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Triplets versus Doublets in NSCLC: An interim analysis

NSCLC is still the leading cause of cancer death in most countries. At the time of diagnosis more than 75% of the patients present with locally advanced or metastatic disease. Treatment with cisplatin-based regimens can improve survival but the optimal regimen still needs to be found. A promising approach is the integration of newer drugs like vinorelbine, gemcitabine and paclitaxel into the therapy of NSCLC.

Treatment with vinorelbine (VNR) as a single agent was associated with a response rate of about 15% and a median survival time (MST) of 31 to 32 weeks. Combination with cisplatin (CDDP) lead to increased response rates of around 30% and a MST of 32 to 40 weeks. Gemcitabine has also proven to be active in patients with NSCLC. Studies using gemcitabine as a single agent reported response rates around 20% and a MST of 8 to 9 months. Combining gemcitabine with cisplatin turned out to be a promising regimen in three clinical trials yielding response rates between 31 % to 41% and an increase in time to progression (5,6 to 6,9 months). But the MST (8,6 to 9,1 months) did not show a significant improvement compared to standard combinations like MIC. Based on this experience it seemed worthwhile to develop triple drug regimens in order to achieve synergistic activity, taking advantageof the non-overlapping toxicity of these drugs. A Phase II study using CDDP-GEM-VNR established the feasability of this combination and reported an overall response rate of 57% and a MST of 50 weeks.

Therefore, a randomised controlled trial was initiated in order to compare Cisplatin-Vinorelbine and Cisplatin-Gemcitabine with triplet combinations. As a fourth arm CDDP-GEMPTX (paclitaxel) was incorporated in the trial after having shown impressive results in a phase II study. By January 1999, 240 patients with NSCLC had been randomised to receive one of the 4 treatment arms (table 1).

According to an interim analysis performed in March 1999, the MST of the entire study population was 10,4 months. The lowest MST (8 months) was found in group C (Vinorelbine-Cisplatin) with a significant difference in the paired comparisons to groups A and D, whereas the difference to group B was of borderline significance.

In the other study endpoints there was also a trend/significant difference favouring the groups A, B and D compared to group C (table 2). Consequently, the recruitment of patients in group C was stopped, while the study continues with the 3 remaining arms targeting at 120 patients per group.

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