REPORT ASCO 2002 ORLANDO : LUNG CANCER Johan F. Vansteenkiste, MD, PhD, Univ. Hospital and Leuven Lung Cancer Group

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1 REPORT ASCO 2002 ORLANDO : LUNG CANCER Johan F. Vansteenkiste, MD, PhD, Univ. Hospital and Leuven Lung Cancer Group In the 2002 edition of the ASCO meeting, a total of 315 abstracts in the field of respiratory oncology were accepted. One hundred and twenty were accepted for publication only, while 195 were presented either as poster (n=147, # ), at a poster discussion session (n=23, # ), or in an oral session (n= in plenary session, # plus #2 and #5). An overview of the topics and types of presentation is given in slide 1. The majority were on advanced non-small cell lung cancer (NSCLC), while there was little encouraging news on small cell lung cancer (SCLC). For the purpose of this review, we have rated the presentations as randomised/large (RL, i.e. at least 100 patients per arm), randomised/small or randomised/secondary (RS, i.e. small or sub analysis on previously reported data), or non-randomised (nr). We will focus mainly on the large randomised data, with addition of some other abstracts which revealed breaking news (BN). NSCLC Early stages The Adjuvant Lung Project Italy (ALPI, #1157 slide 2) tested the potential benefit of adjuvant Cisplatin-based chemotherapy after complete resection of stage I-IIIA NSCLC.

2 The multivariate survival analysis of this 1200 patients trial, expressed as the hazard ratio between active vs. no treatment, did not reveal a significant survival difference across the arms. In an ancillary project on a subset of the patients, the prognostic significance of molecular markers of tumour aggressiveness (p53, K-ras) or proliferation capacity (Ki67) was examined. None of these variables were found to have significant prognostic value. NSCLC Locally advanced stages There were no large randomised data in this field. A small randomised study with only 50 patients per arm (#1159, not on slide) made a comparison between concurrent or sequential radiochemotherapy with Cisplatin-Vinorelbine. Median survival, time-to-progression and 2-year survival (42 versus 15%, P=0.03) were in favour of the concurrent approach. It was questioned whether the important difference in this very small group was not due to suboptimal chemotherapy in the sequential arm. NSCLC Advanced stages One large study, designed to confirm the benefit of Cisplatin-based chemotherapy suggested in the meta-analysis of 1995 in a single trial, suffered from low initial recruitment and was closed before the targeted 800 patients were reached (#1161, slide 3).

3 Very few specialists now still have doubts on the benefit in survival of chemotherapy in fit patients with advanced NSCLC. This study is a solid, but very late, confirmation of the improvement of 2 months in median and 10% in 1- year survival. No differences in quality-of-life were found, but the number of patients available for this analysis was only 273.

4 Three studies compared single agent versus combination chemotherapy (#2, #1162, #1163, slide 4). Lower response rates, but also lower toxicity scores, for the single agent were found in all of these trials. Most evidence is in favour of combination therapy, certainly in regard to median survival. Whether this holds true for clinical benefit and quality-of-life is less clear, if a single agent therapy with a modern drug is considered. Three studies made a comparison of different Cisplatin-based regimens (slide 5). Two of these compared an old and a new Cisplatin-based regimen (#1164, #1180). The use of a new drug added to Cisplatin improved the response rate

5 with 16% in one study, median survival with 2 months, and 1- or 2-year survival rate with at least 10%. A large randomised French, considered for the poster session by the ASCO (!), made an interesting comparison between 2 modern Cisplatin-based therapies (#1296). The outcome parameters of Cisplatin-Docetaxel and Cisplatin- Vinorelbine were very similar, but there was an excess of febrile neutropenia and hospitalisation in the Vinorelbine arm. Three other studies looked at the question whether platinum is still to be preferred (#1165, #1181, #1182, slide 6). In all three, the response and survival outcome was inferior for the non Cisplatin-treated patients, but the differences were not significant. Toxicity was less in the Italian study (#1165), but this resulted in only minor differences in

6 quality-of-life. Febrile neutropenia was more common in the Gemcitabine-Epirubicin arm (#1181) and the Cisplatin- Vinorelbine arm (#1182). These findings, together with the EORTC experience reported at the ASCO 2001 meeting, make us aware that platinum-free treatment may be inferior in terms of outcome, while toxicity is not always improved. SCLC Limited stage The French group, that previously pointed at the importance of correct dosing of the first cycle of chemotherapy, now examined the additional benefit of moderately increased dose in the first cycle (#1172, slide 7). There was no

7 difference in the primary endpoint (2-year disease-free survival), but the higher number of deaths due to cancer in the standard dose arm should be noted. SCLC Extensive Disease As already suggested in previous ASCO meetings, the addition of Paclitaxel to Platinum-Etoposide does not improve outcome in extensive SCLC. A large phase III study now confirmed this finding (#1169, slide 8) and pointed at the substantially increased toxicity and treatment related deaths when these 3 drugs are combined.

8 The second study (#1170,slide 8) compared Cisplatin-Etoposide to Carboplatin-Gemcitabine in poor prognosis SCLC patients (56% extensive and 44% limited). Outcome parameters were very similar, but an other pattern of toxicity was noted in the Carboplatin-Gemcitabine arm with more haematological but less non-haematological sideeffects. In essence, these are the results of a Cis- versus Carboplatin comparison, and one may suppose that comparing to much more standard Carboplatin-Etoposide regimen would have given the same results. Mesothelioma After several ASCO editions without significant news on mesothelioma, one of the plenary presentations of this year concentrated on the pivotal trial comparing Cisplatin-Pemetrexed (a multi-targeted antifolate, MTA) to Cisplatin alone (#5, slide 9). This phase III study has a difficult but sound methodology, and is the largest randomised trial

9 ever reported in this uncommon but increasing disease. After several years of pessimism on this fatal disease, the significant results in favour of a new therapeutic possibility were more than welcome. Molecular agents One study examined the value of adding prinomastat, a matrix metalloproteinase inhibitor (MMPI), to standard Cisplatin-Gemcitabine in the treatment of advanced NSCLC (#1183, not on slide). Like studies on other MMPI s reported in previous ASCO editions, this study was also totally negative.

10 A small randomised trial failed to show promises when Trastuzumab is added to standard Cisplatin-Gemcitabine in NSCLC (#1185, not on slide). The same was true for STI571 when used in 2 nd line treatment of SCLC (#1171, not on slide). In both of these studies, however, the number of patients expressing the molecular target was low. Fortunately, studies with agents that block the Epithelial Growth Factor Receptor (EGFR), did show positive findings. Two randomised phase II trial with ZD1839 ( Iressa ) pointed at remarkable activity of these agents in salvage therapy for NSCLC, after platinum failure (#1188, slide 10), and even after platinum and Docetaxel failure (#1166, slide 10). Furthermore, rapid symptom control is offered, and this at the cost very mild treatment-related toxicity, especially when the dose of 250 mg/d is administered. The results of the studies, in which this agent was added to standard 1 st line treatment, are now eagerly awaited. Take home messages (slides 11 and 12) It is expected that the largest trial ever performed on adjuvant chemotherapy in NSCLC (±2000 patients) will be reported at next year s ASCO meeting. Until then, there is no place for adjuvant chemotherapy in clinical practice.

11 Regarding chemotherapy for advanced disease, the current standard for fit patients remains the combination of platinum and a new drug. Platinum-free regimens may be inferior for fit patients. As for the choice of the new drug, some additional data pointing at the slight superiority of Docetaxel over Vinorelbine were noted. As for the number of drugs, two is the best choice when median survival is considered, although one new drug might be a choice when clinical benefit or quality-of-life are predominant, e.g. in less fit patients. The most breaking news came form the large mesothelioma study, where the superiority of Cisplatin-Pemetrexed over the reference arm was clearly demonstrated, and from the data on the use of EGFR blocking agents in NSCLC, which are the first category of targeted agents showing clinically relevant phase II outcome data.

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