Joshua K. Sabari, MD, reflects on the rapidly advancing landscape of lung cancer.
Joshua K. Sabari, MD
The lung cancer landscape continued to shift dramatically in 2018. Immunotherapy continued to dominate the clinical trial space, next-generation sequencing (NGS) is now regularly used in practice, and liquid biopsies began to be more widely adopted.
One of the pivotal decisions in 2018 was the FDA approval of durvalumab (Imfinzi) for the treatment of patients with locally advanced, unresectable stage III non—small cell lung cancer (NSCLC) who have not progressed following chemoradiotherapy. The decision was based on data from the PACIFIC trial, in which consolidation immunotherapy with durvalumab significantly improved progression-free survival and overall survival (OS) in patients with stage III NSCLC.
In an interview during the 2018 OncLive® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Joshua K. Sabari, MD, assistant professor, Department of Medicine, (NYU Langone’s Perlmutter Cancer Center, reflected on the rapidly advancing landscape of lung cancer.Sabari: In the early-stage setting is the PACIFIC trial, which looked at durvalumab after patients received concurrent chemotherapy and radiation. The results of that study were groundbreaking leading to the FDA approval and the new indication for that regimen. There was a 12-month OS benefit for patients who received durvalumab consolidation therapy after chemotherapy and radiation.
In stage IV disease, [there are] 2 very important studies that were recently presented. First was KEYNOTE-189, which is a combination of pembrolizumab (Keytruda) plus chemotherapy versus chemotherapy alone. Second was the IMpower150 trial, which is a quadruplet regimen similar to what we saw in KEYNOTE-189, but using atezolizumab (Atezolizumab) in combination with carboplatin, paclitaxel, and bevacizumab (Avastin) versus carboplatin, paclitaxel, and bevacizumab alone.That is a controversial topic right now. There is definitely synergy, and by combining drugs that work, you may get a better response rate, a better duration of response, and better OS. What chemotherapeutics are doing specifically, are improving the immune response so the immunotherapies can recognize and attack the cancers.I still order PD-L1 [testing] on my patients, and I still use the cut point of 50% to define whether a patient should receive pembrolizumab alone versus pembrolizumab in combination with chemotherapy. This is for my patients with non—small cell adenocarcinoma and those with non–small cell squamous cell lung cancer. I know out in the community, people are now ordering PD-L1 expression. If you parse the data, no matter how you look at it, people who have a higher PD-L1 expression benefit with immunotherapy. What I like to do with my patients is weigh the risks and the benefits of each therapy. Why add chemotherapy to a regimen for a patient with a PD-L1 expression of 100%?
One of the other key biomarkers that is coming down the pike is tumor mutational burden (TMB). That is actually a lot more controversial right now. There are studies looking at it prospectively and retrospectively. The CheckMate-227 trial was recently presented by Matt Hellmann, MD, of Memorial Sloan Kettering Cancer Center, showing an improvement in patients who had high TMB. The controversy is, what is the definition of TMB-high? A lot of people are not using this assay and not testing for it, so we have a lot more work to do.Liquid biopsy is a novel mechanism to identify circulating tumor DNA in the peripheral blood. By doing that, we are able to identify genetic alterations that we are then able to match patients to targeted therapies. Tumors are heterogeneous, so a metastatic lesion in the lung versus a metastatic lesion in the liver might have different genetic compositions. By testing plasma or blood, we are able to identify what alterations may be circulating in the body.Tissue remains the standard of care, as we need to define histology. But, liquid biopsy is more accessible—it is easier to do and the turnaround time is quicker. Most of our liquid biopsy assays are able to turn around in 7 to 10 days, whereas standard next-generation sequencing (NGS) takes an average of 3 weeks. We did an interesting study where we compared the actual correlation or concordance between tissue NGS and plasma NGS and we did find that if you identified an alteration in the plasma, it was identified in the tissue about 97% of the time.
However, the beauty of plasma and NGS for liquid biopsy was the turnaround time had an average of 9 days, whereas the turnaround time for tissue had an average of 21 days. Getting patients the results they need to get matched to targeted therapy quicker is better for their overall outcome.Most academic centers are ordering NGS on all their patients. It is critical. When I talk to people out in the community, more people are adopting this practice. We have great targeted therapies for our patients, and it is time to identify the patients who will benefit from those drugs.Liquid biopsies are critical in patients who you have a pretest probability of having a genetic driver alteration. Specifically, younger patients, and patients who are never-smokers. These are patients who you do standard immunohistochemistry for EGFR and ALK, and liquid biopsies are extremely helpful in identifying other alterations such as ROS1 and BRAF. [Additionally, they are helpful to identify other markers], such as RET rearrangements, MET exon 14 skipping alterations, as well as HER2 alterations—both mutations and amplifications.The cost is an issue, as well as how physicians are ordering them. If they’re ordering them to monitor disease response or residual disease, there are no indications for that and no prospective studies showing their benefit. Where it is indicated clinically is upfront, or when you identify an alteration in a patient and you are assessing for a secondary resistance mechanism.
For example, if you have a patient with EGFR exon 19 activating deletion and you start them on osimertinib (Tagrisso) and 1 or 2 years later they progress, getting a liquid biopsy makes a lot of sense to identify alterations such as C797S or MET amplification, for which we have great clinical trials at NYU Langone Health’s Perlmutter Cancer Center.Immunotherapy drugs are safe, well studied, and we know a lot about their toxicities. The key thing, is that if you are unfamiliar with these drugs, to talk to a doctor or team that is familiar with them. If you have any questions or concerns about a rash or diarrhea, reach out to your colleagues for help. There are very common irAEs, such as thyroiditis, dermatitis, and colitis, and if these are identified early, we can safely treat patients.
Other irAEs, such as pneumonitis, need to be taken more seriously, and we often will not expose the patient to the drug again. Working with your rheumatology and endocrinology colleagues, as well as dermatologists, is critical in building that infrastructure so you have a good referral system set up for patients when they need your help.SCLC is a tough disease. Chemotherapy works very well with a great response rate rivaling 70% to 80%. Unfortunately, all patients relapse and have chemorefractory disease. There have not been any changes in the last 30 or so years until recently. We saw an FDA approval in the third-line setting, despite a low overall response rate of less than 10%. More recently with the IMpower133 trial, we saw the positive results of pembrolizumab plus platinum-based therapy and etoposide in the first-line setting with a 2-month OS benefit. Although that appears low on first glance, this is a large step forward in this field. What I am exciting about in this space is the multiple immunotherapy options available. We have a lot more to do here.