Targeted Therapies in Advanced NSCLC - Episode 1
Transcript:Mark A. Socinski, MD: The treatment of advanced non-small cell lung cancer, over the past decade, has changed dramatically. A decade or so ago, we viewed non—small cell lung cancer in the advanced stage as one size fits all. What we’ve evolved into, at the time of initial diagnosis, is defining certain genotypes—EGFR mutations, ALK translocations, and others will be coming—where the standard of care is no longer chemotherapy. It’s targeted agents targeting the molecular defect that are known in these cancers. This represents a minority of the cancers we see, and there are lots of issues in that.
The majority of our patients will not have actionable oncogenic drivers, so they fall under the umbrella of standard chemotherapy. In that setting, chemotherapy choices are usually based on histology. We have different options for squamous versus nonsquamous, and we also have the option of antiangiogenic therapy for a subset of those patients who do not have oncogenic drivers.
And then the next paradigm that we’ve defined is the advent of the immunotherapeutic agents, where we have a number of monoclonal antibodies—actually two of them approved in non—small cell lung cancer at the current time for treatment after first-line therapy. But studies are ongoing to see what role these agents will play in the first-line setting. And my belief is that in a certain subset of advanced non–small cell lung cancer, the immunotherapeutic agents will replace platinum-based therapy as the standard of care.
Alice T. Shaw, MD, PhD: Over the last 10 years or so, we made an incredible amount of progress in lung cancer, and actually finally realizing that lung cancer isn’t a single disease, but actually is multiple different diseases that each can be defined by an underlying target or, what we often call, an oncogenic driver.
About 10 years ago, we learned about EGFR mutations defining a small subset of our patients, roughly 10%-15% of our patients in the United States—higher in Asia. And that was very important because we now know that EGFR mutations are the most important predictors for response to EGFR inhibitors like gefitinib, erlotinib, and afatinib. That was really a pivotal discovery in terms of understanding lung cancer pathogenesis and how you can actually target lung cancer specifically with a targeted therapy like these EGFR inhibitors. And that really opened up the field to thinking more about what the other targets in lung cancer are.
Since then, we’ve learned about a lot of other targets. The one after EGFR was ALK, which stands for anaplastic lymphoma kinase. Unlike EGFR, where you have activating mutations which make EGFR oncogenic, ALK is actually activated by chromosomal rearrangement. And that chromosomal rearrangement now leads to aberrant expression and constitutive activation of this ALK protein. Because of this, ALK now serves as another target, a driver in lung cancer, and patients with ALK-positive or ALK-rearranged tumors are very susceptible to ALK inhibitors like crizotinib and ceritinib. We see ALK in roughly 3%-5% of patients, so less frequent than EGFR, but still a fairly sizable population of patients, given how common lung cancer is.
In addition to EGFR and ALK, there are a number of other oncogenic drivers that we know more and more about. One of the most well recognized ones now, after EGFR and ALK, is ROS1. ROS1 is another one of these oncogenic drivers that’s activated by a chromosomal rearrangement event. And somewhat interestingly, ALK and ROS1 are very closely related proteins, so many of the drugs that target ALK, also happen to target ROS1, like crizotinib. And crizotinib is also very active in ROS1 the way it is in ALK-positive patients. ROS1, again, is a small subset of patients, maybe only about 1%.
And then after EGFR, ALK, and ROS1, there are a number of other very important drivers including BRAF, RET, TREK-1, HER2, and many others. When we look at our population of lung cancer patients now, probably over 50%, maybe 50%-60% have known oncogenic drivers. Many of them can be targeted, although a sizable population includes KRAS mutations, which are not yet targetable.
Gregory J. Riely, MD: When we approach a patient with advanced non-small cell lung cancer, what we’re starting to think about is how we’re going to treat the patient. We’ve all been very impressed over the course of the last few years with the dramatic improvements in targeted therapy, as well as dramatic improvements in immunotherapy.
But, for first-line therapy, the vast majority of our patients are still getting conventional chemotherapy. And I will highlight that platinum-based chemotherapy is really a mainstay for all of our patients with advanced lung cancer. Even patients who have targeted therapy options, such as EGFR-mutant patients or ALK-positive patients—those patients, after they progress through EGFR inhibitors or progress through ALK inhibitors, are going to use conventional chemotherapy.
When we think about conventional chemotherapies, our first-line therapies are typically platinum doublets, with or without an antibody, such as bevacizumab. And, a recent consideration is necitumumab for patients with squamous cell lung cancer. These are all very appropriate options, and we see significant response rates on the order of 30%-40% for those patients who have advanced non—small cell lung cancer who receive platinum-based doublets.
The addition of bevacizumab can improve response rate and extend progression-free and overall survival. So these are always an option. Another option is pemetrexed-based chemotherapy, so carboplatin plus pemetrexed and cisplatin plus pemetrexed are probably the two most common chemotherapies I use in the first-line setting. And those can sometimes be combined with bevacizumab as well.
When we move from first-line setting to the second-line setting, again, we’ve all been very impressed by the activity of immunotherapy as well as targeted therapies in the second-line setting. But they’re still not going to work for everybody, and consideration of second-line chemotherapy is a very reasonable one. And the standard second-line chemotherapy, setting aside immunotherapy, is docetaxel. And, docetaxel can be combined with ramucirumab—another VEGF targeting agent like bevacizumab, but one that has significant data as a second-line therapy in combination with docetaxel.
Combining docetaxel plus ramucirumab improves response rate, progression-free and overall survival for patients with non—small cell lung cancer. Importantly, ramucirumab can be given to those patients who would otherwise be considered bevacizumab- ineligible, particularly those patients with squamous cell lung cancer.
After second-line chemotherapy, there’s a broad range of chemotherapies that have been explored, but nothing that has clear efficacy signal and nothing that we can really hang our hat on in terms of randomized clinical trial data.
Transcript Edited for Clarity