H. Jack West, MD
The approach to first-line treatment of advanced non–small cell lung cancer (NSCLC) has been evolving rapidly, particularly with respect to patients with lung adenocarcinoma. In the past decade, one of the first results with major clinical implications was the recognition of superior overall survival (OS) among patients with advanced nonsquamous NSCLC who received cisplatin/ pemetrexed compared with cisplatin/gemcitabine. That was not the case in patients with advanced squamous NSCLC.1
We have also seen the addition of bevacizumab (Avastin) to chemotherapy based on a positive phase III ECOG 4599 trial of carboplatin/paclitaxel alone or with bevacizumab,2
although the modest magnitude of OS benefit along with absence of any OS benefit in another randomized phase III trial3
has led to variable adoption of bevacizumab. As a chemotherapy backbone in the United States, carboplatin is widely favored in light of its very good therapeutic index relative to chemotherapy, which has led to the carboplatin/pemetrexed regimen becoming widely adopted, with or without bevacizumab.
Although any of a wide range of platinum-based doublets can achieve relatively comparable efficacy in advanced lung adenocarcinoma, carboplatin/pemetrexed has become my favored regimen based on the convenient schedule, lack of hair loss, and generally favorable tolerability. I recently led a lung cancer expert summit with 12 national leaders in thoracic oncology; before the live meeting, I asked for specific practice patterns in a survey, which was notable for the complete consensus in favor of a platinum/pemetrexed combination (11 favoring carboplatin, 1 favoring cisplatin), despite the array of acceptable options.4
I have historically been inclined to add bevacizumab for patients with a good performance status and no contraindications, largely based on the impressive efficacy of this regimen demonstrated in the AVAPERL trial of carboplatin/pemetrexed with or without bevacizumab initially, followed by pemetrexed/bevacizumab maintenance,5
but I have been less inclined to favor including bevacizumab for senior patients, based on a subset analysis of the original ECOG 4599 trial that revealed no efficacy benefit and disproportionately greater adverse effects with bevacizumab among patients older than 70 years.6
The views of the aforementioned panel of experts also convey a level of ambivalence about including bevacizumab, as revealed in Figure 1. 7
Figure 1: Survey of Experts on Willingness to Include Bevacizimab with Concurrent Chemotherapy in Bevacizimab-Eligible Patients
However, these heavily trodden chemotherapy options and converging standards have undergone an upheaval, as immune checkpoint inhibitors have been studied and assumed a larger role in first-line treatment of advanced NSCLC. Initially studied and then approved as second-line therapies after demonstrating significantly greater efficacy compared with docetaxel in the second-line setting (or potentially later), anti–PD-1 and PD-L1 checkpoint inhibitors have generally been well tolerated and demonstrated remarkably prolonged responses in a subset of patients. These results led to the obvious question of whether immunotherapy agents would provide even greater benefit in the first-line setting, whether for a selected and enriched population or possibly a broader one, potentially replacing or augmenting the efficacy of conventional chemotherapy as initial therapy. Dozens of trials of immunotherapy agents as monotherapy or in combination with chemotherapy, as well as some with combinations of immunotherapy agents, have been launched and completed enrollment. The first few presented and published since late 2016 have dramatically changed our approach to first-line treatment of advanced NSCLC, particularly among patients with adenocarcinoma that does not harbor a targetable driver, such as an EGFR mutation or ALK or ROS1 rearrangement.