Biomarkers and Histology Play Key Roles in Frontline Metastatic NSCLC Options

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

“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.”

Histology-Based Decisions

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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