ONCAlert | Upfront Therapy for mRCC

Emerging Treatment Strategies for Nonsquamous Non-Small Cell Lung Cancer

Published Online: Nov 20,2017
Although great advances have been made in the treatment of advanced, metastatic, and nonresectable, nonsquamous, non–small cell lung cancer (NSCLC), prognosis remains relatively poor, and recurrence is common. Howard Jack West, MD, medical director of the Thoracic Oncology Program at Swedish Cancer Institute, Seattle, Washington, explained in an abstract that “platinum-based chemotherapy is the current standard of care for patients with newly diagnosed advanced nonsquamous NSCLC. The combination of platinum-based chemotherapy and pemetrexed [Alimta] provides comparable benefit to [patients] as other standard platinum doublets commonly used and has a favorable toxicity profile. However, the survival benefit conferred by this combination leaves considerable room for improvement.”1

The Evolving Components of Combination Therapies

For some patient populations, such as those with high PD-L1 expression, single-agent immunotherapy may be an option; however, for the majority of patients with nonsquamous NSCLC, combination therapy is essential for successful first-line treatment. PD-1 and PD-L1 frequently serve as the backbone of combination immunotherapy regimens. According to Patrick Ott, MD, PhD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, checkpoint inhibitors are favorable because “the established antitumor activity of PD-1/PD-L1 inhibition as monotherapy in a wide spectrum of cancers coupled with its favorable toxicity profile provides a strong rationale for its use as a backbone for combinatorial strategies. Despite the vastly accelerated pace of preclinical and clinical investigation of other cancer immunotherapy agents in recent years, this combination of broad single-agent activity and tolerability seen with PD-1 pathway inhibition is so far unparalleled; there are no other compounds on the horizon that could take the place of PD-1 pathway inhibition for this purpose.”2

Several ongoing and upcoming trials are investigating the combination of immunotherapy with chemotherapy regimens. Chemotherapy is already a part of the approved first-line pembrolizumab combination treatment regimen. Explaining the rationale behind chemotherapy and immunotherapy combinations, Ott wrote, “Chemotherapy-induced cancer cell death can promote tumor antigen presentation, potentially leading to priming of tumor-specific T cells in addition to its capacity to directly stimulate immune effectors and inhibit immune suppressive factors. Therefore, chemotherapy has the potential to convert a non-inflamed tumor into an inflamed one and may thus lead to synergy with PD-1/PD-L1 inhibition particularly in non-inflamed, chemotherapy-sensitive tumors.”2

Pemetrexed, the folic acid analog, is often used in conjunction with carboplatin or cisplatin to form the chemotherapy component of combination immunotherapy. This is primarily due to the favorable safety profile of pemetrexed compared with other options. Martin Edelman, MD, a medical oncologist and chair of the Department of Hematology/Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania, noted that a clinical trial evaluating pemetrexed and gemcitabine found "highly significant advantages for the pemetrexed arm in both hematologic and nonhematologic toxicities."3,4

Another emerging strategy in combination immunotherapy is the use of PD-L1 inhibitors with "the blockade of the non-redundant and complementary checkpoint (cytotoxic T lymphocyte-associated protein 4 [CTLA-4])," according to Ott.2 By targeting multiple immune checkpoints from different angles, the immunotherapy outcomes may be amplified.2 Ipilimumab (Yervoy) is the main CTLA-4 inhibitor being investigated for combination treatment of nonsquamous NSCLC, although tremelimumab is also under investigation in combination with durvalumab (Imfinzi).5 Combining PD-L1 inhibitors with CTLA-4 inhibitors may lead to an increase in immune-related adverse events (AEs).2

Confirming Efficacy and Safety of Pembrolizumab Plus Pemetrexed/Carboplatin

Pembrolizumab (Keytruda) in combination with pemetrexed and carboplatin received accelerated approval from the FDA for patients with nonsquamous NSCLC regardless of PD-L1 expression levels.6 The phase II trial upon which the approval was based evaluated partial responses and progression-free survival (PFS), but the FDA required further evaluation using clinically meaningful endpoints, such as overall survival (OS). Corey Langer, MD, director of Thoracic Oncology at the Hospital of the University of Pennsylvania in Philadelphia and senior author on the phase III KEYNOTE-021 study, explained that the accelerated approval of first-line combination pembrolizumab “is an important milestone, but raises a number of issues since it occurred in the absence of phase III data or a proven survival advantage and was based on a relatively small phase II trial with just 120 enrollees. In this regard, we await the results of the ongoing phase III trial, KEYNOTE-189.”7

KEYNOTE-1898 is ongoing and will compare pembrolizumab plus chemotherapy with chemotherapy alone in 570 chemotherapy-naïve patients with an ECOG performance status (PS) of 0 or 1. After 4 initial cycles of combination therapy or chemotherapy alone, patients will continue pembrolizumab for 35 cycles or until disease progression, intolerable toxicity, or withdrawal. For patients who progress on chemotherapy alone, crossover to pembrolizumab is allowed. Patients will be stratified by smoking status, cisplatin or carboplatin, and PD-L1 status (FIGURE 1).8 Per Langer, “the continued approval of pembrolizumab frontline with chemotherapy will depend on successful outcomes in KEYNOTE-189.”7


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Emerging Treatment Strategies for Nonsquamous Non-Small Cell Lung Cancer
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