Expert Highlights Utility of PD-L1 to Select Immunotherapy in NSCLC

Amishi Desai, MD

When choosing the best treatment for patients with metastatic stage IV non—small cell lung cancer (NSCLC), all decisions should be dependent on PD-L1 status, said Amishi Desai, MD.

Over the past few years, the introduction of immunotherapy has revolutionized the treatment of patients with NSCLC. For example, the PD-1 inhibitor pembrolizumab (Keytruda) has gained regulatory approval in the first- and second-line settings, and most recently, in December 2018, the FDA approved atezolizumab (Tecentriq) for use in combination with bevacizumab (Avastin), carboplatin, and paclitaxel for the first-line treatment of patients with metastatic nonsquamous NSCLC, though PD-L1 expression is not a requirement.

Nivolumab (Opdivo) and atezolizumab are also available in the second-line setting. Although deemed an imperfect biomarker, PD-L1 expression is used as a tool for clinical decision making to determine use of these agents in patients with NSCLC. Data emerging from recent trials are being used to inform treatment decisions as well, according to Desai, who is an assistant professor of medicine at Upstate University Hospital. When deciding on a treatment regimen, patients are divided into 3 groups: those with PD-L1 ≥50%, <50%, and <1%, Desai said.

For example, data from the phase III KEYNOTE-024 trial showed that frontline pembrolizumab more than doubled median overall survival (OS) in patients with ≥50% PD-L1 expression versus standard chemotherapy. The median OS with pembrolizumab was 30.2 months compared with 14.2 months with chemotherapy, representing a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.47-0.86; P = .002).¹ In patients with nonsquamous NSCLC with a PD-L1 expression >50%, Desai suggested a regimen consisting of chemotherapy plus immunotherapy, as shown in the phase III KEYNOTE-189 trial, which evaluated the safety and efficacy of pembrolizumab in combination with pemetrexed/carboplatin versus chemotherapy alone. The addition of pembrolizumab to chemotherapy reduced the risk of death by 51% in patients with NSCLC without EGFR or ALK mutations.^2,3 These positive data led to the full FDA approval of the combination in August 2018.

OncLive: What is the current role of immunotherapy in the NSCLC space?

What are the current treatment approaches for patients with PD-L1 ≥50% and <50%, respectively?

Is immunotherapy still beneficial for patients with very low to no expression of PD-L1? How do you approach treatment?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Desai highlighted new and emerging data regarding the use of immunotherapy in patients with NSCLC.Desai: As everyone knows, immunotherapy is the big thing right now. So much data are coming out on it. Everything is now geared toward PD-L1 status, and mainly I’m talking about metastatic, stage IV lung cancer. It’s all about the molecular markers.Per the KEYNOTE-024 trial, [we know that the] approach [to use] for patients with PD-L1 expression greater than 50% is pembrolizumab. We use 200 mg every 3 weeks; that’s the upfront [treatment] for these patients. We now have a couple of trials that separate [patient populations] into squamous and nonsquamous. However, the bottom line is, for patients with PD-L1 expression <50%, [the approach is] chemotherapy plus immunotherapy. In patients with squamous cell lung cancer, it can be carboplatin and a taxane plus pembrolizumab, [which has been shown to] improve progression-free survival (PFS) and OS [in the phase III KEYNOTE-407 trial]. For patients with nonsquamous NSCLC, the KEYNOTE-189 trial showed that, again, the combination of [chemotherapy] plus pembrolizumab improved PFS and OS.The answer to this question was [provided by] the CheckMate-227 trial, which tells us what to do for patients who have PD-L1 <1%. Remember, these patients also benefit from our standard KEYNOTE-189 and KEYNOTE-407 trials, which suggest combination chemotherapy plus immunotherapy. One other option we have, which is not in prime time yet but we are looking forward to it, is checking tumor mutation burden (TMB). This is a specialized test; you have to do it through special tests like FoundationOne or [similar], and [with this test], you get the answer of whether a patient has high TMB or low. High TMB is considered anything more than 10 mut/mB, and low is anything lower than that. If a patient has high TMB, regardless of their PD-L1 status—even if it is 0%—these patients, as per CheckMate-227, actually experience an improved PFS and OS with a combination of standard chemotherapy based on histology plus nivolumab.

Are there other biomarkers to possibly help select patients for immunotherapy?

What pivotal immunotherapy data have come out in 2018?

What is your take-home message regarding the use of immunotherapy in patients with stage IV NSCLC?

They also tested these patients with just dual immunotherapy— nivolumab and ipilimumab (Yervoy)—and they showed a robust response, an even better response than with chemotherapy plus ipilimumab. Therefore, we do have options for these patients, too.Right now, the primetime [one] is PD-L1, [but] a lot of markers are being evaluated. We’re checking for circulating tumor cells, and like I said, when you do the FoundationOne [test], that gives you more mutations and [information]. Right now, we are only [using] PD-L1, but yes, there are more coming.At the 2018 ASCO Annual Meeting, they spoke about the KEYNOTE-042 trial. Now we know that for patients with PD-L1 ≥50%, we use pembrolizumab, and for patients with less than that, we use a combination of chemotherapy and pembrolizumab. Therefore, the question asked [in the plenary] was, what about just doing single-agent immunotherapy for patients with PD-L1 <50%? The KEYNOTE-042 trial kind of answered that. Patients [with PD-L1 <50%] who received single-agent immunotherapy experienced improved PFS and OS. That is exciting, because we have many patients who are not able to tolerate chemotherapy. For these patients, even if they don’t have PD-L1 ≥50%, there is benefit from just receiving single-agent immunotherapy.The take-home message is: Keep it simple. If we understand the basics of these trials and we understand that for patients with stage IV NSCLC, if they do not have [driver mutations], such as EGFR, ALK, ROS1, then PD-L1 expression is the standard. These patients should be tested for PD-L1, and then, based on these simple numbers—≥50%, <50%, and <1%—we should be targeting our patients. We have data to support that, so we should be doing that.

References

1. Brahmer J, Rodgri&#769;guez-Abreu D, Robinson A, et al. Updated analysis of KEY- NOTE-024: pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS ≥50%. Presented at: the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 17.06. doi: 10.106/j.jtho.2017.09.431.
2. Gandhi L, Rodgri&#769;guez-Abreu D, Gadgeel S, et al. KEYNOTE-189: randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. In: Proceedings from the 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.
3. Gandhi L, Rodgri&#769;guez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.