Correspondence
Erlotinib in Lung Cancer
N Engl J Med 2005; 353:1739-1741October 20, 2005
- Article
To the Editor:
Shepherd and colleagues (July 14 issue)1 report that erlotinib prolongs survival in non–small-cell lung cancer, as compared with placebo, after the failure of first-line or second-line chemotherapy. One disturbing aspect of this trial is that some patients underwent only one prior chemotherapy regimen before randomization. These same authors previously reported that docetaxel is superior to best supportive care after first-line chemotherapy.2 Subsequent studies have confirmed the efficacy of docetaxel and shown that pemetrexed achieves similar results.3 Did Shepherd and colleagues think that random assignment to placebo after the failure of first-line chemotherapy was ethically justifiable? The only patients for whom one could justify the assignment to placebo were those with a performance status of 3, who made up only 8.6 percent of all patients. Contrary to the authors' claim that inclusion of a placebo group was ethical, we believe that some patients were denied a therapeutic option known to be effective. Furthermore, the overall survival in the erlotinib group was inferior to that in published results with docetaxel and pemetrexed, suggesting that erlotinib should be used as third-line chemotherapy.
Chadi Nabhan, M.D.
Jacob D. Bitran, M.D.
Lutheran General Cancer Institute, Park Ridge, IL 60068
cnabhan@oncmed.net Dr. Nabhan reports being an investigator in a study that is sponsored by Sanofi-Aventis.
3 References1
Shepherd FA ,Rodrigues Pereira JR ,Ciuleanu T , et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-132
Full Text | Web of Science | Medline2
Shepherd FA ,Dancey J ,Ramlau R , et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-2103
Web of Science | Medline3
Hanna N ,Shepherd FA ,Fossella FV , et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589-1597
CrossRef | Web of Science | Medline
To the Editor:
Shepherd et al. and Tsao et al.1 (July 14 issue) report an important study (BR.21) showing a survival benefit of erlotinib, but the results of the molecular analysis confused us. Recent East Asian studies2-4 have strongly suggested that the mutational status of the epidermal growth factor receptor (EGFR) is the major determinant of tumor response and survival in patients with non–small-cell lung cancer who are treated with gefitinib, another EGFR tyrosine kinase inhibitor. Response rates among patients with an EGFR mutation were consistently higher than 80 percent in those studies. However, in the BR.21 study, the response rate among such patients was only 16 percent, and mutational status had no significant effect on survival, although the EGFR copy number correlated with responsiveness and survival. In our study,2 the EGFR copy number was associated with gefitinib sensitivity, but we consider it to be a surrogate marker for EGFR mutations, rather than a true determinant. These discrepancies may be due to differences in the ethnic background of the populations, the drugs, the study design, and, most important, the accuracy of the molecular analyses. To avoid fruitless controversy, standard methods for analyzing EGFR mutations and copy number should be established.
4 ReferencesToshimi Takano, M.D.
Yuichiro Ohe, M.D.
National Cancer Center Hospital, Tokyo 104-0045, Japan
yohe@ncc.go. jp 1
Tsao M-S ,Sakurada A ,Cutz JC , et al. Erlotinib in lung cancer -- molecular and clinical predictors of outcome. N Engl J Med 2005;353:133-144
Full Text | Web of Science | Medline2
Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol (in press).
3
Mitsudomi T ,Kosaka T ,Endoh H , et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005;23:2513-2520
CrossRef | Web of Science | Medline4
Han S-W ,Kim T-Y ,Hwang PG , et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005;23:2493-2501
CrossRef | Web of Science | Medline
To the Editor:
Tsao and colleagues suggest that EGFR mutations were not valuable in predicting a benefit of erlotinib in the BR.21 trial. We believe that the mutation data in their report are inconclusive, for several reasons.
First, in Europe and North America,1,2 the frequency of mutations is approximately 10 percent; Tsao et al. report mutations in more than 20 percent of the tumors. Second, only 47 percent of the mutations reported were drug-sensitive exon 19 deletions and L858R substitutions; these make up approximately 90 percent of the EGFR mutations in aggregate in the published data.3 Third, the remaining cases showed “novel variant” mutations whose somatic nature was not established and that were not adequately confirmed. Fourth, these novel mutations were predominantly nucleotide transitions (92 percent), suggesting they were artifacts generated in the polymerase chain reaction (PCR).4
Finally, of the 427 patients treated with erlotinib, only 19 who had EGFR mutations could be evaluated. Among these 19 patients, only 8 had tumors with the well-established, drug-sensitive EGFR mutations. At our institution, 33 patients who had tumors containing one of these two common mutations have received erlotinib or gefitinib, and of these, 32 patients (97 percent) have had a response according to the Response Evaluation Criteria in Solid Tumors; the aggregate published response rate for both drugs and mutations is nearly 80 percent.
4 ReferencesWilliam Pao, M.D., Ph.D.
Marc Ladanyi, M.D.
Vincent A. Miller, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
paow@mskcc.org for the Lung Cancer Oncogenome Group
1
Eberhard DA ,Johnson BE ,Amler LC , et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900-5909
CrossRef | Web of Science | Medline2
Pao W ,Miller V ,Zakowski M , et al. EGF receptor gene mutations are common in lung cancers from “never smokers“ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-13311
CrossRef | Web of Science | Medline3
Pao W ,Miller VA . Epidermal growth factor receptor mutations, small molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:2556-2568
CrossRef | Web of Science | Medline4
Wong C ,DiCioccio RA ,Allen HJ ,Werness BA ,Piver MS . Mutations in BRCA1 from fixed, paraffin-embedded tissue can be artifacts of preservation. Cancer Genet Cytogenet 1998;107:21-27
CrossRef | Web of Science | Medline
Author/Editor Response
Patients entering the BR.21 trial after first-line chemotherapy were considered by their doctors not to be suitable candidates for second-line chemotherapy. Physicians had to attest to this, and reasons were recorded and monitored. Thus, these patients could not be compared with patients who participated in the trials cited by Drs. Nabhan and Bitran. We think, therefore, as did ethics review boards and regulatory authorities, that the inclusion of a placebo-control group was ethical, since further chemotherapy was not an option and alternative systemic treatments were unavailable.
It is inappropriate to compare the results of the BR.21, TAX 317,1 and JMEI2trials, since their patient populations differed considerably. One third of the patients in the BR.21 study had a performance status of between 2 and 3 or 3, as compared with 25 percent of those in the TAX 317 trial and 12 percent of those in the JMEI study. Survival shortens with each successive chemotherapy regimen. In JMEI and TAX 317, 100 percent and 75 percent of patients, respectively, had undergone only one regimen, as compared with 50 percent of the patients in the BR.21 trial. These imbalances in prognostic factors alone could result in shorter survival, independent of treatment.
With regard to patients who were not eligible for second-line chemotherapy, we think that EGFR inhibitor therapy is ethical on the basis of the BR.21 trial. Whether it should be considered electively for patients who are otherwise suitable candidates for chemotherapy awaits the results of an ongoing study comparing docetaxel with gefitinib.
2 ReferencesFrances A. Shepherd, M.D.
Princess Margaret Hospital, Toronto, ON M5G 2MP, CanadaLesley Seymour, M.D.
National Cancer Institute of Canada Clinical Trials Group, Kingston, ON K7L 3N6, Canada1
Shepherd FA ,Dancey J ,Ramlau R , et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-2103
Web of Science | Medline2
Hanna N ,Shepherd FA ,Fossella FV , et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589-1597
CrossRef | Web of Science | Medline
Author/Editor Response
Of 177 tumor samples analyzed in the BR.21 trial, 21 samples (from 20 patients) were exon 19 deletions or L858R substitutions. This rate per patient of 11 percent for classic mutations is similar to that in other reports involving non-Asian patients.1,2 The response rate among patients who could be evaluated who had classic mutations was 25 percent (two of eight). Although the rate is lower than that among Asian patients, it probably falls within the confidence interval of other series involving non-Asian patients who did not have adenocarcinoma.
The patients in the BR.21 trial who had classic mutations did not derive a greater survival benefit from erlotinib (hazard ratio for death, 0.67) than those with novel mutations (hazard ratio, 0.65) or those with wild-type EGFR (hazard ratio, 0.73). In the Tarceva Responses in Conjunction with Taxol and Carboplatin (TRIBUTE) trial,3 29 of 274 (11 percent) of the samples contained mutations (86 percent were classic mutations). Patients who had mutations had longer progression-free survival (P<0.001) and overall survival (P<0.001) than those who did not have mutations, regardless of the type of treatment (chemotherapy with or without erlotinib); the benefit of erlotinib was statistically nonsignificant. Among patients in the placebo group, those with classic mutations had a longer median survival than those with wild-type or novel EGFR variants (9.1, 3.5, and 3.5 months, respectively). This suggests that classic EGFR mutations have a prognostic influence that is independent of treatment and that the superior survival reported for mutation-positive patients in uncontrolled studies may not have been due to heightened sensitivity to the EGFR inhibitor.
Dr. Pao and colleagues suggested that novel variants are PCR artifacts caused by formalin fixation. The probability of the appearance of PCR artifacts correlates inversely with the number of cells used for the PCR.1 However, we found novel mutations more frequently in large biopsy or resection specimens (61 percent) than in small biopsy specimens (41 percent). Chou et al.4 also identified several new mutations (V689M, N700D, S720P, V765A, T783A, and G863D) in formalin-fixed tumors from patients who had a response, and the one patient in our series who had a complete response had a transition mutation (V742A[T→ C]).
The role of mutations in patients with lung cancer receiving EGFR inhibitors is still evolving. We elected to publish all our mutation results and encourage others to do so as well. Only in this way will sufficient numbers accrue for all mutations to permit clinical correlation. We agree with Takano and Ohe that standard methods for EGFR-mutation analysis and copy number should be established. It is premature to say that EGFR-inhibitor therapy should not be prescribed for patients who do not have EGFR mutations.
4 ReferencesMing-Sound Tsao, M.D.
Suzanne Kamel-Reid, Ph.D.
Frances A. Shepherd, M.D.
Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada1
Cappuzzo F ,Hirsch FR ,Rossi E , et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643-655
CrossRef | Web of Science | Medline2
Williams C ,Ponten F ,Moberg C , et al. A high frequency of sequence alterations is due to formalin fixation of archival specimens. Am J Pathol 1999;155:1467-1471
CrossRef | Web of Science | Medline3
Eberhard DA ,Johnson BE ,Amler LC , et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone or in combination with erlotinib. J Clin Oncol 2005;23:5900-5909
CrossRef | Web of Science | Medline4
Chou T-Y ,Chiu C-H ,Li L-H , et al. Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 2005;11:3750-3757
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Austin Duffy, Shivaani Kummar. (2009) Targeting mitogen-activated protein kinase kinase (MEK) in solid tumors. Targeted Oncology 4:4, 267-273
CrossRef2
Christopher G. Azzoli, Bernard J. Park, William Pao, Maureen Zakowski, Mark G. Kris. (2008) Molecularly Tailored Adjuvant Chemotherapy for Resected Non-small Cell Lung Cancer. Journal of Thoracic Oncology 3:1, 84-93
CrossRef
