Phase III Study Shows Combination Treatment to be Effective for NSCLC

A phase III randomized clinical trial, published in JAMA Oncology, found that carboplatin-pemetrexed treatment followed by pemetrexed maintenance to be a valid option for first-line treatment of elderly patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

The clinically significant benefit of the combination with regard to its effectiveness and tolerability suggests that it should be considered as a standard option for treatment in this setting, according to the researchers. 

“With the emerging role of pemetrexed in the treatment of nonsquamous NSCLC and the good tolerability of this drug, there was interest in evaluation of pemetrexed in combination with carboplatin for elderly patients with advanced nonsquamous NSCLC,” the authors wrote. “To the best of our knowledge, our study is the first phase III randomized clinical trial specifically designed for patients 75 years and older with advanced nonsquamous NSCLC.”

In this open-label, multicenter study of 433 patients, participants were randomized to receive either 60 mg/m² of docetaxel monotherapy every 3 weeks or 4 cycles of carboplatin plus 500 mg/m² of pemetrexed every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks. The primary endpoint for the study was overall survival (OS).

The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified hazard ratio (HR) for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = 0.003). Progression-free survival (PFS) was also found to be longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). 

Compared to patients in the docetaxel group, those in the carboplatin-pemetrexed group had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Additionally, dose reductions were less frequent for those treated with carboplatin-pemetrexed.

In an unplanned exploratory post hoc analysis, the OS benefit for carboplatin-pemetrexed vs docetaxel was notable in patients with a performance status (PS) of 0 at baseline. Moreover, PS showed a weak trend toward qualitative interaction with OS, whereas the beneficial effects of carboplatin-pemetrexed on PFS and the rate of adverse events were preserved across PS. 

Notably, the trial was conducted at 79 institutions in Japan, which may limit the generalizability of the results given that Japanese patients with NSCLC generally show better survival than western populations. Further, the low docetaxel dose used in the study is not the standard dose (75 mg/m²) used in the rest of the world. 

“The number of elderly individuals with cancer has increased in recent years, with more than one-third of new lung cancer cases now being diagnosed in patients 75 years or older,” the authors wrote. “In anticipation of a further increase in the number of elderly individuals with advanced NSCLC, it will be important to develop more optimal chemotherapeutic regimens for this patient group.”

Reference:

Okamoto I, Nokihara H, Nomura S, et al. Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer. JAMA Oncology. doi:10.1001/jamaoncol.2019.6828.