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Kartik Konduri, MD, shares insight on molecular developments, recently discussed clinical trials, and steps the field needs to take to continue moving in a biomarker-driven paradigm of non–small cell lung cancer treatment.
Kartik Konduri, MD
Single-agent and combination immunotherapy continue to show positive results in patients with non—small cell lung cancer (NSCLC), especially those who have biomarker-driven disease.
For example, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was reported to improve progression-free survival (PFS) versus chemotherapy in treatment-naïve patients with high tumor mutation burden (TMB), according to a news release of the phase III CheckMate-227 trial.
The same regimen also was found to demonstrate clinical activity in patients with small cell lung cancer (SCLC) who also have high TMB. In an exploratory analysis of the phase I/II CheckMate-032 study, nivolumab combined with ipilimumab induced an objective response rate (ORR) of 46% in these patients, who also had recurrent disease. In those who were treated with nivolumab alone, the ORR was 21%.
Kartik Konduri, MD, medical oncologist at Texas Oncology, co—medical director of the Chest Cancer Research and Treatment Center at Baylor Charles A. Sammons Cancer Center and chair of the chest site tumor committee at Baylor University Medical Center in Dallas, Texas, lectured on identified biomarkers in NSCLC during the 2018 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer.
“The most important thing in lung cancer, at least in the nonsquamous NSCLC area, is that in many trials looking at different molecular mechanisms, one must consider evaluation upfront,” Konduri said. “Then, do not give up, and reevaluate with another biopsy if necessary, whether it be a blood test or tissue test or, in the circumstance that it may be possible for the patient, immunotherapy. Outcomes are certainly changing for patients who [respond to] immunotherapy-based treatment. They can be very long-lasting and, as we fine-tune that information and find the particular patient who fits this type of treatment, we will have an exciting time going forward.”
In an interview during the meeting, he shared insight on these molecular developments, recently presented or discussed clinical trials, and steps the field needs to take to continue moving in a biomarker-driven paradigm of NSCLC treatment.Konduri: The lung cancer landscape is changing and, as we go about on a day-to-day basis, we are finding new discoveries about how patients are potentially noted to have markers that can be utilized for treatment. Some of them can be molecular markers, where you are utilizing targeted therapies, and there are circumstances where secondary mutations of resistance mutations occur. Resistances can occur in the form of escape mechanisms or amplifications of the target, and new drugs have come out, which potentially can be evaluated for treatment.
Clinical trials going on in the space can be evaluated, as well. In terms of immunotherapy, we don’t have a perfect biomarker. We know that PD-L1 has a good response [as a biomarker], at least in a couple of trials, and it has been approved in the frontline setting for high expression with a particular drug.
We know that it is not a perfect biomarker, however, and we are in search of more. TMB and other evaluations, including T-effector gene signatures, are being looked at as possible biomarkers for the future. Multiple clinical trials are looking at immunotherapy biomarkers, and TMB has come to the forefront. Various trials have suggestive benefit—from evaluation in the CheckMate-026 trial, there was a TMB benefit in outcomes of PFS. There were also trials looking at small cell lung cancer, for example, such as in the CheckMate-032 trial. This was a small trial, but it did show benefit for high TMB having good response rates for patients with ipilimumab in combination with nivolumab or nivolumab on its own.
A recent trial that has been spoken about without actual data being presented is CheckMate-227, which is a combination of immunotherapy agents that have been shown to improve PFS for a specific subset of patients who are known to have high TMB. Then, there are trials that have looked at T-effector gene signatures, particularly the IMpower150 study, which has shown improvements in PFS. The trial that has changed practice over the last few years was the KEYNOTE-024 trial. It allowed for high PD-L1 expression to suggest a subset of patients who will have a good benefit in terms of PFS and overall survival in lung cancer.
Evaluations of all the other tumor biomarkers, particularly TMB, are coming to the forefront. We will know more in detail as the next few years come up, but it appears to be promising. Trials have suggested that not all patients who have PD-L1 low expression may benefit from the current treatments. There are other ways to test for these patients who have possibly high TMB, so stay tuned. The biomarker space is improving on a day-to-day basis. How easy will it be for us to try to reproduce these biomarkers in regular practice? Clinical practice is going to be the big question. How efficacious will it be to try to get the testing done? How much of an expense? These are all practical questions that will have serious implications for patients who will need treatment in the future.
With regard to molecular markers, many evaluations are looking for different mutations or resistance mutations that are coming up in terms of therapies. Again, how easy will it be for us to test [for these mutations]? Will we use tissue- or blood-based testing as a means of trying to find these? These will all play an important role in how we end up trying to treat our patients. We all agree that the specificity of liquid biopsies is very high, and if a result comes back to be positive, we are all pretty confident that the patient’s tumor does carry that particular mutation. We lack in terms of sensitivity, and false negative rates are still a matter of concern. These things will change as the testing continues to become fine-tuned.
The other circumstances involve finding meaningful targets for the many genes that can be tested—for example, in next-generation sequencing. They are not necessarily all there for practical consideration on a day-to-day basis for the regular community oncologist. Things will change as we get to know more information. In terms of immunotherapy, every patient who is being evaluated with stage IV NSCLC should be tested for PD-L1. It is the standard biomarker at this point in time; things will change in the future. We may have a complementary or additive test. This is yet to be seen.
In terms of molecular testing for all patients with NSCLC, particularly those with nonsquamous NSCLC, every patient needs to at least be tested for the very common mutations, including EGFR, ALK, ROS1, etc. These are mutations or gene arrangements that have very gratifying results for targeted therapies. This is now recommended by the College of American Pathologists, as well as the National Comprehensive Cancer Network and many other institutions.
Opdivo alone or combined with Yervoy shows encouraging response and survival rates in recurrent small cell lung cancer patients with high tumor mutation burden, in exploratory analysis from phase 1/2 study CheckMate-032 [press release]. Princeton, NJ: Bristol-Myers Squibb Company; October 16, 2017. news.bms.com/press-release/corporatefinancial-news/opdivo-alone-or-combined-yervoy-shows-encouraging-response-and. Accessed February 19, 2017.