Immune Checkpoint Inhibitors: The Dawn of a New Era for Lung Cancer Therapy

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Suresh S. Ramalingam, MD

These exciting results open tremendous possibilities for future research studies and keep our hope alive that cures can be achieved for at least a subset of patients with advanced NSCLC.

—Suresh S. Ramalingam, MD

The therapeutic paradigm for lung cancer has changed rapidly over the past few years toward individualized therapy. For certain subsets of patients, molecularly targeted agents have resulted in robust gains in overall survival and quality of life. However, for the majority of patients with nonsquamous non–small cell lung cancer (NSCLC), and for all patients with squamous NSCLC, chemotherapy remains the cornerstone of treatment. Chemotherapy provides modest therapeutic benefits in patients with advanced-stage disease. This longstanding paradigm is now going through a major shift with the advent of immunotherapy.

Updated Clinical Data

Monoclonal antibodies targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) receptors have demonstrated superiority over chemotherapy in three randomized clinical trials reported at the 2015 ASCO Annual Meeting.

Nivolumab (Opdivo), which targets the PD-1 receptor, was recently approved by the U.S. Food and Drug Administration for the treatment of patients with advanced-stage squamous NSCLC following disease progression on prior platinum-based chemotherapy. This approval was based on a phase III study demonstrating superior overall survival for nivolumab over docetaxel (9.4 months vs 6.0 months, hazard ratio = 0.59).1 The response rate and progression-free survival were also more favorable with nivolumab. Another study that compared nivolumab with docetaxel in patients with advanced nonsquamous histology also met its primary endpoint of improving overall survival (12.2 months vs 9.4 months, hazard ratio = 0.73).2

In both of these studies, the overall toxicity profile was more favorable with nivolumab. Treatment-related grade 3/4 adverse events were observed in 54% of patients treated with docetaxel, compared with 10% of patients treated with nivolumab.

Atezolizumab, a monoclonal antibody against PD-L1, was associated with improved outcomes when compared with docetaxel in a randomized phase II study reported by Spira and colleagues at the 2015 ASCO Annual Meeting.3 Pembrolizumab (Keytruda), another antibody against PD-1, and a number of other agents of this class have also demonstrated single-agent activity in lung cancer.4

Similar Scenario to EGFR Inhibitors

A consistent observation across these studies is the durability of benefits with immune checkpoint inhibitors. For patients who experience an objective response, the duration of response is significantly longer with immunotherapy than with chemotherapy. This finding makes immunotherapy a particularly appealing option for the treatment of lung cancer. However, the response rates for all of these agents are approximately 15% to 20% in unselected patients, which implies that the therapeutic benefits are limited to a subset of patients who receive immune checkpoint inhibitors.

This situation is not unlike the early years of development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors; they were associated with objective responses in approximately 15% of patients, which was attributed later to the presence of an activating EGFR mutation. It is therefore imperative to identify biomarkers to select patients to maximize the impact of these novel therapies in patients with lung cancer.

Expression of PD-L1 in the tumor tissue has emerged as a putative biomarker in the studies reported recently. With atezolizumab, the outcomes were significantly superior for patients with expression of PD-L1 in either the tumor cells or immune-infiltrating cells. The efficacy of pembrolizumab was also higher in patients who had PD-L1–positive tumors, which was defined as positive staining by immunohistochemistry in more than 50% of cells.

In the studies with nivolumab, the predictive potential of PD-L1 expression was variable. In the trial for squamous cell carcinoma, PD-L1 expression was not a predictive marker for efficacy. However, the nonsquamous cell study demonstrated improved efficacy for nivolumab in patients with PD-L1–positive tumors. In PD-L1–negative cancers, the efficacy did not appear to be superior for nivolumab over docetaxel. Based on these observations, it is likely that the approval of certain immune checkpoint inhibitors will be restricted to patients with PD-L1–positive tumors.

PD-L1 Biomarker Limitations

Assessment of PD-L1 expression is subject to several potential limitations. Tumor heterogeneity is well known in NSCLC. This could influence PD-L1 expression, since the majority of biopsies are obtained by a fine-needle approach in patients with advanced lung cancer. Dynamic changes in PD-L1 expression with time and intervening therapy can also limit interpretation of results. This might necessitate fresh tumor biopsy for patients who are under consideration for immune checkpoint inhibitor therapy. The antibody utilized for immunohistochemistry is unique for the companion diagnostic test developed for each checkpoint inhibitor.

Furthermore, for each of the agents under development, the threshold for PD-L1 positivity is defined differently. This will undoubtedly pose challenges to the pathologist and treating physician, since tissue availability is limited in patients with NSCLC. In addition, scoring for the biomarker is subject to interobserver variability.

For all these reasons, assessment of PD-L1 expression is likely to be challenging in some patients. The International Association for Study of Lung Cancer (IASLC) plans to compare the antibodies used for iummunohistochemistry for various checkpoint inhibitors against one another to arrive at a common test that could be used to select treatment. This effort is critical to make biomarker assessment possible in “real-world” settings.

Potential Predictors Under Study

Although PD-L1 testing has been the centerpiece of biomarker evaluation in NSCLC, it is important to continue efforts to identify other potential markers. A recent study reported a strong correlation between mutational load and potential for benefit with checkpoint inhibitors.5 Smoking status is another potential predictor for benefit, with a higher response rate noted in current or former smokers.6 In addition, changes in circulating T-cell subpopulations are under study as potential predictive markers.

Clinical Questions Remain

In the clinical setting, a number of important questions follow the recent success with checkpoint inhibitors. Studies are already underway to compare PD-1 inhibitors with combination chemotherapy in the front-line setting for advanced NSCLC. Combination strategies to evaluate checkpoint inhibitors with chemotherapy are being evaluated.

The optimal duration of therapy is unknown, and the present approach involves treatment until disease progression. It is conceivable that continued treatment might not be necessary in at least certain patient subsets, and hence randomized clinical trials should be conducted to address this issue.

In addition, efforts are underway to integrate immune checkpoint inhibitors in earlier stages of NSCLC. A phase III study is comparing treatment with a checkpoint inhibitor following concurrent chemoradiotherapy for stage III disease that is not amenable to surgical resection. In patients with resected NSCLC, the ALCHEMIST study will compare nivolumab with observation following adjuvant chemotherapy. The role of checkpoint inhibitors in combination with CTLA-4 (cytotoxic T-lymphocyte–associated antigen) inhibitors and certain molecularly targeted agents is also under evaluation.

In summary, recent studies have established immune checkpoint inhibition as an effective treatment strategy for advanced NSCLC. These exciting results open tremendous possibilities for future research studies and keep our hope alive that cures can be achieved for at least a subset of patients with advanced NSCLC. ■

Disclosure: Dr. Ramalingam has served on ad hoc advisory board meetings for and has received honoraria from AstraZeneca, Genentech, Merck, and Bristol-Myers Squibb.


1. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123-135, 2015.

2. Paz-Ares L, Horn L, Borghaei H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract LBA109.

3. Spira AI, Park K, Mazières J, et al: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). 2015 ASCO Annual Meeting. Abstract 8010.

4. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

5. Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Science 348:124-128, 2015.

6. Soria JC, Cruz C, Bahleda R, et al: Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer. 2013 European Cancer Congress. Abstract 3408. Presented September 29, 2013.

Dr. Ramalingam is Professor of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.