I'm Greg Kalemkerian, Professor of Medicine in Division of Hematology Oncology at the University of Michigan. This is lecture is going to cover the use of immunotherapy for people with stage IV non-small cell lung cancer. The objectives of the talk are to review the mechanism of activity of immune checkpoint inhibition and to review the role of immunotherapy as first-line or subsequent therapy in people with stage IV non-small cell. Cancers can utilize multiple mechanisms, including the PDI/ PD-LI pathway, to evade normal immune surveillance. PDI and PD-LI inhibitors, the immune checkpoint inhibitors can block the local inactivation of cytotoxic T-cells. Immune checkpoint inhibitors can induce durable responses and improve survival in people with advanced non-small cell lung cancer. Our pre-lecture question is that a 72 year-old woman presents with dyspnea and right hip pain. She's ambulatory and able to care for herself with a performance status of one. Her pain is controlled with narcotics. CT scan shows a large left upper lobe mass, multiple smaller lung nodules, enlarged bilateral mediastinal lymph nodes and numerous lytic bone metastases. Biopsy of the lung mass reveals poorly differentiated squamous cell with PD-L1 expression in 70% of tumor cells. What is the most appropriate further management? Carboplatin and paclitaxel? Carboplatin, paclitaxel and bevacizumab? Erlotnib, or pembrolizumab? Let's go through the lecture and we'll come back to the answer to question at the end of the talk. For many years, the field of immunotherapy sought to find deficits within the immune system that would allow a cancer to develop and not be recognized by the patient's immune system as abnormal. However, such deficits were never fully identified because in actuality the body does recognize the cancer as abnormal. The immune system recognizes abnormal mutant proteins within the cancer and can utilize its usual mechanism of dendritic cell presentation to T-cells in order to develop cytotoxic T-cells that are primed to attack the tumor cells. Now the tumor can use a variety of mechanisms in order to avoid detection and killing by cytotoxic T-cells that are primed to attack it. One of those mechanisms is the PD-LI, PD-I pathway as noted here. PD-LI is a ligand that is expressed by tumor cells that can bind to the PD-I receptor on the T-cells, thereby, inactivating this T-cell. So now the T-cell will not penetrate into the tumor, and will not kill the tumor cell. So in essence, the tumor cells are co-opting a normal tolerance system utilized by the immune system in order to get the body to recognize the cancer as self and not to kill it. Now what's been developed are a number of monoclonal antibodies including Nivolumab that combine to either the PD-I receptor, or PD-LI1 being made by the tumor and thereby inhibit the binding of PD-LI to PD-I, and inhibit the inactivation of T-cells so that the T-cells remain active and can thereby kill the tumor cells. So the immunotherapy with checkpoint inhibitors that we are utilizing now is an indirect mechanism to kill cancer cells by allowing the the immune system to not only recognize them, but also remain active in killing them. Initially, immunotherapy was evaluated as subsequent therapy after chemotherapy had failed in people with non-small cell lung cancer. The Checkmate 017 trial was one of first studies to evaluate the use of immunotherapy with Nivolumab and anti PD-I monoclonal antibody in patients with relapsed non-small cell lung cancer, who had had one prior regimen of platinum-containing chemotherapy. This study randomized people to receive either Nivolumab or Docetaxel, which is standard second-line chemotherapy. And we see that the response rates were significantly higher in people receiving Nivolumab than receiving Docetaxel, and overall survival was significantly improved from a median of six months up to nine months. And a one year overall survival from 24% up to 42% with single agent immunotherapy. This is called a swimmer's plot in which we look at people who responded to treatment, here with Nivolumab, here with Docetaxel, and the horizontal bar is an individual patient and the length of the bar designates the duration of time in weeks that the response duration occurred. And we see that those who received Nivolumab had an improvement in the duration of response versus those who had Docetaxel. In evaluating whether or not there's a bio-marker that can predict who's going to benefit the most from the Nivolumab, the study looked at people with a variety of different cutoffs from 1% to 5% to 10% PD-L1 tumor cell expression and did not find any significant difference in the ability of people to benefit from treatment based on PD-LI expression levels. So the results of that initial Checkpoint 017 trial are up on top here as we already went through. A similar study was done in non-squamous, non-small cell lung cancer looking at Nivolumab versus Docetaxel, and this study demonstrated an improvement in response, and a similar improvement in overall survival with Nivolumab over Docetaxel. Thereby establishing single agent immunotherapy as a standard second line treatment after first line chemotherapy. The Keynote 10 trial was a similar trial, that evaluated Pembrolisomab, another anti PD-I monoclonal antibody versus Docetaxel in people who relapse small cell lung cancer. This study included patients with a variety of histologic subtypes, all of whom had PD-LI expression greater than 1%. Patients received one of two different doses of Pembrolizuma or Docetaxel, and looking at the overall patient population which is a large population with more than 1% expression of PD-LI, we see an improvement in response rate as well as an improvement in overall survival with Pembrolizumab. And then we look at only a population with very high PD-LI tumorous cell expression of greater than 50% of tumor cells, we see that there's an even greater benefit with regard to response rate and with regard to survival. So in this situation with Pembrolizumab, it appears that PD-LI expression can be a useful bio-marker to predict the degree of benefit. This can be seen on this graphic slide, looking at the overall population with the two Pembrolizumab arms being superior to Docetaxel, but a bigger difference seen here with the Pembrolizumab arms versus Docetaxel when we're amplifying the population for very high P-DLI level expressions. Looking at the data with regard to PD-LI expression a little differently, this is data from the phase I dose expansion with Pembrolizumab in non small cell lung cancer. Looking at different levels of PD-LI expression all on the same curve, looking at progression-free survival and overall survival. With the low expression levels here, and patients with high expression levels up above, greater than 50%, and we see that there's a significant improvement in survival for people with higher levels of PD-LI expression. Another important question that has arisen with regard to immunotherapy and lung cancer is what is the potential benefit for people who have driver mutation tumors? So tumors that harbor driver mutations in EGFR or ALK. And this was a retrospective analysis from Boston that looked at 22 patients with EGFR-mutant lung cancer, 6 patients with ALK positive lung cancer, versus people who had ALK and EGFR wild type tumors. All of these people had received single agent anti PDI or PD-LI therapy. And what was demonstrated was that the overall response rate was lower in people who had EGFR or ALK mutant tumors at about 4% response rate versus those who were wild type with about a 23% response rate. This also tracked with smoking status where there was a 4% rate response in never or light smokers and a 20% response rate in heavy smokers. Again, suggesting that the higher mutational burden found in smokers as well as in people who are EGFR and ALK wild type may help drive immune recognition and immune response. There was also a slightly better progression free survival in those who had EGFR or ALK negative tumors. So the low activity of PDI or PD=LI inhibitors in EGFR-mutated or ALK rearranged or ROSI rearranged non-small cell lung cancer tells us that chemotherapy is probably a better second line option than immunotherapy in people with known driver mutations. After the demonstration of benefit of immunotherapy as subsequent treatment in non small cell lung cancer, studies were done evaluating first line treatment with an immunotherapeutic action. The Keynote 024 study evaluated 1st-line Pembrolizumab vs chemotherapy in people with untreated stage IV non small cell who had high level of PD-LI expression by immunochemistry with over 50% of tumor cells expressing PD-LI. This study was reported with relatively short median follow up of 11 months. But as we can see, it does demonstrate a significant improvement in response rate, up to 45% response rate in people Pembrolizumab as well as an improvement in, a significant improvement in progression free, and overall survival. Admittedly, with short follow up, but clearly showing us that in people who have high levels of PD-LI expression, single agent Pembrolizumab does appear to be superior to chemotherapy in terms of response and survival. Importantly, this trial did not differentiate patients based on histology and utilized a variety of different chemotherapeutic agents depending on histologic subtypes and investigator preference. Graphically, we see that both progression free survival and overall survival are significantly improved with single agent Pembrolizumab versus chemotherapy in people with high levels of PD-LI tumor expression. There is no free lunch so all treatments have potential toxicities. If we look at this table, we see that for any level of toxicity, the toxicity was a bit lower for the Pembrolizumab alone group with grade three, four toxicities lower for the immunotherapy. Approximately 20% of people with immunotherapy had a serious adverse event of grade three or higher with about a 5% treatment related death rate, similar to that of chemotherapy. Now obviously with immunotherapy, we have to be concerned about immune-mediated side effects such as hypothyroidism and pneumonitis. And we can see that as would make sense, the rate of these events is greater than with chemotherapy with about 10% of people having a significant grade 3 or greater immune mediate event. And usually these types of events would require a discontinuation of the immunotherapeutic agent and initiation of steroid therapy to decrease symptoms. So recently, the Keynote-189 trial looked at chemotherapy with or without Pembrolizumab, the anti-PD-I monoclonal antibody. This study looked at a large number, over 600 people with untreated, advanced, non-squamous, non-small cell lung cancer who did not have an EGFR or ALK mutation. And randomized them to get either platinum and Pemetrexed followed by Pemetrexed as a standard treatment arm versus platinum Pemetrexed plus Pembrolizumab followed by Pemetrexed plus Pembrolizumab. And we see that there was an improvement in response rate, an improvement in progression free survival and a significant improvement in overall survival with the addition of Pembrolizumab. Suggesting that the treatment with three drugs, chemo, plus Pembrolizumab was superior to treatment with chemotherapy alone in patients with non-squamous, non small scale lung cancer. Importantly, this study included people with a variety of levels of PD-LI expression, on the left we see PD-LI expression less than 1%, middle is 1% to 49%. On the left, greater than 50% and there's an improvement in survival with Pembrolizumab in all of these sub classifications based on PD-LI expression with the improvement highest in those with the higher all level of PD-LI expression. But all patients seemed to potentially benefit. Again, there are always potential side effects as we see here, looking at the events of interest which are mainly the itises, the inflammatory conditions brought on by stimulation of the immune system to recognize self as abnormal. With about 10% of people having a grade three or greater immune mediated toxicity including lumenitis, hyperthyroidism, and nephritis as specific side effects of interest. So what do we know about immunotherapy with the PDI, PD-LI inhibitors in non-small cell lung cancer? As first line treatment, Pembrolizumab is superior to chemotherapy in patients with high PD-LI tumor cell expression, greater than 50%. Chemotherapy plus Pembrolizumab is superior to chemo alone in non-squamous non-small cell lung cancer regardless of PD-LI expression level. As second line therapy, Nivolumab, Pembrolizumab, and Atezolizumab, Atezolizumab is a PD-LI targeted monoclonal antibody, are all superior to chemotherapy. Nivolumab and Atezolizumab are FDA approved regardless of PD-LI expression whereas Pembrolizumab is FDA approved for people with PD-LI greater than or equal to 1% of tumor cells. So let's return to our question of a 72-old-year woman with shortness of breath and hip pain who is up and around and doing well with a performance status of 1. Her pain is controlled. CT scan shows the left upper lobe mass, lung nodules, mediastinal lymph nodes, and many bony metastases. Biopsy showed a poorly differentiated squamous cell with a high PD-LI expression in 70% of tumor cells. What is the most appropriate further management? Carboplatin and Paclitaxel, Carboplatin, Paclitaxel and Bevacizumab, or Erlotinib, or Pembrolizumab? And this woman who has good functional status and squamous cell with a high PD-LI expression level, the most appropriate treatment would be single agent Pembrolizumab as noted in this question. Another option would be a combination of chemotherapy plus Pembrolizumab, though the Keynote-189 trial did not specifically answer the question of whether Pembrolizumab alone or chemo plus Pembrolizumab is more beneficial in people with high levels of PD-LI expression. So take home points from this lecture, PD-LI pathway suppresses local T-cell surveillance of tumors. PDI, PD-LI inhibitors allow local activation of cytotoxic T-cells and are active in non small cell with durable responses. The activity correlates with tumor PD-LI expression, and these drugs are basically well tolerated, but we do have to be aware of systemic autoimmune toxicities that can cause significant declines in people's quality of life that need to be recognized quickly in order to try and maximize control of symptoms. Thank you.
