Although lung cancer accounts for approximately 15% of all cancer diagnosis, it is the leading cause of cancer deaths for both men and women.1
Squamous NSCLC accounts for approximately 25-30% of all NSCLC and have a particular poor prognosis. In contrast to advancements seen in the treatment of non-squamous NSCLC, therapeutic progress in squamous NSCLC represents a high unmet medical need.2,3 First line therapy in patients with squamous NSCLC remains a platinum-based doublet of cisplatin or carboplatin combined with gemcitabine, vinorelbine or a taxane.4
In NSCLC, activating mutations occur in the EGFR tyrosine kinase domain (exons 18 to 21) and their presence is both prognostic and predictive of responses. Mutations in the EGFR gene occur in 19-48% of adenocarcinoma cases, but in less than 5% of squamous NSCLC.5
Cetuximab, a chimeric EGFR antibody showed improved response rates and OS when combined with cisplatin and vinorelbine in NSCLC, especially in the subgroup of patients with squamous histology. However, it increased the frequency of grade 3 and 4 of febrile neutropenia.6
Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that binds to EGFR with high affinity, competing with natural ligands and thereby preventing receptor activation and downstream signalling.
The phase III clinical trial SQUIRE showed a statistically significant benefit in OS (11.5 vs 9.9 months, HR:0.84) and PFS (5.7 vs 5.5 months, HR:0.75) in patients treated with gemcitabine (1250mg/m2, D1, D8), cisplatin (75mg/m2, D1) and necitumumab (800mg, D1, D8) for stage IV squamous NSCLC.7 Most of the patients (95%) had cancer cells with EGFR. However, there was no evidence for a predictive association between an EGFR score (high vs low) and survival for necitumumab plus chemotherapy in this setting. In contrast with the FLEX trial, the addition of this anti-EGFR treatment was not accompanied with more toxicity.8 In the main study, adding necitumumab to gemcitabine and cisplatin chemotherapy improved survival by just one and a half months without causing significant worsening in overall patient health. The most common side effects with necitumumab (which may affect more than 1 in 10 people) are skin reactions, vomiting, stomatitis, fever, weight loss and low measurements of various serum electrolytes (magnesium, calcium, phosphate and potassium). The most common serious side effects were severe skin reactions (6% of patients) and blood clots (4% of patients). The Agency’s Committee for Medicinal Products for Human Use (CHMP) therefore concluded that necitumumab’s benefits are greater than its risks and recommended that it be approved for use in the EU.
Based on these efficacy data and the acceptable safety profile of necitumumab a phase II clinical study was designed to check the efficacy of necitumumab with a taxane-platinum doublet.9
Spiegel et al. randomised patients to receive first-line treatment of necitumumab (800mg absolute dose iv on D1 and D8) with paclitaxel (P) (200mg/m2 iv on D1) and carboplatin (C) (AUC 6 iv on D1) versus chemotherapy alone with paclitaxel and carboplatin for a maximum of six 3-week cycles.
Patients treated with necitumumab and PC with a response of stable disease (SD) or better after completion of 6 cycles of study therapy continued to receive necitumumab until progression disease (PD), whereas patients treated with PC with a response of SD or better after 6 cycles of study therapy entered the post discontinuation follow-up period until there was a PD.
The primary objective of this study was to estimate the best objective response rate (ORR: CR+ PR) associated with necitumumab + PC in chemotherapy-naive patients with stage IV squamous NSCLC. Secondary end points were OS, PFS and safety of necitumumab in combination with PC chemotherapy.
Among patients assessed for response, the combination of necitumumab + PC resulted in an ORR of 48.9% compared with 40% in patients who received PC alone. Median OS was 13.2 months versus 11.2 months (HR:0.83) and median PFS was 5.4 months versus 5.6 months (HR:1.00) in each treatment arm respectively.
Grade 3 adverse events associated with EGFR monoclonal antibodies showing a >2% increase were hypomagnesemia (5.7% vs 0%) and rash (2.8% vs 0%). Any Grade and Grade 3 febrile neutropenia was reported in 7.3% of the patients in the PC arm and in 6.6% of the patients in the necitumumab-containing arm. Any grade venous thromboembolic events (VTEs) occurred in 3.8% of the patients in the necitumumab + PC arm versus 3.6% of the patients in the PC arm, whereas any grade arterial thromboembolic events (ATEs) occurred in 2.8% and 3.6% of the patients in each respective treatment arm.
After these encouraging results, in the era of immunotherapy, there are some early clinical data available regarding the combination of necitumumab with immunotherapy (pembrolizumab). A multicenter phase 1b study was designed to determine the efficacy and safety of necitumumab combined with pembrolizumab in patients with metastatic NSCLC after first line of treatment. In Part A of the study, escalating doses of necitumumab (600 mg and 800 mg IV) were administered on D1 & D8 (Q3W) together with pembrolizumab (200 mg IV) on D1 (Q3W). Because no dose-limiting toxicity was observed, patients in Part B (expansion cohort) received necitumumab 800 mg iv (Q3W) combined with pembrolizumab (200 mg iv, Q3W). After median follow-up of 6 months, 29% of the patients had partial response, both confirmed and unconfirmed, to the combination of necitumumab and pembrolizumab. Among patients who were PD-L1 negative, the ORR was 18%. Among patients who were PD-L1 positive weak and strong, the ORR was 60% and 40%, respectively. The disease control rate was 68%. At 6 months, 55% of patients receiving the combination of necitumumab and pembrolizumab were progression-free (95% confidence interval [CI], 36%-71%). Median PFS was 6.9 months (95% CI, 2.7 months to not reached). Researchers concluded that the combination of necitumumab and pembrolizumab was effective and safe in patients with metastatic NSCLC who progressed after 1 or more platinum-based chemotherapy regimens.
In conclusion, the study of Spigel et al. was appropriate to evaluate the efficacy and safety of the combination of necitumumab with a standard platinum doublet as first-line treatment of patients with advanced squamous NSCLC. The results confirm that necitumumab with paclitaxel and carboplatin is an active treatment and support the results of the SQUIRE trial with a different platinum doublet chemotherapy.
- Jemal A, Siegel R, Xu J, et al. Cancer Statistics, 2010. CA Cancer J Clin. 2010;60:277-300. PMID:206105432.
- Oliver TG, Patel J, Akerley W. Squamous NSCLC as a distinct clinical entity. Am J Clin Oncol 2015; 38: 220-63.
- Gandara DR, Hammerman PS, Sos ML, Lara PN Jr, Hirsch FR. Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Clin Cancer Res 2015; 21: 2236-434.
- NCCN Guidelines Version 6.2017 Non-Small Cell Lung Cancer
- Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in NSCLC: meta analysis by ethnicity and histology. Ann Oncol 2013; 24: 2371-66.
- Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet 2009; 373:1525-317.
- Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomized, controlled phase 3 trial. Lancet Oncol 2015; 16:763-748.
- Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009; 373:1525-1531. PMID:194107169.
- Spigel DR, Luft A, Depenbrock H, et al. An open-label, randomized, controlled phase II study of paclitaxel-carboplatin chemotherapy with necitumumab versus paclitaxel-carboplatin alone in first-line treatment of patients with stage IV squamous non-small-cell lung cancer. Clin Lung Cancer 2017; S1525-7304(17)30045-1
- In the era of immunooncology, would anti-EGFRs (which lack clinically applicable predictive markers in this setting) still be an option in the first line treatment of advanced squamous NSCLC?
- Would necitumumab be an eligible EGFR monoclonal antibody for combination with immunotherapy in lung cancer?
Ioannis Litos and Eleni Sogka declare no actual, potential, real or apparent interest. The authors declare to have no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.