I'm Greg Kalemkerian Professor of Medicine in the Division of Hematology and Oncology at the University of Michigan, and today's lecture will be covering an overview of Stage IV Non-Small Cell lung cancer. The objectives for this talk are to review the goals of treatment in stage four Non-Small Cell Lung Cancer, review the appropriate predictive biomarkers to guide treatment for stage four, and to review the general treatment strategies for lung squamous cell and adenocarcinoma. About 40 percent of patients with Non-Small Cell Lung Cancer present with stage four disease, and overall about 80 percent of people will develop metastatic disease at some point in the course of their disease. All treatment for stage four Non-Small Cell is palliative, with a five-year survival of less than 5 percent, though this is influx at this time due to newer therapies such as immunotherapy and targeted therapies that are coming down the line. Systemic therapy, which includes chemotherapy, targeted therapy, and immunotherapy, can improve survival and quality of life. We'll start with a pre-lecture question. An 86-year-old man presents with shortness of breath, weakness, and right hip pain. He's in a wheelchair and is unable to get onto the exam table. He's been spending over 80 percent of his day in a bed or in a chair, and his pain is controlled with narcotics. He's somnolent, but he does respond to questions with short answers. CT scan of his chest shows a large right hilar mass with obstructive lobar collapse, multiple lung nodules, enlarged bilateral mediastinal lymph nodes, and numerous liver and lytic bone lesions. Biopsy of the liver reveals poorly differentiated squamous cell carcinoma, and immunohistochemistry for PD-L1 tumor expression is zero percent. What is the most appropriate further management for this man? Chemotherapy, immunotherapy, afatinib or hospice care. We'll go through the lecture and then come back to answer this question at the end of the talk. The general strategy for treatment of stage four Non-Small Cell Lung Cancer requires us to keep in mind several important considerations. Stage four Non-Small Cell is incurable. Yes there are some people who have good long-term survival, but overall we do not have therapy that is reliably curable in this disease. The goals are to improve quality and quantity of life. Systemic therapy is the standard treatment, with cytotoxic chemotherapy, immunotherapy, and molecularly targeted therapy as options. Radiotherapy can be useful for palliation of local symptoms. Systemic therapy primarily benefits fit patients. So, the performance status of our individual patients is very important in choosing our treatment options. The overall survival at one year is approximately 50 percent. At two years approximately 25 percent of people will be alive, and at five years less than five percent of patients with stage four disease will continue to be alive. The potential benefits of systemic therapy are to shrink the cancer down, and if that happens, then we can improve symptoms and improve patient's quality of life, and ultimately we hope to prolong survival. The ultimate goal is to keep people feeling as well as they can feel, for as long as possible. However, there are also potential risks to systemic therapy including the toxicity which has the potential to decrease the quality of life, treatment related mortality which can shorten survival, though luckily that does not happen very much anymore, and there is obviously inconvenience and financial cost to receiving any kind of therapy. The initial step in evaluating and beginning to manage people with stage four Non-Small Cell Lung Cancer is to obtain biomarker evaluation. The biomarkers that we obtained do differ depending on the histology of disease. So, for adenocarcinomas or non-squamous non-small cells, we initially get PD-L1 tumor cell expression testing by immunohistochemistry, and then we test for a number of molecular driver mutations such as EGFR mutational analysis, BRAFV600E analysis, and then evaluation for ALK and ROSI one gene rearrangements. We test for these because each of these biomarkers now has an FDA approved treatment associated with it that can significantly improve survival. Patients with squamous cell carcinoma, the molecularly targeted therapies generally don't have much of a role, but we still do need to test for PD-L1 tumor cell expression by immunohistochemistry. In non-smokers, testing for EGFR mutations does make sense. For all histologies, one can consider next-generation sequencing to evaluate for the routine targets that we just discussed, as well as for other targets that may suggest either off-label types of treatments such as RET, MET and HER2, or other investigational clinical trial types of therapies that patients may be candidates for. Let's move on now to the treatment for patients with Non-Small Cell Lung Cancer. The first-line therapy for stage four Adenocarcinoma is goes in a specific hierarchy of our treatment decision-making. So, if people have positive tumors for EGFR mutations, BRAF mutation, or ELK or ROSI one gene rearrangements, then we need to treat with an appropriate targeted therapy. Now, I'll go into more details on this targeted therapy during the lecture on molecularly targeted therapy for stage four Non-Small Cell Lung Cancer. If people do not have a driver mutation, but have PD-L1 tumor cell expression of greater than 50%, then most of us would treat that person with single-agent pembrolizumab, which is a PD-1 inhibitor. Some might give chemotherapy plus pembrolizumab, and we'll be talking about some of this data in the immunotherapy lecture. For patients who do not have any driver mutations and have PD-L1 expression less than 50 percent, there are a number of chemotherapeutic or chemoimmunotherapeutic options as listed here, that will be discussed in further detail during the chemotherapy lecture. We can give either two drug chemotherapy followed by chemotherapy maintenance, we can give chemotherapy plus antiangiogenic therapy which is Bevacizumab, followed by maintenance therapy, or we could give a combination of chemotherapy and immunotherapy. The pros and cons of these options will be discussed as I said before in a subsequent lecture on chemotherapy. For patients with squamous cell carcinoma, first-line therapy is also depending a bit on the biomarkers, specifically on PD-L1 tumor cell expression. So, if the PD-L1 is expressed in over 50 percent of tumor cells, then primary treatment should be with pembrolizumab, which is a PD1 targeted monoclonal antibody. We'll discuss this further in the immunotherapy lecture. If the PD-L1 expression is less than 50 percent of tumor cells, then there are a number of chemotherapeutic options as noted here that can be utilized and we'll discuss this in the lecture on chemotherapy. For squamous cell carcinoma, there is no proven benefit to the use of any maintenance therapy at this time. Once patients have either responded or subsequently progressed on first-line treatment, then there is potential for subsequent therapy. If they have had immunotherapy or targeted therapy as first-line treatment, then the most appropriate second-line therapy would be with first-line chemotherapy options such as combination chemotherapy regimens. Keep in mind that immunotherapy has a low level of activity for people who have any one of the known driver mutations specifically EGFR, ALK or ROS1. So in these patients, chemotherapy is a better option than immunotherapy. After people have had chemotherapy, then immune checkpoint inhibitors, the PD-1, PD-L1 inhibitors, are the standard second line treatment option because they do work better than second line chemotherapy. We'll discuss this further in the immunotherapy section. But for now, let's just leave it with. Regardless of what the PD-L1 expression level is, patients can receive Nivolumab or Atezolizumab and if the PD-L1 expression level is greater than one percent, then Pembrolizumab becomes an option as well. Once people get beyond chemotherapy and immunotherapy as first-line or second line agents, then the primary treatment is with single-agent chemotherapy. Options such as Docetaxel, Pemetrexed for the non-squamous patients, Gemcitabine or Paclitaxel used as single agents in a sequential manner is the standard therapy. There is an option for Docetaxel plus Ramucirumab, VEGFR inhibitor which does demonstrate some marginal benefit in combination and we'll discuss that later during the chemotherapy lecture. It is also important in these patients to optimize other palliative measures aside from drugs. So, we have to make sure that people understand their disease and the goals of disease, so that they can make good decisions regarding the aggressiveness of care, palliative radiotherapy is always a potential option to relieve a focal symptom, and we need to adequately control pain, shortness of breath, cough, anorexia, and fatigue in order to optimize people's quality of life because their quality of life will eventually drive their quantity of life. So as general treatment guidelines, all treatment is palliative in stage four Non-Small Cell Lung Cancer. Therapy benefits people with good performance status, ECOG PS zero to two. Patients with a poor performance status PS three to four, generally have poor outcomes and more treatment related complications. Though there is some potential for treatment particularly with molecularly targeted therapies which have very high response rates in people who have impaired performance status. Both physicians and patients need to clearly understand and balance the potential benefits and risks of therapy in order to optimize quality of life. Because as I said before, the quality of life will drive the quantity of life. So, for people who have an EGFR mutation, first-line EGFR tyrosine kinase inhibitors or standard therapy, if one has an ALK or ROS1 rearrangement and first-line therapy targeting those abnormalities is most appropriate, if a BRAF V600E mutation is present in the tumor then BRAF plus MEK inhibition is standard treatment. For people with PD-L1 high tumors, then first-line therapy with an imino therapeutic checkpoint inhibitor makes the most sense. For people with non-squamous lung cancer targeted therapies, immunotherapy or chemotherapy are reasonable options, and for those with squamous cell carcinoma immunotherapy or chemotherapy or further reasonable options. We will talk more about these in specific detail in the subsequent lectures on chemotherapy, immunotherapy, and targeted therapy for stage four lung cancer. So let's return to our question of an 86 year-old man with significant symptoms who spends almost all of his day sitting in a chair or lying in bed. His pain is well controlled at this time, so he's really debilitated due to the overall extent of his disease rather than necessarily his pain. He is as awake and alert but rather somnolent, and his scans show extensive involvement of disease with a biopsy showing poorly differentiated squamous cell that has no PD-L1 expression. What is the most appropriate further management? Chemotherapy, immunotherapy, afatinib which is an EGFR inhibitor or hospice care. For this man with performance status of three on his way to four, the most appropriate treatment is with hospice care in order to optimize his quality of life and maximally treat his symptoms. So, there is no proven benefit for treatment with either chemotherapy or immunotherapy in people who have performance status of three particularly in those with a low PD-L1 tumor expression level. So, the take home points for this lecture and the treatment for stage four non-small cell lung cancer is palliative, you need to evaluate for appropriate predictive biomarkers to select optimal therapy, molecularly targeted therapy, immune checkpoint inhibitors and chemotherapy can all improve survival and quality of life when used appropriately in selected patients, performance status remains an important prognostic indicator.
