Targeting KRAS Mutations: A Novel Approach in Advanced NSCLC - Episode 1
Paul Bunn, MD: Arguably, in lung cancer, we’ve made as many therapeutic advances as in any cancers, and since lung cancer is the leading cause of cancer death in the United States and in the world, this is incredibly important.
We can summarize some of those therapeutic advances in terms of molecular therapy, which is understanding molecular underpinnings of some of the lung cancers with specific molecular therapies that go along with those molecular alterations. It’s also understanding immunotherapy, which has made incredibly important therapeutic advances, particularly in those lung cancers that don’t have the molecular drivers. One can divide the therapeutic advances into molecular and immunotherapy to a certain extent at this point in time.
Jonathan Riess, MD, MS: The current state of targeted therapies for non–small cell lung cancer is rapidly changing. We’ve had a lot of exciting developments in the field of targeted therapies in lung cancer, particularly for lung adenocarcinoma, which is the most frequent histologic subtype that we encounter. There’s been a lot of great new developments. We move beyond EGFR-mutant lung cancer, ALK -fusion non–small cell lung cancer, ROS1-fusion non–small cell lung cancer, and BRAF-mutant non–small cell lung cancer, where there are targeted therapies approved for those molecular subtypes. We are expanding the pie further in oncogene-driven subsets of non–small cell lung cancer.
In particular, there have been new approvals for RET-fusion lung cancer, which is about 2% of all non–small cell lung cancer with selpercatinib and also another exciting new agent, BLU-667. For METexon 14 skipping mutations, the MET inhibitor capmatinib has been recently approved. Larotrectinib has also been approved for NTRK non–small cell lung cancer, which is an infrequent subtype, but when you encounter it, it has extremely high response rates and clinical activity. This is all really exciting news as we’re finding more pieces of that pie for oncogene subsets of non–small cell lung cancer to bring really effective targeted therapies to patients.
Alexander Drilon, MD: As we understand that lung cancers are driven by certain gene signatures we’ve come to realize that the proteins that these oncogenes make can be targetable with things like small molecules or tyrosine kinase inhibitors [TKIs]. This started with EGFR of course and then blossomed to include other fusions like ALK, RET, ROS1, and TRK. Now there is really a much longer list of actionable operations, which have changed the way we practice. Many of these targeted therapies are approved for patients with advanced disease, and these result in substantial activity and high response rates, durable disease control, in addition to having favorable safety profiles that make these drugs amenable to long-term administration.
Jonathan Riess, MD, MS: In terms of prognosis of patients who have oncogene-driven non–small cell lung cancer, it really depends on what the mutation is. For example, recently published data look at osimertinib, which is a next-generation EGFR TKI. It was approved as first-line treatment for advanced EGFR-mutant non–small cell lung cancer based on the FLAURA trial, which compared that with first-generation EGFR TKIs. Median overall survival was, on average, about 3 years. For ALK-positive non–small cell lung cancer, a drug such as alectinib—a next-generation ALK inhibitor given in the first line—in those trials, for example, the ALEX trial, median progression-free survival, not overall survival but progression-free survival, of the time it takes for the cancer to start growing again was about 3 years.
For a lot of these oncogene subsets we’re being able to match to highly effective targeted therapies that are improving survival for these patients. Other oncogene-driven subsets as well have pretty dramatic progression-free survival benefits with targeted therapies, so we’re really making a lot of progress. As I mentioned, we’re expanding the pie of identifying and targeting these oncogene-driven subsets such as with RET, MET, and others. Hopefully we’ll continue to find more. What is also exciting is that we now have certain KRAS inhibitors that also appear to be active. We’re constantly looking for new oncogene-driven subsets to target and to match to potent inhibitors. It’s a really exciting time, and we’re continuing to prove the outcomes in these patients moving forward.
Alexander Drilon, MD: Over the last few years, we’ve learned that the molecular signature a particular lung cancer harbors might help dictate how well patients do in terms of factors such as survival. We know, for example, that if a lung cancer harbors an EGFR mutation, or 1 of a variety of different fusions, these patients can have long overall survival compared with historical standards in unselected non–small cell lung cancers. That is in large part mediated, of course, by the availability of highly active targeted therapies that can result in very durable disease control. For patients being diagnosed with a cancer that has 1 of these alterations is a good thing. However, there may be other genes such as KRAS mutations, for example, that in general are known to be poorly prognostic. This is in the era where we looked at things like the response to chemotherapy or how patients with early stage did. By comparison, patients with KRAS-mutant lung cancers tend to fare a little worse than patients who have unselected non–small cell lung cancers or those that harbor other driver-oncogene genes in particular.
Jonathan Riess, MD, MS: Another important point is there still remains unmet needs. We’re looking at KRAS direct inhibitors that appear to have some exciting activity, new drugs for HER2 [human epidermal growth factor receptor 2] non–small cell lung cancer, and also trying to find new ways to overcome intrinsic resistance to immunotherapy. Although immune checkpoint inhibitors, such as pembrolizumab, atezolizumab, nivolumab, and so forth, have really changed the landscape of how we treat non–small cell lung cancer. A lot of patients don’t respond to these, especially those patients who have those oncogene-driven subsets not associated with smoking, such as EGFR. Finding ways to enhance the activity of immunotherapy in patients who don’t respond is another important unmet need that we need to address.
Transcript Edited for Clarity