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Current Treatment Strategies in Nonsquamous Non-Small Cell Lung Cancer

Published Online: Nov 20,2017
Nonsquamous non‒small cell lung cancer (NSCLC) is a heterogeneous disease with multiple treatment options dependent upon staging, presence of metastasis, and patient factors—including presence of comorbidities—among other considerations. As such, current treatment options include surgical resection, chemotherapy, radiation, immunotherapy, and targeted therapy.1 While conventional treatment for patients without driver mutations is platinum-based chemotherapy, much of the field has shifted to first-line use of agents such as bevacizumab (Avastin) or pembrolizumab (Keytruda) plus pemetrexed (Alimta) and carboplatin.

As explained by Thu Oanh Dang, PharmD, BCOP, clinical oncology pharmacist at Memorial Sloan Kettering Cancer Center, New York, “for about 2 and a half decades after cisplatin became widely used in the late 1970s, the therapeutic armamentarium of the medical oncologist for the treatment of NSCLC was limited largely to cytotoxic chemotherapy.”2 Despite advances in chemotherapy, however, "the development of therapeutic resistance to both cytotoxic chemotherapy and targeted therapy is universal" for patients with advanced or metastatic disease. Fortunately, the development and approval of checkpoint inhibitors and anti–VEGF therapies over the past decade provide attractive options for delaying recurrence and improving overall survival (OS).

Accelerated Approval for Pembrolizumab Combined With Pemetrexed/Carboplatin

In May 2017, pembrolizumab, an immune checkpoint inhibitor, was granted accelerated approval by the FDA as a part of first-line combination therapy with pemetrexed and carboplatin for untreated, metastatic, nonsquamous NSCLC, regardless of programmed death ligand-1 (PD-L1) expression levels.3 The accelerated approval expanded on previous indications for pembrolizumab, which was already approved as a first-line monotherapy for patients with NSCLC with high PD-L1 expression or second-line therapy for NSCLC with any PD-L1 expression.1

Approval for pembrolizumab as first-line combination therapy was based on cohort G of the phase II KEYNOTE-021 study that evaluated carboplatin and pemetrexed with or without pembrolizumab. In this cohort, 123 patients with chemotherapy-naïve, stage IIIb/IV, nonsquamous NSCLC were stratified by PD-L1 expression, and were randomly assigned to receive 4 cycles of carboplatin and pemetrexed with or without 24 months of pembrolizumab. Pemetrexed maintenance therapy was allowed in both groups.4

After a median follow-up of 10.6 months, more patients in the pembrolizumab group compared with the chemotherapy group achieved an objective response (55% vs 29%, respectively; P = .0016).4 For patients in the pembrolizumab group, no difference in objective response rate (ORR) was noted for patients with a PD-L1 tumor proportion score (TPS) of less than 1% (57%) or patients with a PD-L1 TPS of at least 1% (54%). The researchers, however, noted an increased ORR among patients with PD-L1 expression of 50% or more compared with those with a score of 1% to 49% (80% vs 26%) (TABLE 1). The incidence of severe treatment-related adverse events (AEs) was similar between the groups (39% vs 26%), with anemia (12%) and decreased neutrophil count (5%) occurring most commonly in the pembrolizumab group (TABLE 2).4


In a news release from Merck, the developer of pembrolizumab, announcing the accelerated FDA approval for pembrolizumab as a first-line combination therapy agent, Corey Langer, MD, lead investigator of the KEYNOTE-021 study, noted, “This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non–small cell lung cancer, irrespective of PD-L1 expression.” Importantly, emphasized, Langer, director of the Thoracic Oncology Program at Penn Medicine in Philadelphia, Pennsylvania, "Physicians should continue to use each patient’s individual characteristics—including biomarker status, histology, and other clinical factors—to determine the best treatment plan for each person."5 Phase III trials confirming these findings are ongoing.6


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Current Treatment Strategies in Nonsquamous Non-Small Cell Lung Cancer
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