I'm Greg Kalemkerian, Professor of Medicine in Division of Hematology and Oncology at the University of Michigan. This lecture is going to cover the use of molecularly targeted therapy for patients with advanced non-small cell lung cancer. The objectives of the lecture are to review appropriate molecular diagnostic testing for advanced non-small cell, review the role of EGFR, ALK, ROSI, and BRAF targeted therapy, and to review promising molecular targets. About 40 percent of people with non-small cell lung cancer present with, and about 80 percent will eventually develop, stage four disease. All treatment for advanced non-small cell lung cancer is palliative, with a five-year survival rate of less than five percent. Molecular diagnostic testing and targeted therapy can improve survival in selected subsets of patients. Our pre-lecture question is that a 48-year-old woman presents with cough. She is a never smoker and has excellent performance status. Her chest x-ray shows multiple small lung nodules, and chest x-ray shows bilateral ground-glass nodules throughout her lung fields. PET scan shows mildly FDG avid lung nodules with no evidence of other metastases. Wedge biopsy of two of the lung nodules reveals well-differentiated adenocarcinoma. CT scan of the brain is normal. What is the most appropriate further management? Initiation of chemotherapy, chemotherapy plus erlotinib, EGFR inhibitor, evaluation for bilateral lung transplantation, or molecular diagnostic testing. Systemic therapy can be divided into several categories. Either chemotherapy, which are generally cytotoxic drugs, most of which were developed empirically. Meaning when they were developed, they were found to just kill cancer cells without clear knowledge of their mechanisms of action. Now, all chemotherapy is actually targeted because all chemotherapeutic drugs interact with some molecule within the cancer cell. For instance, topotecan interacts with topoisomerase one to inhibit its activity. Cisplatinum interacts with DNA in order to cross-link basis. But at the time that they were developed, the mechanism was not clearly driving the design and development of the drug. Molecularly targeted agents, on the contrary, are drugs that were developed with specific knowledge of the intended molecular mechanism of action. So, with the identification of BCR-ABL in chronic myelogenous leukemia, drugs were specifically designed and screened to inhibit the activity of the ABL kinase. So, these are molecularly targeted treatments. So, in the current environment of cancer therapy, biomarkers have become very important. There are a couple of different types of potential biomarkers. There are prognostic biomarkers that are an indicator of patient survival, that is independent of therapy, and this generally reflects the innate tumor aggressiveness. So, a clinical prognostic biomarker might be the stage of the disease because more aggressive disease will have higher stage, and that clearly impacts on the prognosis of the patient. Predictive biomarkers are markers that indicate the outcome based on a specific therapy. So, they could tell you whether or not a tumor is going to be sensitive or resistant to treatment, whether people are going to have response and what their long-term survival is. So, EGFR is an example of a predictive biomarker in that if we treat with an EGFR inhibitor, that will improve the outcome of the patient. So, in 2018, we know that there are a number of different subtypes of adenocarcinoma based on molecular classification. If we look at the pie chart over on the right, we see that there are a number of different genetic abnormalities that can drive the growth of non-small cell lung cancer. Many of these abnormalities now have been determined to have FDA-approved targeted therapies associated with them. Those are the ones in green, namely EGFR, BRAF, ROS1, and ALK. A couple of other biomarkers that are listed here in yellow, RET, MET, and HER2, have some evidence supporting the use of a targeted therapy with potential benefits for patients, but these have not yet been FDA-approved for use in people with non-small cell lung cancer. Subsets also exist for squamous cell carcinoma, where we know there are a number of different types of driver mutations. However, none of these have yet been demonstrated to have clearly targetable benefits for patients with the tumors harboring these abnormalities. So, we're not going to discuss squamous cell carcinoma any further in this lecture. The first target that was identified in lung cancer for which a targeted therapy was developed was epidermal growth factor receptor or EGFR. EGFR is a membrane-associated growth factor receptor that binds to its ligand and is activated through a tyrosine kinase domain in order to signal tumor growth. A number of drugs have been developed that can inhibit the activity of EGFR, including monoclonal antibodies that bind to the extracellular ligand binding domain and inhibit ligand binding, thereby, inactivating the receptor, or small molecule inhibitors, tyrosine kinase inhibitors that can penetrate into the cell, bind to the tyrosine kinase domain, and block signal activation. About 15 years ago now, several groups identified mutations within the tyrosine kinase domain of EGFR. These mutations were found to predict sensitivity to EGFR tyrosine kinase inhibitors. The most common mutations are the exon 19 deletion and the exon 21 L858R point mutation. However, there are a number of other sensitizing mutations that are rarer, as well as a number of mutations that predict resistance to EGFR tyrosine kinase inhibitors. These mutations were found to be much more common in non-smokers, people with adenocarcinoma, women, and East Asians. East Asians meaning Japanese, Chinese, and Koreans. What happens when we target EGFR inhibitors to different patient populations with non-small cell lung cancer? If we take an unselected patient population and treat with an EGFR-TKI, we expect a response rate of around 10 percent, which is the prevalence of EGFR mutations in the unselected Caucasian population. If we select for the clinical factors, these factors up above here, then we can see a response rate of 40 percent because we're enhancing the population for people who have an EGFR mutation. If, however, we look at sequencing to find the mutation and we only treat people who have an EGFR sensitizing mutation, then we will see a response rate of 70 percent. So, by augmenting the particular patient population being treated, we can enhance the potential benefits of therapy. So, a rational question would be, well, if we have someone with an EGFR mutation, is it better to treat them with an EGFR inhibitor or with chemotherapy as first-line treatment? A variety of trials have evaluated this strategy looking at a number of EGFR inhibitors, gefitinib, erlotinib, afatinib, versus a variety of different types of chemotherapy. All of these studies have found an improvement in response rate, anywhere from T2 to threefold improvement in response rate, and about a doubling of progression free survival in people who received the EGFR inhibitor. Now, you'll notice over on the right here that the overall survival is not significantly different in most of these studies because there was clearly a high-level of crossover. So, people who are getting chemotherapy at progression would be switched over to receiving an EGFR inhibitor. So, these studies do clearly demonstrate that the benefits of receiving an EGFR inhibitor upfront are greater than those of receiving chemotherapy upfront if you have an EGFR-mutated tumor. However, these drugs do not last forever. So, the median duration of response with first-line therapy is around 12 months with gefitinib or erlotinib, and those patients will develop resistance and about 50-60 percent of people develop a T790M mutation in the tyrosine kinase domain as their mechanism of resistance. Though a smattering of other mechanisms are known to be possible. These are a listing of the EGFR inhibitors that are currently FDA approved. With the first-generation gefitinib and erlotinib having activity against both wild type and the common mutations, afatinib having activity against the common mutations as well as many of the rare mutations and it is FDA approved now for rare EGFR mutations, and also osimertinib, the most recent addition to the list, not having much activity against wild type. Which means, it's going to have a lower toxicity with regard to the class effect toxicities of the drugs including rash and diarrhea, but does have activity against the mutant forms of EGFR as well as the T790M resistance mutation. So, osimertinib is a mutation-specific EGFR inhibitor. So, what happens when we give osimertinib to people whose tumors have developed the T790M mutation? This is a waterfall plot in which each of the vertical bars represents a patient who is treated with osimertinib. If the bar goes down, then there was shrinkage of the tumor, if it goes up, then there was growth of the tumor. This line is the response rate line with 30 percent or greater shrinkage of tumor, and we see that the response rate is 62 percent in people who had previously had a first-generation EGFR inhibitor and had developed a T7 in their mutation. So, clear benefit for use of osimertinib and also osimertinib has good CNS penetration with a similar response rate in those who have brain metastasis. What happens when we compare osimertinib to chemotherapy and people who have developed a T790M mutation? This is our progression-free survival. We see an improvement in survival with the use of osimertinib versus use of chemotherapy. Well, if osimertinib is a mutation-specific EGFR-TKI that affects the potential resistance mutation that can arise when you treat with first-generation drugs, what happens if we utilize osimertinib as first-line therapy? So, this is the FLAURA trial that compared first-line EGFR tyrosine kinase inhibitor either gefitinib, erlotinib to osimertinib in people with common mutations. With regard to progression-free survival and overall survival, there was an improvement with osimertinib over first-generation EGFR-TKIs. Similarly with regard to CNS progression, there was an improvement with osimertinib. So, in summary of all of these studies, what we have found with EGFR inhibition is that erlotinib, gefitinib, afatinib and also osimertinib approved as first-line therapy in EGFR-mutated Non-small cell lung cancer. Afatinib is approved for the rare sensitizing mutations. T790M resistance mutations do arise within about 50 percent of patients. Osimertinib is mutation-specific EGFR-TKI that is approved for T790M+ Non-small cell after first-first line EGFR tyrosine kinase therapy. Now, osimertinib has been found to improve survival over first-generation EGFR-TKIs, and it has less toxicity. So, it appears that osimertinib should be our new first-line therapy, with an improvement in survival and lower toxicity for people with EGFR mutated non-small cell lung cancer. Question? Forty-three year-old never-smoker showed up with shortness of breath and cough. She's feeling well and is working full time. CT scan shows ground-glass opacities in both lungs. Brain scan is negative. Bronchoscopy with biopsy shows well-differentiated adenocarcinoma, and testing reveals an EGFR L858R mutation. What's the most appropriate further management: chemo plus radiation, chemotherapy plus bevacizumab, osimertinib, or crizotinib? Correct answer is osimertinib based on the data we showed that shows improved survival with the use of osimertinib and people with a sensitizing EGFR mutation. So, the second target that had been identified in lung cancer for which we have a targeted treatment is ALK. ALK is also a membrane-associated growth factor receptor. However, in this situation, ALK becomes oncogenic through a rearrangement on the second chromosome in which it is paired with a aberrant promoter such as with the EML4 gene to create a fusion protein that has hyperactive kinase activity to signal down through the cell. ALK rearrangements occur in approximately four percent of people with non-small cell lung cancer. Almost all have adenocarcinoma and are never or light former smokers. Crizotinib, ceritinib and alectinib are now FDA approved as first-line therapy for people without mutant non-small cell lung cancer. However, resistance also can occur through multiple mechanisms including secondary out point mutations in tyrosine kinase domain that inhibit binding of the inhibitors. Ceritinib, alectinib and brigatinib had been approved as subsequent therapy for people who have had progression on crizotinib. This was the first data that came out looking at ALK inhibition in an expanded phase one study of crizotinib. Again, a waterfall plot where all of the vertical bars are patients who received crizotinib in ALK-positive non-small cell, and we see that the majority of people 64 percent had a response and the vast majority of people, 90 percent of disease control, with some shrinkage of tumor. This is an example of a CT scan showing us what can be achieved with ALK inhibitors and people with ALK non-small cell lung cancer. This is a woman who came in extremely short of breath with a primary tumor here and her lungs filled with innumerable small pulmonary nodules. She was found to have an ALK mutation and treated with crizotinib and six months later, we see that the primary tumor has cavitated, a little bit of atelectasis over here and that blizzard appearance throughout her lungs has been cleared. This was in 2011, she subsequently had slow growth of tumor at about one and a half to two years, and was then subsequently put on a clinical trial with alectinib, and she continues on alectinib with good control of disease to this day. Now, almost seven years out from her initial presentation. So, similar to what we saw with EGFR inhibitors, what happens if we take someone who has an ALK mutation and give them first-line ALK inhibition versus chemotherapy? We see that there's a significant improvement in response rate with crizotinib and in duration of response with crizotinib with better progression-free survival, and no big difference in overall survival because, again, there is high level of crossover here with people on the chemotherapy are getting crizotinib once they progress. However the response to Crizotinib lasts on average about one year at which time resistance develops. The resistance to ALK is not quite as clean as the resistance to EGFR and that there can be a variety of different mutations that can lead to resistance as well as a number of different bypass tracks of other oncogenic drivers that can lead to resistance. Alectinib was developed as a second line alkyne inhibitor with potent activity against a variety of these resistance mutations and we see in people who have previously had Crizotinib and develop resistance, Alectinib can yield a major response in about half of patients. Importantly, brain metastases are very common in people who have ALK mutated lung cancer with about 60 percent developing brain metastases at some point during their disease, and Alectinib has much better brain penetration and brain response rates than Crizotinib does as well as you can see here with a 75 percent response rate in the brain. Well, Alectinib was compared directly to Crizotinib in the ALK trial as first-line therapy, and we see that Alectinib had improved progression-free survival and overall survival versus Crizotinib with a better progression within the brain as well. So Alectinib appears to be the more active ALK inhibitor and this study does suggest that it should be utilized as our best first-line therapy. So what we know regarding ALK inhibition is that the first ALK mutation was identified in non-small cell lung cancer in 2007, and only four years later, we already had an FDA approved ALK inhibitor in Crizotinib. So it tells you how fast the field is moving from the time of discovery of a potential biomarker target to the development of a clinically useful drug. Currently, Alectinib is favored as first-line therapy based on its activity as well as its relatively tolerable toxicity profile. Resistance does develop with other secondary ALK mutations in other mechanisms. Ceritinib, Alectinib and Brigatinib do have high response rates in people who have previously had Crizotinib therapy and most importantly with improved CNS responses. Lorlatinib is an investigational drug that has demonstrated activity in people who have progressed on the other available ALK inhibitors, however it remains investigational in the United States. Let's go to another question. A 38 year-old woman presents with vague left chest pain. She's otherwise in good health and is caring for her two young children. She is non-smoker. Scan reveals multiple lung nodules of left pleural effusion. Scan of the head is negative. Cytology on pleural fluid reveals adenocarcinoma. Molecular testing shows an EML4-ALK rearrangement. What's the appropriate further management? Chemotherapy plus bevacizumab, Alectinib, Crizotinib plus chemotherapy, or hospice care. Well based on the data we've looked at today, Alectinib would be the most appropriate treatment for this young woman in good shape with a EML4-ALK rearranged adenocarcinoma of the lung. Another biomarker that has been identified in non-small cell lung cancer is ROS I. ROS I is very similar to ALK in that it is a membrane-associated growth factor receptor that can be rearranged yielding a fusion protein that is hyperactive. ROS I mutations are found in only 1 to 2 percent of people with non-small cell. Almost all adenocarcinomas are never or light smokers. Crizotinib which was our previously noted ALK inhibitor is also a ROS 1 inhibitor with a response rate of over 70 percent and a duration of response of 18 months. Crizotinib is now been FDA-approved for people with ROS I-rearranged non-small cell. However, resistance can occur mostly through secondary ROS I mutations. Ceritinib, one of the other ALK inhibitors also does have ROS I activity but it does not appear to work well after Crizotinib and has not yet been approved as a ROS I inhibitor. The final biomarker that has an FDA-approved targeted treatment associated with it in lung cancer is the BRAF V600E mutation, the same mutation that occurs in a large number of people with melanoma, occurs in only one to two percent of people of lung adenocarcinomas. These are all mostly current or former smokers, so this is very different than people who have EGFR, ALK or ROS I mutations or almost all non-smokers. Single-agent BRAF inhibitors Dabrafenib and Vemurafenib do have some potential for response. However, the response is seen with Dabrafenib plus Trametinib, so a BRAF inhibitor plus a mech inhibitor or greater with a response rate of over 60 percent and a median duration of response of approximately 10 months. This combination has now been approved by the FDA for use in people with BRAF-mutated non-small cell lung cancer. There are a number of other emerging biomarker targets in people with adenocarcinoma of the lung. All of these occur in a fairly small percentage of people on the order of one to two percent. These include RET rearrangements for which we do have several drugs that have been approved in thyroid cancer that do have some potential for response. There are the HER2 mutations for which Trastuzumab emtansine, otherwise known as 80 trastuzumab or T-DM1 has been shown in a small trial to yield a response rate of 44 percent. Then there are MET exon 14 splice mutations for which Crizotinib is active with a response rate of about 40 percent. So none of these treatments have been FDA-approved yet for non-small cell lung cancer but can be obtained for use in our patients in an off-label basis. For people who have adenocarcinoma of the lung, it is important to obtain biomarker testing when they first present with advanced stage disease. What do we test for? Tests for EGFR mutations, BRAF mutations and the ALK and ROS I rearrangements. This is the bare minimum of what needs to be tested along with PDL1 testing as we discussed previously in our immunotherapy talk. If possible, it is reasonable to do next-generation sequencing for further mutations such as the RET, HER2 or MET mutations as well as other mutations that may be present that can potentially guide patient enrollment into investigational clinical trials of new promising therapies. Who needs to be tested? Well, people at stage IV adenocarcinoma should have testing for all four of these genes. People who are non-smokers with any histologic's type of stage IV lung cancer should be tested for EGFR mutations. Currently, there's no role for molecular therapy in people at stage I, II, or III of non-small cell lung cancer. So the most cost effective approach is not to do EGFR testing in those people. If they recur, then one can obtain a biopsy at that time in order to determine whether there is any driver mutation or one can use the old biopsy in order to determine driver mutation presence. So coming back to our pre-lecture question, a 48 year-old woman came in with a cough. She was a never smoker was in good shape. Her scans showed bilateral ground-glass nodules with no other evidence of metastases and a biopsy showed a well differentiated adenocarcinoma. What is the most appropriate further management? Treatment with chemotherapy or chemotherapy plus erlotinib, evaluator for bilateral lung transplantation, or obtain molecular diagnostic testing. In 2018, the appropriate answer is obtain molecular diagnostic testing for EGFR, BRAF, ALK, and ROS I as well as PDL1 tumor cell expression analysis. So our take home points are that molecular subsets based on predictive biomarkers have been identified in lung adenocarcinoma, EGFR sensitizing mutations should be treated with a first or second line EGFR inhibitor, if there's an ALK rearrangement, then first and second line ALK inhibitors are available, ROS I rearrangements should be treated with first line Crizotinib, and BRAF V600E mutation should be treated with first-line Dabrafenib plus Trametinib. Other targets and targeted therapy pairs are currently showing promising results and we're looking forward to being able to utilize these in the future as standard of care. Thank you.
