Leading Researchers Dissect PD-1/PD-L1 Evidence in NSCLC

Christina Loguidice
Published: Thursday, Sep 15, 2016
Benjamin Levy, MD

Benjamin Levy, MD

Although lung cancer remains the leading cause of cancer-related mortality in the United States and 5-year survival rates are low at 17.8%,1 the grim picture for this tumor type is starting to shift to a more hopeful one as its biology is becoming better understood, facilitating treatment selection and providing researchers with new therapeutic targets.

The introduction of immunotherapies aimed at checkpoint blockade mechanisms during the past 18 months is a key reason for the brighter outlook in non–small cell lung cancer (NSCLC), which accounts for 85% of lung cancers in this country.2

During a recent OncLive Peer Exchange panel discussion entitled “Latest Advances in Lung Adenocarcinoma,” the panelists provided an overview of the latest data on immunotherapy in advanced NSCLC presented in journals and at medical meetings, and discussed the challenges of testing for the PD-L1 biomarker in treatment decision making.

In the fast-moving field, updates from CheckMate 026, which explored nivolumab in NSCLC, suggest new data that may change views on how best to utilize these emerging agents. This information, which has not yet been published or presented, was released after the Peer Exchange session.

Immunotherapies in Advanced NSCLC

Currently, nivolumab (Opdivo) and pembrolizumab (Keytruda) are the only immunotherapies approved by the FDA for advanced NSCLC, but several others are in development, including atezolizumab (Tecentriq) and durvalumab. Nivolumab and pembrolizumab are humanized monoclonal antibodies targeting PD-1, while atezolizumab and durvalumab are antibodies that inhibit PD-L1.

In clinical trials, nivolumab and pembrolizumab have been compared with docetaxel, a standard second-line treatment, and found to have an overall survival (OS) benefit. However, because these trials included different patient populations, their approvals are slightly different. Although both agents are approved for patients with squamous and nonsquamous advanced NSCLC, pembrolizumab is approved with the caveat that there must be PD-L1 tumor expression, as shown on the companion PD-L1 IHC 22C3 pharmDx test.

The panelists agreed that patients receiving immunotherapies are showing durable responses unlike anything observed before. “I think immunotherapy, importantly, has bent the survival curves, but perhaps more importantly has lifted the tail of the curve,” said moderator Benjamin Levy, MD.

He proceeded to note, however, that only 20% of patients are showing these responses, indicating a need for better patient selection and treatments.

Nevertheless, because responses in those who respond are so favorable and there is overall low toxicity, many panelists favor using them over other therapies, particularly in second and subsequent lines. “When you see that patients who get these drugs can live for years with really minimal, if any, toxicity, and really good quality of life for so long, I’m very enthusiastic about them,” said Sarah B. Goldberg, MD, MPH.

In contrast to the other panelists, Mark G. Kris, MD, reported using these agents in the first line, regardless of the presence of EGFR or ALK mutations, for which targeted therapies exist. “[I offer them in the] first line because if you’ve seen these patients who have had these multiyear, disease-free outcomes, there is no other therapy in stage IV disease that can offer that,” he said.

He acknowledged that these agents are not curative, but that they have the potential to be curative, particularly when given in the adjuvant setting, but noted that interest in using them in that way is lacking.

Ramaswamy Govindan, MD, suggested more data are needed before these agents are ready for frontline use. “We are trying to decide how to move them forward in the frontline setting and how to combine them with other drugs to enhance activity,” he said. “I’m not so sure I would offer nivolumab to EGFR-mutant patients in the frontline setting, but definitely in the second- or third-line setting I would consider that.”

Goldberg described the most common adverse events (AEs) with nivolumab and pembrolizumab. She noted that pneumonitis and colitis are most common, with the latter occurring more frequently when given concomitantly with CTLA-4 inhibitors. Other notable AEs include endocrinopathies, thyroid dysfunction, and adrenal insufficiency, which can be managed with hormone replacement. Despite the overall favorable AE profile, she cautioned that close patient monitoring is warranted because these AEs have been associated with several deaths and that clinicians should also be alert to any new and unusual symptoms. “I tell my patients, and the way that I think about it myself, is any new symptoms that come up when a patient is on an immunotherapy, or even off it after a period of time, can be associated with an immune-related toxicity until proven otherwise.”

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