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Immune Checkpoint Blockade
Immune Checkpoint Blockade in Advanced Lung Cancer Patients: Optimizing Treatment Duration

Released: September 30, 2016

Expiration: September 29, 2017

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The advent of the immune checkpoint inhibitors nivolumab, pembrolizumab, and if approved, atezolizumab, is changing the care of our patients with NSCLC. However, in our clinics we face a “Goldilocks dilemma” regarding the optimal duration of these agents. How long is too long, and how long is too short? Here, I want to highlight my thoughts on these 2 sides of this issue.

Pseudoprogression on Immune Checkpoint Inhibitors
The concerns with continuing treatment too long arise from a phenomenon called pseudoprogression. In a minority of patients receiving these immune checkpoint inhibitors, imaging may reveal what appears to be growth of existing lesions followed by a sustained tumor shrinkage or the emergence and then disappearance of new lesions. These patterns of response to PD-1/PD-L1 inhibitors are different from the classical responses to chemotherapy or targeted therapy that are familiar to all of us. This pseudoprogression is thought to be mediated by immune cells infiltrating tumors and making them, potentially including previously subclinical lesions, initially appear larger as part of the immune response that ultimately degrades the tumor.

In cancers like melanoma, pseudoprogression occurs in approximately 5% to 10% of cases. In NSCLC, pseudoprogression is rare with an incidence in the range of 1% to 3%. But knowledge of the potential for pseudoprogression can lead to misinterpretation of worsening scans that is actually due to true disease progression. It is important for us as clinicians to understand how infrequently pseudoprogression occurs in the setting of lung cancer and that the clinical picture is of a patient who is clinically improving with, for example, less pain and an increasing appetite, despite an apparent increase in disease burden on their scan. By contrast, when the scans look worse and the patient is faring worse with continuing weight loss, increasing pain, or loss of energy, that is overwhelmingly likely to be conventional progression.

For this majority of patients with progressive disease, there are real consequences of continuing immune checkpoint therapy too long. Switching to conventional chemotherapy can be an effective life‑prolonging option, both for patients getting chemotherapy after first‑line immune checkpoint therapy and for patients in the salvage setting who would usually be getting a monotherapy agent such as docetaxel. However, this opportunity is time sensitive and performance-status dependent, and the window may close if an ineffective treatment persists too long.

This dilemma about whether to continue treatment that may be ineffective is an ongoing concern, especially as immune checkpoint inhibitors move from the second‑line to the first‑line setting as data emerge from an increasing number of trials. If we as clinicians are not judicious about the use of these agents, it is possible that the benefits may be undermined leading to the potential of harm to our patients.

Duration of Immunotherapy in Responding Patients
Whereas pseudoprogression and the concept of continuing therapy in patients who are not obtaining clinical benefit is on one end of the treatment spectrum, the other end is the question of when or if we should curtail treatment in patients who are clearly responding to a PD-1 or PD-L1 inhibitor. We really have no evidence yet to address this question, because, in our limited trial experience, PD-1/PD-L1 agents were administered indefinitely in the absence of prohibitive toxicity or clinically significant progression. But there are significant potential negative effects that may outweigh the benefits of indefinite immune checkpoint inhibitor therapy. In addition to the significant financial costs of indefinite therapy—for example, the

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Approximately what percentage of your patients with metastatic NSCLC who have progressed following platinum-based chemotherapy are you prescribing an immune checkpoint inhibitor?
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