This is the first study to summarize the clinical outcomes of patients with advanced/metastatic NSCLC enrolled in phase I clinical trials in which the majority of therapeutic regimens contained targeted agents. The overall RR was 9.5% and SD lasting >4 months was observed in an additional 19% of patients (total, 28.5%), which was similar to previously published data from non–disease-specific phase I clinical trials (RR, 4.1%–10.6%) [27
]. In addition, data obtained from our phase I clinic on 683 participants having various tumor types showed that patients treated with low dose levels did not fare worse [31
]. Previously reported RRs in heavily pretreated NSCLC patients treated in disease-specific phase I clinical trials were in the range of 3%–15% [32
]. Most of our patients with NSCLC (77 of 85, 90.5%) were enrolled in studies that administered targeted agents. Patients receiving targeted therapy combined with chemotherapy were most likely to achieve a PR (38.5%). Patients treated with single-agent targeted therapy were least likely to achieve a PR (2%); however, they were also the most heavily pretreated. The ability of combined targeted therapy and cytotoxic agents to induce response has been previously documented [35
]. For instance, the anti–vascular endothelial growth factor monoclonal antibody bevacizumab, which yielded no objective response as a single agent in a dose-escalation phase I study, showed activity in combination [35
]. In our study, the median OS time was about 3 months longer in patients who achieved a PR, but this did not reach statistical significance, perhaps because of the relatively small number of patients attaining a PR or possibly because having a response did not impact survival.
The median OS time in our study was 10.6 months. The median OS time observed in our analysis compares favorably with previously reported medians of approximately 5 months from other phase I clinical trials in heavily pretreated NSCLC patients [33
]. The median PFS interval in our study was 2.8 months, similar to previously reported data [37
]. However, some studies of less heavily pretreated or treatment-naïve patients with NSCLC reported better outcomes, with median PFS times of 4–5 months [32
]. In advanced/metastatic NSCLC, the median OS time on first-line therapy rarely exceeds 11 months and the median PFS duration is usually around 5 months [39
]. In the second-line setting, the median OS time is typically around 7–8 months [5
]. The median PFS time usually does not exceed 3 months, which is similar to what we observed in our patient population. The OS time on phase I therapy was similar to the OS times reported from large phase III randomized trials with frontline therapies, which could be explained by selection bias. It is likely that patients with NSCLC treated in phase I clinical trials have a better prognosis than that observed in an unselected patient population. In our phase I study–treated population, the median PFS time on previous lines of therapy was similar (6.1 months on first-line and 3.4 months on second-line therapy) to the above-mentioned previously published data.
Most phase I protocols require a life expectancy ≥90 days for enrollment. Several retrospective studies evaluated prognostic factors for survival to determine the risks for early mortality in the phase I setting [43
]. A group from Royal Marsden Hospital in London developed a prognostic score for predicting survival, which included albumin, LDH, and number of metastatic sites, and validated it in a prospective study with 78 patients [49
]. Previously, we reported a retrospectively developed prognostic score that included the presence of liver metastases, a history of thromboembolism, and an elevated platelet count (>440 × 109
]. In our retrospective study, among other prognostic factors, we evaluated both prognostic scores in patients with NSCLC. The number of metastatic sites, presence of liver metastases, a history of thromboembolism, and an elevated platelet count (>440 × 109
/L), but not LDH and albumin, had prognostic significance in a univariate analysis. None of these factors remained statistically significant in the multivariate analysis. Among other prognostic factors in the univariate analysis, patients with a PS score of 0–1, patients who never smoked, and patients with a hemoglobin level ≥12 g/dL had significantly longer survival times. On multivariate analysis, a PS score of 0–1 and a history negative for smoking remained statistically significant factors for longer survival.
Patients evaluated in this study were treated with various regimens, which precluded detailed toxicity analyses. In general, drug-related grade 3 or 4 toxicity occurred in 27% of patients. The most common grade 3 or 4 drug-related toxicity was myelosuppression, followed by diarrhea and hand–foot syndrome. The incidence was lower in patients treated with targeted therapy than in patients who received chemotherapy. These observations were similar to those of previously published reports [46
]. Treatment-related mortality in phase I trials is generally low [29
]. In our study, there were no treatment-related deaths.
Our study has several limitations, including its retrospective design. Patients were treated in different trials, frequently with diverse outcomes. The median time from an advanced disease diagnosis to phase I clinical trial initiation was 17.5 months. That time frame suggests that our patients had an overall better prognosis than usually seen in advanced NSCLC patients.
In recent years, with the advent of targeted therapies, studies have demonstrated that patients who participate in cancer trials have a very low risk for treatment-related death, although RRs also remain low [29
]. Observations from select studies suggest that matching patients with targeted drugs based on molecular profile can, however, result in high RRs, even in the phase I setting, [51
], and for some categories of patients, these treatments may prove better than the available approved care [45
]. In our patients with NSCLC, the median PFS interval was modest (2.8 months), and was shorter than that for their prior second-line therapy by 18 days, a time period of borderline statistical significance. These observations suggest that clinical trials are a reasonable alternative for patients with NSCLC who have completed two lines of conventional therapies.