Giorgio V. Scagliotti, MD
The precision medicine movement continues to spread across malignancies with treatments targeted against driver mutations; however, especially in lung cancer, immunotherapy should also be given as a tailored, not blanket, treatment approach.
“I do not believe that any type of immunotherapeutic approach should be considered as a one-size-fits-all approach, but it should be included in a more tailored approach [as a] precision medicine strategy,” said Giorgio Vittorio Scagliotti, MD, PhD, chief of the Medical Oncology Division at the S. Luigi Hospital, Orbassano (Torino), and head of the Department of Oncology at University of Torino, Italy.
Biomarkers, including PD-L1 expression and tumor mutational burden (TMB), continue to be used as a gauge for patient selection for checkpoint inhibition in patients with non–small cell lung cancer (NSCLC). In the phase III KEYNOTE-042 trial,1
for example, patients with NSCLC who were treated with frontline pembrolizumab (Keytruda) lived 4 to 8 months longer than those who received standard chemotherapy, depending on their level of PD-L1 expression.
Data showed that the overall survival (OS) was associated with greater levels of PD-L1 expression. With a tumor proportion score (TPS) ≥50%, the OS was 20 months with pembrolizumab versus 12.2 months with chemotherapy (HR, 0.69; 95% CI, 0.56-0.85; P
= .0003). For TPS ≥1%, the median OS was 16.7 versus 12.1 months (HR, 0.81; 95% CI, 0.71-0.93; P
= .0018) for pembrolizumab versus chemotherapy, respectively. However, an exploratory analysis showed that in all patients with PD-L1 TPS of 1% to 49%, the median OS was 13.4 months with pembrolizumab versus 12.1 months for chemotherapy (HR, 0.92; 0.77-1.11).
TMB was a focus in data of the CheckMate-227 study, which was presented at the 2018 AACR and ASCO Annual Meetings and published in the New England Journal of Medicine
Results of the phase III trial, which evaluated the frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with advanced NSCLC, showed a 1-year progression-free survival (PFS) rate of 43% in those with high TMB ≥10 mutations/megabase regardless of PD-L1 status with the combination. This was compared with a PFS rate of 13% in those given chemotherapy. In June 2018, the FDA accepted a supplemental biologics license application for this combination in this setting.
Beyond PD-L1 and TMB, other markers are in the early stages of investigation, such as neoantigens, explained Scagliotti. During the 19th Annual International Lung Cancer Congress,
he presented results focused on the available BRAF
-mutant treatments as well as the crossroads between immuno-oncology and precision medicine in lung cancer. In an interview with OncLive
during the meeting, Scagliotti focused on the latter, highlighting the progress and challenges with PD-L1 and TMB with a forward look to potential biomarkers on the horizon.OncLive®: Where does the field currently stand in relation to immunotherapy and precision medicine?Scagliotti
: Immunotherapy is one of the emerging pillars in the systemic treatment of NSCLC in general, and also in other types of classic malignancies. This type of approach should be, at least in my view, appropriately considered in the context of precision medicine. In other words, I do not believe that any type of immunotherapeutic approach should be considered as a one-size-fits-all approach, but it should be included in a more tailored approach [as a] precision medicine strategy.
We started looking to one specific biomarker that you can easily assess in clinical practice—that is PD-L1 expression. That is just one of the potential biomarkers. Based on the data that we currently have, it can be considered as an enrichment factor because of the data we got from several trials. It is true that the objective response rates (ORRs) and duration of response are much longer for those tumors that are PD-L1–positive.
One of the issues we have in the PD-L1 assessment is the tumor heterogeneity. [Also], in terms of expression, we don’t know if the time of [assessing] the markers make any difference. [This is affected when] testing PD-L1 expression on tissues in the field of second-line treatment, but even in the context of frontline treatment. We are not assessing the marker at the same time before starting treatment.
Obviously, there are controversial data about this marker. Sometimes [we are] getting a good correlation between the PD-L1 expression and the outcomes, but the next question is to look at the different values that the investigators tested across several trials. There is a general consensus [stemming from] clinical data that led to the registration of pembrolizumab: if [a patient has] more than 50% PD-L1 expression on their tumor cells, [they will have] much more benefit from immunotherapy when compared with chemotherapy.