Molecular Testing in Metastatic mNSCLC

Neal Navani, MRCP, MSc, PhD: We all understand the importance of reflex testing all our patients with lung cancer, particularly in the advanced setting, to get a rapid molecular profile as soon as possible. Solange, are there still centers out there—or perhaps, are there some settings—where immunotherapy is being used up front without waiting for mutation testing? Does this still happen, and what are the consequences?

Solange Peters, MD, PhD: Unfortunately, yes. There’s the standard of chemotherapy–I/O [immuno-oncology], which can be given—we’re speaking about nonsquamous, non–small cell lung cancer [NSCLC]—regardless of any biomarkers. Sometimes, because of practical issues—because of the biopsy and the quality you have—the simplest way to go is to give chemotherapy–I/O to your patient, particularly if they’ve smoked. Remember, a smoking habit doesn’t prevent EGFR-mutated non–small cell lung cancer. You’re just not reaching a smoker when you speak about these diseases. Meaning that if you take the short way, there will be a difficult biopsy. You know it’s nonsquamous, so you can give chemotherapy–I/O. But why is it not a good idea? Because first, for this patient population—you should give the best treatment first. For patients with EGFR mutation, that’s not chemotherapy–I/O and it’s probably not I/O in the front line. Second, if you had to learn it later on—your NGS [next-generation sequencing] comes back in 10 days—if you’ve given 1 cycle of pembrolizumab, then you’re stuck for weeks before you’re allowed to give osimertinib because of the risk of pharmacological overlap leading to significant lung toxicity. By that time, it’s too late to switch. A mechanism for patients with EGFR-mutated NSCLC who are nonsquamous to be assessed systematically should be in place where you work.

Neal Navani, MRCP, MSc, PhD: Thank you. Christian, if you’re faced with a patient who has advanced metastatic lung cancer and is unwell, and you want to start treatment quickly, what’s your approach in this setting if you don’t have the EGFR status straightaway?

Christian Grohé, MD: We still use clinical performance status, comorbidities, and scoring systems to understand the overall performance we’d like to anticipate for the recommended treatment option we have. We still must wait, even if we do our best molecular profiling; it takes 7 to 10 days to have the total set of data back. Regarding these circumstances, we still initiate certain treatments for patients who have a high comorbidity—infiltrating tumors, tumors that cause pain. We start with a basic chemotherapy combination, and we may even combine that initially with certain radiation treatment options. Overall, most of our patients are tested as part of reflex testing with an NGS panel from the nNGM [national Network Genomic Medicine] in Germany, incorporating up to 40 kinds of signatures. But the readout—how these patients will perform in the long run—we still have to wait for. We’ve initiated that here in our city [Berlin, Germany]. We correlate these data sets and have very interesting data sets for them, but this must await real-world evidence reprogramming.

In terms of the clinical studies we have, we’d like to offer the best treatment options to all our patients. But with a high tumor burden, certain patients might have a benefit from initiating treatment. That said, up to 25% of patients will fail—whatever treatment option you have—if you don’t have a trial mutation. For a patient with a trial mutation, in particular with patients with EML4 and ALK mutations, we see incredible benefit early on. But there are patients who don’t have a trial mutation—we still have a significant proportion of patients who don’t benefit at all from any treatment options. This is the most important target population we’re interested in at the moment: molecular profiling for patients who fail early on. It’s really important to treat all patients with trial mutations from the beginning. But in the real-life setting, we still see some patients who’ve been offered at least 1 cycle of any kind of chemotherapy to reduce tumor burden and improve clinical performance status.

Neal Navani, MRCP, MSc, PhD: Thank you. It sounds as if you have very few barriers to obtaining molecular testing relatively quickly. You’re getting the majority of your results within 7 to 10 days, and it sounds as if you have an excellent national network of testing, a framework. Gary, what are some of the barriers to obtaining molecular testing, perhaps in your setting?

Gary Doherty, MRCP, PhD: One of the biggest barriers is a timed biopsy, so we need to make sure patients with lung cancer get quick biopsies and that they get good biopsies. What I mean is vision material for NGS testing, and that these patients are tested in a quick way so we can isolate what’s wrong and the analysis has a quick turnaround time. There are efficiencies at all these stages, but NGS takes time, and there will be some improvement made with automated extractions of DNA and RNA with automated algorithms that make interpretation much simpler. We’re still going to have a time delay from a patient needing a biopsy to getting those NGS results, and patients can deteriorate quickly.

We need to think about other ways to treat our patients, and ctDNA [circulating tumor DNA] has a role here. Patients who have ctDNA, whenever they have radiological imaging that suggests metastatic lung cancer, sometimes you can get the results back within a few days—often before the biopsy happens, depending on the expediency of biopsies in your region. Whenever you get a biopsy that confirms lung cancer, you’re good to go. It’s not ideal. We should be doing this on tissue, ideally, but that’s 1 way to speed up things for these patients. I don’t think we should forget about the best supportive care for these patients as well. Not every patient is salvageable regarding their performance status. Many factors come into play, including whether we should be giving a cycle of chemotherapy if we don’t have the information. It has to be a very patient-centric decision. But we can’t forget about optimal supportive and palliative care for these patients, as well as the role of palliative radiotherapy. It’s a very complex decision, but we need to improve all these to help improve patients’ outcomes.

Neal Navani, MRCP, MSc, PhD: Thank you. You had a nice point about the supportive care aspect for those patients. We have clinical trial data as well that actually show improved survival rates for patients who have early supportive care in their pathway.

Transcript Edited for Clarity