Jason M. Broderick
Corey Langer, MD
Over the past year, there has been a multitude of exciting developments in the treatment of patients with non-small cell lung cancer (NSCLC): Anti-PD-1 and PDL1 immunotherapies in lung and other tumors made a big splash at ASCO 2013 and continue to generate tremendous excitement in the field; guidelines for molecular testing in lung cancer were published in the Journal of Thoracic Oncology
; second-generation ALK inhibitors have shown promise in patients who become resistant to crizotinib (Xalkori); and afatinib (Gilotrif) and erlotinib (Tarceva) have been approved in the first-line metastatic NSCLC setting. For expert analysis of these critical issues, we sat down with Corey Langer, MD, at the 14th Annual International Lung Cancer Congress. Langer is the director of Thoracic Oncology at the Abramson Cancer Center and a professor of Medicine in the Hematology/Oncology Division at the University of Pennsylvania.OBTN: Can you discuss the breakthroughs with immunotherapy in lung cancer?Langer
: I scarcely consider myself an expert in immunotherapy but this is actually a very exciting field, even though, historically, I’ve categorized myself as an “immuno-skeptic” based in part on my past experience over 20 years ago with highly toxic immunotherapy agents. We conducted trials in that era looking at those agents, including IL-2 and beta-interferon, not just in melanoma and kidney cancer, but in non-small cell lung cancer; and by and large, very few patients responded and toxicity was horrible.
Now we are in a new era. Specifically, there are emerging data in advanced non-small cell lung cancer, particularly in squamous histology, where a phased approach—essentially grafting ipilimumab onto the third cycle and beyond of standard chemotherapy— looks better than standard chemotherapy alone. A randomized phase II study was reported last year and suggested about a 3- or 3.5-month improvement in median survival for patients receiving combination chemotherapy with ipilimumab (during the 3rd and subsequent cycles) versus chemotherapy alone and that has set the stage for a major phase III trial that will isolate the role of ipilimumab in patients with advanced NSCLC and squamous histology.
In the last 2 years, we have seen data for monoclonal antibodies targeting PD-1 and PD-L1. These are single-agent studies in heavily pretreated patients, many of whom have exhausted standard cytotoxic therapy—basically patients out of standard therapeutic options. Patient response rates have ranged from 18% to as high as 25% to 30%, with much less toxicity than we saw historically with interleukin-2 and beta interferon. The schedules of these agents are still being worked out. Whether these agents can combine easily with standard treatment either in the first line or second line is still being worked out as well, but you can bet there are and will be multiple randomized phase II, and more importantly, phase III registration trials that will establish whether these agents truly have a role. So far, at face value, they appear to have a major role.
There is some speculation that patient tumors need to harbor PD-L1 for these agents to be active. Certainly, response rates appear to be considerably higher in those individuals whose tumors express PD-L1, but responses are also seen in PD-L1–negative tumors, so I think the notion that we have a very dichotomous marker—if you have PD-L1 you’re eligible and if you don’t you can’t get these agents—that notion falls by the wayside.Which patients with non-small cell lung cancer should receive molecular testing?
As far as I am concerned, any patient with advanced NSCLC with nonsquamous histology is a reasonable subject for molecular testing. Many groups, particularly academic centers, will test every patient regardless of histology. I think when it is tough to get adequate specimens, we have to be a little bit careful about applying this strategy generally or uniformly. Certainly, a patient with squamous histology, an older male patient, a heavy smoker, a non-Asian—that patient’s likelihood of having an actionable mutation or translocation is probably less than 1% to 2%. On the other hand, if they do have it, the presence of this molecular abnormality completely alters the nature of the patient’s therapy. We go from a conventional cytotoxic regimen to a potentially more active, less toxic, molecularly directed treatment. There is this ongoing debate now between uniform testing—global testing—versus more targeted testing. I would say at this point in 2013, the vast majority of patients who have advanced non-small cell lung cancer will be tested for actionable molecular markers if adequate tissue is available.