Biomarkers and Histology Play Key Roles in Frontline Metastatic NSCLC Options


In light of recent advancements, the current paradigm for choosing first-line therapy for patients with metastatic non–small cell lung cancer who do not harbor an actionable driver oncogene depends upon PD-L1 expression level and histology.

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.

Monotherapy Based on PD-L1 Status

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.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).

Histology-Based Decisions

“There’s no clear benefit for pembrolizumab over chemotherapy in this context,” Riely said, of the 1% to 49% group. “The hazard ratio is nearly 1 and the confidence intervals overlap. This tells us that it’s probably not reasonable to move the bar down from 50% to 1% but we can think about that when we see our patients.” Nonsquamous NSCLC

When choosing combination immunotherapy and chemotherapy, the decision about which option hinges on histology, Riely said.

For patients with nonsquamous disease, there are 2 regimens with recently reported results: (1) pembrolizumab plus carboplatin and pemetrexed, and (2) atezolizumab with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP).

In the phase III KEYNOTE-189 trial, the pembrolizumab combination demonstrated an improvement in OS compared with chemotherapy alone regardless of PD-L1 expression status. The 12-month OS rate was 69.2% (95% CI, 64.1-73.8) with the pembrolizumab regimen compared with 49.4% (95% CI, 42.1-56.2) for those who received chemotherapy (HR for death, 0.49; 95% CI, 0.38-0.64; P <.001). Among participants with a TPS <1%, the 12-month OS rate was 61.7% with the pembrolizumab regimen versus 52.5% with chemotherapy alone, which translated into an HR for death of 0.59 (95% CI, 0.38-092).3

In the phase III IMpower150 trial, the addition ABCP regimen resulted in improvements in progression-free survival (PFS) and OS compared with bevacizumab, carboplatin, and paclitaxel (BCP). At 12 months, the PFS rate with ABCP was 36.5% (95% CI, 31.2-41.9) versus 18.0% (95% CI, 13.4-22.6) with BCP (stratified HR, 0.62; 95% CI, 0.52-0.74; P <.001). At 24 months, the OS rate with ABCP was 43.4% (95% CI, 36.9-49.9) versus 33.7% (95% CI, 27.4-40.0) with BCP, for a stratified HR of 0.78 (95% CI, 0.64-0.96; P = .02).4

Squamous NSCLC

For patients with squamous histology, Riely pointed to findings from the KEYNOTE-407 study, which tested carboplatin/paclitaxel or nab-paclitaxel (Abraxane) with and without pembrolizumab.

After a median follow-up of 7.8 months, the median OS for the pembrolizumab-containing regimen was 15.9 months (95% CI, 13.2-not reached) versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .001). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.5

Additionally, the phase III Impower131 study showed an improvement in PFS with the addition of atezolizumab to frontline carboplatin and nab-paclitaxel. At a median follow-up of 17.1 months, the median PFS was 6.3 months (95% CI, 5.7-7.1) with the addition of atezolizumab versus 5.6 months (95% CI, 5.6-5.7) with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.85; P = .0001). The 12-month PFS rates were 24.7% versus 12.0%, respectively.6

However, the immunotherapy regimen has not yet translated into an OS improvement. At the first interim OS analysis, the median OS was 14.0 months (95% CI, 12.0-17.0) with the atezolizumab triplet compared with 13.9 months (95% CI, 12.3-16.4) with chemotherapy alone (HR, 0.96; 95% CI, 0.78-1.18; P = .6931). The 12- and 24-month OS rates were 55.6% versus 56.9% and 31.9% versus 24.1%, respectively.6

Riely noted that the trial findings are from an early analysis and that OS data might change with further follow-up.


  1. Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. N Engl J Med. doi: 10.1056/NEJMoa1606774.
  2. 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. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago, IL. Abstract LBA4.
  3. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
  4. Socinski MA, Jotte R, Cappuzzo F, et al; Impower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.
  5. Paz-Ares L, Luft A, Vicente D, et al; KEYNOTE-4017 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1810865.
  6. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. 2018;36 (suppl; abstr LBA9000).
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