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PD-L1 testing, while an imperfect biomarker, is the key determinant of frontline immunotherapy selection in the NCCN guidelines for non–small cell lung cancer.
Matthew Gubens, MD
PD-L1 testing, while an imperfect biomarker, is the key determinant of frontline immunotherapy selection in the NCCN guidelines for non—small cell lung cancer (NSCLC), reported Matthew A. Gubens, MD, at the 2019 NCCN Annual Meeting.1
“PD-L1 testing is really the name of the game,” said Gubens, of the University of California at San Francisco Helen Diller Family Comprehensive Cancer Center. He explained that the KEYNOTE-024 trial showed that pembrolizumab (Keytruda) in patients with NSCLC more than doubled median overall survival (OS) compared with chemotherapy if PD-L1 expression was at least 50%, making that level an important cutoff point in treatment decisions. If PD-L1 expression is below 50%, treatment decisions turn on whether the cancer is squamous or nonsquamous.
Gubens also noted several guidelines that took effect in January 2019 combine pembrolizumab with chemotherapy. Although this brings greater toxicity, he said, clinicians and patients alike “will consider the higher disease burden with the idea that, ‘I want a response now, I may not get to second line.’”
In a comprehensive review at the NCCN meeting, Gubens discussed the significance of the 50% PD-L1 threshold, the role of disease histology, and the potential for additional biomarkers in the evolving NCCN guidelines for frontline immunotherapy in NSCLC.Single-agent pembrolizumab is preferred as first-line therapy for NSCLC when PD-L1 expression is 50% or greater. This is a Category 1 guideline, which means there is uniform consensus that the intervention is appropriate. This guideline applies to both adenocarcinoma and squamous cell carcinoma, however, patients with EGFR or ALK mutations should receive targeted agents, not immunotherapy, according to Gubens. The FDA approved pembrolizumab for this indication in October 2016.
The NCCN recommendation is based on the phase III KEYNOTE-024 trial, in which single-agent pembrolizumab more than doubled median OS compared with standard chemotherapy in patients with NSCLC and PD-L1 expression ≥50% whose tumors were not ALK or EGFR positive. The median OS with the PD-1 inhibitor was 30.2 months versus 14.2 months with chemotherapy, representing a 37% reduction in the risk of death (hazard ratio, 0.63; 95% CI, 0.47-0.86; P = .002).2
While single-agent pembrolizumab is the preferred Category 1 recommendation for frontline immunotherapy in patients with NSCLC and a PD-L1 level ≥50%, pembrolizumab- or atezolizumab (Tecentriq)-based chemoimmunotherapy regimens are also Category 1 recommendations that may be suitable for some patients. According to Gubens, factors to consider in potentially selecting these regimens include disease burden, symptom burden, and patient fitness. Several of these chemoimmunotherapy regimens are described in the next section, as they are the preferred options for patients with a PD-L1 level under 50%.At this time, single-agent pembrolizumab is not recommended in the NCCN guidelines as a frontline treatment for patients with NSCLC and PD-L1 status <50%. The FDA is reviewing an application for pembrolizumab monotherapy for the frontline treatment of patients with locally advanced or metastatic nonsquamous or squamous non—small cell lung cancer (NSCLC) with a PD-L1 expression level of ≥1% and no EGFR or ALK genomic tumor aberrations.
The application is based on findings from the phase III KEYNOTE-042 trial, in which the median OS was 16.7 months with frontline pembrolizumab monotherapy compared with 12.1 months with standard chemotherapy in patients with advanced or metastatic NSCLC and PD-L1 ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P = .0018).3 Across all patients with PD-L1 status of 1% to 49%, which was an exploratory analysis, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11). The FDA is scheduled to make its decision on or before April 11, 2019.
For patients with nonsquamous advanced or metastatic NSCLC (ECOG performance status 0-1), and PD-L1 <50% the new NCCN guideline update added the regimen of pembrolizumab combined with pemetrexed (Alimta) and either cisplatin or carboplatin as a preferred Category 1 initial systemic therapy option (if no contraindications to adding pembrolizumab).
The recommendation is based on the phase III KEYNOTE-189 trial, in which patients were randomized 2:1 to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab or placebo. Patients could cross over if they progressed on the control arm.
The results showed the addition of pembrolizumab to pemetrexed and either cisplatin or carboplatin in the first-line setting reduced the risk of death by 51% in patients with NSCLC without EGFR or ALK mutations.4,5 The median OS was not reached with the pembrolizumab cohort compared with 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. At a median follow-up of 10.5 months, the estimated 12-month OS rate was 69.2% (95% CI, 64.1-73.8) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1-56.2) in the control group (HR, 0.49; 95% CI, 0.38-0.64; P <.001).
While survival was more pronounced on those with 50% or greater PD-L1 expression, the pembrolizumab OS benefit was observed across PD-L1 subgroups, including the <1% expression group (12-month OS rate, 61.7% vs. 52.2%; HR, 0.59; 95% CI, 0.38-0.92); the 1% to 49% cohort (12-month OS rate, 71.5% vs. 50.9%; HR, 0.55; 95% CI, 0.34-0.90); and those with a score of 50% or greater (12-month OS rate, 73.0% vs. 48.1%; HR, 0.42; 95% CI, 0.26-0.68).
The KEYNOTE-189 trial was also the basis for the FDA granting a full approval to the pembrolizumab regimen in this setting in August 2018.
For patients with nonsquamous NSCLC who are not eligible to take pemetrexed, Gubens said the guidelines for frontline immunotherapy list atezolizumab combined with bevacizumab carboplatin, and paclitaxel (ABCP regimen) as a Category 1 recommendation. The FDA approved this regimen in December 2018.
The NCCN guideline update and FDA approval are based on findings from the phase III IMpower150 trial, in which the ABCP regimen reduced the risk of death by 22% compared with bevacizumab and chemotherapy (BCP) in patients with advanced wild-type NSCLC.6,7
Additionally, the median OS with the addition of atezolizumab was 19.2 months (95% CI, 17.0-23.8) compared with 14.7 months (95% CI, 13.3-16.9) in the BCP arm (HR, 0.78; 95% CI, 0.64-0.96; P = .0164). The 24-month OS rate with atezolizumab was 43% compared with 34% for BCP. ABCP also improved median progression-free survival by 1.5 months compared with BCP (8.5 vs 7.0 months; HR, 0.71; 95% CI, 0.59-0.85; P <.0002).
For patients with squamous NSCLC, the preferred Category 1 recommendation is for pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane), which the FDA approved for this indication in October 2018. The approval and NCCN recommendation are based on the phase III KEYNOTE-407 trial.
In KEYNOTE-407, combining pembrolizumab with chemotherapy reduced the risk of death by 36% compared with chemotherapy alone in patients with metastatic squamous NSCLC.8 The median OS was 15.9 months (95% CI, 13.2 — not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.Gubens said as important as PD-L1 testing is now, this is the just the beginning. He covered the growing importance of understanding patients with high tumor mutation burden as a distinct population from those with high PD-L1 expression and said forthcoming blood assays could be promising in predicting which immunotherapies will work.
“In 5 years, PD-L1 might be archaic. Stay tuned for multidimensional and serial testing,” concluded Gubens, referring to tests that occur throughout cancer treatment, not just at the start.