Author's response to reviews

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1 Author's response to reviews Title: Evaluation of Safety and Efficacy of Gefitinib ('Iressa', ZD1839) as Monotherapy in a series of Chinese Patients with Advanced Non-small-cell Lung Cancer: Experience from a Compassionate-use Programme Authors: Xin-Lin Mu (muxinlin@sina.com) Long-yun Li (lyl263@163.com) Xiao-Tong Zhang (xtzhang111@163.com) Shu-Lan Wang (wslan369@163.com) Meng-Zhao Wang (wmz888@163.com) Version: 2 Date: 11 July 2004 see over Author's response to reviews:

2 Answer to reviewer: Reviewer's report1 Title: Evaluation of Safety and Efficacy of Gefitinib ('Iressa', ZD1839) as Monotherapy in a series of Chinese Patients with Advanced Non-small-cell Lung Cancer: Experience from a Compassionate-use Programme Version: 1Date: 16 June 2004 Reviewer: John D Hainsworth Reviewer's report: In this manuscript, Mu et al describe the results of gefitinib therapy in a small group of Chinese patients with non-small cell lung cancer. These patients were treated as part of an expanded access (compassionate use) program. The manuscript is well written. MAJOR COMMENTS Question 1: The authors state repeatedly throughout the manuscript that these patients were treated as part of an expanded access program. However, on page 9 they discuss a two-stage design, as if this was a single institution phase II study. This issue needs to be resolved, since the usual expanded access program requirements are much less stringent than for actual clinical trials. Were the quality of life assessments mandated by the expanded access program, or was this an addition of the authors at their own institution. Before this study, no data on efficacy and adverse effect of gefitinib on Chinese patients can be obtained. In order to avoid sever adverse we decided to recruit 15 patients to enroll the EAP in advance though it was a compassionate use program. If poor efficacy or severe adverse effect occurred, the program would be stopped. In fact, it was surprising that efficacy of gefitinib was encouraging. Of course, the study was not a stringent clinical trial; description of two-step design was missense. According to Pro. Hainsworth, in statistical analysis paragraph, sentences A two-stage design was employed in the study. In the first stage, 15 patients were enrolled into the patient series. If the DCR did not reach 20%, enrolment would be stopped. If the DCR was 20%, then another 15 patients were enrolled 1

3 (stage 2). were deleted. Expanded access program did not mandated QoL assessment in our institution. Regarding the importance of QoL as an endpoint, QoL assessment was added in the study. Question 2: It would be useful to have updated progression-free and overall survival information. Since the last patient was entered in October 2003, the authors should be able to add at least months of additional follow-up data. An actuarial survival curve, containing median and 1-year survivals, would be helpful. According to the advice from Pro. Hainsworth, we added the follow-up data, and actual PFS and overall survival were listed in patient response section in our manuscript. MINOR COMMENTS Question 1: The objective response rate was substantially higher in this study than has been achieved with single-agent gefitinib in other groups of refractory lung cancer patients. Unfortunately, the cause for this is difficult to determine, due to the small sample size. However, the similarity to the Japanese data is of interest, and deserves follow-up. Did the authors note any differences in response rates between the adenocarcinoma and squamous carcinoma groups. The objective response was higher in our study similarity to the Japanese data. The actual reason was not clear up to now. Two studies (1,2) published recently showed that mutations of exon18, 19 and 21 in EGFR gene were correlated with response to gefitinib therapy and mutation rate was higher in Japanese patients. Now we are detecting mutation of EGFR in Chinese NSCLC. 11 samples including 2 squamous carcinomas and 9 adenocarcinomas have been detected. No mutation of exon18, 19 and 21 was founded in the two squamous carcinomas; EGFR mutation was founded in 5 adenocarcinomas (5/9, 55.6%). It needs further study whether the higher EGFR mutation rate is associated with higher response rate in the 2

4 study. Similar to EGFR mutation, higher response rate was founded in adenocarcinoma groups [10/20 (50%) in adenocarcinoma vs. 1/10 (10%) in squamos carcinomas], we added the result in patient response paragraph. Ref. 1) J. Guillermo Paez, Pasi A. Janne, Jeffrey C. Lee, et al, EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy, Science. 2004, 304(5676): ) Thomas J. Lynch, Daphne W. Bell, Raffaella Sordella, et al. Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non Small-Cell Lung Cancer to Gefitinib, N Engl J Med 2004, 350; 21:2129. Question 2: Table 1 - when describing previous chemotherapy, the use of "previous regimens" rather than "previous cycles" would make this description more clear. We revised it in our manuscript. Question 3: The data contained in Tables 5 and 6 is somewhat difficult to interpret. Perhaps this same information could be displayed graphically to better effect. The significance of "control" and "prevention" in this population of patients is questionable, since other lung cancer studies have not reported these QOL parameters. We revised it. All data listed in Table 5 and 6 were displayed graphically. See figure 1. 3

5 Reviewer's report2 Title: Evaluation of Safety and Efficacy of Gefitinib ('Iressa', ZD1839) as Monotherapy in a series of Chinese Patients with Advanced Non-small-cell Lung Cancer: Experience from a Compassionate-use Programme Version:1Date: 25 June 2004 Reviewer: Johan Vansteenkiste Reviewer's report: The authors present the preliminary results in 31 patients treated within the Expanded Access Program (EAP) with Gefitinib in China. They report clinical benefit and symptom relief in a substantial proportion of the patients. Major comments Question 1: Taking into account the possible differences in efficacy of Gefitinib between Western and Japanese patients, this report of a group of Chinese patients is of interest. The report is much too long and much too wordy however. This is because it is a mixture of review, phase II reporting, and EAP reporting. A much more brief report on 31 patients treated in the EAP would be appropriate, focusing on the specific aspects in China. In this respect: The background section does not need a review of the well known data on Gefitinib, and can be reduced to a few sentences. In the methods section, the paragraph on evaluation could be briefer, regarding the QoL all is needed is the first sentence, the entire description can be deleted. As this a report on EAP use of Gefitinib, no statistical section is needed. In the result section, the paragraph on QoL and symptom improvement can be shortened. The discussion can be a bit shortened as well. QoL and symptom control data can be given in one table (in stead of 4 to 7). According advice from Pro. Vansteenkiste, the manuscript was shortened. In background paragraph, sentences At least four strategies have been developed to inhibit EGFR, including monoclonal antibodies (MAbs), small molecule EGFR tyrosine kinase 4

6 inhibitors (EGFR-TKIs), recombinant proteins containing transforming growth factor alpha or EGF fused to toxins, and antisense oligonucleotides or ribozymes [7,8]. Of these approaches, MAbs (eg humanised MAbs IMC-C225) and small molecule EGFR-TKIs (eg gefitinib [ Iressa, ZD1839] and erlotinib [ Tarceva, OSI-774]) are at advanced stages of clinical development., Preclinical studies have revealed that, in addition to reducing cell proliferation, gefitinib induces cell-cycle arrest, increases apoptosis and has anti-angiogenic activity [9]. In Phase I and II trials of gefitinib, dose-related adverse events (AEs) were observed but the disease control rate (DCR) did not increase with dose escalation. Most drug-related AEs were mild and reversible and quite different from those typically associated with cytotoxic agents. Encouraging tumour response rates and improvements in quality of life (QoL) were also obtained. Based on data from Phase I trials and two large, randomised, Phase II trials (IDEAL [ Iressa Dose Evaluation in Advanced Lung cancer] 1 and 2), once-daily gefitinib 250 mg tablets were recommended for monotherapy [10-15]. were deleted. In assessment of QoL paragraph, sentences The QLQ-C30 contains 30 questions organised into 5 functional scales (physical, role, cognitive, emotional and social), a global health/qol scale, 3 symptom scales (fatigue, pain, and nausea and vomiting) and a number of single-item scales assessing dyspnoea, appetite loss, sleep disturbance, constipation, diarrhoea and financial impact. The QLQ-LC13 is a supplementary module of EORTC QLQ for use in a wide range of lung cancer patients receiving treatment with chemotherapy and/or radiotherapy. The lung cancer module comprises 13 questions used to assess symptoms associated with lung cancer (cough, haemoptysis, dyspnoea and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain medication. were deleted. In QoL and symptom improvement paragraph, sentences The two most frequently reported general symptoms (fatigue and appetite loss) and three disease-related symptoms (dyspnoea, coughing and haemoptysis) were evaluated and the results are shown in Table 6. were deleted. In discussion paragraph, sentences As most AEs such as skin rash were attributed to the 5

7 mechanism of gefitinib inhibiting EGFR autophosphorylation [10], we postulated that the occurrence of stomatitis was due to the same reason, as EGFR was also expressed in oral mucosa [26]. Severe AEs were rare; only one patient withdrew from the trial due to an AE of grade 3 skin rash and worsening dysphagia. The dysphagia was ascribed to the increased volume of lymph node metastases in mediastinum but it was also possible that dysphagia was a drug-related side effect related to expression of EGFR in the oesophagus [27]., for a number of reasons. Firstly, patients with advanced NSCLC suffer from symptoms that affect their normal activities, such as fatigue, appetite loss, coughing and dyspnoea. Secondly, patients with advanced NSCLC cannot be cured by currently available therapy and thirdly, as a targeted agent, gefitinib produces only mild AEs, in contrast to conventional cytotoxic agents. Therefore, some Phase I trials and two Phase II trials (IDEAL 1 and 2) have included QoL as an important endpoint. were deleted. The data on Qol and symptom was displayed graphically according the advice from Pro. Hainsworth. Question 2: On the other hand, some important characteristics that describe the population and potentially China-specific features are missing. Previous therapy. Do the authors mean 'one cycle' or one 'line' of therapy. If it is only one cycle of cisplatin in some patients, then this population is clearly very different from other reported series on the EAP with Gefitinib, and this should be clearly mentioned in the abstract and in the body of the text. If it is different 'lines', then these lines should be described. Interstitial lung disease (ILD). This is an important aspect in an Asian population. Therefore, a detailed description of the methods to monitor for ILD should be given in methods section. "We pain close attention" as written on page 14 is largely insufficient. Of interest is also to know if certain subgroups in this Chinese cohort did better than the others, e.g. dependent on histology, gender, smoking status, In the manuscript, perhaps one line or one regimen can describe prior treatment clearer than one cycle. We revised it in patient characteristics paragraph, and list drugs used in 6

8 different regimens. Also in table 1, cycle was substituted with regimen Regarding interstitial lung disease, we paid attention to clinical respiratory symptoms (e.g. dyspnea, cough) and radiographic findings of patients, and monitored PaO 2 during therapy. Of course, it is insufficient only We pain close attention" was described in the manuscript. In the revised manuscript, Logistical regression test models were used to identify baseline factors (gender, PS, histology, TNM stage and prior chemotherapy) that might independently predict tumor response. Result showed only histology was correlated with tumor response and was described in patient response paragraph. Minor remarks Question 1: Abstract is no longer correct, better leave out the figure, say 'about ', as it changes quickly. In abstract, >39,000, not 39,000, was used, perhaps it represents current status. Question 2: Page 4 The text suggests that 5-year survival in advanced NSCLC is <14%, true, but is in fact <1%. <14% were cited from reference Haura EB. Treatment of advanced non-small-cell lung cancer: a review of current randomized clinical trials and an examination of emerging therapies. Cancer Control 2001;8: Question 3: Page 5 7

9 -Refer to core papers of IDEAL studies i.e. Fukuoka 2003 and Kris "Paucity" of current data on Gefitinib is a major underestimation. Perhaps we did not express clearly, here we meant few data about difference response and adverse effect of gefitinib between different races could be obtained currently. We revised it in our manuscript as But Owing to the paucity of current data on gefitinib between defferent races, the possibility of differences in the toxicity and efficacy of gefitinib for ethnicity cannot be excluded.. Question 4: Page 11 -Actuarial data are given for PFS, please do the same for survival. -Questionnaires returned: calculate % on total number of patients. We added the follow-up data, and actual PFS and overall survival were listed in our manuscript. Regarding questionnaires returned, perhaps calculating % on total number of patients who were still alive when they returned questionnaires might present well the compliance with QoL assessment (see ref. below). Ref.: Langendijk JA, Aaronson NK, De Jong, JMA, et al. Quality of life after curative radiotherapy in stage I non-small-cell lung cancer, Lung 2002, 53(4): In addition, in order to shorten the manuscript, appendix A and B were deleted in revised manuscript, which will affect the understanding of the article. 8