Trastuzumab in the treatment of advanced non-small-cell lung cancer

Is there a role? Focus on Eastern Cooperative Oncology Group Study 2598

Corey J. Langer, Patricia Stephenson, Ann Thor, Mark Vangel, David H. Johnson

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1180-1187
Number of pages8
JournalJournal of Clinical Oncology
Volume22
Issue number7
DOIs
StatePublished - 2004

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Non-Small Cell Lung Carcinoma
Paclitaxel
Carboplatin
Therapeutics
Stroke Volume
Trastuzumab
Survival
Arthralgia
Peripheral Nervous System Diseases
Neutropenia
Nausea
Disease-Free Survival
Area Under Curve
Fatigue
Survival Rate
Bone Marrow
Maintenance
Kidney
Cell Line
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Trastuzumab in the treatment of advanced non-small-cell lung cancer : Is there a role? Focus on Eastern Cooperative Oncology Group Study 2598. / Langer, Corey J.; Stephenson, Patricia; Thor, Ann; Vangel, Mark; Johnson, David H.

In: Journal of Clinical Oncology, Vol. 22, No. 7, 2004, p. 1180-1187.

Research output: Contribution to journalArticle

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title = "Trastuzumab in the treatment of advanced non-small-cell lung cancer: Is there a role? Focus on Eastern Cooperative Oncology Group Study 2598",
abstract = "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.",
author = "Langer, {Corey J.} and Patricia Stephenson and Ann Thor and Mark Vangel and Johnson, {David H.}",
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AU - Stephenson, Patricia

AU - Thor, Ann

AU - Vangel, Mark

AU - Johnson, David H.

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AB - 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.

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