By Gregory A. Masters, MD, FACP, FASCO, and Dhaval Shah, MD
- Immune checkpoint inhibitors show promise in combating lung cancer and other malignancies by altering the tumor microenvironment and blocking the immune system evasion that allows cancers to grow and proliferate.
- Two anti–PD-1 antibodies, nivolumab and pembrolizumab, are now in clinical use. PD-L1 antibodies such as atezolizumab and MEDI-4736 are in clinical development.
- Platinum-based combination chemotherapy remains the standard first-line treatment for advanced NSCLC. Pemetrexed and/or bevacizumab are often used as maintenance treatment in patients with responding or stable disease. Second-line treatment in patients with advanced NSCLC has traditionally involved switching the chemotherapeutic agent, with docetaxel as one standard option.
- Although progress has been made, a number of questions remain. How do we apply our knowledge of the science of medicine, oncology, and now immunology to a group of patients with advanced lung cancer in a time of limited resources? How can we best help our patients and our society? How do we quantify the progress we are making?
A recent online search of “immunotherapy and lung cancer” produced 1,280,000 results; this is a reflection of the exploding field of immunotherapy in the management of this disease.
Immunotherapy research for cancer treatment predates even standard chemotherapy as cancer treatment. The idea of harnessing the body’s own immune response to fight a “foreign” invader sounds appealing, but overcoming the enemy of malignant cells that evolve from the body’s own cellular architecture has been much more daunting than initially perceived.
Early immunotherapy trials examined ways to harness or stimulate a natural defense. Vaccine therapy tried to try to teach the body’s immune system to recognize immunogenic proteins on cancer cells. Other immune stimulators have included interferon, an endogenous substance intended to non-specifically boost the immune response.
Unfortunately, these techniques failed to produce reliable, durable, and reproducible responses in advanced cancer or to decrease the risk of cancer recurrence in the adjuvant setting following local therapy.
More recently, immune checkpoint inhibitors have been developed and show great promise in combating lung cancer and other malignancies by altering the tumor microenvironment and blocking the immune system evasion that allows cancers to grow and proliferate.
Immunotherapy and Checkpoint Inhibition
The human immune system tries to eliminate malignant cells through various mechanisms. One of the most important regulators is the adaptive immune system, through the formation of cancer-specific T lymphocytes. In addition, natural killer cells, macrophages, and inflammatory cells penetrate the tumor microenvironment, and these antigen-presenting cells activate T cells, forming CD4 and CD8 cells. This immune pathway destroys cancer cells. However, in cancer, two normal inhibitory pathways (CTLA-4 and PD-1 pathways) have been found to suppress this T-cell response.
CTLA-4 is an immunoglobulin normally expressed by activated T cells that downregulates the early-phase T-cell response. Ipilimumab, an anti–CTLA-4 monoclonal antibody, was the first immune checkpoint inhibitor developed in the treatment of cancer. It was initially approved in treatment of metastatic melanoma based on an overall survival (OS) benefit seen in two randomized phase III trials. It has recently been approved for the adjuvant treatment of patients with completely resected stage III melanoma. However, because of broad-based expression of CTLA-4, treatment with ipilimumab can be associated with significant inflammatory and autoimmune toxicities.
The second pathway controlling the T-cell immune response is the PD-1 receptor and its ligands PD-L1 and PD-L2. After persistent antigen exposure, PD-1 gets expressed on the surface of the T cells. It then interacts with its ligand, PD-L1, which is normally expressed on immune cells such as natural killer cells and macrophages, as well as on the surface of cancer cells. This interaction leads to inhibition of kinase-mediated signaling pathways, and thus, inhibition of T-cell activation and response. PD-1 activation primarily affects the later stages of T-cell immune response, thus affecting the effector T cells and cytotoxic T lymphocytes in the lymph node and tissue microenvironment, such as that seen in and around tumor cells. PD-1 and PD-L1 pathway inhibition can, therefore, reactivate tumor-specific T lymphocytes, leading to a prolonged antitumor response. This research has led to the approval of two anti–PD-1 antibodies, nivolumab and pembrolizumab, now in clinical use. PD-L1 antibodies such as atezolizumab and MEDI-4736 are in clinical development.
Treatment of Advanced Non–Small Cell Lung Cancer
Platinum-based combination chemotherapy remains the backbone for treatment of advanced non–small cell lung cancer (NSCLC).1 Prior to 2008, histology was not considered important in the selection of a chemotherapy regimen. However, a randomized study published by Scagliotti et al.2 in 2008 showed the importance of histology in the treatment of NSCLC, establishing the value of a platinum agent with pemetrexed as a standard first-line treatment of non-squamous NSCLC. Bevacizumab can be incorporated in patients with non-squamous NSCLC. Pemetrexed and/or bevacizumab are often continued as maintenance treatment in patients with responding or stable disease. Second-line treatment in patients with advanced NSCLC has traditionally involved switching the chemotherapeutic agent, with docetaxel as one standard option.
Molecular characterization of NSCLC has become increasingly important as a predictive and prognostic marker to guide therapy. Gene alterations of EGFR, ALK, and ROS1 predict response to oral tyrosine-kinase inhibitors. Patients with these mutations have a better overall prognosis. However, nearly all of these patients with advanced disease will ultimately develop tumor progression, and, until recently, this left them with few standard options.
Immunotherapy in NSCLC
Based on the need for more effective treatment options for refractory NSCLC, the suspected high immunogenicity of these tumors with their abundant genetic mutations, and the proven efficacy of immune checkpoint inhibitors in melanoma, clinical trials were designed to evaluate the efficacy of PD-1 and PD-L1 inhibitors in lung cancer.
In a phase I expansion trial of nivolumab, 129 patients with advanced NSCLC who were heavily pretreated were treated with three different doses of nivolumab (1, 3, or 10 mg/kg) every 2 weeks. Median OS was 9.9 months, and patients receiving the dose of 3 mg/kg (the eventual U.S. Food and Drug Administration [FDA]-approved dose) had impressive OS rates of 56%, 42%, and 27% at 1, 2, and 3 years, respectively. Treatment was well tolerated, with 14% of patients experiencing grade 3/4 adverse events. Three deaths from presumed treatment-related pneumonitis occurred. Responses were seen in patients with both squamous and non-squamous histology.3
Two subsequent phase III trials confirmed the benefit of nivolumab over docetaxel as second-line treatment in patients with advanced NSCLC. In the CheckMate 017 trial of 272 patients with squamous NSCLC, median OS was 9.2 months with nivolumab versus 6.0 months with docetaxel.4 Hazard ratio (HR) for death was 0.59 with nivolumab (p < 0.001), and the 1-year OS rate was 42% with nivolumab versus 24% with docetaxel. Similarly, the CheckMate 057 trial evaluated nivolumab versus docetaxel in patients with advanced non-squamous NSCLC.5 Median OS was 12.2 in patients treated with nivolumab versus 9.4 months in patients treated with docetaxel. HR for death was 0.73 with nivolumab (p = 0.002), and 1-year OS rate was 51% with nivolumab versus 39% with docetaxel. Subgroup analysis from this trial showed higher efficacy for all endpoints in patients with PD-L1–positive tumors.
The KEYNOTE-010 trial evaluated role of pembrolizumab in patients with previously treated advanced NSCLC.5 Patients enrolled on this trial had at least 1% of tumor cells with PD-L1 expression. A total of 1,034 patients received either pembrolizumab 2 mg/kg or 10 mg/kg versus docetaxel 75 mg/m2 every 3 weeks. With pembrolizumab, median OS was 10.4 months at the 2 mg/kg dose and 12.7 months on 10 mg/kg versus 8.5 months with docetaxel. OS was improved with both the doses of pembrolizumab compared with docetaxel. In patients with at least 50% of tumor cells expressing PD-L1, OS was 14.9 months with pembrolizumab 2 mg/kg and 17.3 months with pembrolizumab 10 mg/kg versus 8.2 months with docetaxel.6
Based on these trials, the FDA has approved both nivolumab and pembrolizumab as single agents for the second-line therapy of patients with advanced NSCLC. Nivolumab use does not require testing for PD-L1 expression. Pembrolizumab is currently approved for patients with PD-L1 overexpression.
Toxicities of both of these antibodies can include immune-related adverse side effects, with 10% to 14% of patients experiencing grade 3 or higher side effects. The most common side effects with PD-1 antibodies are rash and pruritus. Grade 3/4 diarrhea or colitis is seen in about 1% of patients, and grade 3/4 pneumonitis is seen in about 2% of patients. Other less-common immune-mediated side effects include transaminitis, nephritis, thyroiditis, hypophysitis, iritis, uveitis or conjunctivitis, and pericarditis.
In 1995, I wrote an editorial in a pro/con debate on whether there was any role for systemic treatment of advanced NSCLC.7 At that time, my coauthor and I argued that the improved survival, from 3 to 6 months with supportive care alone, to 7 to 10 months with chemotherapy, should justify the use of systemic therapy in patients with advanced NSCLC. We hoped that we could change the mindset on treating these patients to foster new research into more effective, safer, and better-tolerated treatment options.
In 2016, we see a world of difference in options and attitudes, but many of the questions from 20 years ago linger. How do we apply our knowledge of the science of medicine, oncology, and now immunology to a group of patients with advanced lung cancer in a time of limited financial resources? How can we best help our patients and our society? How do we quantify the progress we are making?
The recent advances in immuno-oncology open many new doors in our ability to treat patients but also pose new questions on fair allocation of scarce resources with the ongoing rise of oncology drug prices.
To answer these questions, we will need to pursue further research in this field. Here are a few concepts to address in the near future:
- How can we best define the optimal patients with advanced NSCLC to receive immunotherapy, and will this be based on clinical demographics or molecular characteristics of the tumor? Are there appropriate biomarkers, such as PD-L1 testing, that we can use to guide us as to who will benefit most? We cannot be satisfied with response rates in the 20% range. Some trials show that PD-L1 expression predicts for a more robust response, but not all studies support this. Furthermore, PD-L1 testing is not well standardized. PD-L1 expression can be heterogeneous within a tumor and the tumor environment, and the level of expression may be different between the primary tumor and metastatic lesions.
- Which drugs are most effective and, indeed, most cost-effective, and how do we maximize the value of this care? We will need cost–benefit analyses to inform these decisions.
- Is there really a “tail” on the survival curves with these drugs? Who reaches that tail, and how do we get more of our patients to that endpoint? Is the tail on these curves truly a “cure,” and how do we best discuss this possibility with our patients to help them make informed decisions?
- What is the role of PD-L1 antibodies, such as atezolizumab and durvalumab, now being studied in patients with advanced NSCLC? In addition, trials are evaluating role of PD-1 or PD-L1 antibodies in combination with chemotherapy in the upfront or second-line setting in treatment of advanced NSCLC. We will need to clarify the role for dual inhibition of immune checkpoints as new studies look at the addition of CTLA-4 antibodies to PD-1 or PD-L1 inhibitors.
- Studies are also underway to investigate the role of immune checkpoint inhibition in earlier stages of NSCLC, such as in the adjuvant setting after surgery or in conjunction with radiation or chemo-radiotherapy in stage III disease.
Immunotherapy improves the outcome in second-line therapy of advanced disease; its role in first-line therapy, in combination with chemotherapy, targeted therapy, or other immune agents, and in early-stage disease will be further clarified in the near future. What lies ahead are the tough questions of how we can afford to give our patients what we think they need and how to convince a skeptical society and government that this is money well spent. As cancer physicians and advocates, the road ahead is bumpy. But let’s not forget the lessons learned over the last 20 years: accepting the status quo is not good enough for our patients.
About the Author: Dr. Masters is an attending physician at the Helen F. Graham Cancer Center and Research Institute and serves as an associate professor at the Thomas Jefferson University Medical School. Dr. Shah is an attending physician at the Helen F. Graham Cancer Center and Research Institute.