Non–Small Cell Lung Cancer: Emerging Concepts for Checkpoint Inhibitors

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With checkpoint inhibitors vitally important in the treatment of advanced non–small cell lung cancer (NSCLC), clinicians must become familiar with the nuances of their use. At the 2017 Debates and Didactics in Hematology and Oncology Conference in Sea Island, Georgia, Suresh S. Ramalingam, MD, presented his thoughts on this topic. Dr. Ramalingam, a lung cancer specialist, is the Roberto C. Goizueta Chair for Cancer Research, Assistant Dean for Cancer Research, and Deputy Director of the Winship Cancer Institute at Emory University, Atlanta.

Pembrolizumab Plus Chemotherapy: When?

In combination with chemotherapy, pembrolizumab (Keytruda) can be used regardless of the expression of the programmed cell death ligand 1 (PD-L1). The drug was approved in combination with chemotherapy based on the results of the phase II KEYNOTE-021 trial of 120 patients. Median progression-free survival was 13 months with the combination and 8.9 months with chemotherapy alone.1 Confirmatory studies to test this combination in a larger population are underway, he said. 

Unfortunately, the study was not informative as to which patients benefit most from pembrolizumab plus a platinum doublet, since subsets according to PD-L1 thresholds were small. “So at this point in my own practice, for patients with ≥ 50% PD-L1 expression, I use pembrolizumab as monotherapy because of the solid efficacy results2 in this population,” he said. 

Adding [checkpoint inhibitors] earlier in the disease in efforts to improve cure rates for lung cancer remains a top priority.
— Suresh S. Ramalingam, MD

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“If the patient has PD-L1 < 50%, I consider chemotherapy plus pembrolizumab as one of the options,” he continued. “For instance, if the patient is not doing well, has severe symptom burden, and probably has one shot—that is, one line of therapy is likely all that the patient will receive—I give all three drugs at one time. On the other hand, if the patient is doing well and I feel like we can wait and give the checkpoint inhibitor later, then I treat those patients with chemotherapy in the front line and use the checkpoint inhibitor later. It’s a patient-to-patient discussion.”

Bevacizumab (Avastin) is also approved in the front-line setting for nonsquamous NSCLC. However, whether there is value to adding it to pembrolizumab plus chemotherapy is unknown, and its inclusion with the pembrolizumab/chemotherapy regimen is not recommended. For patients who received single-agent pembrolizumab in the first line and then had disease progression, bevacizumab could be added to the platinum doublet in the second line, he said.

Relapsed NSCLC: Which Agent?

The key clinical trials for pembrolizumab, nivolumab (Opdivo), and atezolizumab (Tecentriq) were similar in design, each comparing the checkpoint inhibitor to docetaxel. The hazard ratios for overall survival were consistent across those trials—0.71 to 0.73—suggesting their efficacy (and toxicity) are similar, he said. 

“The choice among the checkpoint inhibitors comes down to which drug you are comfortable with and perhaps to the administration schedule,” he said. While nivolumab is dosed more frequently (every 2 weeks), this is not necessarily a drawback. “Some patients like the idea of being seen more frequently by their physician, especially if they don’t live too far from the treatment center,” he added. 

Histology: Relative Benefits? 

Early on, we thought patients with squamous cell disease did a little better with checkpoint inhibitors, compared to patients with nonsquamous histology, but at this point we consider those differences to be relatively modest,” he said. “Compared to the standard of care, the use of checkpoint inhibitors is superior in both histologies, but we cannot make the case that any one drug is preferred in one histology or the other, vs another in the class.” 

Dual Checkpoint Inhibition

CheckMate 012 evaluated nivolumab plus ipilimumab (Yervoy) and analyzed data according to dose/schedule and PD-L1 expression.3 Interestingly, the results were different from what has been observed for this combination in melanoma, according to Dr. Ramalingam. 

“In melanoma, if you have a PD-L1–high tumor, nivolumab alone does well. If expression is low, then the combination makes up for what you don’t have in terms of PD-L1 status. In lung cancer, however, it’s the opposite,” he explained. 

In CheckMate 012, for patients with ≥ 1% PD-L1 expression, response rates (depending on dose/schedule) ranged from 21% to “not reached,” while they were only 11.5% for nivolumab alone. For patients with < 1% expression, however, response rates were 14% to 22% with the combination and 15% with the single agent. 

“In the low expressors, response rates were relatively modest with the combination and not much different from nivolumab alone,” he noted. “So at this point, based on what we know from a relatively small number of patients, PD-L1–high patients appear to do better with combined checkpoint inhibition.”

These data, however, should not necessarily be used in treatment selection, he cautioned. “The data are too early to make that decision,” he commented. 

Furthermore, the combination of nivolumab plus ipilimumab is not approved in NSCLC, so patients must be treated with this regimen on a clinical trial. Data from those ongoing trials will determine whether the combination should be used, based on PD-L1 expression, he said.

He has found that this doublet is “slightly more toxic but manageable,” vs single-agent checkpoint inhibition. “The dose of ipilimumab determines the severity.” The suggested dose for NSCLC is nivolumab at 3 mg and ipilimumab at 1 mg (every 6 weeks).

Positive Results for Durvalumab 

Dr. Ramalingam noted that yet another checkpoint inhibitor—durvalumab (Imfinzi)—may soon enter the mix, based on results recently announced (with details to be presented at the 2017 European Society for Medical Oncology Annual Congress). In the PACIFIC trial, durvalumab, given for up to 1 year, improved progression-free survival in patients with stage III unresectable disease who had completed chemotherapy and radiotherapy. 

“Durvalumab as a single agent for consolidation was superior to placebo,” he noted. “This would be a new indication for a checkpoint inhibitor.”

Checkpoint Inhibition in Early-Stage Disease

“Adding these drugs earlier in the disease in efforts to improve cure rates for lung cancer remains a top priority,” Dr. -Ramalingam said. The ongoing ALCHEMIST trial will be important in determining their benefit there, as well as the benefit of targeted agents in patients with mutations. In patients lacking targetable mutations, nivolumab will be compared to observation.

Assays: Room for Improvement

Refinement in the use of assays for PD-L1 expression is much needed, Dr. Ramalingam emphasized, pointing out that the companion diagnostics use four different assay clones for slide staining (SP142, 22C3, 28-8, and SP263), and they yield different results. 

“There is significant variation among these antibodies, perhaps most notably for the SP142 antibody that is used with atezolizu-mab. It’s associated with a lower ability to detect PD-L1 compared to the other antibodies. It undercalls PD-L1 expression, so if a patient is negative by SP142, could that patient be positive with SP263?” he asked. This might explain, he added, why atezolizumab produced responses even in some “PD-L1–negative” patients in the OAK trial.

“Our question is whether we can cross-interpret the results of these assays, regardless of which drug we decide to give,” he said. “The academic and cooperative trials groups need to arrive at a consensus on the one antibody we could all use consistently, instead of using the separate companion diagnostics.” 

Other Potential Biomarkers 

Dr. Ramalingam predicted that “liquid biopsies” may someday help determine treatment response, based on his lab’s finding of increased programmed cell death protein 1 (PD-1)–positive CD8 T cells in the peripheral blood of patients treated with an anti–PD-1 agent.5 

“We showed that by studying PD-1 changes early in the course of therapy, we may be able to identify patients who derive benefit,” he said. “It was based on a small group of patients, but we saw a trend.”

Costimulation of Immune System 

Dr. Ramalingam cautioned that the best results with immunotherapy will come from more than simply blocking PD-1/PD-L1. “Our group showed that PD-1 blockade by itself does not provide the immune system with all it needs to have a strong antitumor response,” he said. 

Their study showed that rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent.6 CD28, therefore, could be a biomarker for response as well as a treatment target.

“CD28 costimulation may be a critical factor,” he said. “The first step might be to look at CD28 in the tumor to see if that will predict for benefit from PD-1 inhibition. If you don’t get the costimulatory signals from CD28, no matter how effectively you block the PD-1 pathway, you may not get a response.” ■

DISCLOSURE: Dr. Ramalingam serves on ad hoc advisory boards for AstraZeneca, Ariad, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Genentech, and Merck.


1. Langer CJ, Gadgeel SM, Borghaei H, et al: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 2016

2. Reck M, Rodríguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823-1833, 2016.

3. Rizvi NA, Gettinger SN, Goldman MD, et al: Safety and efficacy of first-line nivolumab (anti-programmed death-1 [PD-1]) and ipilimumab in non-small cell lung cancer. 2015 World Conference on Lung Cancer. Abstract 786. 

4. Barlesi F, Park K, Ciardello F, et al: Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in advanced NSCLC. 2016 ESMO Congress. Abstract LBA44. Presented October 9, 2016.

5. Kamphorst AO, Pillai RN, Yang S, et al: Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci USA 114:4993-4998, 2017

6. Kamphorst AO, Wieland A, Nasti T, et al: Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423-1427, 2017.