metastases, 33 (89%) had discontinued nivolumab, mainly for PD [n=18 (55%)] or death [n=9 (27%)]. Four patients (11%) with CNS metastases continued treatment.

Safety. Safety data are reported in Table II. Treatment-related AEs (grade 2 skin reaction and mucositis) led to discontinuation in one/33 (3%) patients with CNS metastases who discontinued treatment. CNS events (seizure, loss of balance, postural instability, disorientation, and stupor) were reported in five patients (14%) with CNS metastases; none of these events were grade 3-4 in severity or considered to be treatment-related.

No treatment-related deaths were reported in the overall study population. Treatment-related AEs with a potential immunologicaI aetiology were addressed using protocol-defined toxicity management algorithms. Treatment-related AEs led to discontinuation in 14/281 (5%) patients in the overall population who discontinued treatment.

Efficacy. Efficacy results are reported in Table III.

View this table:
Table II.

Frequency [n (%)] of treatment-related adverse events occurring in ≥1% of all patients.

View this table:
Table III.

Response to treatment.

The OS rate at 1 year was 35% for patients with CNS metastases and 39% for the overall population (Figure 1A). Median OS was 5.8 (95%CI=1.8-9.8) months for patients with CNS metastases and 7.9 (95%CI=6.2-9.6) months for the overall population.

The PFS rate at 1 year was 31% for patients with CNS metastases and 27% for the overall population (Figure 1B). The median PFS was 4.9 (95%CI=2.7-7.1) months for patients with CNS metastases and 4.2 (95%CI=3.4-5.0) months for the overall population.

Discussion

Nivolumab was well tolerated in patients with squamous NSCLC and CNS metastases from the Italian EAP cohort, and the safety profile appeared to be similar to that of the overall EAP population. The frequency of grade 3-4 treatment-related AEs was comparable in patients with CNS metastases (8%) and in the overall EAP population (6%). The percentage of patients who discontinued nivolumab treatment because of a treatment-related AE was 3% in the subgroup with CNS metastases and 5% in the overall EAP population.

Efficacy with nivolumab in the subset of EAP patients with CNS metastases appeared to be similar to that observed in the overall EAP population: the 1-year OS rates were 35% and 39%, respectively, and the 1-year PFS rates were 31% and 27%, respectively.

Some limitations of this study should be considered: possible patient selection bias and inconsistencies in assessment timing, absence of formal and specific radiological assessment, the small patient number and exclusion of patients with symptomatic CNS metastases, PD-L1 expression was not detected.

Our data were consistent with results reported for the nivolumab arm of CheckMate 017 (3), where the 12-month OS rate was 42% and 1-year PFS rate was 21%. Grade 3-4 treatment-related AEs occurred in 7% of patients in the nivolumab arm, and 3% of patients discontinued the drug because of a treatment-related AE.

Response in CNS lesions have been reported in clinical trials and in case reviews, in patients treated with nivolumab alone or in combination with other therapies (2, 15). Based on encouraging results, the Radiation Therapy Oncology Group has begun a randomized phase III study, RTOG 3505, to evaluate post-chemoradiation nivolumab compared to placebo in patients with unresectable stage 3 NSCLC (16).

Cases of pseudo-progression (an apparent tumor size increase, possibly due to lymphocyte infiltration) with nivolumab in lung cancer have been reported (17), and physicians must make decisions about continuing or discontinuing nivolumab for disease progression based on their assessment of the risks and potential benefits.

Acknowledgements

The Authors thank the patients and their families who made this EAP possible, as well as the clinical study teams who were involved in this program. Professional medical writing and editorial assistance was provided by William Watkins of StemScientific, funded by Bristol-Myers Squibb. Editorial assistance was provided by Luca Giacomelli, Ph.D., Laura Brogelli, and Aashni Shah (Polistudium srl.), supported by internal funds.

Footnotes

  • Authors' Contributions

    All Authors contributed to the drafting of and making the decision to submit the article for publication. All remaining Authors have no relationships to disclose.

  • Conflicts of Interest

    LC received fees for speakers' bureau participation from AstraZeneca, Bristol-Myers Squibb, and Novartis. DG received fees for speakers' bureau participation from Boehringer Ingelheim and Lilly, and travel, accommodation, and expenses from Bristol-Myers Squibb. AA received honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, and Lilly, and served in a consulting/advisory role for Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, and MSD Oncology. DC received honoraria from Roche, MSD, Boehringer Ingrlheim and served in a consulting/advisory for MSD, BMS, Boehirnger Ingelheim, AZ. FG received honoraria from Bristol-Myers Squibb, MSD, AstraZeneca, Roche and served in a consulting/advisory role for Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche, Pierre Fabre, Astra Zeneca. MRM received Honoraria /advisory role from Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, Pfizer.

  • Funding

    Bristol-Myers Squibb, Inc.

  • Nivolumab Expanded Access Program in Squamous NSCLC: Investigators in Italy

    Mario Airoldi, Città della Salute e della Scienza di Torino, Torino; Oscar Alabiso, Azienda Ospedaliero Universitaria Maggiore della Carità di Novara, Novara; Giuseppe Altavilla, Policlinico di Messina, Messina; Paola Antonelli, Ospedale di Busto Arsizio, Busto Arsizio; Antonio Ardizzoia, Ospedale Alessandro Manzoni, Lecco; Andrea Ardizzoni, Policlinico Sant'Orsola-Malpighi, Bologna; Salvatore Artale, Azienda Ospedaliero Sant'Antonio Abate di Gallarate, Gallarate; Fabrizio Artioli, Ospedale di Carpi, Carpi; Editta Baldini, Azienda USL 2 Lucca, Lucca; Carmelo Bengala, Ospedale di Grosseto, Grosseto; Antonio Bernardo, Fondazione Maugeri, Pavia; Alessandro Bertolini, Azienda Ospedaliera Valtellina e Valchiavenna, Sondrio; Paolo Bidoli, Ospedale San Gerardo, Monza; Sergio Bracarda, Azienda USL 8, Arezzo; Alba Brandes, Ospedale di Bellaria, Bologna; Emilio Bria, Università degli Studi di Verona, Verona; Luana Calabrò, Policlinico Le Scotte, Siena; Giacomo Cartenì, Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli, Napoli; Fausto Barbieri, Azienda Ospedaliero Universitaria di Modena, Modena; Federico Cappuzzo, Presidio Ospedaliero di Livorno, Livorno; Luigi Cavanna, Ospedale Guglielmo da Saliceto, Piacenza; Antonio Chella, Azienda Ospedaliero Universitaria Pisana, Pisa; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Napoli; Saverio Cinieri, Presidio Ospedaliero Antonio Perrino, Brindisi; Libero Ciuffreda, Città della Salute e della Scienza di Torino, Torino; Mario Alberto Clerico, Ospedale degli Infermi, Biella; Francesco Cognetti, Istituto Nazionale Tumori Regina Elena, Roma; Pier Franco Conte, Istituto Oncologico Veneto, Padova; Enrico Cortesi, Policlinico Umberto I, Roma; Lucio Crinò, Azienda Ospedaliero Perugia, Perugia; Domenico Cristiano Corsi, Ospedale Fatebenefratelli San Giovanni Calibita, Roma; Andrea De Censi, Ospedali Galliera, Genova; Filippo De Marinis, Istituto Europeo di Oncologia, Milano; Elvira De Marino, Ospedale Sant'Andrea, Vercelli; Sabino De Placido, Azienda Ospedaliero Universitaria Federico II, Napoli; Alessandro Del Conte, Azienda Ospedaliero Santa Maria degli Angeli, Pordenone; Angelo Delmonte; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola; Francesco Di Costanzo, Azienda Ospedaliero Universitaria Careggi, Firenze; Angelo Di Leo, AUSL4 - Nuovo Ospedale di Prato - Santo Stefano, Prato; Marco Di Lieto, Azienda USL 3 di Pistoia, Pistoia; Liberato Di Lullo, Presidio Ospedaliero F. Veneziale, Isernia; Daniele Fagnani, Azienda Socio-Sanitaria Territoriale di Vimercate, Vimercate; Alfredo Falcone, Azienda Ospedaliero Universitaria Pisana Spedali Riuniti di Santa Chiara, Pisa; Gabriella Farina, Ospedale Fatebenefratelli, Milano; Gianpiero Fasola, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine; Francesco Ferraù, Ospedale San Vincenzo, Taormina; Luisa Fioretto, Ospedale Santa Maria Annunziata, Bagno a Ripoli; Paolo Foa, Azienda Ospedaliero San Paolo, Milano; Guido Francini, Policlinico Le Scotte, Siena; Antonio Frassoldati, Arcispedale Santa Anna, Ferrara; Domenico Galetta, Istituto Tumori Giovanni Paolo II, Bari; Marco Galliano, Ospedale Acqui Terme, Aqui Terme; Teresa Gamucci, Presidio Ospedaliero SS Trinità, Sora; Marina Garassino, Istituto Nazionale Tumori, Milano; Luca Gianni, Ospedale San Raffaele, Milano; Carmelo Giannitto, Ospedale Gravina e Santo Pietro, Caltagirone; Lucio Giustini, Ospedale di Fermo, Fermo; Cesare Gridelli, Azienda Ospedaliero San Giuseppe Moscati, Avellino; Francesco Grossi, Azienda Ospedaliero Universitaria San Martino – Istituto Nazionale per la Ricerca sul Cancro, Genova; Alfonso Illiano, Azienda Ospedaliero dei Colli, Napoli; Lorenzo Livi, Azienda Ospedaliero Universitaria Careggi, Firenze; Paolo Marchetti, Ospedale Sant'Andrea, Roma; Maria Rita Migliorino, San Camillo Forlanini, Roma; Enrico Mini, Azienda Ospedaliero Universitaria Careggi, Firenze; Vincenzo Montesarchio, Azienda Ospedaliero dei Colli, Napoli; Alessandro Morabito, Istituto Pascale, Napoli; Alessandro Mozzicafreddo, Ospedale Umberto Parini, Aosta; Donato Natale, Ospedale Santo Spirito, Pescara; Gianmauro Numico, Azienda Ospidaliera Nazionale SS Antonio e Biagio e Cesare Arrigo, Alessandria; Gennaro Palmiotti, Ospedale di Venere, Bari; Lorenzo Pavesi, Fondazione Maugeri, Pavia; Antonio Pazzola, Ospedale Civile SS Annunziata, Sassari; Paolo Pedrazzoli, Policlinico San Matteo, Pavia; Francovito Piantedosi, Azienda Ospedaliero dei Colli, Napoli; Graziella Pinotti, Ospedale di Circolo e Fondazione Macchi, Varese; Carmine Pinto, Arcispedale Santa Maria Nuova di Reggio Emilia, Reggio Emilia; Fausto Roila, Azienda Ospedaliero Santa Maria, Terni; Enzo Maria Ruggeri, Ospedale Belcolle, Viterbo; Antonio Santo, Gruppo Interdisciplinare Veronese Oncologia Polmonare – Azienda Ospedaliero Universitaria Integrata di Verona, Verona; Armando Santoro, Istituto Clinico Humanitas, Milano; Maria Giuseppina Sarobba, ASL3 Nuoro San Francesco, Nuoro; Alessandro Scoppola, Istituto Dermopatico dell'Immacolata, Roma; Salvatore Siena, Niguarda cancer Center Ospedale Niguarda ca' Granda, Milano; Rosa Rita Silva, Azienda Sanitaria Unica Regionale Marche, Fabriano; Hector Soto Parra, Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele, Catania; Giammarco Surico, Ospedale Vito Fazzi, Lecce; Pierosandro Tagliaferri, Policlinico Mater Domini Germaneto, Catanzaro; Davide Tassinari, Ospedale Rimini, Rimini; Natale Tedde, Presidio Ospedale di Olbia, Olbia; Marcello Tiseo, Azienda Ospedaliero Universitaria di Parma, Parma; Carlo Tondini, Ospedale Papa Giovanni XXIII, Bergamo; Giuseppe Tonini, Campus Biomedico, Roma; Marco Tucci, Policlinico di Bari, Bari; Daniele Turci, Ospedale S. Maria delle Croci, Ravenna; Francesco Verderame, Azienda Ospedaliera “Villa Sofia – Cervello,” Palermo;; Guido Vietti Ramus, Ospedale San Giovanni Bosco, Torino.

  • Received May 28, 2019.
  • Revision received June 20, 2019.
  • Accepted June 21, 2019.

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Italian Cohort of the Nivolumab EAP in Squamous NSCLC: Efficacy and Safety in Patients With CNS Metastases
DIEGO CORTINOVIS, RITA CHIARI, ANNAMARIA CATINO, FRANCESCO GROSSI, FILIPPO DE MARINIS, FRANCESCA SPERANDI, FRANCOVITO PIANTEDOSI, MILENA VITALI, HECTOR J. SOTO PARRA, MARIA RITA MIGLIORINO, CARLO TONDINI, DAVIDE TASSINARI, ANTONIO FRASSOLDATI, FRANCESCO VERDERAME, ANTONIO PAZZOLA, FRANCESCO COGNETTI, GENNARO PALMIOTTI, PAOLO MARCHETTI, ARMANDO SANTORO, DIANA GIANNARELLI, FRANCESCA COLONESE, ANGELO DELMONTE
Anticancer Research Aug 2019, 39 (8) 4265-4271; DOI: 10.21873/anticanres.13590
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