Although the ASCO Plenary session presentation on ALK inhibition with crizotinib was a darling of the entire conference and led to a post I wrote about on the way back from the meeting, there was actually a second presentation on lung cancer in the plenary session that received far less attention, including by us here at GRACE. It asked the question of whether doublet therapy or single agent chemo for elderly patients with advanced NSCLC leads to better outcomes, and specifically superior survival. Without a novel targeted agent, it's been overshadowed, but it demonstrated a clear answer to a question that is very relevant, so it's high time to review its findings.
Dr. Quoix from France reviewed the IFCT-0501 trial, which randomized previously untreated stage III or IV NSCLC patients of age 70-89, with a good or more marginal performance status, to either carboplatin/Taxol (paclitaxel), with carbo all on the first day and the Taxol divided into three weekly doses every 4 weeks (4th week being an off week), vs. a single agent chemo arm of either Navelbine (vinorelbine) or Gemzar (gemcitabine) as two weekly doses in a three week cycle (3rd week being an off week), at the treating physician's discretion. All patients were to received Tarceva (erlotinib) as planned second line therapy.
In general, either single agent or doublet chemotherapy for elderly patients (most typically defined as 70 and older) has been considered a very reasonable choice, as summarized in a prior post. Subset analyses of patients of any age have generally suggested that patients over 70 with a good performance status tend to perform very comparably to younger fit patients, and specifically that they tend to receive a survival benefit from platinum-based doublet chemotherapy if they are fit enough to tolerate it. A trial of marginal performance status patients demonstrated that doublet chemotherapy with carbo/Taxol in a molecularly unselected US population (presumably very disproportionately with no EGFR mutation) had a far superior survival with first line chemo than with the EGFR inhibitor Tarceva (erlotinib).
The French trial closed early, after an interim analysis of 451 enrolled patients with a median follow-up of 21.3 months revealed that the recipients of the carboplatin/Taxol doublet had a significantly longer median survival than those on the single agent arm. In fact, all of the efficacy endpoints were clearly superior with doublet chemotherapy. The median overall survival (OS) was 10.3 vs. 6.2 months (P = 0.0004), 1 year OS 45% vs. 27%, response rate 29% vs. 11% (P < 0.00001), and median progression-free survival 6.1 vs. 3.0 months (P = 0.00001).
A multivariate analysis looking at results as a function of various individual variables demonstrated that recipients of the doublet chemotherapy had a superior survival regardless of age, performance status, smoking history, or NSCLC histology. If the variable of what chemo was given is removed, patients with a good performance status had a better survival, as did those with no smoking history or an adenocarcinoma; these findings have been observed in many other trials of NSCLC.
Not surprisingly, doublet chemotherapy was more challenging and had significantly more frequent and severe side effects in several categories, including moderate to severe neutropenia (low WBC: 54% vs. 10%, P < 0.00001), fevers with neutropenia (10% vs. 3%, p = 0.004), moderate to severe thrombocytopenia (low platelets: 6% vs. 1%, P = 0.004), and moderate to severe neuropathy (3% vs. 0%, P = 0.015).
Though it's possible to criticize this trial for not including the same agent in both arms (such as carbo/Taxol vs. single agent Taxol, or carbo/Gemzar vs. Gemzar), there really isn't a clear standard single agent first line chemo for elderly patients, and all of these regimens are rather commonly used and very reasonable choices. The differences in outcomes shown here are convincing and also corroborate another trial, out of Japan, that looked just at cisplatin/Taxotere (docetaxel) vs. Taxotere alone in patients 70-74 and also showed that the doublet was superior.
At this point, I'd have to conclude that the data have been pretty consistent supporting the idea that platinum-based doublet chemotherapy, with a carboplatin-based regimen to be recommended for the clear majority of elderly patients by most oncologists, is associated with better survival. Doublet chemotherapy is going to be excessive for at least some elderly patients, and other patients may simply want to prioritize minimal side effects and be more inclined for single agent chemo, but it's become increasingly clear that there is an incremental benefit to first line doublet chemotherapy in older patients, just as in younger patients with advanced NSCLC.