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, randomised, controlled phase 3 trial
Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer.
Methods
We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058.
Findings
Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations.
Interpretation
Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease.
Funding
Eli Lilly and Company.
Introduction
Squamous cell carcinomas account for 30% of non-small-cell lung cancers worldwide.1 In addition to histopathological differences, the mutational profiles of squamous and non-squamous non-small-cell lung cancers are distinctive, with both of these aspects potentially affecting treatment selection.2 For patients with squamous non-small-cell lung cancer, although some potentially targetable molecular lesions have been identified in tumours,1, 3 including PIK3CA amplification, FGFR1 amplification, MET amplification, and DDR2 mutation, none of these biomarkers have yet been validated in this setting as predictive for particular targeted therapies, and available first-line regimens have remained essentially unchanged for the past two decades. In general, such regimens comprise a platinum-based doublet of cisplatin or carboplatin combined with gemcitabine, vinorelbine, or a taxane.1, 4 By contrast, for patients with non-squamous non-small-cell lung cancer, the availability of pemetrexed and bevacizumab as components of first-line or maintenance regimens has widened the choice of possible treatments and provided the opportunity to improve overall survival in this patient group.5, 6, 7, 8, 9 Additionally, a few recurring somatic tumour mutations have been described in adenocarcinomas, offering the potential for selective pathway-directed systemic therapy.10, 11, 12 In particular, EGFR mutations and ALK translocations are predictive of outcome in relation to specific targeted drugs,13, 14 but these mutations are very rare in squamous non-small-cell lung cancer.1, 15 Thus, although clear advances have been made in the first-line treatment of non-squamous non-small-cell lung cancer, especially adenocarcinoma, a substantial unmet need persists to improve outcomes for patients with advanced squamous non-small-cell lung cancer. We note in this context the recent US FDA approval of additional second-line options for patients progressing on or after platinum-based chemotherapy: the PD-1 antibody nivolumab for metastatic squamous non-small-cell lung cancer;16 and the human immunoglobulin G1 VEGFR-2 antibody ramucirumab, in combination with docetaxel, for treatment of metastatic non-small-cell lung cancer (including that of squamous histology).17 However, only about half of patients continue to second-line treatment,18 and neither drug is indicated in the first-line setting.
Research in context
Evidence before this study
In the development of the study design and protocol, we did a systematic review of the published scientific literature. We searched PubMed, with no time restrictions; abstracts of major oncology congresses; and trial websites including ClinicalTrials.gov, for English-language preclinical reports and clinical trials assessing chemotherapy in patients with lung cancer, EGFR therapies in these patients, and the combination of these methods. Search terms for clinical trials of molecular targeted therapies included “lung cancer” and “EGFR”. Clinical data in support of this trial included a phase 1 pharmacological study of necitumumab in patients with advanced solid malignancies that showed necitumumab was well tolerated and had anti-tumour activity at therapeutically relevant trough concentrations. On the basis of our review of the literature and discussions with clinicians, researchers, and regulatory bodies, we postulated that combining chemotherapy with an EGFR-targeted therapy might improve treatment efficacy in patients with advanced squamous non-small-cell lung cancer.
Added value of this study
Our study shows a significant reduction in risk of death and an overall acceptable safety profile in patients who received necitumumab plus gemcitabine and cisplatin. The improvement in overall survival in this patient population compared with those who received gemcitabine and cisplatin chemotherapy alone was supported by a corresponding significant improvement in progression-free survival and a high consistency of the effects of the treatments in subgroup analyses. We recorded no evidence for a predictive association between an EGFR H-score of 200 or more and survival for necitumumab plus gemcitabine and cisplatin in this setting.
Implications of all the available evidence
The SQUIRE trial design was appropriate for the first-line treatment of a patient population with squamous non-small-cell lung cancer and can be generalised to clinical practice. The results confirm the benefit of the addition of an EGFR antibody to standard chemotherapy in this setting and represent clinically meaningful progress in the treatment of squamous non-small-cell lung cancer.
Most non-small-cell lung cancer tumours express EGFR protein, the high-level expression of which is more common in squamous than in non-squamous disease.19, 20 In the phase 3 FLEX trial,20 the addition of the chimeric EGFR antibody cetuximab to cisplatin and vinorelbine improved overall survival in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer, unselected (adenocarcinoma, squamous cell carcinoma, and other) by histological subtype (hazard ratio [HR] 0·871 [95% CI 0·762–0·996]; p=0·044). However, the survival benefit was greatest in the subgroup of patients with squamous non-small-cell lung cancer (HR 0·80 [95% CI 0·64–1·00]), but was accompanied by a higher frequency of febrile neutropenia overall.
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. In murine non-small-cell lung cancer xenograft models, the addition of necitumumab to gemcitabine and cisplatin—an established chemotherapy regimen for the first-line treatment of advanced squamous non-small-cell lung cancer21, 22—resulted in a substantial increase in anti-tumour activity.23 Our randomised, phase 3 study (SQUamous NSCLC treatment with the Inhibitor of EGF REceptor [SQUIRE]) assessed the efficacy and safety of necitumumab plus gemcitabine and cisplatin as first-line treatment for patients with advanced squamous non-small-cell lung cancer. In parallel, the phase 3 INSPIRE study24 assessed the efficacy and safety of necitumumab plus pemetrexed and cisplatin as first-line treatment for patients with advanced non-squamous non-small-cell lung cancer.
Section snippets
Study design and participants
We did this open-label, multicentre, randomised, phase 3 study at 184 investigative sites in 26 countries (listed in the appendix). The full inclusion and exclusion criteria are provided in the appendix. Briefly, patients aged 18 years or older with histologically or cytologically confirmed stage IV (according to the AJCC Cancer Staging Manual, seventh edition25) squamous non-small-cell lung cancer were eligible for enrolment. Other key inclusion criteria were an Eastern Cooperative Oncology
Results
Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 eligible patients and randomly assigned them to necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Seven patients in each group did not receive study treatment, and therefore the safety population comprised 1079 patients (figure 1). The baseline characteristics of the treatment groups were well balanced (table 1); notably, 605 (55%) of 1093 patients had metastases to more than two organ systems and 96
Discussion
Our findings show that the addition of necitumumab to gemcitabine and cisplatin was associated with a statistically significant improvement in overall survival in patients with advanced squamous non-small-cell lung cancer. This treatment effect was supported by a corresponding statistically significant improvement in progression-free survival. In this broad patient population, which is typical of one seen in clinical practice, outcome improvements were recorded across major subgroups at a
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Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC)
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FDA drug approval summary: bevacizumab (Avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer
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Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer
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PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer
This retrospective study aimed to investigate the effectiveness and safety of bronchial arterial chemoembolization with drug-eluting beads (DEB-BACE) plus chemotherapy versus chemotherapy alone in patients with stage III and IV lung squamous cell carcinoma (LSCC) who are not appropriate candidates for radiochemotherapy.
In this retrospective analysis, we screened all adult patients undergoing either DEB-BACE plus chemotherapy or chemotherapy alone for stage III or IV LCSS at authors’ center from January 2018 to August 2021. Each 21-day chemotherapy cycle consisted of intravenous injection of gemcitabine (1.0 g/m2) on days 1 and 8 and cisplatin 75 (mg/m2) on day 1. The planned cycles were 4. DEB-BACE consisted of microcatheter infusion of CalliSpheres beads carrying cisplatin (75 mg/m2) and gemcitabine (1.0 g/m2), at 3 weeks prior to chemotherapy. The primary outcome was overall survival (OS). The secondary outcomes included progression-free survival (PFS), pulmonary response, and adverse events (AEs).
The final analysis included 95 patients in the chemotherapy group and 41 patients in the combination treatment group. The median OS was 14 months (95 % CI 11.0–17.0) in the chemotherapy group and 19 months (95 % CI 18.0–24.0) in the combination group (P = 0.015). In multivariate Cox regression analysis, DEB-BACE plus chemotherapy was associated with lower risk of death versus chemotherapy only (HR 0.16, 95 % CI 0.05–0.52; log rank test P = 0.003). The median PFS was 6 months (95 % CI 4.0–7.0) in the chemotherapy group and 8 months (95 % CI 6.0–8.0) in the combination group (P = 0.015). The pulmonary objective response rate (ORR) and disease control rate (DCR) were 48.4 % and 62.1 % in chemotherapy group versus 82.9 % and 90.2 % in combination group (P < 0.001 and = 0.001, respectively). AEs occurred in 133 patients (97.8 %). The rate of bone marrow suppression was 48.4 % (46/95) in the chemotherapy group versus 7.3 % (3/41) in the combination group (P < 0.001).
Compared with chemotherapy alone, DEB-BACE plus chemotherapy was associated with longer survival outcomes and lower rate of bone marrow suppression.
In the Netherlands, the clinical benefit of systemic anti-cancer treatments (SACTs) is assessed by the Committee for the Evaluation of Oncological Agents (cieBOM). For non-curative SACTs, the assessment is based on the hazard ratio (HR) for progression-free survival and/or overall survival (OS), and the difference in median survival. We evaluated the impact of different thresholds for effectiveness by reassessing the clinical benefit of SACTs.
We reassessed SACTs that were initially assessed by cieBOM between 2015 and 2017. Four scenarios were formulated: replacing an “OR” approach (initial assessment) by an “AND” approach (used in all scenarios), changing the HR threshold from < 0.70 (initial assessment) to < 0.60, changing the threshold for the difference in median survival from > 12 weeks (initial assessment) to > 16 weeks, and including thresholds for OS rates. The outcomes of these scenarios were compared to the outcomes of the initial assessment.
Reassessments were conducted for 41 treatments. Replacing the “OR” approach by an “AND” approach substantially decreased the number of positive assessments (from 33 to 22), predominantly affecting immunotherapies. This number further decreased (to 21 and 19, respectively) in case more restrictive thresholds for the HR and difference in median survival were used. Including thresholds for OS rates slightly mitigated the impact of applying an “AND” approach.
The scenario-specific thresholds had a substantial impact; the number of negative assessments more than doubled. Since this was not limited to treatments with marginal survival benefits, understanding the potential challenges that may arise from applying more restrictive thresholds is essential.
Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM).
Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints.
OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity.
A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the current recommended option for the first-line treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). Resistance to first-generation TKIs led to the development of second- and third-generation TKIs with improved clinical outcomes. However, sequential administration of TKIs has led to the emergence of new EGFR resistance mutations and persistent tumor cell survival. This evidence highlights the potential role of EGFR in transducing growth signals in NSCLC tumor cells. Therefore, dual inhibition of EGFR using combinations of anti-EGFR monoclonal antibodies (mAbs) and EGFR-TKIs may offer a unique treatment strategy to suppress tumor cell growth. Several clinical studies have demonstrated the benefits of dual blockade of EGFR using anti-EGFR mAbs coupled with EGFR-TKIs in overcoming treatment resistance in patients with EGFR-mutated NSCLC. However, a single treatment option may not result in the same clinical benefits in all patients with acquired resistance. Biomarkers, including EGFR overexpression, EGFR gene copy number, EGFR and KRAS mutations, and circulating tumor DNA, have been associated with improved clinical efficacy with anti-EGFR mAbs in patients with NSCLC and acquired resistance. Further investigation of biomarkers may allow patient selection for those who could benefit from anti-EGFR mAbs in combination with EGFR-TKIs. This review summarizes findings of recent studies of anti-EGFR mAbs in combination with EGFR-TKIs for the treatment of patients with EGFR-mutated NSCLC, as well as clinical evidence for potential biomarkers towards personalized targeted medicine.
Epidermal growth factor receptor (EGFR) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and in some somatic cells at a limited level, rendering it an attractive antitumor target. In this study, we engineered chimeric antigen receptor (CAR)-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural ligands of EGFR. We showed that this approach yielded CAR-T cells with favorable phenotypes and CAR positivity. They exhibited potent antitumor activity against NSCLC both in vitro and in vivo. When administered to tumor-bearing mice and non-tumor-bearing cynomolgus macaques, they did not elicit toxicity despite their cross-reactivity to both murine and simian EGFRs. In total we tested three ligands and found that the CAR candidate with the highest affinity consistently displayed greater potency without adverse events. Taken together, our results demonstrate the feasibility and safety of targeting EGFR-expressing NSCLCs using ligand-based, piggyBac-engineered CAR-T cells. Our data also show that lowering the affinity of CAR molecules is not always beneficial.
Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown.
This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS).
A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8–5.3), 13.3 months (95% CI: 9.6–16.5), and 27.3% (95% CI: 18.3–37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths.
GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.