By Hossein Borghaei, DO, MS
Posted: August 14, 2019
In 2015, the use of checkpoint inhibitors in the second-line setting for metastatic lung cancer became the standard of care with the approval first of nivolumab followed by pembrolizumab and later atezolizumab. In all randomized trials with these agents, the comparator arm was docetaxel because it represented the standard-of-care post-therapy with a platinum-based chemotherapy doublet at that time. Clearly, we have observed a substantial shift in the use of these drugs in metastatic lung cancer, with recent trials showing a significant advantage for the combination of chemotherapy and immunotherapy as frontline treatment compared to platinum-based chemotherapy alone. This approach is now the standard of care in the United States and most parts of Western Europe; at this point, in the absence of an oncogenic driver, the majority of patients with newly diagnosed metastatic lung cancer, regardless of histology, receive a platinum-based chemotherapy doublet plus a checkpoint inhibitor upfront.
JAVELIN Lung 200 was a randomized phase III trial designed to test the efficacy of avelumab versus docetaxel in patients with metastatic NSCLC after progression on standard platinumdoublet chemotherapy.1 This multinational study, conducted in 31 countries, did not meet its primary endpoint in the intent-to-treat patient population. The eligibility requirements were standard for a trial of this nature. Overall, 792 patients were enrolled and randomly assigned to the two arms. PD-L1 status was positive in approximately 67% of patients in either arm. The median overall survival was not different in this group of patients, at 11.4 months for avelumab and 10.3 months for docetaxel. In a prespecified exploratory analysis, patients with higher PD-L1 expression (50% and 80%) receiving avelumab had, in fact, better median survivals compared to those receiving docetaxel. As reported, toxicities with avelumab were fairly consistent with those observed with other checkpoint inhibitors, with the possible exception of infusion-related reactions, which occurred in approximately 17% of patients treated with avelumab.
One Checkpoint Inhibitor May Not Be the Same as Another
There are several possible explanations for why avelumab failed to meet expectations. Overall survival is affected by subsequent therapies. In the PD-L1–positive group, 48% of patients in the docetaxel arm received post-study treatment, of whom 26% had some form of immunotherapy with a checkpoint inhibitor. This constitutes a higher rate of post-progression use of a checkpoint inhibitor than prior studies. This makes sense because these active agents are now available in most regions of the world, and patients have better access to potentially active drugs. Is this number enough to have changed the outcome of the trial? Because I am not a statistician, I cannot comment on this any further, but one can certainly speculate.
Study Design
Is it possible that avelumab was somehow less effective as a checkpoint inhibitor? This issue of whether there is a superior checkpoint inhibitor has been debated by many in the field, but there is no clear answer. Certainly, the number of positive trials with pembrolizumab, either alone or in combination with standard chemotherapy, makes one wonder if there is a superior checkpoint inhibitor. However, I believe that better patient selection, better-designed studies, and clearly defined biomarker endpoints are more likely to be the reason for the success of these trials rather than the nature of the drug itself. Of note, a recent unconfirmed report suggesting that the rate of antidrug antibodies, which tend to be neutralizing, are different among the checkpoint inhibitors could provide an explanation for the different results we have been seeing. This must be investigated further.
Patient Selection
Patient selection could have been a factor in this trial. In the avelumab arm of the trial, approximately 10% of participants had brain metastasis at baseline compared with 8% in the docetaxel arm. This patient population generally has a worse outcome. In isolation, this factor by itself is not likely to have resulted in the lack of a survival benefit, but it is conceivable that in combination with other factors, it could have been a contributing factor.
PD-L1 Expression Status
PD-L1 testing in this trial was conducted using the 73-10 pharmDx antibody. The Blueprint 2 analysis shows that this antibody is a high-quality assay that stains more PD-L1–positive tumor cells, and the 80% or higher PD-L1 cutoff with this antibody has high concordance with the 50% or higher cutoff for the 22C3 antibody used in the pembrolizumab trials. Thus, it is unlikely that biomarker testing is responsible for the results observed. Ultimately, it is difficult to ascertain why this study did not succeed where others have. The real reasons are probably multifactorial. Certainly, other studies with avelumab are ongoing, and this drug appears to be as effective as others in this class. Occasionally, a trial fails unexpectedly. Sometimes a clear explanation is evident, but in many cases, the answer remains elusive. The negative results of the JAVELIN trial appear to be a case of the latter. ✦
About the Author: Dr. Borghaei is chief of the Division of Thoracic Medical Oncology, professor in the Department of Hematology/Oncology, codirector of the Immune Monitoring Facility, and Gloria and Edmund M. Dunn Chair in Thoracic Oncology at Fox Chase Cancer Center.
Reference:
1. Barlesi F, Vansteenkiste J, Spigel D, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 2018;19:1468-1479.
