1 Krankenhaus Grosshansdorf, Grosshansdorf, Germany; 2 Cross Cancer Institute, Edmonton, Canada; 3 The Netherlands Cancer Institute, Amsterdam, The Netherlands; 4 Princess Margaret Hospital, Toronto, Canada; 5 Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; 6 Roche Products Ltd, Welwyn Garden City, UK; 7 McGill University, Montreal, Canada
Received 29 May 2003; revised 4 September 2003; accepted 30 September 2003
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ABSTRACT |
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Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabinecisplatin) in patients with HER2-positive NSCLC.
Patients and methods:
Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine 1250 mg/m2 (days 1 and 8) and cisplatin 75 mg/m2 (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression.
Results:
Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabinecisplatin and 50 with gemcitabinecisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabinecisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabinecisplatin were comparable to those of trastuzumab alone.
Conclusions:
Trastuzumab plus gemcitabinecisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabinecisplatin on trastuzumab pharmacokinetics was observed.
Key words: cisplatin, gemcitabine, HER2, non-small-cell lung cancer, trastuzumab
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Introduction |
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Trastuzumab (Herceptin®) is a humanized monoclonal antibody rationally developed to target HER2-overexpressing cells. Trastuzumab has additive or synergic antitumor activity in combination with various cytotoxic agents in preclinical models of breast cancer and NSCLC [46]. In the study by Bunn et al. [5], the synergy of trastuzumab with cisplatin or gemcitabine was greater in HER2-positive NSCLC cell lines than it was in breast cancer cell lines. In breast cancer, preclinical observations such as these have been used to identify regimens for clinical study. Such clinical studies have shown that the use of trastuzumab in combination with chemotherapy provides significant clinical benefits, including a significant increase in survival, in patients with HER2-positive metastatic breast cancer [7]. The feasibility of combining trastuzumab with platinum analogs and gemcitabine has also been demonstrated in patients with HER2-positive breast cancer [8, 9]. Several studies have shown that women with metastatic breast cancer that is HER2 3+ by immunohistochemistry (IHC) or shows HER2 gene amplification by fluorescence in situ hybridization (FISH) obtain the greatest benefit [7, 10, 11].
HER2 overexpression has been reported in up to 59% of NSCLCs, and the 2+/3+ overexpression rate is 520% (up to 30% in adenocarcinomas) [1217]. Such HER2 overexpression is an indicator of poor prognosis [18, 19] and has been shown to contribute to tumorigenesis in lung tumor cell lines [5, 20]. Trastuzumab causes cytotoxicity in HER2-positive NSCLC cell lines [5, 20]. These observations create a rationale for targeting HER2 in patients with HER2-positive NSCLC. However, HER2 overexpression in NSCLC differs from that in breast cancer. In NSCLC, the majority of tumors are IHC 2+ and FISH positivity is uncommon [16, 17]. When this trial was designed, it was not known whether the efficacy of trastuzumab in NSCLC would be limited to the relatively small subgroup of patients with IHC 3+/FISH-positive disease, or whether patients with lower-level overexpression would also benefit. Therefore, HER2 positivity was defined as IHC 2+/3+ overexpression or HER2 amplification or elevated circulating serum HER2 extracellular domain (ECD) in patients with no tissue available.
Gemcitabinecisplatin combination therapy is commonly used in Europe and has efficacy superior to that of cisplatin monotherapy and other combinations [21, 22]. The known efficacy of trastuzumab in HER2-positive breast cancer and of the gemcitabinecisplatin combination in NSCLC, the preclinical synergy between trastuzumab and gemcitabine and cisplatin [5], and the differing toxicity of trastuzumab and gemcitabinecisplatin provide a clear rationale for investigating trastuzumab in combination with gemcitabinecisplatin in HER2-positive NSCLC.
This randomized, open-label, phase II study was designed to assess the efficacy and safety of trastuzumab with gemcitabinecisplatin compared with gemcitabinecisplatin alone in patients with HER2-positive NSCLC. The study also aimed to collect information on the pharmacokinetics of trastuzumab in the presence of gemcitabinecisplatin.
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Patients and methods |
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Patients
Patients had to fulfill the following criteria: age 18 years with histologically or cytologically proven stage IIIB or IV NSCLC; Eastern Cooperative Oncology Group (ECOG) performance status 02; at least one bidimensionally measurable lesion; ability to comply with the protocol; and recovered from any surgical procedure(s) as judged by the investigator. Only patients who were suitable candidates for chemotherapy alone were recruited. Exclusion criteria included dyspnea at rest or requirement for supportive oxygen therapy; CNS metastases (trastuzumab is known not to penetrate the bloodbrain barrier) or invasive malignancies other than NSCLC; pregnancy; any investigational drug within 30 days before treatment start; prior chemotherapy or anti-HER2 therapy; radiotherapy within 3 weeks of study start; or prior radiotherapy to indicator lesions unless objective recurrence or progression of these lesions was documented. Patients with New York Heart Association (NYHA) class III/IV congestive heart failure (CHF), known left ventricular ejection fraction (LVEF) <40% by multigated radionucleotide angiography (MUGA) or echocardiography (Echo), or myocardial infarction within 6 months of treatment were also excluded, as were patients with abnormal baseline laboratory values: hemoglobin <10 g/dl; neutrophils <1.5 x 109/l; platelets <100 x 109/l; serum total bilirubin >1.5x the upper limit of normal (ULN); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5x ULN; alkaline phosphatase >2.5x ULN; and creatinine clearance <60 ml/min. The study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committees of the participating institutions. Written, informed consent was obtained from all patients.
Patients fulfilling these general inclusion/exclusion criteria underwent HER2 testing as described below. Those with HER2-positive disease who were subsequently shown to have an LVEF >40% by MUGA or Echo were enrolled.
HER2 testing
HER2 status was assessed by IHC using the HercepTestTM kit (DAKO, Glostrup, Denmark), FISH or enzyme-linked immunosorbent assay (ELISA) to measure shed ECD concentration. Tumor specimens were paraffin-embedded and fixed in neutral buffered formalin. Tissue blocks were sectioned at 45 µm. HER2 overexpression/amplification was defined as a score of 2+ (complete, moderate membrane staining of >10% of tumor cells) or 3+ (complete, intense membrane staining of at least 80% of tumor cells) by IHC or gene amplification (HER2/chromosome 17 ratio 2) by FISH (PathVysion HER-2 DNA Probe Kit; Vysis, Stuttgart, Germany). Serum HER2 ECD concentrations were measured only for patients with no tissue available for HER2 testing, and concentrations >15 ng/ml by ELISA were judged to be positive.
HER2 status was determined both locally and at a central testing laboratory. A HER2-positive status determined locally was sufficient for trial enrollment, regardless of central test results. Patients with HER2-negative disease based on local testing could be enrolled if HER2 positive on central testing.
Study treatment
All patients received gemcitabine 1250 mg/m2 intravenously (i.v.) over 30 min on days 1 and 8 of a 21-day cycle in combination with cisplatin 75 mg/m2 i.v. over 1 h on day 1 with mannitol diuresis. Chemotherapy was scheduled for up to six cycles. Participating institutions used their standard administration regimen, including choice of anti-emetic agent and hydration. In the experimental arm, trastuzumab was administered before chemotherapy as a 4 mg/kg initial dose i.v. over 90 min on day 1, followed by 2 mg/kg i.v. over 30 min weekly until disease progression. Trastuzumab was administered alone following completion of chemotherapy.
Gemcitabine and cisplatin doses were modified in response to non-hematological toxicities according to a predefined scheme. National Cancer Institute Common Toxicity Criteria (NCI CTC) grade 3 increases in bilirubin levels led to a 50% reduction in gemcitabine dose and grade 4 increases to gemcitabine being withheld. Creatinine clearance of 3059% led to a 50% reduction in both gemcitabine and cisplatin dose, whereas clearance of <30% led to both drugs being withheld until recovery. For all other toxicities, gemcitabine and cisplatin dose was reduced by 50% for NCI CTC grade 2 toxicity and withheld for grade 3 or 4 toxicity. At the first occurrence of a grade 3 or 4 non-hematological toxicity, trastuzumab treatment was interrupted and resumed at the same dose after resolution to grade 2 or better. For hematological toxicities, chemotherapy dose modification was based on values from the end of each 21-day cycle. In patients with an absolute neutrophil count (ANC) <1.5 x 109/l or platelet count <100 x 109/l, treatment was delayed for 1 week or until ANC and platelets had returned to values 1.5 x 109/l and
100 x 109/l, respectively. If the preceding cycle was accompanied by febrile neutropenia, thrombocytopenia with bleeding, or platelets <25 x 109/l, doses were reduced to 80% of the preceding dose and not increased thereafter. Trastuzumab was continued in the event of chemotherapy dose adjustment.
Evaluation of response and toxicity
Tumors were assessed according to World Health Organization (WHO) criteria at baseline, every 6 weeks thereafter, and within 2 weeks of study completion.
Adverse events were graded using the NCI CTC, version 2.0. Serious adverse events were defined as any event that was fatal, life-threatening, required hospitalization or prolongation of existing hospitalization, or resulted in a persistent or significant disability/incapacity.
Evaluation of cardiac function
Cardiac function was monitored by Echo or MUGA scans at baseline, after cycles 4, 8 and 16, and every eight cycles thereafter. Patients experiencing a decrease in LVEF of 15%, or an absolute value of <30% during the study, were withdrawn.
Pharmacokinetic assessments
In patients in the trastuzumab arm, pre-dose and end of infusion samples (5 ml) were taken to measure serum trastuzumab at baseline and in cycles 16, 8 and 14. In addition, pre- and post-dose blood samples were taken on day 8 of the specified cycles. In a separate subprotocol, pharmacokinetic samples were taken more frequently from 10 selected patients in each of three centers. Serial blood samples were collected on day 1 of cycles 1 and 4. These samples were collected pre-dose, immediately after the end of infusion, and at 4, 8, 12, 24, 48, 96 and 168 h thereafter. Additional pre- and post-dose samples were collected on days 1, 8 and 15 of cycles 13. Serum samples were prepared and analyzed using a validated ELISA assay (Genentech, San Francisco, CA, USA) (data on file).
Assessment of ECD
Serum HER2 ECD concentration was measured at baseline and on day 8 of cycles 1, 4, 8 and 14. Blood samples were taken and serum samples prepared and analyzed using a validated ELISA assay (data on file).
Statistical analysis
Sample size was calculated to ensure that the lower one-sided confidence limit would be 0.7% (i.e. above 0%, indicating a difference) if response rates of 10% and 24% were obtained for the control and trastuzumab arms, respectively. Assumptions about response rates were based on observations that patients with HER2-positive breast cancer have lower response rates than the overall population of patients with breast cancer. Thus, although response rates to gemcitabine plus cisplatin are generally in the range 2040% for unselected patients with NSCLC [21, 22], the response rate in patients with HER2-positive disease was assumed to be lower. The magnitude of benefit for the addition of trastuzumab was expected to be large, as seen in the pivotal randomized study of chemotherapy with or without trastuzumab in patients with HER2-positive breast cancer [7]. The planned sample size should provide a good indication of whether trastuzumab provides a similar level of benefit.
Final analysis was performed when all patients had completed at least 1 year of treatment or had withdrawn. For analysis of efficacy, the best response rate was reported with 95% PearsonClopper confidence intervals (CIs). Two separate analysis sets were used: safety analysis set comprising all patients who were randomized and received at least one dose of study medication (groups defined by actual medication received); and the full analysis set (intention-to-treat population) comprising all randomized patients. The primary focus was on descriptive statistics such as rates and two-sided 95% CIs. Significance level or type I error probability was set to 5%.
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Results |
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Safety
Treatment was well tolerated in both arms and toxicity profiles were similar (Figure 3). Gastrointestinal toxicities were the most frequent adverse events, with nausea and vomiting most common in both treatment groups. However, there was a higher incidence of fatigue in the trastuzumab arm than in the gemcitabinecisplatin arm. Hematological toxicities were well balanced between the two treatment groups, with grade 3/4 neutropenia (58% of patients in the gemcitabinecisplatin arm versus 57% in the trastuzumab arm), thrombocytopenia (34% versus 35%) and leukopenia (36% versus 33%) being the most common events. Grade 3/4 anemia was observed in 12% and 16% of patients, respectively. These results indicate that the major cause of toxicity was the chemotherapy regimen.
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Discussion |
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The majority of patients (>90%) in this study had HER2 2+ NSCLC as determined by IHC. In this population, the addition of trastuzumab to gemcitabinecisplatin did not appear to provide any benefit, and the response rate to gemcitabinecisplatin therapy was within the expected range based on data from prior trials in patient populations unselected for HER2 status [21, 22]. However, there is increasing evidence to demonstrate that those patients with breast cancer with very strong HER2 overexpression (IHC 3+) or HER2 gene amplification (FISH positive) respond best to trastuzumab [10, 24]. In this study, few patients had HER2 3+/FISH-positive disease, although those treated with trastuzumab had a relatively high response rate (five of six patients responded) and PFS (8.5 versus 6.1 months in the group of patients with IHC 2+ NSCLC) compared with other patients in the trial. However, this can only be considered to be an interesting observation. Further evaluation in a larger patient population would be desirable, but <2% of the patients screened for this trial had IHC 3+ or FISH-positive disease, and ongoing trials have either not reported the proportions of 2+ and 3+ patients or have similarly small numbers [2527]. Tran et al. [26], using the regimen and doses described here, reported a response rate of 42% and disease stabilization in a further 42% in HER2-positive patients (IHC 1+ and/or
15 ng/ml serum HER2 ECD). The proportion and outcomes of patients with IHC 3+ NSCLC were not reported. Trastuzumab has also shown promise in combination with paclitaxel and carboplatin, producing a response rate of 18% at 6-month follow up in an ongoing ECOG trial [25]. Although this response rate does not appear to be higher than would be expected with chemotherapy alone, it is interesting that eight of 10 patients (80%) with IHC 3+ disease on study treatment were still alive at 6-month follow-up, compared with 64% of the overall population. The mature results of this trial will help to identify the benefit of combining trastuzumab with chemotherapy for patients with IHC 3+ disease. However, overall the data suggest that any benefit of trastuzumab in NSCLC will be confined to a group of patients (IHC 3+ or FISH positive) likely to constitute <5% of the total population of patients with advanced NSCLC. This will make recruitment to future trials problematic and the likely clinical utility of trastuzumab in NSCLC limited.
Pharmacokinetic analysis of trastuzumab in combination with gemcitabinecisplatin demonstrated that trastuzumab serum concentrations rise steadily from cycle 1, potentially achieving steady state concentration at around cycle 9. Data from beyond cycle 9 are not reliable because of the small number of samples (n = 4). Comparison of concentrations over time in this study with that in the pivotal monotherapy study suggests that co-administration of gemcitabine and cisplatin does not significantly affect exposure to trastuzumab [10].
It is notable that the trastuzumab-containing combination was generally as well tolerated as chemotherapy alone, and that trastuzumab did not appear to exacerbate the toxicity of gemcitabinecisplatin. This supports findings from trials in breast cancer and other tumor types, where trastuzumab has demonstrated favorable tolerability both as monotherapy and in combination with chemotherapy [7, 10, 28, 29]. The absence of tumor-specific trastuzumab-associated adverse events is encouraging for the development of studies in other indications in which a proportion of tumors are strongly HER2 positive.
The most clinically significant adverse event that is known to be associated with trastuzumab therapy is cardiac toxicity. This was initially observed in a retrospective analysis [30] and has since been observed in other trials, but at a lower rate [31, 32]. Data from trials in breast cancer suggest that trastuzumab-related cardiac toxicity occurs primarily when the drug is used in combination with anthracyclines and tends to be both manageable and reversible [33]. In this trial in patients with NSCLC, only patients in the trastuzumab arm experienced large decreases in LVEF (>15%), decreases to an absolute LVEF value of <40% or CHF. However, symptomatic CHF occurred in only two or possibly three patients, and there were other significant factors contributing to these patients symptoms (previous pneumonectomy; previous myocardial infarction, cardiac dysrhythmias and pericardial effusion; progressive lung cancer and new onset atrial fibrillation). No correlation was observed between serum trastuzumab concentrations and cardiotoxicity.
These cardiac toxicity data are important for several reasons. First, this population was not previously or concurrently exposed to anthracyclines, which are known to cause cardiotoxicity and to increase the likelihood of trastuzumab-associated cardiotoxicity [30, 34]. Because neither cisplatin nor gemcitabine is particularly associated with cardiotoxicity, these data provide an indication of the cardiac effects of the addition of trastuzumab to relatively non-cardiotoxic drugs in patients not exposed to anthracyclines. However, it should be noted that although not anthracycline exposed, the population is likely to be at increased risk for cardiotoxicity due to the high percentage of smokers enrolled. This may explain some of the decrease in cardiac function observed in the control arm. Furthermore, the inclusion criteria allowed patients with an LVEF of only 40% at baseline to be enrolled. In most trials of trastuzumab to date, an LVEF of at least 50% has been stipulated. Current recommendations state that a careful riskbenefit assessment needs to be made in patients with a baseline LVEF of <50%, because such patients are at increased risk of cardiac events [33]. Finally, this is one of the few trastuzumab studies to include men, and it appears that the effects on cardiac function are similar in men and women. Thus, although trastuzumab appears to have a negative effect on cardiac function in a population that is at increased risk due to the incidence of smoking and the inclusion of patients with LVEF <50%, even in the absence of anthracycline exposure, the effects are limited to relatively few patients, do not tend to be symptomatic, and are reversible with appropriate management.
In conclusion, HER2 overexpression was seen in 17% of NSCLCs screened, although only <2% of the population screened showed IHC 3+ and/or HER2 amplification (as measured by FISH). The overall population did not appear to obtain any benefit from the addition of trastuzumab to gemcitabinecisplatin, and the small numbers of patients with strongly HER2-positive disease makes it difficult to assess whether it might improve efficacy in these patients. ECD levels do not appear to predict therapeutic response, although a pooled analysis of several studies is needed to provide more conclusive data. The addition of trastuzumab to gemcitabinecisplatin was well tolerated and the safety profile of the combination was as expected. Interestingly, cardiotoxicity, the most clinically significant adverse event associated with trastuzumab therapy, occurred infrequently (6%). Ongoing studies with other chemotherapeutic agents may further define the role of trastuzumab in NSCLC, but future trials should focus on patients with high HER2 overexpression or gene amplification.
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FOOTNOTES |
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