Lung cancer is by far the leading cause of cancer death in the United States and worldwide, comprising nearly 25% of all cancer deaths.¹ Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined.² This dismal outcome is due, in part, to the fact that the disease is often insidious—more than half of patients present with metastatic lung cancer at the time of diagnosis.³

Approximately 85% of newly diagnosed lung cancer cases are non–small cell lung cancer (NSCLC). NSCLC has a poor prognosis, and survival time is often short because of limited treatment options.^4,5

Evolving Treatment of NSCLC

Over the past 2 decades, advances in research have yielded major breakthroughs in the understanding, diagnosis, and management of lung cancer. Historically, advanced NSCLC was treated as a single disease, and platinum-based chemotherapy was the first-line treatment of choice for all unresectable patients. However, in recent years, treatment guidelines have evolved to reflect the availability of new therapeutic options, as well as improvements in clinical and biological patient selection.^6,7

The discovery of specific driver mutations—such as the abnormal fusion of the anaplastic lymphoma kinase (ALK) and mutation of the epidermal growth factor receptor (EGFR)—and the subsequent development of agents to target these alterations has led to a notable improvement in the treatment of metastatic NSCLC. In those patients with actionable mutations, progression-free survival is significantly improved when treated with targeted therapy compared to chemotherapy. Among patients who carry EGFR, ALK, ROS1, and BRAF mutations, response rates range from 50% to 80% with targeted therapy.⁵

For patients without oncogenic drivers, immune checkpoint inhibitors are now the cornerstone of therapy in the first-line setting for advanced NSCLC, either alone or in combination with chemotherapy and/or another immune checkpoint inhibitor.⁸ The incorporation of immunotherapy has led to improved outcomes for patients.

PD-L1–Negative NSCLC

PD-L1 is a coregulatory molecule that can be expressed on tumor cells, helping the cancer cell evade T-cell–mediated death. Immune checkpoint blockade removes the inhibitory signals of T-cell activation—enabling the restoration of immune system surveillance by stimulating tumor-reactive T cells to overcome regulatory mechanisms and induce cancer cell apoptosis.

For patients with negative PD-L1 expression, no definite optimal therapeutic strategy has been identified. Due to a lack of phase III head-to-head clinical trials comparing chemotherapy, antiangiogenic therapy, and immunotherapeutic agents, the optimal first-line treatment for patients with advanced PD-L1–negative NSCLC has yet to be established.¹⁰

The reported prevalence of PD-L1 expression < 1% in patients with NSCLC varies among clinical trials, ranging from one-third to almost one-half of those diagnosed.^11-13 A retrospective, observational real-world analysis suggests that among patients with advanced NSCLC who receive first-line immunotherapy plus chemotherapy, tumor PD-L1 expression levels > 50% are associated with longer median overall survival, regardless of histology. The subset of patients with tumor PD-L1 expression < 1% reported the shortest median overall survival.¹⁴ Moving forward, the oncology community awaits additional analyses outlining potential treatment options for patients with PD-L1–negative NSCLC.

The guidelines for the treatment of NSCLC vary based on PD-L1 expression; patients with high PD-L1 expression (> 50%) can often be treated successfully with a single immunotherapeutic agent, but this approach may not be effective in patients with PD-L1–negative disease.¹⁵ “In my experience, there is limited activity in using immunotherapy monotherapy in patients who are PD-L1 negative,” stated Ani Balmanoukian, MD, Director of Thoracic Oncology, Associate Director of the Phase I Immune-Oncology Program, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles. “However, we’ve seen compelling and promising results in treating patients with dual immunotherapy combinations in the setting of negative PD-L1 expression.”

We've seen compelling and promising results in treating patients with dual immunotherapy combinations in the setting of negative PD-L1 expression. Ani Balmanoukian, MD

Dual Immunotherapy Combinations

Prior to the study of dual immunotherapy combinations in NSCLC, this approach had already proven successful in multiple tumor types.^16,17 The most commonly used immune checkpoint inhibitors for patients with NSCLC include monoclonal antibodies against PD-1, PD-L1, and anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4).

Because lung cancer is a heterogeneous malignancy with diverse pathologic features, the combination of immune checkpoint inhibitors with two distinct but complementary mechanisms of action—such as an anti–PD-(L)1 antibody combined with a CTLA-4 antibody—is a potential treatment approach for some patients. “Blocking both the CTLA-4 and the PD-(L)1 pathways leads to a synergistic effect in terms of immune activation and anti-tumor activity,” explained Dr. Balmanoukian.

Blocking both the CTLA-4 and the PD-(L)1 pathways leads to a synergistic effect in terms of immune activation and anti-tumor activity Ani Balmanoukian, MD

Chemotherapy Plus Dual Immunotherapy Combinations

Although combining two immunotherapeutic agents is beneficial alone, there remains a need in some patients for prompt disease control during the first few weeks of treatment. Due to its cytotoxic effect, chemotherapy at the beginning of treatment can quickly reduce the bulk of malignant cells. “Clinically, I favor using a combination of immunotherapy and chemotherapy when I need an immediate cytoreductive effect from chemotherapy, especially in patients who are very symptomatic at the time of diagnosis,” said Dr. Balmanoukian.

In addition to rapid disease control, chemotherapy can induce immunogenic cell death and increase PD-L1 expression on malignant cells.^18-20 Another benefit of this approach includes the shorter duration of chemotherapy treatment. The indiscriminate toxic effect of many platinum-based chemotherapies may necessitate discontinuation or alteration of therapy. Utilizing short-course chemotherapy may increase the likelihood that patients will be able to complete treatment.²¹

Considerations and Unique Patient Subsets When Determining First-Line Therapy

Without a direct comparison of all available immunotherapy-based treatment options, selecting the most appropriate first-line treatment can pose a challenge for clinicians. According to Dr. Balmanoukian, choosing therapy is a decision based on multiple clinicopathologic factors. “I tend to consider all aspects of an individual in my treatment decision planning,” she explained. “The most important factors that go into the decision-making process include the result of the next-generation sequencing and whether the patient has a targetable mutation. I also look at the PD-L1 status and the bulk and location of a patient’s disease.”

Targetable Mutations and PD-L1 Status

For newly diagnosed patients with metastatic NSCLC who test negative for PD-L1, Dr. Balmanoukian ensures that a comprehensive next-generation sequencing panel has ruled out a targetable mutation. “In patients without a targetable mutation and a negative PD-L1, I tend to favor using combination chemotherapy and immunotherapy in the upfront setting,” she explained.

Tumor Size, Load, and Location

The bulk of a patient’s tumor burden, as well as the presence of liver metastasis, also factors into Dr. Balmanoukian’s decision-making process. “If a patient has a significant tumor burden with liver metastasis, I will favor using combination chemotherapy and immunotherapy. If a patient has a low tumor burden, I will favor using immunotherapy,” she said.

Conclusion

The treatment of PD-L1–negative NSCLC changed substantially with the discovery of immunotherapy. Treatment algorithms continue to evolve and expand to include novel treatment options and new strategies to maximize the survival potential of multiple drug classes. Emerging data and clinical trials will continue to expand the treatment armamentarium available to clinicians—and hopefully improve the understanding of how the various first-line treatment combinations can meet individual patient needs—to treat this complex and aggressive disease.

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