Immunotherapy Requires Precision Approach for NSCLC

Giorgio Scagliotti, MD, PhD

Several biomarkers are beginning to emerge for immunotherapy in non—small cell lung cancer (NSCLC), and the collection of these markers, when used together, could further help to predict which patients are likely to respond to these therapies alone or in combination, according to Giorgio Scagliotti, MD, PhD, at the19th AnnualInternational Lung Cancer Congress.

“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 Scagliotti, 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. “A few years from now we are not going to focus on one single biomarker; it is quite likely that to identify the best subgroup of patients who will have benefit [in] any type of solid tumor, it’s quite likely that it will be [from] a combination of biomarkers.”

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 NSCLC. In the phase III KEYNOTE-042 trial, 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.¹

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). 

“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,” said Scagliotti. “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.”

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 theNew England Journal of Medicine.^2,3Results 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.

“In principle, when we are talking about TMB, you need to ask yourself, ‘When to assess the TMB, how, and where?’ Where is because it can be in the tissue, but it can also be in the blood, and the cut-offs are totally different when you are testing tumor mutational load in the tumor or in the blood. Also, the specificity and sensitivity could change,” he said. “For when—it can be at baseline, but you need to also [detect] the mutational load assessment later on, during treatment, because, at least in the melanoma field, there is a clear correlation between the efficacy of immunotherapy and the contraction of TMB over time.”

Beyond PD-L1 and TMB, other markers are in the early stages of investigation, such as neoantigens, explained Scagliotti. These will likely emerge as being more important than TMB or PD-L1 alone, he said.

“The quality and the type of antigens are becoming relevant. That is the reason why a lot of investigators are looking at the amount of neoantigens,” he said. “There is some correlation between the mutational load and the number or proportion of neoantigens, and that is what the current research is trying to investigate. However, there is no clear or direct evidence of that. However, neoantigens need to be investigated carefully; [these] are the key players in inducing the immune response, which are a different number from the total number of antigens in the context of a tumor.”

At this phase in its development, Scagliotti felt the neoantigen research was still very early. He cautioned against jumping too far ahead, as rushing to conclusions could delay further advances. One thing is becoming clear, he noted, next-generation sequencing (NGS) is growing in popularity for tailoring therapy; however, challenges with reimbursement persist, especially in the European Union.

“I’m not saying one system is better than another, but it’s much easier to get the test reimbursed in the United States; it’s less possible in the European setting,” he said. “Consequently, at least from my European point of view, NGS is still a research tool.”

References

1. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. In: Proceedings from the 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA4.
2. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT077. 2017;35(suppl 4S; abstr 350).
3. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 378(22):2093-2104. doi: 10.1056/NEJMoa1801946.