Originally published as JCO Early Release 10.1200/JCO.2004.04.105 on February 23 2004

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Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer: Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598

From the Fox Chase Cancer Center, Philadelphia, PA; Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; Oklahoma University Health Science Center, Oklahoma City, OK; and Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN

Address reprint requests to Corey J. Langer, MD, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; e-mail: CJ_Langer{at}fccc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Multiple non–small-cell lung cancer (NSCLC) cell lines and 20% to 50% of pathologic specimens express HER-2/neu, the target of trastuzumab, and HER-2/neu expression has proven to be an independent, unfavorable prognostic factor in resected patients with NSCLC. Trastuzumab, in vitro, has demonstrated growth-inhibiting synergy with platinating agents, and additivity with paclitaxel. The Eastern Cooperative Oncology Group therefore launched a phase II study evaluating combination carboplatin, paclitaxel, and trastuzumab in patients with advanced NSCLC.

MATERIALS AND METHODS: Eligibility stipulated the following: measurable tumor, HER-2/neu positivity (1+ to 3+ by Herceptest [Dako Corp, Carpinteria, CA], confirmed by central review), Eastern Cooperative Oncology Group PS 0 to 1, adequate marrow, hepatic and renal function, and left ventricular ejection fraction 45%. Patients received paclitaxel 225 mg/m²/3 hours, and carboplatin (area under the curve, 6) every 3 weeks, and trastuzumab 4 mg/kg intravenously on day 1, then 2 mg/kg weekly for 1 year.

RESULTS: Between August 1999 and May 2000, 139 patients were screened; seven specimens (5%) were indeterminate. Fifty patients (36%) were HER-2/neu negative, 38 (27%) were HER-2/neu 1+, 31 (22%) were 2+, and 13 (9%) were 3+. Fifty-six patients were enrolled; 53 were eligible (22 [42%] were 1+, 23 (43%) were 2+, and eight (15%) were 3+). Thirteen (24.5%) of 52 assessable patients (95% CI, 13.8 to 38.3) responded. The incidence of grade 3 neutropenia and thrombocytopenia was 57% (34%) and 16% (2%), respectively. Asymptomatic grade 2 reduction in left ventricular ejection fraction occurred in 7%. Other nonhematologic toxicities, including nausea, fatigue, arthralgias, and peripheral sensory neuropathy, were mild to moderate and matched those expected with carboplatin and paclitaxel alone. Eighteen patients (35%) received maintenance trastuzumab. Median progression-free survival was 3.3 months; median survival was 10.1 months, and 1-year survival rate was 42%.

CONCLUSION: Combination paclitaxel, carboplatin, and trastuzumab is feasible. Toxicity appears no worse than cytotoxic therapy alone. Overall survival is similar to historical data using carboplatin and paclitaxel alone. However, patients with 3+ HER-2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of NSCLC. Critical assessment of trastuzumab's role in advanced NSCLC will require phase III trials.

	INTRODUCTION

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Lung cancer is a devastating illness. Over the past 30 to 40 years, the 5-year survival rate has risen from 8% to 10% to roughly 14%.¹ With supportive care alone, the 1-year survival rate is 15% to 20%, and the 2-year survival rate is 6% in advanced stage, metastatic, or recurrent disease.² With conventional systemic therapy, the 1-year survival rate has improved to 30% to 35%, and 2-year survival rate has increased to 10% to 15%; however, 5-year survival remains a rarity.^2-5 In multiple studies, paclitaxel and carboplatin in combination has demonstrated de facto equivalence to more toxic, cisplatin-based regimens, and has become a standard of comparison in multiple phase III trials testing new targeted agents.^3-5

The Role of HER-2/neu in Thoracic Malignancy
HER-2/neu expression has been demonstrated in multiple adenocarcinoma and squamous cell carcinoma cell lines.⁶ In addition, in preclinical work, overexpression has been associated with intrinsic multidrug resistance.^7,8 p185 c-erb B2 is an independent, unfavorable prognostic factor in resected pulmonary adenocarcinoma; Kern et al⁹ demonstrated a median survival of 83 weeks for those patients whose tumors expressed c-erb B2 versus 188.5 weeks for resected patients who did not express c-erb-2. Multiple investigators have retrospectively analyzed surgical specimens and have demonstrated HER-2/neu expression rates (1+ to 3+) in the 20% to 50% range; many of these retrospective series documented a negative prognostic effect for HER-2/neu expression.^9-11

Single-chain monoclonal antibodies specific for p185 c-erb-2, coupled with Pseudomonas exotoxin can inhibit non–small-cell lung cancer (NSCLC) cells that overexpress HER-2/neu and in cells that express slightly higher protein levels than normal. This immunoconjugate has also reduced and, in some cases, eliminated HER-2/neu+ tumors in preclinical models, and, in some instances, eliminated tumor burden after orthotopic transplantation.¹² Monoclonal antibodies directed against c-erb B2 have demonstrated synergy with platinum, gemcitabine, and vinorelbine, and additivity with taxanes and vinblastine in human breast and ovarian cell lines.^13-15

Role of Trastuzumab in Breast Cancer
In the treatment of HER-2/neu+ human breast carcinoma, Slamon et al^16,17 and Norton et al¹⁸ have demonstrated superior survival for combination trastuzumab (Herceptin; Genentech Inc, South San Francisco, CA) and either combination cyclophosphamide/doxorubicin (CA), or single agent paclitaxel versus chemotherapy alone. The initial study documented median survival and 1-year survival rate of 22.1 months and 73%, respectively, for combination paclitaxel/trastuzumab versus 18.4 months and 61% for paclitaxel alone. Investigators also demonstrated median survival and 1-year survival rates of 33.4 months and 83%, respectively, for combination CA/trastuzumab versus 24.5 months and 73% respectively for cytotoxic therapy alone (P = .04). However, the combination of cytotoxics and trastuzumab resulted in a significant incidence of cardiac dysfunction. Patients receiving paclitaxel and trastuzumab had an 11% incidence of grade 3 or 4 cardiac dysfunction versus 1% for those receiving paclitaxel alone; those receiving CA/trastuzumab had a 28% incidence, compared to a 7% rate in those receiving CA alone. Nevertheless, this critical study firmly established the role of trastuzumab in HER-2/neu+ breast carcinoma.

Rationale for Investigation in NSCLC
On this basis, we deemed it reasonable to proceed with a feasibility trial to assess the role of combination trastuzuman and paclitaxel/carboplatin in the treatment of NSCLC. Because the primary end point was toxicity, we included patients with 1+ HER-2/neu expression as well as 2+/3+ expression on immunohistochemical staining. In addition, we wanted to determine the frequency of HER-2 positivity in NSCLC, and also ascertain if lung cancer behaved (biologically) like breast cancer.

	MATERIALS AND METHODS

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Objectives
The primary objective of this phase II study was to assess toxicities associated with the combination of paclitaxel, carboplatin, and trastuzumab in patients with advanced NSCLC who were HER-2/neu positive. Secondary objectives included median and 1-year progression-free survival (PFS) and overall survival rates. In addition, we intended to evaluate objective response rate.

Eligibility
Eligibility stipulated advanced non–small-cell lung carcinoma, either recurrent, stage IV, or stage IIIB, on the basis of pleural or pericardial effusion. One or more bidimensionally measurable indicator lesions were necessary. Additional eligibility requirements included: HER-2/neu positivity (1+ to 3+ by immunohistochemistry [IHC] staining using the Herceptest [Dako Corp, Carpinteria, CA]); Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1; age 18 years; and adequate physiologic indices, as defined by absolute neutrophil count 1,500/µL; platelets 100,000/µL; creatinine 2 mg/dL; bilirubin 1.5 mg/dL; and transaminases 5 x upper limit of normal. Exclusion criteria included: active infections; pregnancy; uncontrolled brain metastases; other active, invasive malignancies; prior chemotherapy; evidence of pre-existing grade 2 peripheral sensory neuropathy or uncontrolled arrhythmias; and congestive heart failure or myocardial infarction in the previous three months. In addition, a minimum ejection fraction of 45%, documented by either cardiac ultrasound or multiple-gated acquisition (MUGA) scan, was required.

Blood counts were obtained weekly during cytotoxic therapy. History and physical, height, weight, ECOG performance status, CBC, differential and platelets, and serum chemistry were obtained every cycle (3 weeks). Every 6 weeks, patients underwent MUGA scan or echocardiogram and relevant imaging studies to gauge tumor response. Finally, those patients receiving maintenance trastuzumab were reassessed every 2 months with reimaging of tumor, routine history and physical evaluation, record of height, weight, and ECOG PS and blood testing including CBC, differential, platelets, and serum chemistries (electrolytes, blood urea nitrogen, creatinine, glucose, total bilirubin, alkaline phosphatase, AST/ALT, lactate dehydrogenase, calcium, albumin, creatinine).

Patient Registration
This trial involved both a preregistration and a registration process. In order to preregister, potentially eligible patients were required to provide signed, written informed consent. Pathology materials were then submitted to the ECOG Pathology Coordinating Office (Boston, MA) for HER-2/neu receptor status determination. Patients found to be HER-2/neu positive were registered via the Central Randomization Desk at the ECOG Coordinating Center. Although patients could be screened locally for HER-2/neu status, only patients determined to be HER-2/neu positive (1+ to 3+) on central review were able to register on the study.

Study Schema
The study as designed used full dose trastuzumab (4 mg/kg intravenously [IV] day one [load], then 2 mg/kg IV weekly) and standard doses of paclitaxel (225 mg/m² three hour infusion every 3 weeks) and carboplatin (area under the curve 6 every 3 weeks). Patients were reassessed every two cycles (6 weeks) during treatment (Fig 1). Those with progressive disease were removed from the study. Those with stable disease or response at 6 weeks continued treatment and received up to six full cycles of combination cytotoxic-targeted systemic therapy, at which point, those without progressive disease had the option to continue trastuzumab alone for up to one full year.

View larger version (24K): [in this window] [in a new window]   Fig 1. Eastern Cooperative Oncology Group study 2598 schema for advanced non–small-cell lung cancer. *Option to continue trastuzumab alone up to 1 year in nonprogressors after six full cycles of treatment. IHC, immunohistochemistry; AUC, area under the curve; d, day; wk, week; PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response.

Statistical Design
In this phase II trial, the primary end point was the toxicity rate. Unacceptable toxicity was defined as grade 4 or 5 hematologic toxicity or infection. A two-stage design was used to discriminate between the null hypothesis of 60% rate of unacceptable toxicities (grade 4 plus grade 5) versus the alternative hypothesis of a 80% rate. The design would also discriminate between grade 5 unacceptable toxicity rates of 5% and 20%.

At the initial stage, 22 patients were targeted for enrollment, assuming at least 20 proved eligible. Among the initial 20 eligible patients, if there were 16 cases of unacceptable grade 4 or grade 5 toxicity or 4 cases of attributable grade 5 toxicity, the study would be terminated early and declared unacceptably toxic. If this rate of toxicity was not observed, the second stage of accrual targeted 22 additional enrollees assuming 20 eligible subjects. This would yield a maximum of 44 patients, of which 40 would be eligible. If 28 cases of unacceptable toxicity (grade 4 plus grade 5) and four cases of unacceptable grade 5 toxicity were observed among the 40 eligible patients, then the treatment would be considered worth testing further. Assuming a 30% positivity rate for HER-2/neu, it was anticipated that 147 patients would be preregistered and screened in order to accrue 44 HER-2/neu positive patients. Under the null hypotheses ( 60% rate of grade 4 plus grade 5 and 5% rate of grade 5 unacceptable toxicities), the probability of stopping early was 65% and the probablility of eventually accepting the regimen was 86%. Under the alternative, the probability of accepting the regimen as worthy of further testing was 0.012. A parallel assessment of cardiac dysfunction was also conducted, with provision to suspend accrual if 6 of the first 20 eligible patients experienced grade 3 cardiac toxicity.

Confidence intervals for the toxicity rate were estimated using exact binomial confidence intervals adjusted for the two-stage design. Exact binomial confidence intervals were calculated for the overall objective rate and the proportion of patients alive at 1 year. Survival curves were estimated by the Kaplan-Meier method. All reported P values were associated with two-sided tests.

	RESULTS

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Screening Status
The study opened in May 1999 with the first patient preregistered for screening in June 1999, and the first patient registered for treatment in July 1999. The study underwent scheduled suspension for toxicity analysis in November 1999, and, in the absence of untoward toxicity, reopened in January 2000. Accrual terminated in March 2000.

One hundred and thirty-nine patients were screened. Fifty patients (36%) proved HER-2/neu negative. Eighty-two patients (59%) had some degree of HER-2/neu expression; 1+ in 38 patients (27.3%), 2+ in 31 patients (22.3%), and 3+ in 13 patients (9.3%). We were unable to determine HER-2/neu status on seven patients; three patients had insufficient tissue; three patients had inadequate documentation of pathology; and one patient reversed consent.

Enrollment
Of 82 patients who had some degree of HER-2/neu positivity on screening, 56 patients from 21 separate institutions (40% of those initially screened and 68% of those whose specimens stained 1+ to 3+) were enrolled. We did not prespecify additional collection data on those patients whose tumors proved positive on screening, but did not enroll; however, the reason(s) were available in seven patients—in three, the explanation was declining PS. Table 1 details screening and entrance status and eligibility status. Of the 56 patients ultimately enrolled, 53 proved eligible. One patient received chemotherapy before registration, one failed to undergo mandatory MUGA scan before enrollment, and a third had dry stage IIIB disease with no evidence of pleural or pericardial effusion.

Survival Status
With a median potential follow-up of 34 months, median survival was 10.1 months (95% CI, 6.7 to 14.6). Six patients (11.3%) remain alive. Median PFS was 3.25 months with Kaplan-Meier 1- and 2-year PFS of 6.1% and 2%, respectively. Overall 1-year survival rate was 42% (95% CI 28.1, 55.9), and the Kaplan-Meier estimate for 2-year survival is 14.7%. PFS and overall survival curves are included in Figures 2 and 3. Curves broken down by HER-2/neu status are delineated in Figures 4 and 5. While the number of patients in any subcategory of patients is small, it is notable that individuals with 3+ expression experienced a survival exceeding that of historical controls on ECOG 1594.³

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall survival.

View larger version (14K): [in this window] [in a new window]   Fig 3. Progression-free survival.

View larger version (21K): [in this window] [in a new window]   Fig 4. Overall survival by HER-2/neu positivity. IHC; immunohistochemical Her-2 expression.

View larger version (18K): [in this window] [in a new window]   Fig 5. Progression-free survival by HER-2/neu positivity.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

Ultimately, critical assessment of the role of trastuzumab in the treatment of advanced NSCLC will require formal phase III randomized testing (cytotoxics ± trastuzumab), but it is unclear if sufficient patient resources exist, even through the intergroup mechanism, to mount such a study. If mounted, should such a phase III trial be limited to 3+/fluorescent in situ hybridization (FISH) positive patients? Should it be expanded to 2+ patients? Moreover, to conduct such a trial, it is not clear if we could afford to screen the number of patients we would need. Ultimately, agents that target the coexpression of EGFr and HER-2/neu may be better suited to this task.

We do not know the natural history of HER-2+ advanced NSCLC treated with chemotherapy alone. Retrospective prognostic data in early stage disease would suggest an inferior survival, but this is difficult to verify. Only one investigator has ever attempted to address this issue in advanced NSCLC. Verma et al¹⁹ evaluated 56 patients who received platinum-based chemotherapy alone; of these, seven had HER-2/neu positive tumors. The median time to progression and median survival in the HER-2/neu positive group were 3.8 months and 5.1 months, respectively, compared to 5.1 months and 9.4 months in the HER-2/neu negative group.

In ECOG 2598, central screening demonstrated 2+/3+ HER-2/neu expression in more than 30% of NSCLC patients tested, but it should be noted that many investigators prescreened their patients. Hence, the 30% figure may represent an inflation of the real rate of HER-2/neu positivity in untreated NSCLC. The observation that only 3% of the 2+/3+ patients had squamous cell histology is unsurprising, as Hirsch et al²⁰ documented similar figures. These investigators reported that 38 (16%) of 238 NSCLC patients tested had a positive Herceptest (2+/3+), though only 10 (4%) proved 3+. Herceptest was positive in 35% of those with adenocarcinoma and in 20% of those with large cell carcinoma; but only 1% of those with squamous carcinoma had a positive Herceptest. In addition, Hirsch et al's work showed that gene amplification detected by FISH was much more specific than immunohistochemical staining. In a separate analysis by Hirsch et al,²⁰ of 53 patients with NSCLC who were tested, using both methodologies, 13 proved IHC-positive, but only five were FISH-positive, and all but one had adenocarcinoma (Table 5). Thus, HER-2/neu amplification appears far less common in NSCLC compared with breast cancer. This observation is reinforced by the work of Nakamura et al²¹; true gene amplification was observed in only one (2%) of 50 cases evaluated, whereas overexpression of the protein (2+ or 3+) was seen in 26%, and increase in DNA copy number of HER-2 gene was observed in 44%.⁴ A correlation between IHC and FISH will be performed on the archival specimens of patients enrolled on ECOG 2598, and will be discussed in a separate manuscript.

Other Studies Integrating Trastuzumab and Cytotoxic NSCLC Therapy
Investigators at M.D. Anderson Cancer Center (Houston, TX) conducted a single arm phase II trial of standard dose trastuzumab in combination with cisplatin 75 mg/m² on day 1 and gemcitabine 1,250 mg/m² days 1 and 8, in patients with newly diagnosed HER-2/neu overexpressing metastatic NSCLC.²⁶ Patients receive six 3-week courses of induction chemotherapy plus trastuzumab, followed by maintenance trastuzumab weekly until disease progression. The gemcitabine combination was chosen in large part because of demonstrated growth-inhibiting synergy between gemcitabine and anti-HER-2/neu antibody in preclinical models. Eligibility stipulated evidence of HER-2/neu overexpression by IHC, or enzyme-linked immunosorbent assay (ELISA), and adequate ejection fraction at entry.²⁶ Two hundred seventy-nine patients were screened, of whom 43 (15.4%) registered 2+ or 3+ by IHC. One hundred two patients had both IHC and ELISA. By IHC, 20 (20%) were IHC-positive, of whom seven (33%) had ELISA 15 mg/mL; by ELISA, 17 (17%) had levels 15 mg/mL, of whom only six (36%) of 17 patients were HER-2-positive. Twenty-one patients were enrolled; 19 were assessable. Median age was 60 years (range, 46 to 82 years). There was no decrease of ejection fraction 40%. Toxicities matched those expected for cytotoxics alone. The major response rate was 42%; an additional 42% had stable disease. Pharmacokinetic analysis showed that trastuzumab did not alter the gemcitabine or cisplatin clearances, nor was disposition of trastuzumab altered by the chemotherapeutics. Median survival time had not yet been reached at the time of the presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting in May, 2002 (Orlando, FL).²⁷

Recently, an international, multi-institutional consortium²⁸ conducted a randomized phase II study of cisplatin and gemcitabine ±trastuzumab. Eligibility stipulated HER-2/neu positivity as defined by one of the following: 2+ or 3+ expression by IHC; gene amplification documented by FISH; or measured receptor 15 mg/mL on serum ELISA. Nearly 600 patients were screened at 60 sites. One hundred three patients were enrolled; 101 were assessable. Only three patients in the trastuzumab arm experienced a decrease in left ventricular ejection fraction of more than 15%, one of whom developed congestive heart failure. The response rate and time to progression in the chemotherapy-only group were 41% and 7.2 months, respectively, versus 36% and 6.3 months for patients receiving combination gemcitabine/cisplatin/trastuzumab.²⁹ Of note, the median PFS was 8.7 months for those whose tumors proved FISH positive or who had 3+ expression and received the three drug combination (six patients total).

Krug et al³⁰ mounted a phase II study of weekly paclitaxel 90 mg/m² x 6 every 8 weeks or docetaxel 36 mg/m² IV weekly x 6 every 8 weeks, in combination with trastuzumab. Entry allowed both HER-2-positive and negative status. Pathology specimens from 97 separate patients were analyzed. Six patients (7%) had 3+ expression; 12 (12%) had 2+ expression; 26 (26%) had 1+ expression; and more than half (53%) were HER-2/neu-negative. None of the 2+/3+ patients had squamous cell histology. As of the ASCO 2001 meeting (San Francisco, CA), 48 patients had been randomly assigned to either docetaxel and trastuzumab (n = 23) or paclitaxel and trastuzumab (n = 25). Toxicity was relatively mild. Only two patients experienced any decline in their ejection fraction below the lower limit of normal, thereby prompting discontinuation of trastuzumab. One patient had a history of coronary artery disease, the other atrial fibrillation. There was no clinical congestive heart failure. The overall response rate was 23% in the docetaxel plus trastuzumab group, and 26% in the paclitaxel plus trastuzumab group. HER-2/neu-positive patients had a 25% response rate compared to 24% in the HER-2-negative group. The relative median and 1-year survival rates were 14 months and 51% for the HER-2/neu-positive patients, and 19 months and 62% for the HER-2/neu-negative patients.³¹

Other groups are also evaluating trastuzumab. Kern et al (unpublished data) is evaluating single agent trastuzumab once a week x 26 (Cancer and Leukemia Group B 98-10). In the salvage setting, the University of Colorado is assessing combination gemcitabine/trastuzumab; the Southwest Oncology Group intends to assess combination docetaxel/trastuzumab; and a Chicago consortium will evaluate single agent trastuzumab in this setting. Mature data from these studies are still pending.

Whether trastuzumab ultimately has any role in the treatment of advanced NSCLC remains unclear, particularly as other targeted therapies directed against epidermal growth factor receptor, farnesyl transferase, and neoplastic angiogenesis emerge. These bioactive agents will likely apply to a much larger portion of the NSCLC population than trastuzumab.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Corey J. Langer, ImClone, Bristol Myers Squibb, Aventis, Pharmacia, Intrabiotics, GlaxoSmithKline, TAP Pharmaceutical Products Inc, Amgen, AstraZeneca; Ann Thor, Genentech; David H. Johnson, Genentech. Received more than $2,000 a year from a company for either of the last 2 years: Corey J. Langer, Bristol Myers Squibb, Aventis, Pharmacia, Lilly, OrthoBiotech; David H. Johnson, Genentech.

	Acknowledgment

 
We thank Susan Edgerton for her technical and interpretive contributions to erbB-2 testing.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted April 14, 2003; accepted November 21, 2003.

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