Deborah B. Doroshow, MD, PhD
Roy S. Herbst, MD, PhD
We are in the midst of a paradigm shift in lung cancer. In the past 2 years, the anti–programmed cell death protein 1 (anti–PD-1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) were found to improve overall survival in the second-line setting compared with docetaxel for patients with both squamous and adenocarcinoma subtypes of non–small cell lung cancer (NSCLC).1-3 The obvious next step was to assess the efficacy of these agents in the first-line setting as compared with standard platinum-doublet chemotherapy.
In the KEYNOTE-024 study, the results of which were just published in The New England Journal of Medicine and are reviewed in this issue of The ASCO Post, 305 patients with previously untreated advanced NSCLC and programmed cell death ligand 1 (PD-L1) expression of more than 50% by immunohistochemistry were randomized to receive treatment with pembrolizumab at 200 mg every 3 weeks or the investigator’s choice of platinum-doublet chemotherapy. Patients with mutations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) rearrangements were excluded from the study. Crossover was allowed in the instance of disease progression; ultimately, 43.7% of patients crossed over from chemotherapy to pembrolizumab. The primary endpoint was progression-free survival; secondary endpoints included overall survival, objective response rate, and toxicity.
Practice-Changing Implications
The results of the KEYNOTE-024 study were exciting. The median progression-free survival was significantly improved in patients receiving first-line pembrolizumab (10.3 months; 95% confidence interval [CI] = 6.7 months to not reached) compared with those receiving chemotherapy (6.0 months, 95% CI = 4.2–6.2 months), with a hazard ratio (HR) for disease progression or death of 0.5 (P < .001). Overall survival at 6 months was 80.2% in the pembrolizumab group vs 72.4% in the chemotherapy group (HR = 0.6, 95% CI = 0.41–0.89, P = .005), with median overall survival not reached in either group. The response rate was also superior in the pembrolizumab group (44.8% vs 27.8%), which experienced fewer adverse events, including those of grade 3 or higher. The trial was stopped early given the clear overall survival advantage of pembrolizumab.4
The future is bright for immunotherapy, as long as we continue to question why new agents are effective in some patients but not in others.— Deborah B. Doroshow, MD, PhD, and Roy S. Herbst, MD, PhD
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These findings are practice changing. On October 25, the U.S. Food and Drug Administration (FDA) approved the use of pembrolizumab in the first-line setting for patients with advanced NSCLC and PD-L1 expression of 50% or greater. These results also necessitate that PD-L1 testing become standard for all patients with advanced NSCLC.
Questions Remain
Yet many questions remain. Of the patients randomized, all of whom had PD-L1 expression of 50% or greater, the response rate was only 44.8%. Clearly, PD-L1 staining is an imperfect marker. Even as PD-L1 assays become more standardized, there is imperfect interoperator reliability in assessing positivity. Other means of stratification, such as gene signatures and epitope load, may need to be used in conjunction with PD-L1 expression to better predict response to immune checkpoint inhibitors.
Moreover, we need to ensure we are assessing PD-L1 expression in the correct part of a tumor specimen. Recently discovered tertiary lymphoid structures associated with lung cancers may prove to be a missing piece of this puzzle.5
Patient outcomes in KEYNOTE-024 were promising. Yet the median duration of follow-up is still only 11.2 months. It will be critical to evaluate progression-free and overall survival at later time points, given the phenomenon of the “long tail of survival” for patients who derive durable responses to immune checkpoint inhibitors. Furthermore, the more than 40% of patients who crossed over from chemotherapy to pembrolizumab make interpretation of these results difficult. Was the overall survival benefit of pembrolizumab due to a true benefit of this drug in the first-line setting, or did it result from the more than 50% of patients who did not receive pembrolizumab in the second line?
Patient selection, while in line with previous studies of immune checkpoint inhibitors, leaves questions about those excluded from the study but who might be reasonable candidates for first-line pembrolizumab. For example, patients with untreated brain metastases were excluded from the trial. However, a recently published phase II study of pembrolizumab in patients with melanoma or NSCLC and at least one untreated or progressive brain metastasis found that the drug had an acceptable safety profile in this population and produced responses in the brain in some patients.6
As is the case with all trials of immune checkpoint inhibitors, patients with preexisting autoimmune diseases were excluded. However, a retrospective study of 52 patients with advanced melanoma and preexisting autoimmune conditions who were treated with either pembrolizumab or nivolumab found that although approximately one-third of patients experienced a flare of their autoimmune disease, they were easily treated, and objective response rates were in line with previously published studies of both agents.7
Finally, KEYNOTE-024 excluded patients whose tumors had mutations in EGFR or rearrangements of ALK. Although these patients appear to have lower response rates to PD-1 inhibitors, they almost always develop resistance to targeted therapy.8 Prospective studies evaluating response rates of such patients to PD-1 inhibitors are warranted, as responses to immune checkpoint inhibitors can often be more durable than responses to drugs that target EGFR or ALK.
KEYNOTE-024 vs CheckMate 026
Enthusiasm about the potential for using nivolumab in the first-line setting was somewhat tempered by the findings of the CheckMate 026 phase III trial of first-line nivolumab compared with platinum-based doublet chemotherapy in patients with advanced NSCLC, which were recently presented at the 2016 European Society for Medical Oncology (ESMO) Congress.9 In that study, the investigators found that in patients with 5% or greater PD-L1 expression, progression-free survival was actually slightly worse (although not statistically significantly so) in patients who received nivolumab (4.2 months with nivolumab vs 5.9 months with chemotherapy, HR = 1.15, 95% CI = 0.91–1.45, P = .25) and that overall survival was no different (14.4 months with nivolumab vs 13.2 months for chemotherapy, HR = 1.02, 95% CI = 0.80–1.30).
Why KEYNOTE-024 was such a success while CheckMate 026 was not is unclear. The latter evaluated patients who expressed PD-L1 at levels of 1% or higher, but the response rate to first-line nivolumab among the subgroup with 50% or more PD-L1 expression (34%) was lower than the objective response rate to pembrolizumab in KEYNOTE-024 (44.8%). This finding is unlikely to be a reflection of real differences between the two agents, which share the same target. Instead, the discrepancy may be a result of patient selection. For example, fewer patients in the nivolumab group had more than 50% PD-L1 expression (32.5% vs 46.7%) and thus were less likely to respond.
Striving to Do Better
Where do we go from here? The durable responses achieved with single-agent PD-1 blockade are impressive, but the clinical trials community should strive to do even better. New studies such as KEYNOTE-042 are examining pembrolizumab in patients with more than 1% PD-L1 expression as well as the potential benefits of combining immunotherapy with chemotherapy. The KEYNOTE-021 study, recently reported in The Lancet Oncology,10 found that pembrolizumab given with chemotherapy for patients with chemotherapy-naive, advanced nonsquamous NSCLC without EGFR or ALK aberrations resulted in improved objective response rates and progression-free survival vs those randomized to chemotherapy alone. This may prove to be an important strategy for patients, especially with low PD-L1 expression.11
Another group of ongoing studies, including CheckMate 227 and the MYSTIC trial, are assessing the role of dual immune checkpoint blockade (ipilimumab [Yervoy] plus nivolumab and durvalumab plus tremelimumab, respectively) in the first-line setting. The future is bright for immunotherapy, as long as we continue to question why new agents are effective in some patients but not in others. ■
Disclosure: Drs. Doroshow and Herbst reported no potential conflicts of interest.
Dr. Doroshow is a Clinical Fellow in Medicine (Medical Oncology) at Yale Comprehensive Cancer Center, and Dr. Herbst is Chief of Medical Oncology; Director, Thoracic Oncology Research Program, Yale Comprehensive Cancer Center.
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. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627-1639, 2015.
3. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 387:1540-1550, 2016.
5. Joshi NS, Akama-Garren EH, Lu Y, et al: Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43:579-590, 2015.
6. Goldberg SB, Gettinger SN, Mahajan A, et al: Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: Early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17:976-983, 2016.
8. Gainor JF, Shaw AT, Sequist LV, et al: EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A retrospective analysis. Clin Cancer Res 22:4585-4593, 2016.
10. 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.
11. Herbst RS, Sznol M: Diminished but not dead: Chemotherapy for the treatment of NSCLC. Lancet Oncol 17:1464-1465, 2016.
