Biomarkers and Histology Play Key Roles in Frontline Metastatic NSCLC Options

Anita T. Shaffer @Shaffer1
Published: Tuesday, Nov 13, 2018

Gregory J. Riely, MD, PhD from Memorial Sloan Kettering

Gregory J. Riely, MD, PhD

After a blizzard of recent study findings in non–small cell lung cancer (NSCLC), the current paradigm for choosing first-line therapy for patients with metastatic disease who do not harbor an actionable driver oncogene depends upon PD-L1 expression level and histology, according to Gregory J. Riely, MD, PhD.

Patients with PD-L1 expression ≥50% would be candidates for single-agent immunotherapy with pembrolizumab (Keytruda) while those whose status is below that level would be considered for combination PD-1/PD-L1–targeting immunotherapy and chemotherapy. The choice of the combination would then depend upon histology.

That was the succinct overview of the new landscape for NSCLC that Riely presented during a presentation at the 2018 New York Lung Cancers Symposium.

Riely noted the rapid pace of clinical trial findings during the past 7 months that have prompted the evolution in first-line options. “It’s transformed how we treat patients with initial therapy,” said Riely, a medical oncologist who is vice chair of Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center.

Before delving into the details of treatment options, Riely emphasized that the matter of establishing whether a patient has a driver oncogene also is becoming more multifaceted. He said the standard of care requires testing for mutations in EGFR and BRAF and fusions in ALK and ROS1 genes. However, Riely noted that therapies targeting RET, MET exon 17, NTRK, and HER2 alterations also are in development, demonstrating the value of conducting more extensive testing.

In all, 4 immune checkpoint inhibitors are FDA approved for treating patients with NSCLC: the PD-1 inhibitors pembrolizumab and nivolumab (Opdivo) and the PD-L1 inhibitors atezolizumab (Tecentriq) and durvaulamb (Imfinzi). Pembrolizumab is approved in frontline settings as monotherapy for patients with metastatic NSCLC with PD-L1 expression ≥50% and in combination with chemotherapy regimens. Nivolumab and atezolizumab are indicated for patients who have progressed during or following platinum-containing chemotherapy, while durvalumab is approved for unresectable stage III disease that has not progressed after chemoradiotherapy.

Monotherapy Based on PD-L1 Status

The efficacy of single-agent pembrolizumab for patients with PD-L1 expression ≥50% was first established in findings from the phase III KEYNOTE-024 study.1 In all, 305 patients with previously untreated NSCLC were randomized 1:1 to receive pembrolizumab at 200 mg IV every 3 weeks versus platinum doublet chemotherapy. The estimated 6-month overall survival (OS) rate was 80.2% with pembrolizumab versus 72.4% with chemotherapy (HR for death, 0.60; 95% CI, 0.41-0.89; P = .005).1

Moreover, participants treated with pembrolizumab experienced fewer treatment-related adverse events (AEs) of any grade than did those who received chemotherapy (73.4% vs 90.0%, respectively) and fewer AEs grade ≥3 (26.6% vs 53.3%).1 However, Riely noted that pembrolizumab is associated with immune-related AEs and that patients should be monitored for these effects, particularly those affecting thyroid function.

The findings made “it clear that this was the new standard of care for patients with ≥50% PD-L1” expression, so the next question became whether this would be the case for those whose status was below that threshold.

In the phase III KEYNOTE-042 study, pembrolizumab monotherapy was tested against the chemotherapy doublet of carboplatin plus paclitaxel or pemetrexed (Alimta) in 1274 patients with previously untreated locally advanced or metastatic NSCLC of any histology with a tumor proportion score (TPS) ≥1%. TPS is defined as the percentage of tumor cells with membranous PD-L1 staining.2

The findings confirm the benefit of pembrolizumab therapy for patients with TPS ≥50%, according to results presented at the 2018 ASCO Annual Meeting.2 The median OS for this group was 20 months (95% CI, 15.5-24.9) with pembrolizumab compared with 12.2 months (95% CI, 10.4-14.2) with the combination of carboplatin and either paclitaxel or pemetrexed (HR, 0.69; 95% CI, 0.56-0.85; P = .0003).

The benefit was less pronounced for participants with lower TPS scores. For TPS ≥20%, the median OS with pembrolizumab was 17.7 months (95% CI, 15.3-22.1) versus 13.0 months (11.6-15.3) with chemotherapy (HR, 0.77; 95% CI, 0.64-0.92; P = .0020). For TPS ≥1%, the median OS was 16.7 months (95% CI, 13.9-19.7) with pembrolizumab versus 12.2 months (95% CI, 11.3-13.3) with chemotherapy (HR, 0.81; 95% CI, 0.71-0.93; P = .0018). For all patients with TPS ≥1% to 49%, the median OS with pembrolizumab was 13.4 months (95% CI, 10.7-18.2) compared with 12.1 months (95% CI, 11.0-14.0) with chemotherapy (HR, 0.92; 95% CI, 0.77-1.11).

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