Overview of Targeted Therapies, Improved Outcomes, and Unmet Needs in Advanced NSCLC

Benjamin Levy, MD: Our increased understanding of non–small cell lung cancer (NSCLC) biology has led to the important development of novel therapies and improved outcomes for our patients. This has been the whole personalized therapy story in solid tumor oncology, which has been led by the lung cancer field. We have a better understanding of the genomic underpinnings of the tumor. We can now wed particular targeted therapies to these molecular niches. This has been exciting for physicians, but, more importantly, it’s been a big win for patients. We have data [showing] that if we know the patient’s [genetic] target or mutation and give them a targeted therapy, they do better than if they have a target and don’t receive targeted therapy. But you can’t give genotype-directed therapy unless you know the genotype. We started out with EGFR, but the list of relevant alterations that we can now test for in patients with lung cancer is growing. By defining or identifying these mutations, we can wed patients to therapies. This has led to improved outcomes, quality of life, and the potential ability to circumvent the need for chemotherapy. It’s been incredibly exciting to be in this field. I’m just talking about targeted therapies and haven’t even mentioned immunotherapies. Again, understanding the biology of a tumor also may help leverage specific immunotherapies. Clearly, the story has been about identifying mutations and wedding those mutations to targeted therapies to improve outcomes for our patients with advanced stage lung cancer.

Stephen Liu, MD: We now have FDA-approved treatments for specific biomarker-defined subsets of lung cancer that include ALK, ROS, RET, and NTRAK. These are important to target the EGFR set, the paradigm. We now have extremely effective and well tolerated agents for ALK [-positive disease]. Crizotinib and ceritinib were superior to chemotherapy, and alectinib, brigatinib, and lorlatinib were all superior to crizotinib. All 5 of these drugs are approved [by the FDA]. The newer agents (alectinib, brigatinib, and lorlatinib) are typically effective for years and are given as pills that you can prescribe via a pharmacy today. These drugs have been fully approved and work, on average, for about 3 years and, for some, much longer. It is quite remarkable, and we have important efforts ongoing to further improve outcomes. [We are] never satisfied with what we have. For ROS1 [-positive tumors], we have 2 drugs that are FDA-approved. Crizotinib is a very versatile agent, and, most recently, entrectinib was approved by the FDA in 2019. Another agent, repotrectinib, or TPX-0005, has been given a breakthrough therapy designation [by the FDA] in early results, [but it is] not yet approved. RET fusion [-positive tumors], which currently represent about 1% to 2% of lung cancer cases, can also be effectively targeted. For many years, we were repurposing drugs off the shelf that were approved for other cancers, like kidney cancer and thyroid cancer. Drugs like cabozantinib and vandetanib have shown modest activity and notable toxicity from a lot of their off-target activity. We have selective inhibitors that are much less toxic, extremely well-tolerated, and highly effective. When used as initial therapy, pralsetinib, an FDA-approved RET inhibitor, produced a response rate of 88% in the first-line setting, which was really remarkable. With a 96% disease control rate, [you can] go in and know with confidence that this drug will work. Selpercatinib, another FDA-approved RET inhibitor, showed a frontline response rate of 85%. These responses are rapid, they're deep, they're very durable, and, in many cases, they last for years. Likewise, for tumors with end-track fusions, we have approval of larotrectinib and entrectinib, another versatile drug. These are FDA approved, have high response rates, and are potent gene inhibitors. What's unique about these drugs is they're both active and are both FDA-approved across different tumor types. 

Mark A. Socinski, MD: In NSCLC, there are several unmet needs. Largely, there is the percentage of patients that gets comprehensive genomic testing. It still is far below the plateau that it should be, which is 90-plus percent of patients. The list of either mutations or alterations, amplifications, fusions, or all the alterations we see in NSCLC is growing and, hopefully, will continue to grow. The list of targeted therapies approved by the FDA for specific biomarker-defined populations is also growing. We have just had the first drug for the G12C subset of the KRAS mutations, which is a phenomenal advance in the overall therapeutic options for these patients. All of these really good drugs have a nice therapeutic index, a clinical activity that we typically don't see with chemotherapy or I-O [immuno-oncology] therapy in these populations, [but] none of them can be used unless you make the molecular diagnosis. And we still see that comprehensive genomic testing covering all the actionable alterations is still not at the level where we need it to be. There are lots of different reasons for that in a lung cancer population. For example, it's often not easy to get adequate tissue from this population. There's been underuse of plasma-based next-[generation] sequencing. And there has been some misunderstanding of the pros and cons of different testing platforms in terms of what you can expect. We need to continue educational efforts to stress the importance of comprehensive testing. The standard of care for both accuracy and efficiency is next-generation sequencing. All of my patients with stage IV disease get tissue-based testing and plasma-based testing on an NGS [next-generation sequencing] platform that does both DNA and RNA. The one thing you'd never want to miss in a lung cancer population is a targetable driver alteration, again, because of the activity of these agents.

Transcript edited for clarity.