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Survival outcomes unchanged after second-line treatment with pemetrexed plus carboplatin
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Second-line treatment of advanced non–small cell lung cancer with pemetrexed plus carboplatin did not improve survival outcomes when compared with single-agent pemetrexed, according to study results.
Several trials and meta-analyses indicate that two-drug combination chemotherapy, particularly platinum-based doublets, leads to a statistically significant improvement in survival and quality of life when compared with best supportive care in metastatic NSCLC.
However, to halt progression of NSCLC after first-line therapy, researchers are investigating the efficacy of cytotoxic drugs, such as docetaxel and pemetrexed, in second-line chemotherapy treatment.
“An open issue in the second-line treatment of NSCLC remains the possible superiority of combination chemotherapy, particularly platinum doublets, over single-agent therapy, as has been clearly demonstrated in the first-line setting,” Andrea Ardizzoni, MD, of Azienda Ospedaliero-Universitaria in Parma, Italy, and colleagues wrote. “A series of randomized studies comparing doublets versus single-agent chemotherapy has led to conflicting results.”
Aridizzoni conducted the study to compare PFS in pretreated patients with advanced NSCLC who received a combination regimen of pemetrexed plus carboplatin vs. pemetrexed alone as second-line therapy.
The researchers randomly assigned 239 patients to receive either an infusion of pemetrexed 500 mg/m2 intravenously over approximately 10 minutes on day 1 of a 21-day cycle (control arm), or the same pemetrexed infusion followed by carboplatin area under the curve (AUC) 5, intravenously over approximately 30 minutes on day 1 of a 21-day cycle (experimental arm).
Treatment was to be repeated for a total of four courses in the absence of progressive disease, unacceptable toxicity and patient refusal.
During the design of this trial, researchers discovered that a nearly identical randomized phase 2 study intended to compare PFS of pemetrexed alone with pemetrexed plus carboplatin in 240 patients with NSCLC had recently commenced in the Netherlands (NVALT7 trial). To accommodate this secondary study, the researchers planned that the results of the two studies would be combined in a pooled analysis to assess possible differences in terms of OS.
According to study results, there were no statistically significant differences in response rate, OS, or toxicity between the two treatment groups.
Median PFS was 3.6 months for patients in the control arm vs. 3.5 months for patients in the experimental arm (HR=1.05; 95% CI, 0.81-1.36). Among the 479 patients included in the pooled analysis, the addition of carboplatin to pemetrexed did not improve OS (HR=0.90; 95% CI, 0.74-1.10).
“Although clearly defined in the first-line treatment of advanced NSCLC, the role of combination chemotherapy, particularly with platinum-based regimens, is still matter of debate in second-line treatment,” Ardizzoni and colleagues wrote. “The results of [this trial] provide convincing evidence that carboplatin does not add any significant benefit in terms of RR, PFS, or OS, as compared with pemetrexed alone, in the second-line treatment of patients with advanced NSCLC pretreated with platinum-based first-line chemotherapy.”
Disclosure: The researchers report receiving honoraria from Eli Lilly.
Perspective
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Grace K. Dy, MD
The main study result is not surprising, as multiple other clinical trials exploring the benefit of doublet regimens, typically with carboplatin combination, for second-line therapy of non–small-cell lung cancer consistently show lack of OS benefit with this approach.
The subgroup analysis, which suggested that carboplatin combination led to improvement of PFS in squamous histology, is just a reflection of the fact that pemetrexed is an inferior drug for this histologic subtype and that carboplatin combination may be able to overcome this suboptimal efficacy. Thus current literature, including this study, supports monotherapy in the second-line setting for non–small-cell lung cancer.
While the authors suggested that longer treatment-free interval was not predictive of platinum sensitivity, it should be noted that they used 3 months as a demarcation, which may not be the most appropriate time point in determining clinical platinum sensitivity. In ovarian cancer, the treatment is typically used for 6 months or longer.
Perspective
Back to TopPatrick C. Ma, MD, MS
The article by Ardizzoni and colleagues is a phase 2 clinical study that compared the efficacy of pemetrexed vs. pemetrexed plus carboplatin in pretreated patients with advanced NSCLC. A total of 239 patients with advanced NSCLC during or after first-line platinum-based chemotherapy were randomized to receive pemetrexed or pemetrexed plus carboplatin. Primary endpoint was PFS. A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed with respect to OS.
While there was no statistically significant differences in response rate, OS or toxicity observed between the two treatment arms, OS was found to be improved by the addition of carboplatin to pemetrexed in the pooled analysis with a total of 479 patients. Interestingly, patients with squamous histology treated with the doublet was found to have a statistically significant improvement of OS from 5.4 months to 9 months (adjusted HR=0.58; 95% CI, 0.37-0.91; P interaction test=.039) in the subgroup analysis.
This trial addresses an important practical question of whether there is a role of doublet chemotherapy, especially with platinum-based regimen in second line and beyond chemotherapy of advanced NSCLC patients, while single-agent chemotherapy is considered to be the standard of care by most at present. While this study provides some intriguing results to suggest that there is potential clinical benefit with carboplatin addition to pemetrexed in squamous tumors, there are still a number of unanswered questions that require further investigations. One example is the real value of pemetrexed in patients with squamous cell histology. On the other side of the coin, the true added value of carboplatin added to pemetrexed in nonsquamous cell NSCLC remains to be fully defined in the first-line setting.
In the end, in this era of personalized lung cancer therapy, I would argue that everything about the patient could matter in the personalized context, age (biologic rather than chronologic), gender, PS, histology, and also importantly molecular genotype of the tumor. Incorporation of these criteria into the interpretation of clinical trial studies would be important in making reference of the study trial results to apply to an individualized treatment decision process for a patient, whom might not be fully represented in a particular clinical trial study.
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