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Necitumumab for the treatment of stage IV metastatic squamous non-small-cell lung cancer Expert Rev. Respir. Med. Early online, 1–10 (2015)

Paola Claudia Sacco1, Paolo Maione1, Antonio Rossi1, Assunta Sgambato2, Francesca Casaluce2, Giovanni Palazzolo3 and Cesare Gridelli*1 1 Division of Medical Oncology, “S.G. Moscati” Hospital, Avellino, Italy 2 Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy 3 USLL5, Cittadella, Italy *Author for correspondence: [email protected]

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Over the past two decades, progress in the treatment of patients with metastatic squamous non-small-cell lung cancer has been limited. The EGFR is involved in tumor progression and invasion and therefore it has become the target of several studies in lung cancer. Strategies to block this pathway are focused on the development of small molecule (tyrosine kinase inhibitor) and monoclonal antibodies (mAbs). Some mAbs have been studied in patients with advanced non-small-cell lung cancer. For the first time, a fully human immunoglobulin G (IMC-11F8), subclass 1 (IgG1) mAb targeting the EGFR, in combination with standard chemotherapy (cisplatin + gemcitabine), has been shown to increase overall survival in chemo-naı¨ve patients with metastatic confirmed squamous cell histology. KEYWORDS: anti-EGFR . monoclonal antibody . NSCLC . squamous . target therapy

Lung cancer is the leading cause of death by cancer in the USA and most other countries. Non-small-cell lung cancer (NSCLC) accounts for around 90% of all lung cancer, approximately 25–30% of NSCLCs are of squamous cell histology [1]. The treatment is chosen in accordance with histology. For patients with stage IV non-squamous NSCLC, we can use various treatments while for patients with squamous histology, the platinum-based chemotherapy is the only option. In fact, progress in its treatment over the past two decades has been limited and results in a worse outcome when compared with non-squamous histology. Today, the EGFR is the target of several current and developing anticancer therapies in NSCLC. EGFR expression is detected in up to 85% of tumors. It is a member of the ErbB family of transmembrane tyrosine kinase receptors and is activated by the binding of the EGFR ligands to the EGFR, including the EGF and the TNF-a. This induces a conformational change and dimerization of the receptor and, subsequently, leads to the activation of the intrinsic tyrosine kinase receptor activity and to autophosphorylation of specific residues within the receptor’s cytoplasmic domain. These phosphorylated residues serve 10.1586/17476348.2015.1027688

as docking sites for other molecules involved in the regulation of intracellular signaling cascades like Ras/MAP kinase, PI3K/AKT. The following cascade of intracellular events results in cell proliferation, differentiation, invasion, angiogenesis, metastasis and decreased apoptosis [2]. However, both EGFR expression and EGFR-mediated activation of downstream signaling pathways are related to poor outcome in many types of cancer [3]. Strategies to block EGFR function have focused on the use of EGFR-directed monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKIs). TKIs are small molecules that block the ATP binding site of the cytoplasmic domain of the EGFR [2]. The EGFR-TKIs erlotinib, gefitinib and afatinib are established treatment options for patients with advanced NSCLC, above all in patients with activating EGFR mutations. The majority of antibodies currently being used for targeted therapy belong to the IgG class of immunoglobulin. The effectiveness of an antibody-based therapeutic depends on its ability to induce one of several biological mechanisms. For example, mAbs bind to the surface of the EGFR, blocking the binding of the EGF. Antibody receptor complexes are internalized and degraded, resulting in the

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Sacco, Maione, Rossi, Sgambato, Casaluce, Palazzolo & Gridelli

median of 4.8 months in the experimental group and in chemotherapy-alone group [7]. The adverse events related to FLEX BMS-099 cetuximab plus chemotherapy were acne, CBDCA + docetaxel or paclitaxel Treatment arms CDDP + VNR skin rash and diarrhea. Interestingly, early vs vs onset acne-like rash of any grade was CBDCA + docetaxel or CDDP + VNR + cetuximab associated with better outcome [8]. Morepaclitaxel + cetuximab over, hypersensitivity reaction was Primary end point OS PFS observed in approximately 20% of the patients receiving cetuximab and has Histology NSCLC with EGFR NSCLC been associated with pre-existing IgE expression antibodies against the murine heavy chain Overall survival 11.3 vs 10.1 months 9.69 vs 8.38 months variable domain of cetuximab [9,10]. Hazard ratio 0.871 0.89 The BMS-099 trial evaluated the addiProgression-free survival 4.8 vs 4.8 months 4.40 vs 4.24 months tion of cetuximab to carboplatin plus Hazard ratio 0.943 0.902 paclitaxel in the same patients setting. FLEX study [7]; BMS-099 study [11]. Results of this trial were similar to those CDDP: Cisplatin; FLEX: First-Line Erbitux in Lung Cancer; NSCLC: Non-small-cell lung cancer; OS: Overall in the FLEX study showing an improvesurvival; PFS: Progression-free survival; VNR: Vinorelbine. ment in OS (~1.3 months increase in downregulation of the EGFR on the surface of tumor cells. median OS) and a reduction in the death risk (11–13%). mAbs may also act via immunological mechanism such as, BMS-099 lacked the power to detect a difference of this magantibody-dependent cellular cytotoxicity (ADCC) and nitude with statistical significance [11]. Further, a meta-analysis complement-mediated cytotoxicity. The ability to mediate both including 2018 chemo-naı¨ve patients from four randomized triADCC and complement-mediated cytotoxicity is dependent on als confirmed the survival benefit of chemotherapy plus cetuxithe isotype of the mAb. For example, human monoclonal mab compared with chemotherapy alone in patients with immunoglobulin G1 (IgG1) and IgG3 bind with significantly advanced NSCLC [12]. Interestingly, tumor EGFR expression higher affinity to human Fc receptors and are much more levels seemed to be associated with better clinical outcome in effective mediators of ADCC than IgG2 and IgG4. This is an FLEX study patients. In fact, the data from a subgroup analysis important mechanism of antitumor activity related to comple- of this study showed that a high EGFR expression (a tumor ment activation and triggering of immune effector cell [4]. immunohistochemistry [IHC] score of 200 or more) was the only effective and predictive pre-treatment biomarker for a clinOther anti-EGFR antibodies in NSCLC ical benefit from chemotherapy plus cetuximab [13]. DisapSome mAbs have been studied in patients with advanced pointingly, the role of KRAS as a predictive marker for the use NSCLC like cetuximab, matuzumab, panitumumab and nimo- of the cetuximab with platinum-based systemic treatment was tuzumab. None of these therapeutic options has been approved recently discredited, suggesting that KRAS status is not a pretoday for the treatment of advanced NSCLC. dictor of response to these agents in the treatment of metastatic Cetuximab is used in head and neck cancer, and in RAS NSCLC [14]. wild-type advanced colorectal cancer patients. Multiple ranMatuzumab is a humanized mAb of the IgG1 subclass tardomized trials, using cetuximab as a treatment option, have geting EGFR. In a randomized Phase II study, the addition of shown improvements in response rates (RR) and survival end matuzumab to pemetrexed as second-line therapy for patients points when this mAb has been added to platinum-based che- with advanced NSCLC showed a superior RR (16 vs 2%) and motherapy in metastatic NSCLC [5]. Cetuximab is a chimeric a trend for improvement in median OS (12.4 vs 7.9 months) human/murine IgG1 antibody that inhibits EGFR activation when compared with chemotherapy alone [15]. No further studbinding it with high specificity and affinity. In addition, the Fc ies have been conducted. portion of IgG1 mAb can induce ADCC [4,6]. Two Phase III Panitumumab is a fully human mAb targeting EGFR. The trials have been conducted to evaluate cetuximab efficacy in use of this agent was associated with less frequent hypersensitivadvanced NSCLC patients (TABLE 1). In the First-Line Erbitux in ity reactions and less evident antitumor activity related to Lung Cancer (FLEX) Phase III trial, the addition of cetuximab ADCC. The addition of panitumumab to platinum-based cheto chemotherapy (cisplatin plus vinorelbine) followed by main- motherapy in patients with advanced NSCLC failed to show tenance cetuximab, in chemo-naı¨ve patients with advanced an increase in RR, PFS or OS [16,17]. EGFR-positive NSCLC, has been shown to increase overall Nimotuzumab is an IgG1 humanized mAb that attaches the survival (OS). This small (median OS: 11.3 vs 10.1 months, extracellular domain III of the EGFR to a moderate affinity [18]. hazard ratio [HR] for death: 0.87; p = 0.044) but significant Clinical efficacy has been shown in adults with head and neck survival benefit was seen in all histological subgroups. cancer, and in children with high-grade brain tumors; its antituProgression-free survival (PFS) time was similar, showing a mor activity was observed in absence of severe skin, renal and

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Table 1. Phase III trials of cetuximab in combination with chemotherapy in patients with non-small-cell lung cancer.

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Necitumumab for the treatment of stage IV metastatic squamous NSLC

gastrointestinal mucosa toxicities [19,20]. In NSCLC, two Phase I trials have shown the tolerability of nimotuzumab at doses of up to 400 mg in conjunction with external palliative radiation [21,22]. Moreover, in a randomized Phase II study, 110 patients with stage IIIB/IV NSCLC were randomized to receive nimotuzumab (200 mg once weekly) plus chemotherapy with carboplatin and docetaxel or chemotherapy alone. The overall response rate was significantly higher in the nimotuzumab group than in the control group (54 vs 34.5%, respectively) with a similar safety profile between the two groups. No significant differences in median PFS and OS were observed [23]. Necitumumab

Necitumumab (IMC-11F8) is a fully human IgG1 mAb targeting the EGFR, designed with specific characteristics. It was obtained by a non-immunized human Fab phage display library screened for Fab fragments that would bind A431 epidermoid carcinoma cells expressing high levels of EGFR [24,25]. These cells were stimulated with EGF to obtain the EGFR activation. Four Fab clones were selected and only one (termed IMC-11F8) was able to inhibit with a dosedependent mechanism of the EGFR activation in EGFstimulated A431 cells [26]. IMC-11F8 recognizes a remarkably similar EGFR epitope to that described for cetuximab, so these two antibodies have a similar mode to inhibit EGFR [27]. Shiqing et al. have analyzed the IMC-11F8 binding to the isolated EGFR extracellular region (sEGFR) to understand how this antibody inhibits EGF activation of EGFR. First, Fab11F8 interacts primarily with the EGFR extracellular region domain III, blocking the ligand-binding site. This strong interaction has a distribution coefficient (Kd) value of 3.3 ± 0.5 nM and competes with both the EGF and the cetuximab for receptor binding. The Kd value for the cetuximab Fab binding to sEGFR is of 2.3 ± 0.5 nM. Second, the complex Fab11F8-sEGFR adopts the tethered configuration. Therefore, the binding of the antibody might also sterically inhibits the conformational change that must occur for dimerization (necessary for activation) [28]. In addition to binding very similar epitopes, Fab11F8 and FabC225 (cetuximab) adopt almost identical orientations when bound to sEGFR. Thus, the mechanism of inhibition of ligand-induced dimerization and activation of EGFR for both antibodies is likely similar. A critical difference is that the variable domains of IMC-11F8 are of human origin, whereas the variable region of cetuximab is of mouse origin, which elicits immune reactions in about 20% of cases [9,29]. In addition, as a fully human IgG1, necitumumab can increase the ADCC by human peripheral blood mononuclear cells to EGFR-expressing cancer cells. Preclinical data

The antitumor effects of necitumumab in preclinical studies were similar to those observed with cetuximab [IMCLONE SYSTEMS, UNPUBLISHED DATA]. In vitro, necitumumab inhibited the proliferation of A431 (epidermal), BxPC3 (pancreatic) and DiFi (colorectal) tumor cells (IC50 = 0.8–1.0 nmol/l) [26]. In NSCLC cell lines informahealthcare.com

Drug Profile

(HCC827, NCI-H1650 and EKVX), necitumumab as cetuximab induces more rapid degradation and internalization of EGFR, and potent ADCC against NSCLC tumor cells. Interestingly, the intensity of ADCC induced by necitumumab correlates with the level of EGFR expression on the cell surface being similar to the cetuximab mechanism [30]. Necitumumab has shown significant antitumor activity in a variety of wellestablished human tumor xenografts in athymic mice, as epidermoid (A431) and pancreatic (BxPC-3) [31]. It has been also evaluated in a colon tumor xenografts model showing a synergistic antitumor effect in all tumor models when combined with irinotecan [32]. Prewett et al. evaluated necitumumab in combination with cisplatin + gemcitabine in two models of NSCLC (A549 and NCI-H1650). This combination significantly inhibited the growth of xenograft tumors as compared with either therapy alone. In A549 tumors, treatment with necitumumab plus chemotherapy showed a percentage treated/control (T/C%) of 18% compared with 50 and 58% for necitumumab monotherapy and cisplatin + gemcitabine, respectively, with a partial tumor regression in 33% of necitumumab + cisplatin + gemcitabine-treated mice. In the NCH-H1650 tumor model, the T/C% for combination therapy was 16 versus 39% and 54% for necitumumab and cisplatin + gemcitabine, respectively. There was a 58% partial tumor regression in mice treated with mAb plus chemotherapy [33]. A dose toxicology study was performed in cynomolgus monkeys after 5 weeks of treatment. At doses up to 40 mg/kg as intravenous (iv.) infusion weekly, necitumumab did not cause any toxicologically significant adverse events and was well tolerated. In only one of 24 evaluable animals, anti-necitumumab antibodies were found. In the toxicology study, clinical signs of dermal irritation were observed. No systemic adverse event including hematological, biochemical, cardiac rhythm abnormalities have been reported (ImClone System). Clinical development Phase I trials

In a Phase I study, 60 enrolled patients with advanced solid malignancies, with no prior newly diagnosed or symptomatic brain metastases, and with no prior EGFR-targeted therapy, and were refractory to other standard treatment options were randomized into one of two arms to receive IMC-11F8 infusion at their assigned cohort dose level. In arm A, patients received treatment once a week and in arm B they received treatment once every 2 weeks. The minimum dose was 100 mg with the maximum dose of 1000 mg. Overall, the treatment was well tolerated. The most common drug-related adverse events were: skin toxicity (80% of patients) including acneform rashes, dry skin, skin fissures and pruritus; headaches (42% of patients); nausea (33% of patients) and vomiting (20% of patients). These events were predominately grade 1 or 2 in severity. Only two patients in arm B who received IMC-11F8 at 1000 mg dose level experienced a dose-limiting toxicity, which consisted of grade 3 headaches associated with nausea, vomiting and fever. These adverse effects occurred doi: 10.1586/17476348.2015.1027688

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Sacco, Maione, Rossi, Sgambato, Casaluce, Palazzolo & Gridelli

immediately after receiving the first dose of treatment. Both the qualitative aspects and temporal onset of these toxicities suggest that they were not related to the action mechanism of necitumumab or to the schedule of the administration but, were non-specific manifestations of the high doses of biological protein administered. In fact, necitumumab was reintroduced with a dose reduction from 1000 to 800 mg, with no recurrence of these events. Skin toxicity related to necitumumab occurred with approximately similar frequencies across all dose groups. The incidences of dry skin, acneiform dermatitis and skin fissures seemed to increase slightly at dose levels >600 mg; however, the differences were modest. No hypersensitivity or infusion reactions were observed. In preclinical studies, concentrations of ‡40 mg/ml were achieved at the lower doses associated with antitumor activity. This concentration level was achieved in all patients with necitumumab doses of ‡600 mg administered either once a week or once every 2 weeks. Moreover, in patients treated with 800 mg every 2 weeks, trough concentrations (14 days post-treatment and immediately prior to the next treatment) averaged 83 mg/ml after the final dose of cycle 1 exceeding biologically relevant target concentrations by greater than twofold throughout the entire treatment period. Therefore, a necitumumab dose of 800 mg on either a weekly or an every 2-week schedule has been recommended for disease future evaluation. A total of 23 of 29 patients in arm A and 24 of 31 patients in arm B were considered evaluable for response. Two patients showed confirmed partial responses (a patient with melanoma and a patient with metastatic colorectal cancer). The best overall response of stable disease was observed in 16 patients (8 in each arm), stable disease was most commonly observed in patients with colorectal cancer. Seventeen (28%) patients remained alive and progression free for >3 months and 9 (15%) for >6 months [34]. A Phase I study was conducted in Japanese patients with advanced solid tumors who did not respond to standard therapy or for whom no standard therapy was available. Patients received necitumumab administered iv., once every 2 weeks or on days 1 and 8 every 3 weeks for 6 weeks (one cycle) and have included in three cohorts with a different mAb dosage. In the cohort 1, patients received necitumumab at the dose of 600 mg iv., days 1 and 8 every 3 weeks. In the cohort 2, necitumumab was administered at dose of 800 mg every 2 weeks and in the cohort 3 patients received the same necitumumab dose with different schedule: days 1 and 8 every 3 weeks. After one cycle of treatment, patients who had an objective response or stable disease continued to receive necitumumab at the same dose and schedule until disease progression or other withdrawal criteria were met. A minimum of three patients were enrolled in each cohort. Dose escalation in successive cohorts occurred once all patients completed one cycle of therapy. This study was to establish the safety and pharmacokinetic profile of IMC-11F8. The study has been completed but, the results are not available [35]. The NCT01763788 study [36] is a Phase Ib/II study evaluating necitumumab in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced (stage IV) doi: 10.1586/17476348.2015.1027688

squamous NSCLC. In the Phase Ib, necitumumab is administered at dose of 800 mg on days 1 and 8 of every 21-day cycle, gemcitabine is administered at dose escalation of 1000 or 1250 mg/m2 on days 1 and 8 of every 21-day cycle for a maximum of 4 cycles and cisplatin at dose of 75 mg/m2 on day 21 of every 21-day cycle for a maximum 4 cycles. The purpose of the Phase Ib portion of the study is to investigate how the body tolerates necitumumab, in combination with gemcitabine and cisplatin chemotherapy as first-line treatment in participants and to determine the recommended dose for the subsequent Phase II portion of the study. The purpose of the Phase II portion of the study is to evaluate the efficacy of necitumumab in combination with gemcitabine and cisplatin chemotherapy in patients enrolled. This study is currently recruiting participants [36]. Phase II trials

Some Phase II trials have been conducted in NSCLC evaluating necitumumab in combination with chemotherapy (TABLE 2). In the NCT01769391 Phase II trial, patients with advanced histological confirmed squamous NSCLC have been randomized in two arms. In the experimental arm, they have received necitumumab 800 mg administered iv. on days 1 and 8 of every 3-week cycle associated with paclitaxel 200 (mg/m2) administered iv. on day 1 of every 3-week cycle and carboplatin area under the curve 6 (mg.min/ml) administered iv. on day 1 of every 3-week cycle. The combination of paclitaxel–carboplatin and necitumumab may continue for a maximum of 6 cycles. Necitumumab may continue until progressive disease, toxicity requiring cessation, protocol non-compliance or withdrawal of consent. In the control arm, patients have received only chemotherapy at the same dose as the experimental arm. The main purpose of this study is to evaluate if necitumumab added to standard chemotherapy of paclitaxel and carboplatin is more effective to treat cancer than the chemotherapy of paclitaxel and carboplatin alone. The study is ongoing but is not recruiting [37]. In other two Phase II trials, necitumumab is been combined to cisplatin plus gemcitabine chemotherapy. One of these trials, the NCT01606748, enrolled patients with documented advanced or metastatic solid tumors (except for colorectal tumors with KRAS mutation) who are resistant to standard therapy and for which no standard therapy is available. The study is ongoing but is not recruiting [38]. The second trial, NCT01788566, is a single-arm study evaluating the addition of necitumumab to chemotherapy in the first-line treatment of patients with advanced squamous NSCLC. Necitumumab was administered iv. at 800 mg on days 1 and 8 of each 3-week cycle, gemcitabine at 1250 mg/m2 on days 1 and 8 of each 3-week cycle for a maximum of 6 cycles and cisplatin at 75 mg/m2 on day 1 of each 3-week cycle for a maximum of 6 cycles. The purpose is to evaluate the efficacy of combination treatment and to see how safe the drugs are in combination. The study is ongoing but is not recruiting [39]. Another Phase II study has been conducted in patients with advanced solid tumors. In this trial, patients received necitumumab as single agent at the dose of 800 mg administered once a Expert Rev. Respir. Med.

Necitumumab for the treatment of stage IV metastatic squamous NSLC

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Table 2. Phase II studies evaluating necitumumab in combination with chemotherapy in squamous NSCLC. Treatment

Study design

Disease studied

ClinicalTrials.gov ID

Study status

Necitumumab + CBDCA + paclitaxel vs CBDCA + paclitaxel

Open-label, Phase II

Stage IV squamous NSCLC

NCTO1769391 [37]

Ongoing but not recruiting

Necitumumab + gemcitabine + cisplatin

Open-label, Phase II

Malignant solid tumors

NCT01606748 [38]

Ongoing but not recruiting

Necitumumab + gemcitabine + cisplatin

Open-label, Phase II

Stage IV squamous NSCLC

NCT01788566 [39]

Ongoing but not recruiting

Necitumumab + gemcitabine + cisplatin

Open-label, Phase Ib/II

Stage IV squamous NSCLC

NCT01763788 [36]

Currently recruiting

CBDCA: Carboplatin; NSCLC: Non-small-cell lung cancer.

week as an iv. infusion. The purpose of this study is to determine whether treatment with necitumumab monotherapy affects the QT/QTc interval among patients with advanced solid tumors. The study is ongoing but is not recruiting [40]. Phase II results on necitumumab added to chemotherapy are derived from the study on colorectal cancer. Tabernero et al. evaluated the addition of necitumumab to standard chemotherapy (5-fluorouracil/folinic acid and oxaliplatin) in treatmentnaı¨ve patients with locally or metastatic colorectal carcinoma, irrespective of KRAS mutation status. ORR was 68% and median PFS has not been reached with a median follow-up of 11 months [41]. Phase III trials

Two studies have been conducted in patients with NSCLC. The first Phase III trial, INSPIRE, was focused on patients with non-squamous NSCLC and the second study, SQUIRE, focused on patients with squamous NSCLC. The INSPIRE trial, was a randomized, multicenter, openlabel, Phase III study with patients with stage IV nonsquamous NSCLC. Patients were randomized into first-line treatment with cisplatin + pemetrexed + necitumumab or cisplatin + pemetrexed alone every 21 days for up to 6 cycles. Enrollment in this trial was stopped after 633 patients enrolled following an Independent Data Monitoring Committee recommendation based an observed imbalance in fatal thromboembolic events between the two arms. These events were seen predominantly during the first 2 cycles [42]. In the Phase III SQUIRE trial, 1093 patients with histological or cytological confirmed stage IV squamous NSCLC, who had received no prior therapy for metastatic disease, were randomized to receive one of two iv. administered regimens. Patient selection was not based on EGFR protein expression. In the experimental arm, patients received necitumumab at a dose of 800 mg on days 1 and 8 of every 3-week cycle in combination with gemcitabine at a dose of 1250 mg/m2 on days 1 and 8 of every 3-week cycle and cisplatin at a dose of 75 mg/m2 on day 1 of every 3-week cycle. Those in the control arm received a combination of gemcitabine and cisplatin at the same doses given in the experimental arm. Patients in the experimental arm informahealthcare.com

with no progression after 6 treatment cycles continued treatment only with necitumumab until progressive disease or intolerable toxicity. The primary end point was OS, secondary end points included PFS, ORR and safety. EGFR protein expression level by IHC (H-score) in tumor tissue was an exploratory analysis. Most of the patients were male (83 and 84% in the two arms), more than 90% were smokers. This was a heavily metastatic population, with more than two sites of disease in over 50% of the patients. The study met its primary end point by showing a statistically significant improvement in OS. This was significantly better in the necitumumab group, with a median of 11.5 versus 9.9 months representing a HR of 0.84 (p = 0.012). The 1-year survival rates were 47.7 and 42.8%, and the 2-year survival rates were 19.9 and 16.5% in the necitumumab plus chemotherapy and chemotherapy-alone arms, respectively. The PFS difference was very small, at 5.7 months with necitumumab and 5.5 months without it, but this did reach significance with an HR of 0.85 (p = 0.020). A pre-specified subgroup analysis of OS demonstrated a consistent treatment effect, including patients with Eastern Cooperative Oncology Group performance status 2. The ORR was 31.2% in the experimental arm compared with 28.8% in gemcitabine–cisplatin arm, but this was deemed to be a nonsignificant difference (p = 0.40). The disease control rate, defined as the rate of complete response, partial response and stable disease, was significantly superior with the addition of necitumumab to chemotherapy (82 vs 77%; p = 0.043) (TABLE 3). Post-progression anticancer therapy was similar in the two treatment groups; 47.3% in the necitumumab plus chemotherapy arm received further therapy compared with 44.7% in the chemotherapy-alone arm. Notably, the study found that EGFR expression as measured by the H-score was not predictive of outcome, suggesting the lack of a clear biomarker. Necitumumab combined with chemotherapy showed an acceptable safety profile. The rates of grade ‡3 adverse events were 72.1% in the necitumumab/chemotherapy arm versus 61.6% in the chemotherapy-alone arm. Adverse events leading to the discontinuation of treatment occurred at a rate of 31.2 and 24.6% in the experimental and standard treatments, respectively. There was no increase in hematologic toxicity with the addition of doi: 10.1586/17476348.2015.1027688

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Table 3. SQUIRE Phase III study. GEM-CDDP + NECI q3w Necitumumab 800 mg day 1, 8 Gemcitabine 1250 mg/m2 day 1, 8 Cisplatin 75 mg/m2 day 1

GEM-CDDP q3w Gemcitabine 1250 mg/m2 day 1, 8 Cisplatin 75 mg/m2 day 1

Patient number

545

548

Metastatic sites 1 sites/2 sites/>2 sites %

9/35/55

9/35/56

OS

11.5 months

9.9 months

Hazard ratio (95% CI) p-value (log rank test)

0.84 (0.74, 0.96) 0.012

PFS

5.7 months

5.5 months

ORR (ORR, CR + PR)

31.2%

28.8%

DCR (DCR, CR + PR + SD)

81.8%

77.0%

CDDP: Cisplatin; CR: Complete response; DCR: Disease control rate; GEM: Gemcitabine; NECI: Necitumumab; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; q3w: Every 3 weeks; SD: Stable disease. Adapted from [43].

necitumumab. Grade ‡3 adverse events that occurred significantly more often in the necitumumab/chemotherapy arm were hypomagnesemia (9.3 vs 1.1%), skin rash (7.1 vs 0.4%) and venous thromboembolic events (5.0 vs 2.6%) [43]. Conclusion

Today, the treatment of lung cancer is chosen in accordance with histology and it is different for non-squamous and squamous NSCLC. Patients with non-squamous histology are eligible for many treatments, such as the addition of pemetrexed or bevacizumab to platinum-based chemotherapy. Moreover, activating mutations are more frequent in these patients so they may receive personalized therapy according to the identification of genetic alterations in tumor tissue such as gefitinib, erlotinib or afatinib with activating mutation in EGFR, and crizotinib and ceritinib with rearrangements of the anaplastic lymphoma kinase gene. On the contrary, patients with squamous histology are not eligible for many treatments and their first-line therapeutic option is based on chemotherapy with a platinum-based agent (carboplatin or cisplatin) in combination with a thirdgeneration agent (with the pemetrexed exclusion). Thus, patients with advanced squamous NSCLC have a worse outcome than patients with non-squamous histology. Clinical research is focused on blocking the EGFR activation, which is considered the promoter of cell progression and invasion. mAbs have been developed to inhibit it and can act in two ways. First, they compete with ligand to bind receptor and on the other hand induce the ADCC. In unselected patients with advanced NSCLC, cetuximab, a chimeric human/murine monoclonal IgG1 antibody, has been evaluated in combination with chemotherapy (cisplatin plus vinorelbine) as first-line treatment. The results of this trial (FLEX Phase III trial) showed a better OS for patient in the experimental arm than for patients treated with chemotherapy alone as described above. These results have been confirmed in a meta-analysis doi: 10.1586/17476348.2015.1027688

including 2018 patients from four randomized trials. Despite these positive results, in unselected patients for biomarker, both the US FDA and the European Medicines Agency rejected the licensing of cetuximab in combination with chemotherapy for first-line therapy of advanced NSCLC. The small OS benefit of the addition of cetuximab to chemotherapy should be weighed against its side effects (in the FLEX study, a rash skin grade 3 was reported in 10% of patient and particularly 22% of febrile neutropenia including grade 3 and 4), the weekly administration and costs. Moreover, the authority denied the approval of cetuximab even in high score EGFR expression NSCLC (a high IHC EGFR score >200 is identified as predictive pre-treatment biomarker for clinical benefit from chemotherapy plus cetuximab) because the data came from a subgroup analysis and required a confirmatory prospective trial. This article describes a new mAb necitumumab. This is a fully human IgG1 that is able to bind with high affinity and specificity to the EGFR extracellular domain, blocking its activation. The mechanism of inhibition of ligand-induced dimerization and activation of EGFR for both necitumumab and cetuximab is likely similar. A critical difference is that the variable domains of necitumumab are of human origin, whereas the variable region of cetuximab is of mouse origin, which elicits immune reactions in about 20% of cases. Thus, necitumumab reproduces all of cetuximab’s promise, but lacks its disadvantages (TABLE 4). In fact, the adverse events occurred with grade ‡3, such as neutropenia, anemia, hypersensitivity reaction and particularly febrile neutropenia are less likely in patients treated with chemotherapy and necitumumab than patients treated with chemotherapy and cetuximab (24.3% of patients with neutropenia grade ‡3 vs 14% of patients with grade 3 and 38% of patients with grade 4; 10.6% of patients with anemia grade ‡3 vs 12% of patients with grade 3 and 1% of patients with grade 4; 0.4% of patients with hypersensitivity reaction grade ‡3 vs 3% of patients with grade 3 and

Necitumumab for the treatment of stage IV metastatic squamous non-small-cell lung cancer.

Over the past two decades, progress in the treatment of patients with metastatic squamous non-small-cell lung cancer has been limited. The EGFR is inv...
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