Next Article in Journal
Situational Awareness: Regulation of the Myb Transcription Factor in Differentiation, the Cell Cycle and Oncogenesis
Next Article in Special Issue
Desmoplasia and Chemoresistance in Pancreatic Cancer
Previous Article in Journal
Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer
Previous Article in Special Issue
Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 6
Issue 4
10.3390/cancers6042035
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Gefitinib Plus Interleukin-2 in Advanced Non-Small Cell Lung Cancer Patients Previously Treated with Chemotherapy

by
Melissa Bersanelli
1,*,
Sebastiano Buti
1,
Roberta Camisa
1,
Matteo Brighenti
2,
Silvia Lazzarelli
2,
Giancarlo Mazza
3 and
Rodolfo Passalacqua
2
1
Oncology Unit, University Hospital of Parma, Via Gramsci, 14, 43126 Parma, Italy
2
Oncology Unit, Azienda Istituti Ospitalieri di Cremona, Largo Priori, 1, 26100 Cremona, Italy
3
Radiology Division, Spedali Civili di Brescia, P.le Spedali Civili,1, 25123 Brescia, Italy
*
Author to whom correspondence should be addressed.
Cancers 2014, 6(4), 2035-2048; https://doi.org/10.3390/cancers6042035
Submission received: 28 June 2014 / Revised: 21 August 2014 / Accepted: 15 September 2014 / Published: 30 September 2014
(This article belongs to the Special Issue Cancer Drug Resistance)
Browse Figures
Versions Notes

Abstract

:
The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3–4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2–3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2–3.8) and 4.1 (CI 95% = 2.6–5.7) months; a median overall survival of 20.1 (CI 95% = 5.1–35.1) and 6.9 (CI 95% = 4.9–8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16–0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18–0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib.

1. Introduction

Gefitinib (Iressa) is an oral selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) nowadays approved for the first line treatment of non-small-cell lung cancer (NSCLC) in the presence of EGFR gene mutations and also for NSCLC patients without activating mutations in further lines of treatment, on the basis of three pivotal phase III trials [1,2,3,4], more recently supported by further randomized controlled trials on naive patients harboring EGFR mutations [5,6]. Gefitinib was the first oral EGFR-TKI to become commercially available; at the beginning of the present study, it was clinically available only for compassionate use.
Interleukin-2 (IL-2), a cytokine signaling molecule necessary for growth, proliferation and differentiation of T-lymphocytes, has demonstrated antitumor activity in renal cell cancer and melanoma; previous studies on patients with NSCLC treated with IL-2 reported relatively long survival [7,8,9,10].
The imbalance of the IL-2/IL-2 receptor system in advanced NSCLC, with the decline in IL-2 levels and the significantly high soluble IL-2 receptor (sIL-2R) concentrations, has been evidenced and suggested to represent a marker of disease with potential prognostic value [11]; on the other hand, the role of IL-2 activation in the restoration of the immunocompetence of lymphocytes against lung cancer has been demonstrated [12].
The strategy of harnessing the immune system, previously relatively abandoned in lung cancer treatment, has actually had a rebound of interest with the emerging of new therapeutic targets in immunotherapy [13,14,15,16]. Vaccination strategies are also promising: a phase IIB/III study is currently ongoing to evaluate the efficacy of TG4010 (recombinant vaccinia virus of the Ankara strain), a genetically modified virus expressing both mucinous glycoprotein 1 (MUC1) and IL-2, in advanced NSCLC patients [17]. In this renewed focus on the use of immunotherapy in lung cancer, in particular when combined with standard therapies in order to potentiate their efficacy, also T-lymphocytes and their activating cytokines have been reconsidered [18]. Combination therapy of EGFR-TKI with cytokines has recently been experimented upon with some positive results in order to reverse resistance to TKI in NSCLC [19,20]. Recent evidence indicated that lymphocytes are activated by gefitinib treatment via activation of platelets, which release serum regulated on activation normal T-cell expressed and secreted (RANTES) and regulate chemokine secretion, inducing lymphocyte migration. Moreover, plasma soluble P-selectin, RANTES and serum sIL-2R levels increased significantly in patients receiving gefitinib [21,22]. Other authors found that EGFR-TKI affects the cancer related networks of pro-inflammatory cytokines and activates the lymphocytic responses; this evidence suggests a possible synergism between the EGFR molecular pathway inhibition and immune system modulation in promoting tumor shrinkage [23,24].
In this pilot study, we explored the possible synergism between IL-2 and gefitinib in terms of response rate, survival and toxicity, with the purpose of evaluating the efficacy of this association in advanced NSCLC.

2. Patients and Methods

2.1. Patients Selection

Eligibility criteria included: age ≥18 years; histologic or pathologic confirmation of NSCLC; prior treatment with at least one chemotherapy regimen for recurrent or metastatic disease, including at least one platinum-based combination; measurable disease by the Response Evaluation Criteria In Solid Tumors (RECIST) Group response criteria [25]; and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) from 0 to 2. Patients were required to have adequate baseline hematologic (absolute neutrophil count ≥1,500/μL, platelets ≥100,000/μL and hemoglobin ≥8 g/dL), renal (serum creatinine level ≤2.0 mg/dL or calculated creatinine clearance ≥50 mL/min) and hepatic (alkaline phosphatase, AST and ALT levels ≤2.5 × upper limit of normal and total bilirubin ≤1.5 × upper limit of normal) function parameters. Patients with asymptomatic brain metastases who were adequately treated at least 3 weeks before enrollment and were not receiving corticosteroids were eligible. Cases of prior treatment with any other experimental drug within two months since this study entry were excluded. Patients with serious autoimmune disease or a significant history of cardiac disease and patients undergoing major thoracic or abdominal surgery within 30 days before the first administration of therapy were also excluded. Prior radiation therapy was to be completed at least 3 weeks before enrollment and could not have been given to the only site of measurable disease unless there was documentation of disease progression post-irradiation. Prior chemotherapy must have been completed at least 30 days before the first administration of experimental treatment. A 12-lead electrocardiogram (ECG), a chest radiography (RX) and a chest and abdomen computed tomography (CT) scan were performed within 28 days before treatment. A bone scintigraphy, a CT scan or magnetic resonance (MR) imaging of the brain was also performed within 28 days before experimental treatment at the physician’s discretion; other examinations were performed if considered necessary to the evaluation of lesions. Medical history, physical examination, assessment of ECOG PS, cell blood count differential, platelet count and a chemistry panel were completed within 14 days of treatment. A negative urine or serum pregnancy test was required for women of childbearing potential within 72 h before treatment. The study had the approval of the local ethical committee; written informed consent was provided for each patient.

2.2. Study Design and Treatment Plan

From September, 2003, to November, 2006, 70 consecutive eligible chemotherapy pretreated patients with advanced, progressive NSCLC were included in this study and planned to receive oral gefitinib 250 mg daily in a compassionate use program at a single institution, in the Oncology Unit of Istituti Ospitalieri of Cremona (Italy). This is a phase II, non-randomized, pilot trial combined with a cohort design, each having a different outcome event. The phase II portion was a Fleming one-stage design used to determine the sample size for estimating the response rate as the primary endpoint; it was decided to set p0 = 0.5 (expected response rate with only gefitinib therapy in non-selected pretreated advanced NSCLC) and pA = 0.10 (expected response rate with gefitinib plus IL-2). Considering a one-sided significance level test α = 0.05 with 80% power (β = 0.2), the number of patients to accrue were 31: if the number of treatment response were ≥5, the null hypothesis H0 was rejected: pA ≥ p0. For the first 39 consecutive patients (cohort portion), the administration of gefitinib alone (G group) was scheduled until disease progression or intolerable toxicity, and no specific design was applied to this group, even if the data were prospectively collected; the remaining 31 consecutive patients were intended to constitute a separate group (phase II portion) receiving gefitinib in association with subcutaneous IL-2 (GIL-2 group), according to the following eight-week schedule (Table 1): 1 MIU/m2 twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for 4 consecutive weeks with a 4-week rest period until disease progression or intolerable toxicity. A premedication with paracetamol (500 to 1,000 mg) was permitted before the administration of IL-2. Aside from disease progression, treatment could be suspended at any time on the investigators’ opinion for the appearance of serious adverse events or unexpected reactions or for patient’s refusal; these cases were equally considered as assessable. Temporary discontinuation and/or dose reduction of 50% of one or both drugs was allowed for whatever toxicity at least of Grade 3.
Table
Table 1. Schedule of IL-2 treatment repeated for 4 consecutive weeks with a 4-week rest period until progression of the disease or intolerable toxicity.
Table 1. Schedule of IL-2 treatment repeated for 4 consecutive weeks with a 4-week rest period until progression of the disease or intolerable toxicity.
Day of Week1234567
IL-2 bidxx
IL-2/die xxx
IL-2 bid: subcutaneous Interleukin-2 one million IU/m2 twice a day. IL-2/die: subcutaneous Interleukin-2 one million IU/m2 once a day.

2.3. Assessments

The above described pretreatment evaluations were planned. Physical and laboratory examinations were performed every 28 days. Response assessments based on RECIST criteria [25] were scheduled every 10–12 weeks (or before, in the case of clinical suspicion of disease progression). The cases of clear clinical progression were considered as disease progression, even in the absence of radiological assessment when not feasible. Responses had to be confirmed by an external radiologist with repeated assessments no less than 4–6 weeks after the initial claim of disease response. Time to progression (TTP) was defined as the time from the beginning of treatment to disease progression (or death, if it was first). Overall survival (OS) was defined as the time from the beginning of the treatment to death for any cause. All adverse reactions were assessed according to National Cancer Institute Common Toxicity Criteria (version 3.0) [26]. In the case of Grade 3 acne-like rash (rash/desquamation) or diarrhea, gefitinib therapy was discontinued for up to four consecutive weeks. If the toxicity resolved to a grade ≤2 by the following period, treatment could have been resumed.

2.4. Statistical Analysis

The primary endpoint of this study was to the assess response rate (RR), intended as the sum of partial and complete responses according to RECIST criteria [25], of combination therapy with gefitinib and IL-2; the secondary endpoints were the evaluation of survival, TTP and safety with the exploratory comparison between the two groups of treatment. The analysis of data has been conducted according to the principle of the “intention-to-treat”. The product of the limit method (Kaplan-Meier) has been used for the curve of survival and the log-rank test for the comparison among the curves. Models of regression (Cox) have been adopted for the analysis of the prognostic factors.

3. Results

3.1. Patients Characteristics

From September, 2003, to November, 2006, 70 consecutive patients with advanced, previously treated progressive NSCLC received treatment according to this study plan: 39 patients were in the G group, while 31 were in the GIL-2 group. All patients were EGFR-TKI naive. Patient demographics and disease characteristics are summarized in Table 2.
Table
Table 2. Patients’ demographics and disease characteristics.
Table 2. Patients’ demographics and disease characteristics.
PARAMETERGefitinib Only No. of PatientsGefitinib + IL-2 No. of PatientsAllPatients
Demographic characteristics
Number of patients39 (56%)31 (44%)70
Males28 (72%)17 (55%)45 (64%)
Females11 (28%)14 (45%)25 (36%)
Age, years
Median716970
Range39–8444–8039–84
ECOG PS
014 (36%)17 (55%)31 (44%)
117 (44%)13 (42%)30 (43%)
≥ 28 (20%)1 (3%)9 (13%)
Smoking History
Yes35 (90%)23 (74%)58 (83%)
No3 (8%)7 (23%)10 (14%)
Unknown1 (2%)1 (3%)2 (3%)
Histology
Adenocarcinoma24 (62%)24 (77%)48 (69%)
Squamous cell carcinoma5 (13%)3 (10%)8 (11%)
Bronchoalveolar-cell2 (5%)2 (6%)4 (6%)
Undifferentiated8 (20%)2 (6%)10 (14%)
Number of disease sites
1–212 (31%)9 (29%)21 (30%)
≥3 (range 3–8)27 (69%)22 (71%)49 (70%)
Lung disease
Yes37 (95%)30 (97%)67 (96%)
No2 (5%)1 (3%)3 (4%)
Liver metastasis
Yes10 (26%)1 (3%)11 (16%)
No29 (74%)30 (97%)59 (84%)
Bone metastasis
Yes12 (31%)12 (39%)24 (34%)
No27 (69%)19 (61%)46 (66%)
Node metastasis
Yes26 (66%)18 (58%)44 (63%)
No13 (33%)13 (42%)26 (37%)
Adrenal metastasis
Yes5 (13%)4 (13%)9 (13%)
No34 (87%)27 (87%)61 (87%)
Brain metastasis
Yes8 (21%)5 (16%)14 (20%)
No31(79%)26 (84%)56 (80%)
Previous Chemotherapy for metastatic disease
One line31 (79%)22 (71%)53 (76%)
Two lines6 (15%)7 (23%)13 (18%)
Three lines2 (5%)2 (6%)4 (6%)
Previous platinum therapy
Yes34 (87%)30 (97%)64 (91%)
No5 (13%)1 (3%)6 (9%)
Further therapy after progressive disease on treatment study
Yes9 (23%)13 (42%)22 (31%)
No30 (77%)18 (58%)48 (69%)
ECOG PS: Eastern Cooperative Oncology Group Performance Status.
Two thirds of patients were male. The median age was 70 years (range 39 to 84 years). Thirty one patients (44%) had a baseline ECOG PS = 0, 30 (43%) PS = 1 and nine (13%) PS ≥ 2. Fifty-three (76%) patients received only one prior chemotherapy regimen, while 17 (24%) received ≥2 prior lines of treatment. Forty-eight (69%) patients had adenocarcinoma, eight (11%) had squamous cell carcinoma, and four (6%) had bronchoalveolar-cell carcinoma subtype; the remaining 10 (14%) had undifferentiated NSCLC. Only 10 (14%) patients presented a never-smoking history. According to the intention-to-treat principle, all patients have been considered in the evaluation of TTP, OS and toxicity. The median duration of the follow-up was 25.2 months (range: from 8.3 to 39.4 months): 27.5 months (range 8.3–36.9) and 21.8 months (range 8.8–39.4) for the G and GIL-2 groups, respectively.

3.2. Responses, Effectiveness and Survival

At the end of the observation period (November, 2006), 17 (24%) patients were still alive. All patients were considered evaluable for response; two complete responses (CR, 3%) and five partial responses (PR, 7%) were recorded in the overall population, with an objective RR of 10%; 22 patients had stable disease (SD, 31.4%) as the best response. The overall disease control rate was 41.4%, and the actuarial one-year survival rate was 40%. Median TTP was 3.7 months (CI 95% 2.7–4.3) and median overall survival (OS) was 7.9 months (CI 95% 4.9–10.8).
When comparing patients who received IL-2 and gefitinib with patients who received gefitinib alone, we respectively observed an objective RR of 16.1% (with two cases of CR, 6.4% of GIL-2 patients) and 5.1% (with only partial response in the G group). The disease control rate was 41.9% and 41%, respectively. The median TTP was 3.5 (CI 95% 3.2–3.8) and 4.1 months (CI 95% 2.6–5.7) in the GIL-2 and G groups, respectively, without reaching statistical significance (Figure 1).
Cancers 06 02035 g001 550
Figure 1. Time to progression in G (gefitinib) and GIL-2 (gefitinib and IL-2) groups (p = not significant).
Figure 1. Time to progression in G (gefitinib) and GIL-2 (gefitinib and IL-2) groups (p = not significant).
Cancers 06 02035 g001
The median OS in the GIL-2 group was 20.1 months (CI 95% 5.1–35.1), while in the G group, it was 6.9 months (CI 95% 4.9–8.9) (Figure 2), with statistical significance in favor of the combined treatment (p = 0.002) and actuarial one-year survival rates of 54% and 30%, respectively.
Cancers 06 02035 g002 550
Figure 2. Overall survival in G and GIL-2 groups (p = 0.002).
Figure 2. Overall survival in G and GIL-2 groups (p = 0.002).
Cancers 06 02035 g002
Multivariate analysis according Cox’s regression, including PS, gender, smoking, skin toxicity of any grade and use of IL-2, revealed that only skin toxicity (p < 0.001; HR 0.29; CI 95% 0.16–0.54) and use of IL-2 (p < 0.001; HR 0.33; CI 95% 0.18–0.60) were significantly associated with improvement in OS independently of other factors.

3.3. Toxicity

Toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (version 3.0) [25] (see Table 3).
Table
Table 3. Overall population toxicity.
Table 3. Overall population toxicity.
ToxicityEvents(No. of Patients, %)WHO grade (No. of Patients, %)
Grade 1Grade 2Grade 3Grade 4
Rash31 (44.3%)8 (11.4%)18 (25.7%)4 (5.7%)1 (1.4%)
Asthenia18 (25.7%)8 (11.4%)7 (10%)3 (4.3%)0
Anorexia15 (21.4%)9 (12.9%)5 (7.1%)1 (1.4%)0
Diarrhea12 (17.1%)7 (10%)05 (7.1%)0
Dyspnea8 (11.4%)6 (8.6%)2 (2.9%)00
Transaminase alteration4 (5.7%)3 (4.3%)01 (1.4%)0
Fever18 (25.7%)4 (5.7%)14 (20%)0
Fatigue7 (10%)07 (10%)0
Arthralgias4 (5.7%)04 (5.7%)0
Gefitinib was generally well-tolerated: five (7%) patients had Grade 3–4 skin toxicity, four (6%) had Grade 3 asthenia/anorexia and five had Grade 3 diarrhea. In four cases, gefitinib was permanently discontinued because of Grade 3–4 toxicity. Only two patients had gefitinib suspension due to causes other than toxicity or imaging documentation of the progression of disease: in one case, the suspension was related to the occurrence of new diseases (acute myocardial infarction and new primary cancer); in the other case, interruption was requested by the patient.
About IL-2 toxicity, most patients experienced erythema and induration at the IL-2 injection site and constitutional symptoms, such as fever, chills, fatigue and malaise; these symptoms were present only during the days of IL-2 administration and completely regressed during the days of suspension and at the end of the IL-2 cycles. Main Grade 2–3 toxicity in the GIL-2 group was represented by fever in 46%, fatigue in 23% and arthralgias in 13% of patients, besides the gefitinib-related toxicity. Incidence and grade of IL-2 toxicity were independent from the association with gefitinib or not (in cases of temporary discontinuation of gefitinib); moreover, in the same patient, they tended to decrease with the succession of the cycles. Permanent discontinuation of treatment due to toxicity occurred in three cases in the G group and in only one patient of the GIL-2 group.

4. Discussion and Conclusions

In the current phase II pilot trial, a new molecular therapy with consolidated activity in advanced NSCLC, such as gefitinib, has been associated with an immunotherapy treatment, IL-2, currently considered obsolete when used as single agent in this setting. IL-2 has in fact been studied in the past with poor results in patients with solid tumors other than melanoma and renal cell carcinoma, lacking randomized trials in NSCLC and making difficult the possibility of drawing reliable conclusions on the issue [27]. Its activity in lung cancer has nevertheless been suggested by encouraging evidence in neoadjuvant and adjuvant settings [28], despite conflicting results from various studies, which hinder a definitive pronouncement on the use of IL-2 in advanced disease [7,8,9,10,29,30,31,32,33,34,35,36]. The possibility to reintroduce IL-2 in NSCLC treatment in order to potentiate the effectiveness of a TKI constitutes a novel strategy that can be supported by the recent interesting findings in the field of immunomodulation, both related to lung cancer and operated by gefitinib [11,22,23,24], as previously described in our Introduction, providing a rationale for this association.
The outcomes of the present trial in terms of RR are noteworthy: with the limit of the restricted number of patients, the RR in the GIL-2 group is threefold compared to that of gefitinib alone (16% versus 5%); moreover, only with IL-2 there were also CR among disease responses. Despite this amazing result, the disease control rate was similar in the two groups of treatment; also, in terms of TTP, no significant differences have been reached, suggesting that the more efficient tumor shrinkage obtained does not result in an increase of the disease control duration.
The independent predictive value for survival of gefitinib-related skin toxicity endorses also in this study the evidence that has already emerged from the recent literature, which confirmed skin rash as a predictive and prognostic factor in NSCLC patients treated with anti-EGFR TKI [37,38].
The safety profile of gefitinib was shown not to be affected by the association with IL-2; in fact, the overall rates of toxicity of any grade in terms of skin rash, diarrhea, asthenia and anorexia do not exceed those reported in the pivotal trials [1,2], even better evidencing a good tolerability with a low incidence of Grade 3–4 adverse events. On the other hand, the toxicity profile of IL-2 with the schedule used in our study demonstrated this to be easily manageable and often overcome in the course of successive cycles of therapy, allowing the combination therapy without significantly affecting the overall tolerability of treatment.
The secondary endpoint, represented by OS, with the limit of a non-randomized trial, is greatly achieved, reaching statistical significance and obtaining an almost tripled survival with the association of IL-2 to gefitinib with respect to the controls with gefitinib alone (20 versus 7 months), whose OS is aligned with those reported for gefitinib in phase III randomized trials in pretreated, unselected patients [2,3,4]. Nevertheless, due to imbalances in patients’ characteristics between the two groups and the small sample size of the study, the interpretation of survival curves is limited. Our undoubted limit of a non-selected population based on EGFR status is due to the fact that the role of this molecular predictive marker was not already demonstrated at the opening of this study. The potential benefit of administering IL-2 plus gefitinib in an unselected population loses real significance when most ongoing studies in lung cancer are currently investigating targeted agents in molecularly-selected patient populations. Our outcome results may be surely improved in populations harboring EGFR mutations, whilst the mutational status of our patients, treated with gefitinib at the time of the expanded access program, was unknown, but more robust data from larger, randomized studies are needed. Over and above the fault of an outdated study, other great limits of our trial are represented by the small sample size and the lack of randomization, with potential selection bias and imbalance of clinical characteristics and prognostic factors, which could have affected the outcome in the two groups: on the one hand, the incidence of EGFR-mutated tumors may have been favored in the GIL-2 group by a higher rate of female and non-smoker patients; on the other hand, a great number of patients with poor PS was reported for the G group. In addition, higher rates of further therapies after the study treatment in the GIL-2 group might also have influenced the survival results.
In conclusion, the results of this phase II pilot study suggest that the addition of IL-2 may improve the objective RR of gefitinib monotherapy in advanced NSCLC, with some tolerable adverse events caused by IL-2, thus maintaining a good safety profile of treatment. Further investigations with randomized controlled trials would be needed to definitely verify the efficacy of these drugs associations for NSCLC patients.

Author Contributions

Melissa Bersanelli wrote the article after having collected, elaborated and analyzed all of the data of the clinical trial and the state of the art. Sebastiano Buti, Matteo Brighenti, Silvia Lazzarelli and Rodolfo Passalacqua directly participated in the study planning and execution. All authors contributed to the drafting of the article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Mok, T.S.; Wu, Y.L.; Thongprasert, S.; Yang, C.H.; Chu, D.T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 2009, 361, 947–957. [Google Scholar]
  2. Kim, E.S.; Hirsh, V.; Mok, T.; Socinski, M.A.; Gervais, R.; Wu, Y.L.; Li, L.Y.; Watkins, C.L.; Sellers, M.V.; Lowe, E.S.; Sun, Y.; et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008, 372, 1809–1818. [Google Scholar]
  3. Douillard, J.Y.; Shepherd, F.A.; Hirsh, V.; Mok, T.; Socinski, M.A.; Gervais, R.; Liao, M.L.; Bischoff, H.; Reck, M.; Sellers, M.V.; et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: Data from the randomized phase III INTEREST trial. J. Clin. Oncol. 2010, 28, 744–752. [Google Scholar]
  4. Thatcher, N.; Chang, A.; Parikh, P.; Rodrigues Pereira, J.; Ciuleanu, T.; von Pawel, J.; Thongprasert, S.; Tan, E.H.; Pemberton, K.; Archer, V.; et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa survival evaluation in lung cancer). Lancet 2005, 366, 1527–1537. [Google Scholar]
  5. Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 2010, 11, 121–128. [Google Scholar]
  6. Maemondo, M.; Inoue, A.; Kobayashi, K.; Sugawara, S.; Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.; Kinoshita, I.; et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 2010, 362, 2380–2388. [Google Scholar]
  7. Ardizzoni, A.; Bonavia, M.; Viale, M.; Baldini, E.; Mereu, C.; Verna, A.; Ferrini, S.; Cinquegrana, A.; Molinari, S.; Mariani, G.L. Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer. Cancer 1994, 73, 1353–1360. [Google Scholar]
  8. Schiller, J.H.; Morgan-Ihrig, C.; Levitt, M.L. Concomitant administration of interleukin-2 plus tumor necrosis factor in advanced non-small cell lung cancer. Am. J. Clin. Oncol. 1995, 18, 47–51. [Google Scholar]
  9. Lissoni, P.; Meregalli, S.; Fossati, V.; Paolorossi, F.; Barni, S.; Tancini, G.; Frigerio, F. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs. chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori 1994, 80, 464–467. [Google Scholar]
  10. Tester, W.J.; Kim, K.M.; Krigel, R.L.; Bonomi, P.D.; Glick, J.H.; Asbury, R.F.; Kirkwood, J.M.; Blum, R.H.; Schiller, J.H. A randomized Phase II study of interleukin-2 with and without beta-interferon for patients with advanced non-small cell lung cancer: An Eastern Cooperative Oncology Group study (PZ586). Lung Cancer 1999, 25, 199–206. [Google Scholar]
  11. De Vita, F.; Turitto, G.; di Grazia, M.; Frattolillo, A.; Catalano, G. Analysis of interleukin-2/interleukin-2 receptor system in advanced non-small-cell lung cancer. Tumori 1998, 84, 33–38. [Google Scholar]
  12. Chen, Y.M.; Yang, W.K.; Whang-Peng, J.; Tsai, W.Y.; Hung, Y.M.; Yang, D.M.; Lin, W.C.; Perng, R.P.; Ting, C.C. Restoration of the immunocompetence by IL-2 activation and TCR-CD3 engagement of the in vivo anergized tumor-specific CTL from lung cancer patients. J. Immunother. 1997, 20, 354–364. [Google Scholar]
  13. Brahmer, J.R. Harnessing the immune system for the treatment of non-small-cell lung cancer. J. Clin. Oncol. 2013, 31, 1021–1028. [Google Scholar]
  14. McCarthy, F.; Roshani, R.; Steele, J.; Hagemann, T. Current clinical immunotherapy targets in advanced nonsmall cell lung cancer (NSCLC). J. Leukoc. Biol. 2013, 94, 1201–1206. [Google Scholar]
  15. Reck, M. What future opportunities may immuno-oncology provide for improving the treatment of patients with lung cancer? Ann. Oncol. 2012, 8, 28–34. [Google Scholar]
  16. Shepherd, F.A.; Douillard, J.Y.; Blumenschein, G.R., Jr. Immunotherapy for non-small cell lung cancer: Novel approaches to improve patient outcome. J. Thorac. Oncol. 2011, 6, 1763–1773. [Google Scholar]
  17. Quoix, E. Phase IIB/III of TG4010 immunotherapy in patients with stage IV non-small cell lung cancer (TIME). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01383148?term=NCT01383148&rank=1 (accessed on 18 September 2014).
  18. Iwai, K.; Soejima, K.; Kudoh, S.; Umezato, Y.; Kaneko, T.; Yoshimori, K.; Tokuda, H.; Yamaguchi, T.; Mizoo, A.; Setoguchi, Y.; et al. Extended survival observed in adoptive activated T lymphocyte immunotherapy for advanced lung cancer: Results of a multicenter historical cohort study. Cancer Immunol. Immunother. 2012, 61, 1781–1790. [Google Scholar]
  19. Gupta, P.; Emdad, L.; Lebedeva, I.V.; Sarkar, D.; Dent, P.; Curiel, D.T.; Settleman, J.; Fisher, P.B. Targeted combinatorial therapy of non-small cell lung carcinoma using a GST-fusion protein of full-length or truncated MDA-7/IL-24 with Tarceva. J. Cell Physiol. 2008, 215, 827–836. [Google Scholar]
  20. Emdad, L.; Lebedeva, I.V.; Su, Z.Z.; Gupta, P.; Sarkar, D.; Settleman, J.; Fisher, P.B. Combinatorial treatment of non-small-cell lung cancers with gefitinib and Ad.mda-7 enhances apoptosis-induction and reverses resistance to a single therapy. J. Cell Physiol. 2007, 210, 549–559. [Google Scholar]
  21. Kanazawa, S.; Muramatsu, M.; Kinoshita, Y.; Yamaguchi, K.; Nomura, S. Gefitinib has the potential of activating cell immunity against malignant cells. J. Clin. Oncol. 2005, 23, 3865–3856. [Google Scholar]
  22. Kanazawa, S.; Yamaguchi, K.; Kinoshita, Y.; Komiyama, Y.; Muramatsu, M.; Nomura, S. Elevation of soluble interleukin-2 receptor in patients with non-small cell lung cancer treated with gefitinib. J. Cancer Res. Clin. Oncol. 2006, 132, 719–725. [Google Scholar]
  23. Umekawa, K.; Kimura, T.; Kudoh, S.; Suzumura, T.; Oka, T.; Nagata, M.; Mitsuoka, S.; Matsuura, K.; Nakai, T.; Yoshimura, N.; et al. Plasma RANTES, IL-10, and IL-8 levels in non-small-cell lung cancer patients treated with EGFR-TKIs. BMC Res. Notes 2013, 6, e139. [Google Scholar]
  24. Yamamoto, N.; Honma, M.; Suzuki, H. Off-target serine/threonine kinase 10 inhibition by erlotinib enhances lymphocytic activity leading to severe skin disorders. Mol. Pharmacol. 2011, 80, 466–475. [Google Scholar]
  25. Therasse, P.; Arbuck, S.G.; Eisenhauer, E.A.; Wanders, J.; Kaplan, R.S.; Rubinstein, L.; Verweij, J.; van Glabbeke, M.; van Oosterom, A.T.; Christian, M.C.; et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. Cancer Inst. 2000, 92, 205–216. [Google Scholar]
  26. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available online: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (accessed on 24 June 2014).
  27. Grande, C.; Firvida, J.L.; Navas, V.; Casal, J. Interleukin-2 for the treatment of solid tumors other than melanoma and renal cell carcinoma. Anticancer Drugs 2006, 17, 1–12. [Google Scholar]
  28. Masotti, A.; Morandini, G.; Ortolani, R.; Fumagalli, L. Phase-II randomized study of pre-operative IL-2 administration in operable NSCLC. Lung Cancer 1998, 20, 191–202. [Google Scholar]
  29. Recchia, F.; Saggio, G.; Nuzzo, A.; Biondi, E.; Di Blasio, A.; Cesta, A.; Candeloro, G.; Alesse, E.; Rea, S. Multicenter phase 2 study of interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced non-small-cell lung cancer. J. Immunother. 2006, 29, 87–94. [Google Scholar]
  30. Mantovani, G.; Madeddu, C.; Gramignano, G.; Lusso, M.R.; Mocci, M.; Massa, E.; Ferreli, L.; Astara, G.; Macciò, A.; Serpe, R. Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: Phase II study evaluating clinical, quality of life, and laboratory parameters. J. Exp. Ther. Oncol. 2003, 3, 205–219. [Google Scholar]
  31. Yang, S.C.; Owen-Schaub, L.; Grimm, E.A.; Roth, J.A. Induction of lymphokine-activated killer cytotoxicity with interleukin-2 and tumor necrosis factor-alpha against primary lung cancer targets. Cancer Immunol. Immunother. 1989, 29, 193–198. [Google Scholar]
  32. Yang, S.C.; Grimm, E.A.; Parkinson, D.R.; Carinhas, J.; Fry, K.D.; Mendiguren-Rodriguez, A.; Licciardello, J.; Owen-Schaub, L.B.; Hong, W.K.; Roth, J.A. Clinical and immunomodulatory effects of combination immunotherapy with low-dose interleukin 2 and tumor necrosis factor alpha in patients with advanced non-small cell lung cancer: A phase I trial. Cancer Res. 1991, 51, 3669–3676. [Google Scholar]
  33. Valone, F.H.; Gandara, D.R.; Deisseroth, A.B.; Perez, E.A.; Rayner, A.; Aronson, F.R.; Luce, J.; Paradise, C. Interleukin-2, cisplatin, and 5-fluorouracil for patients with non-small cell lung and head/neck carcinomas. J. Immunother. 1991, 10, 207–213. [Google Scholar]
  34. Jansen, R.L.; Slingerland, R.; Goey, S.H.; Franks, C.R.; Bolhuis, R.L.; Stoter, G. Interleukin-2 and interferon-alpha in the treatment of patients with advanced non-small-cell lung cancer. J. Immunother. 1992, 12, 70–73. [Google Scholar]
  35. Lissoni, P.; Tisi, E.; Barni, S.; Ardizzoia, A.; Rovelli, F.; Rescaldani, R.; Ballabio, D.; Benenti, C.; Angeli, M.; Tancini, G. Biological and clinical results of a neuroimmunotherapy with interleukin-2 and the pineal hormone melatonin as a first line treatment in advanced non-small cell lung cancer. Br. J. Cancer 1992, 66, 155–158. [Google Scholar]
  36. Mantovani, G.; Macciò, A.; Mulas, C.; Massa, E.; Madeddu, C.; Mura, L.; Contu, P.; Versace, R. Dose-intense phase II study of weekly cisplatin and epidoxorubicin plus medroxyprogesterone acetate and recombinant interleukin 2 in stage IIIB-IV non-small cell lung cancer. Oncol. Rep. 2002, 9, 661–670. [Google Scholar]
  37. Petrelli, F.; Borgonovo, K.; Cabiddu, M.; Lonati, V.; Barni, S. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: A literature-based meta-analysis of 24 trials. Lung Cancer 2012, 78, 8–15. [Google Scholar]
  38. Liu, H.B.; Wu, Y.; Lv, T.F.; Yao, Y.W.; Xiao, Y.Y.; Yuan, D.M.; Song, Y. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: A systematic review and meta-analysis. PLoS One 2013, 8, e55128. [Google Scholar]

Share and Cite

MDPI and ACS Style

Bersanelli, M.; Buti, S.; Camisa, R.; Brighenti, M.; Lazzarelli, S.; Mazza, G.; Passalacqua, R. Gefitinib Plus Interleukin-2 in Advanced Non-Small Cell Lung Cancer Patients Previously Treated with Chemotherapy. Cancers 2014, 6, 2035-2048. https://doi.org/10.3390/cancers6042035

AMA Style

Bersanelli M, Buti S, Camisa R, Brighenti M, Lazzarelli S, Mazza G, Passalacqua R. Gefitinib Plus Interleukin-2 in Advanced Non-Small Cell Lung Cancer Patients Previously Treated with Chemotherapy. Cancers. 2014; 6(4):2035-2048. https://doi.org/10.3390/cancers6042035

Chicago/Turabian Style

Bersanelli, Melissa, Sebastiano Buti, Roberta Camisa, Matteo Brighenti, Silvia Lazzarelli, Giancarlo Mazza, and Rodolfo Passalacqua. 2014. "Gefitinib Plus Interleukin-2 in Advanced Non-Small Cell Lung Cancer Patients Previously Treated with Chemotherapy" Cancers 6, no. 4: 2035-2048. https://doi.org/10.3390/cancers6042035

APA Style

Bersanelli, M., Buti, S., Camisa, R., Brighenti, M., Lazzarelli, S., Mazza, G., & Passalacqua, R. (2014). Gefitinib Plus Interleukin-2 in Advanced Non-Small Cell Lung Cancer Patients Previously Treated with Chemotherapy. Cancers, 6(4), 2035-2048. https://doi.org/10.3390/cancers6042035

Article Metrics

Back to TopTop