Leonid Shunyakov, MD, discusses the impact genomics has on personalized therapy and the roster of available therapies that continues to grow as a result of identifiable genomic drivers.
Leonid Shunyakov, MD
The use of next-generation sequencing (NGS) is a novel means of improving cancer care, but there are other methods of improving care that extend beyond the panel itself, explained Leonid Shunyakov, MD, a hematologist/oncologist at Central Care Cancer Center.
In November 2017, the FDA approved the use of Memorial Sloan Kettering Cancer Center’s integrated mutation profiling of actionable cancer targets (MSK-IMPACT). It is the first 468-gene oncopanel to be authorized by the FDA to identify somatic mutations.1
The application of NGS was well reflected in the phase III CheckMate-227 trial, in which high tumor mutational burden (TMB) was associated with greater response to immunotherapy. Treatment-naïve patients with non—small cell lung cancer who received the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) more than tripled the 1-year progression-free survival (PFS) rate versus those who received chemotherapy.
Patients with TMB ≥10 mutations/megabase treated with the combination showed a PFS of 43% at 1 year as opposed to 13% in those treated with platinum-doublet chemotherapy. Investigators also reported a 42% reduction in the risk of disease progression or death (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).2,3 However, Shunyakov noted that the number of patients who benefit from NGS hovers around 15% to 20%. In addition to streamlining existing assays, Shunyakov says that further investigation of the biology and pathways of patients’ tumors will better guide treatment selection.
He also added that proteomics and the microbiome will assume greater responsibility in predicting response to therapy in the future.
In an interview during the 2018 OncLive® State of the Science SummitTM on A Summer of Progress: Updates from ASCO 2018, Shunyakov discussed the impact genomics has on personalized therapy and the roster of available therapies that continues to grow as a result of identifiable genomic drivers. Shunyakov: Genomics is a huge subject. It’s important because we all use genomics in our practice. There are limitations to NGS. There is significant discordance between different assays. FoundationOne and Guardant360 are the 2 most commonly used assays in our practice, but they don’t really match up. The discordance rate is about 70% and the concordance rate is about 20% to 25%. That’s one of the problems with using NGS. The second issue is how to use NGS in novel ways. We used to use NGS to guide our therapy [decisions in a patient with a] single driver mutation, but most cancers are much more complex and have more than one driver.
[We now know that we can] assess TMB. There was a publication in the New England Journal of Medicine in May 2018 by Dr Matthew D. Hellmann about the use of high TMB as a predictive response to the combination of nivolumab and ipilimumab in lung cancer. At 1 year, the study showed a 43% PFS in the combination group compared with 13% in chemotherapy. Assessing TMB is one of the novel ways of using NGS.
Gaining knowledge at the molecular level about how genes work and using [that knowledge] to guide therapy is another novel way [of using NGS]. In kidney cancer, one of the most commonly mutated genes is PBRM1. It’s associated with activation of a certain inflammatory pathway, and whenever it’s activated, there is a higher likelihood of response to immunotherapy.
I also wanted to point out that NGS is not the final answer to everything. In addition to NGS, we also have proteomics. Exosomes are produced by cancer [and expulse] microRNA. The tumor has a 3-dimensional structure. That’s why there is tumor heterogeneity. Solid biopsies may not reflect everything. To get a more complete picture, we may use the combination of liquid and solid biopsies.
There is also a very important role for the microbiome. At the 2018 ASCO Annual Meeting, we learned that akkermansia muciniphila bacteria are associated with marked improvement in response to immunotherapy. Certain bacteria, such as bacteroidales, are associated with “cold” immune signatures and lower responses to immunotherapy. To [quote] Winston Churchill, “Perfection is an impediment to progress.” NGS is not perfect, but it is becoming more and more useful in our everyday practice.Last year, there was a report from Memorial Sloan Kettering Cancer Center on MSK-IMPACT. At the 2018 ASCO Annual Meeting, there was a report from The University of Texas MD Anderson Cancer Center [on the IMPACT study]. For the first time, we saw the report on the experience in the community based on 3 healthcare systems in Michigan, Wisconsin, and California. In academic institutions, about 35% of actionable mutations were identified using available platforms. In the community setting, about 71% of NGS reports [identified] actionable mutations. The number of patients who truly benefit from NGS is on the lower side. It’s on the order of 15% to 20%. Are there specific genes that are more difficult to target than others? One of the great stories from the 2018 ASCO Annual Meeting is FGFR inhibition with erdafitinib in urothelial cancer. Overall, more than 70% of patients had tumor shrinkage when they were treated continuously with erdafitinib daily.
We also know that NTRK inhibitors like larotrectinib (LOXO- 101) have been associated with a 75% response rate across tumors. At the 2018 ASCO Annual Meeting, there was a very exciting report about LOXO-292, which is a very selective inhibitor of RET fusion genes. That has a huge role because the studies showed benefit regardless of the tumor type. Patients with mutations in lung cancer, thyroid cancer, and pancreatic cancer had excellent responses similar to those seen with larotrectinib on the order of 76% to 78%.The KRAS gene is a “holy grail,” especially for lung cancer specialists. Up to 30% to 40% of patients with lung cancer are going to have a KRAS mutation. There are certain reports about the possibility of using MEK inhibitors in KRAS-mutated patients, but I don’t think there is anything close to fruition.I hope that we have more knowledge about driver mutations. We’ll have more drugs targeting those single driver mutations. We need to learn more about the biology of the cancer and the pathways to be able to give the right [therapy] for actionable mutations.
I also hope that we will be able to use proteomics more in the future and analyze the microbiome more frequently. There is another exciting area of research about identifying the T-cell repertoire. The possibility of the immune system to respond to certain neoantigens depends on what kind of T-cell receptors we have. That could be assessed in the academic setting by technologies that are not quite ready for prime time yet. We are hoping to have them several years down the road.