I'm Greg Kalemkerian Professor of Medicine and Division of Hematology Oncology at the University of Michigan. This lecture will cover chemotherapy for patients with stage four non-small cell lung cancer. The objective of the talk is to review the potential benefits and risks of systemic chemotherapy for people with stage four non-small cell, and to review the role of antiangiogenic therapy in people with advanced non-small cell lung cancer. Approximately 40 percent of people with non-small cell will present with stage four disease, and at some point about 80 percent of people will develop metastatic disease. All treatment for stage four non-small cell is palliative with a five-year survival of less than five percent. Systemic therapy which includes chemotherapy, targeted therapy, and immunotherapy can improve overall survival and quality of life. We'll start off with a pre-lecture question and then we will come back at the end of the talk to discuss the answer to this question. A fit 73 year-old man presents with back pain. He has 100-pack-year smoking history. His performance status is one, is fully functional, CT scan shows a three centimeter right lower lobe mass, enlarged mediastinal lymph nodes, and multiple lytic lesions in the thoracic spine. CT-guided biopsy of the T7 vertebral body reveals squamous cell carcinoma with a PD-L1 expression of 20 percent. He's treated with palliative radiation to T7 followed by carboplatin and Gemcitabine. What are the goals of care for this man? Improve symptoms of disease, prolong overall survival, eradicate the disease, a and b or a, b, and c. Several important considerations to keep in mind when taking care of people with stage four non-small cell lung cancer are that stage four is incurable with goals of care being palliative. The potential benefits of chemotherapy are to shrink the cancer, improve symptoms and quality of life, and improve overall survival. In other words to keep people failing as well as they can feel for as long as possible. The potential risks of chemotherapy or that the toxicity can decrease people's quality of life. There can be treatment related mortality so it is possible to shorten people's lives though luckily this does not occur all that often anymore in our treatment of people with this disease. There's always inconvenience and financial cost with the financial costs increasing greatly over the last 15 years or so. Over 20 years ago now a number of studies did evaluate chemotherapy versus best supportive care in order to determine the overall benefit of chemotherapy in this scenario with stage four non-small cell lung cancer. These studies did demonstrate that there was improved overall survival with says platinum-based chemotherapy, with a median improvement of approximately two months and improvement in one year survival of 10 to 20 percent. There also was demonstration of improved quality of life, with improved performance status and decreased symptoms and about two-thirds of people reported improved quality of life despite the side effects of chemotherapy. Also demonstrated around that time was that chemotherapy was cost effective. Historically, with best supportive care, we can achieve median survivals of approximately six months with a 10 to 21 percent year survival rate. With platinum-based chemotherapy we can get about another two to four months of survival up to eight to 10 months median, with a one-year survival rate of 30 to 40 percent. With newer strategies that include anti-angiogenic agents, maintenance therapy or immuno therapy. We can now achieve a median survival of approximately 18 months with a one-year survival rate of 50 to 60 percent. For these newer strategies there also are some patients who do achieve much longer-term survival measured in years. Going back a number of years to ECOG 1594, this was a trial that randomized patients to four different chemotherapy two drug regimens with a platinum base three of them included Cisplatin and one Carbonplatin. We can see from this gross survival curve that all of the treatments were equal, there was no winner here with all two drug regimens demonstrating similar overall survival, as well as similar response rates and progression-free survival. This was the plateau that we had hit around 2000. Subsequently we learned that histology made a difference prior to that time all non-small cell lung cancer was treated the same. But then we learned that histology made a difference both with regard to the potential safety of certain drugs as well as the efficacy of certain drugs. So, from a safety standpoint we learned that Bevacizumab anti-VEGF monoclonal antibody can cause massive hemoptysis in about a quarter of people with squamous cell carcinoma. So, clearly we do not want to use Bevacizumab in people who have squamous cell. From an efficacy standpoint we learned that Pemetrexed was not active in squamous cell and is only utilized in Adenocarcinoma where it has significant benefits. We learned that targeted kinase therapy targeting specific driver mutations is primarily active in people with Adenocarcinoma harbor driver mutations. We learned that Necitumumab which is anti-EGFR monoclonal antibody did not have benefits in Adenocarcinoma but may have a small benefit in a subset of people with squamous cell carcinoma. So let's look at the chemotherapeutic approaches that we use for people with non-squamous or Adenocarcinoma stage four non-small cell lung cancer. So angiogenesis is the process by which tumors develop a blood supply in order to give them nutrients and oxygen. As we can see from this figure a tumor cannot get beyond about two millimeters in size without having a blood supply. So tumors can make the substances such as VEGF, Vascular Endothelial Growth Factor that is secreted into the stroma and can bind to receptors on endothelial cells increasing their proliferation as well as chemo taxes towards the tumor. So we can get blood vessels to grow into the tumor through the production of VEGF and a number of other substances. Once the blood vessels start growing into the tumor the tumor can then take off without really any substantial limit as far as its growth potential. So we see a Angiogenesis is a very important pathway in lung cancer development as well as a number of other tumors types. So we have learned how to potentially inhibit Angiogenesis by blocking the VEGF pathway with a drug such as Bevacizumab. Bevacizumab is a monoclonal antibody that targets VEGF thereby blocking it's ability to bind to VEGF receptors on endothelial cells. So this strategy of using chemotherapy plus Antiangiogenic therapy was evaluated in ECOG 4599 which was a phase three study looking at Paclitaxel and Carboplatin with or without Bevacizumab. In people who got the Bevacizumab on the bottom of this table we see that they subsequently also got maintenance therapy with Bevacizumab. This study included a large number over 800 patients with previously untreated stage for non-squamous, non-small cell lung cancer. Again as we noted earlier we do not use Bevacizumab in patients with squamous cell carcinomas or they were excluded from this study as were people with brain metastases and those on Anticoagulation or who had hemoptysis because of concerns about bleeding risk. So the results of ECOG 4599 are on this table, and we see that patients who had received Bevacizumab in addition to chemotherapy had an improvement in response rate, as well as an improvement in their overall survival with about a two month improvement in median and about a seven-eight percent improvement in one and two year survivals. So some patients are clearly benefiting from the addition of Bevacizumab. Shortly thereafter studies were conducted looking at maintenance chemotherapy. Studies have been conducted looking at maintenance chemotherapy for many years but unfortunately until the mid 2000's we didn't really have drugs that could be maintained. So it's not really possible to maintain people with Paclitaxel or Docetaxel or Gemcitabine because of their cumulative toxicities. However, with a drug like Pemetrexed that is relatively well-tolerated without a lot of cumulative side effects on one can provide maintenance chemotherapy. So the paramount trial looked at continuation maintenance in people with non-squamous non-small cell. Again only non-squamous because Pemetrexed only has activity in non-squamous non-small cell who had good performance status. Study was large accruing over 900 people who initially got Cisplatin and Pemetrexed sit for four cycles. Then those who had stable disease or response to therapy were randomized to receive either Pemetrexed continuation maintenance continuing from the initial induction therapy or a Placebo. So, this slide shows us the results of the Paramount trial, where we see that people who had receive pemetrexed maintenance therapy did have a modest improvement in progression-free survival, as well as an improvement in median overall survival, and one and two year overall survival that was statistically significant. Now, importantly, only about 4 percent of people who were on the placebo arm got pemetrexed at subsequent progression. So, this would have been very reasonable therapy because the pemetrexed in these people had been stopped because it was a planned discontinuation. Rather than that, it was no longer working. Nevertheless, the trial does demonstrate that starting pemetrexed as maintenance therapy after initial chemotherapy does have potential benefit for some people. So, for maintenance therapy, the way I handle it is that, if people are symptomatic from their disease and have tolerated treatment well, then maintenance therapy may be beneficial. If they're symptomatic from their treatment, or they have very marginal fitness overall, then perhaps taking a drug holiday with close surveillance is the most reasonable option. There's no proven benefit to any maintenance therapy in squamous cell carcinoma, and no real proven benefit for drugs other than pemetrexed aside from one study demonstrating a marginal improvement with erlotinib in an unselected population. Ultimately, we need to maintain performance status because quality of life will determine quantity of life. So, if maintenance therapy is tolerable and is helping people to control the disease, then it makes sense. If it is causing excessive toxicity, then it does not make sense. The subsequent PointBreak trial evaluated two chemotherapeutic and antiangiogenic regimens in order to determine which one might be most beneficial. This was again a relatively large study looking at over 900 people with untreated advanced non-squamous, non-small cell lung cancer. Using a standard therapy of carbo, paclitaxel, and bevacizumab for four cycles followed by bevacizumab, the regimen that was evaluated in 4599, versus Carboplatin, pemetrexed, and bevacizumab followed by pemetrexed plus bevacizumab, a regimen that is generally a bit better tolerated than the taxel containing regimen. The results of the PointBreak trial showed that there was no significant difference between these two regimens in progression-free or overall survival, and importantly, the study was not absolutely powered to be a non-inferiority trial. So technically, what was demonstrated was that the pemetrexed containing arm was not superior to the paclitaxel containing arm. However, looking at these survival curves, and with the large number of patients enrolled on this trial, one would have to say that these two treatments appear to be relatively equivalent with somewhat lower toxicity in the pemetrexed containing regimen. The subsequent pronounced trial evaluated again two different treatment regimens, one of which contained an antiangiogenic drug, and one of which did not. So, this study evaluated a standard arm of Carboplatin, and paclitaxel, and bevacizumab followed by bevacizumab. Again, the superior arm in ECOG 4599, versus a relatively standard treatment as demonstrated in a number of studies such as the paramount study, a platinum pemetrexed treatment followed by pemetrexed maintenance therapy. This study accrued about 360 patients with advanced non-squamous, non-small cell lung cancer. The primary endpoint on this trial was a little bit of odd in that it was progression-free survival without grade four toxicity. However, the secondary endpoints did include overall survival, progression-free survival, the usual things that we evaluate in clinical trials. Again, in the pronounced study, the progression-free and overall survival were not significantly different between these two arms, raising the question of whether or not the antiangiogenic therapy is necessary when one is using maintenance therapy with a cytotoxic chemotherapeutic agent. The most recent advance within the field of chemotherapy, and immunotherapy, and stage four non-small cell lung cancer is keynote 189. This was a large randomized trial in previously untreated patients with non-squamous advanced, non-small cell lung cancer who did not have a driver mutation in EGFR or ALK, and had good performance status. The study randomized patients to have a platinum pemetrexed combination followed by maintenance pemetrexed, a standard treatment, or a platinum pemetrexed regimen with the same doses plus pembrolizumab and anti PD-1 monoclonal antibody, an immune checkpoint inhibitor, followed by maintenance therapy with pemetrexed and pembrolizumab. We can see that the results of this study demonstrated a significant benefit for the addition of pembrolizumab, both in terms of response rate with a significant improvement from 19 percent to 48 percent, and progression-free survival from 4.9 months to 8.8 months. With regard to overall survival in the graph, we see an improvement from 49 percent, one year survival with the chemotherapy only arm, to 69 percent,one year survival in the immunotherapy containing arm. Importantly, this was relatively early data with a fairly short overall median follow-up time, but clearly, the results are compelling with regard to overall survival improvement in these patients. Importantly, the study included people with all levels of PD-L1 expression, so there was no exclusion based on PD-L1 tumor cell expression level. We see on this series of graphs that carry from less than one percent PD-L1 expression on the left, to one to 49 percent in the middle, and then over 50 percent on the right, that there is an improvement in overall survival in all levels of PD-L1 expression for the pembrolizumab containing arm, though that benefit does appear to increase as you get higher levels of PD-L1 expression. Now, anytime you add a third drug, you're going to add more toxicity regardless of how potentially tolerable that drug might be. For the immunotherapies, clearly the most concerning toxicities are the idisis, the inflammatory conditions that can arise due to stimulation of the immune system and the overcoming of auto immune protection. So, if we look at the top line, we can see that any grade toxicities were just about double with the pembrolizumab combination. But most of these were early grade, though there was an increase up to about 9 percent of grade three, four, and five adverse events of interests. These included hypothyroidism and pneumonitis, as we see on the top, and also interestingly, nephritis which hasn't been reported too often in prior studies but here, about one and a half percent of people had grade three/four nephritis noted with pembrolizumab and chemotherapy. So, one has to be aware that immunotherapy is being utilized and we have to be on the lookout for these immune mediated side effects in addition to the side effects of chemotherapy if using the two drugs in combination. So, what do we know at this point regarding chemotherapy for stage four adenocarcinoma of the lung? I'll note that on this slide, I am utilizing trade names rather than generic names for drugs in order to fit everything on to the slide. We know that platinum-based two-drug regimens are all equivalent in efficacy though they do differ in terms of their toxicities, with Carboplatin containing regimens being less toxic, and Carboplatin containing regimens being the more rational choice in a palliative treatment situation. We know that Carboplatin, Taxol, and Avastin followed by Avastin maintenance is better than Carboplatin Taxol. We found that Carboplatin and Alimta followed by Alimta maintenance was better than Carboplatin and Alimta alone. We found that Carboplatin Taxol and Avastin followed by Avastin maintenance appear to be equivalent to Carboplatin and Alimta Avastin followed by Alimta and Avastin used as maintenance therapy. That Carboplatin Taxol and Avastin followed by Avastin was relatively equivalent to Carboplatin and Alimta followed by Alimta, raising the issue of whether the Avastin treatment is necessary in this situation. Most recently, that Carboplatin Alimta and Keytruda, which is pembrolizumab, followed by maintenance therapy with Alimta and Keytruda was superior to Carboplatin and Alimta followed by Alimta without immunotherapy. So, we have an interim question here on chemotherapy for Adno Carcinoma. A 56 year-old man presents it right upper quadrant pain. He works full time and has an 80-pack-year smoking history. CT scan shows a five centimeter left upper lobe mass, multiple lung nodules, enlarged mediastinal lymph nodes, and numerous solid liver lesions. MRI of the brain is normal. CT-guided biopsy of the liver lesion reveals poorly differentiated non small cell with PD-L1 expression of 30%. Molecular diagnostic testing reveals no driver mutations. What is the most appropriate further management? Chemotherapy alone, chemotherapy plus pembrolizumab, palliative radiotherapy to the liver, or hospice care, and this man who has a good functional status and is relatively young with a PD-L1 level below 50%, the most appropriate further management would be chemotherapy plus pembrolizumab that has demonstrated improvement in survival over chemotherapy alone. So let's move on to stage four non-small cell squamous cell carcinoma. One of the first trials that demonstrated a difference in histological response to chemotherapy was this study from Scagliotti and friends looking at the use of Cisplatinum and Gemcitabine versus Cisplatinum and pemetrexed in all comers with non-small cell lung cancer. As a secondary analysis, the patients were separated out with regard to non-squamous or squamous histology. On the left we see the graph of survival for the non-squamous patients with an improvement in survival with the pemetrexed containing regimen over the Gemcitabine containing regimen. Whereas in the right side, we see the squamous cell patients where the curves are flipped with the Gemcitabine containing regimen having a better survival than the pemetrexed regimen. Subsequently we found out that pemetrexed that is really not very active in squamous cell carcinomas and does not have an indication for squamous cell. So, this studies started to give us some differentiation in different regimens that may be useful for different histologic subtypes. The squire trial evaluated whether or not adding a third drug to chemotherapy regimen would be beneficial. The third drug that was added was Necitumumab. Necitumumab is a anti EGFR monoclonal antibody. In the next study we looked at stage four squamous cell carcinomas with advanced stage disease and good performance status who had not had any prior treatment. As initial treatment patients who were given Cisplatinum and Gemcitabine or Cisplatinum and gemicitabine plus Necitumumab with maintenance Necitumumab for those with response or stability. This was a very large trial with about 1100 patients accrued. The results of this squire trial are listed here. We see no significant improvement in response rate with the addition of Necitumumab. No major improvement in progression-free survival though a little bit of improvement in six month progression-free survival and a modest six-week improvement in median overall survival with a small improvement in one year survival that was statistically significant based on the large size of the trial. So, in evaluating this data one would have to look at the potential risks of adding Necitumumab along with the potentially small marginal gains to be obtained in some patients with this approach. Thus far there had been many attempts to find biomarkers to suggest a population that benefits the most and there's some suggestion that EGFR amplification might be a relevant biomarker, but further studies are necessary in order to demonstrate that fully. So for first line treatment for squamous cell carcinoma, if the PD-L1 tumor cell expression is over 50% then treatment with pembrolizumab is the most sense because that is better than treatment with chemotherapy and we'll cover that further in the lecture on immunotherapy. If PD-L1 expression is less than 50%, then there are a number of chemotherapeutic regimens that are potentially useful including Carbo-Gemcitabine, carbo Paclitaxel, carbo nab-Paclitaxel, or a combination of platinum gemcitabine and Necitumumab, Necitumumab maintenance. Now there is no proven benefit to maintenance therapy with cytotoxic chemotherapy in patients with squamous cell carcinoma. Let's move on to subsequent chemotherapy after first-line treatment. So, when people have progression of disease on chemotherapy or first-line immunotherapy, then the standard approach would be to use single-agent chemotherapy in either squamous or non-squamous histology with Docetaxel, Pemetrexed only for the non-squamous, Gemcitabine or Paclitaxel. Another option would be Docetaxel plus Ramucirumab based on data that we'll look at in a minute, and we also have to remember to optimize palliative measures. We have to help people with decision-making regarding the aggressiveness of care by making sure they understand fully the benefits and potential risks of treatment. Palliative radiotherapy can be useful for alleviating focal symptoms and we always have to optimally control pain, dyspnea, cough, anorexia, and fatigue in order to optimize quality of life. So the revel trial evaluated a two drug combination regimen a second line therapy for people with any histologic type of advanced non-small cell lung cancer who had a good performance status. The treatment on the control arm was Docetaxel alone which is standard FDA approved therapy, and the treatment on the experimental arm was Docetaxel at the same dose with Ramucirumab. Ramucirumab is a monoclonal antibody that targets VEGF receptor two. So, it's an antiangiogenic therapy, and treatment was continued until patients had progression or unacceptable toxicity. We can see here that on the progression-free survival and overall survival curves there was an improvement in survival with the addition of Ramucirumab for overall survival. That improvement again came out to around five to six weeks of improvement. So, in evaluating this data we have to look at the potential benefits and risks in order to determine whether or not this treatment with overall potentially benefit a small group of people. Unfortunately, there are no biomarkers yet identified to help guide us as far as determining who is going to benefit the most from Ramucirumab treatment or for that matter from any antiangiogenic therapy. So, let's come back to our initial question. A fit 73 year-old man presents with back pain. He has 100-pack-year smoking history. Performance status is good. CT scan shows a lower lobe mass, mediastinal lymph nodes, and many bone lesions. Biopsy of a bone lesion shows squamous cell carcinoma with a low PD-L1 expression level. He's treated with radiation to the painful bony lesion and then receive Carboplatin and Gemcitabine. What are the goals of care for this man? Improve symptoms of disease, prolong overall survival, eradicate the disease, a and b, or a, b and c. Well the answer is a and b; to improve symptoms of disease and to prolong overall survival since the goals here are to optimize quality and quantity of life and keep them feeling as well as he can feel for as long as possible. So take-home messages for this lecture; On the treatment for stage four non-small cell is palliative. Chemotherapy can improve survival and quality of life and people with good performance status. The addition of anti-angiogenic therapy to chemotherapy may improve survival both in first-line therapy as well as in subsequent therapy, and the addition of immunotherapy can improve response rates and overall survival in first-line therapy for non-squamous non-small cell lung cancer. Thank you.
