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Atezolizumab in NSCLC
Atezolizumab: A New Treatment Option for Progressive Metastatic NSCLC

Released: December 20, 2016

Expiration: December 19, 2017

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Following the recent FDA approval of the PD-L1 inhibitor atezolizumab, which joins the PD-1 inhibitors nivolumab and pembrolizumab as immune checkpoint therapy options for the treatment of advanced NSCLC with progression on or after platinum-based chemotherapy, my partners have already been asking me which of these 3 drugs I will be using to treat my patients with progressive advanced NSCLC. I’ll discuss my strategy, but first, here are the data that should be considered.

Phase III OAK: Atezolizumab vs Docetaxel for Progressive Advanced NSCLC
The approval of atezolizumab was based on data from the pivotal phase III OAK trial, which randomized 1225 patients with squamous and nonsquamous NSCLC to atezolizumab vs docetaxel as second-line or third-line therapy following previous platinum-based chemotherapy. This trial required that all patients have their tumor tested for PD‑L1 expression. However, no minimal level of PD‑L1 expression was required for enrollment. The major results of the OAK trial were strongly in favor of atezolizumab—patients treated with atezolizumab lived longer and had fewer adverse events than patients treated with docetaxel. The median OS was 13.8 months with atezolizumab vs 9.6 months with docetaxel (HR: 0.73; 95% CI: 0.62-0.87; P = .0003). Furthermore, an atezolizumab benefit was observed regardless of PD-L1 expression levels and was consistent across all patient subgroups examined, except for EGFR mutant NSCLC.

Phase III Trials of Nivolumab and Pembrolizumab vs Docetaxel for Progressive Advanced NSCLC
The results of the OAK trial are similar to those reported for the phase III trials leading to the approval of nivolumab and pembrolizumab for use in treatment-experienced patients with advanced NSCLC. In CheckMate 017 and CheckMate 057, median OS was significantly improved with nivolumab vs docetaxel for squamous NSCLC (9.2 vs 6.0 months; HR: 0.59; 95% CI: 0.44-0.79; P < .001) and nonsquamous NSCLC (12.2 vs 9.4 months; HR: 0.73; 96% CI: 0.59-0.89; P = .002), respectively, regardless of tumor PD-L1 expression. In KEYNOTE-010, pembrolizumab also achieved significant improvements in median OS vs docetaxel in patients with both histologies of NSCLC, but all enrolled patients were required to have ≥ 1% PD-L1–positive tumor cells based on an IHC assay. For patients ≥ 1% PD-L1–positive tumor cells, the median OS was 10.4, 12.7, and 8.5 months for 2-mg/kg pembrolizumab, 10-mg/kg pembrolizumab, and docetaxel, respectively (HR for 2 mg/kg vs docetaxel: 0.71, 95% CI: 0.58-0.75, P = .0008; HR for 10 mg/kg vs docetaxel: 0.61, 95% CI: 0.49-0.75, P < .0001). For patients with ≥ 50% PD-L1–positive tumor cells, the median OS was 14.9, 17.3, and 8.2 months for 2-mg/mL pembrolizumab, 10-mg/mL pembrolizumab, and docetaxel, respectively (HR for 2 mg/kg vs docetaxel: 0.54, 95% CI: 0.38-0.77, P = .0002; HR for 10 mg/kg vs docetaxel: 0.50, 95% CI: 0.36-0.70, P < .0001).

FDA Approval of Checkpoint Inhibitors for Progressive Advanced NSCLC
Based on the results of these pivotal phase III trials, nivolumab and now atezolizumab are both approved for all patients with metastatic NSCLC who progress on or after platinum-based chemotherapy and, if EGFR or ALK positive, appropriate FDA-approved targeted agents, regardless of PD‑L1 expression. By contrast, pembrolizumab is approved for patients with metastatic NSCLC who progress on or after platinum-based chemotherapy and, if EGFR or ALK positive, appropriate FDA-approved targeted agents, whose tumors are PD-L1 positive by an FDA-approved IHC assay. Originally, the PD-L1 positivity threshold for pembrolizumab eligibility in the progressive disease setting was staining of ≥ 50% of tumor cells. However, very recently, the definition of PD-L1 positive in this setting was changed to ≥ 1% PD-L1 tumor cell staining. Because there is a sizeable percentage of patients whose tumors lack PD-L1 expression (ie, 20% to 30%), testing for PD‑L1 is still required to use pembrolizumab in the progressive disease setting despite this expanded indication.

Choice of Checkpoint Inhibitor for Progressive Advanced NSCLC
Based on currently available data, atezolizumab, nivolumab, and pembrolizumab appear to have similar efficacy and safety. Although atezolizumab targets PD‑L1, whereas nivolumab and pembrolizumab target PD‑1, they all serve to block the interaction between PD‑1 and PD‑L1 and they all improve OS by approximately 3 months vs docetaxel. Their adverse event profiles seem to be similar as well. In general, all 3 drugs are better tolerated than docetaxel, with some of the adverse events typical of chemotherapy (eg, hair loss, cytopenia, anemia, neutropenia, thrombocytopenia, and neuropathy) being completely absent. Although PD‑1 and PD‑L1 inhibitors do have immune-related adverse events, these tend to be mostly grade 1 and mild grade 2 that can be managed in such a way that patients are able to go about living their lives.

In my view, the one difference among these 3 agents that may affect our choice of a specific checkpoint inhibitor is administration frequency: Nivolumab is administered once every 2 weeks, whereas atezolizumab and pembrolizumab are administered once every 3 weeks. For patients who travel great distances to be treated, coming in once every 3 weeks for treatment is attractive because it means one less visit each month. When travel is an issue, I can see patients and their physicians choosing atezolizumab or pembrolizumab vs nivolumab. Furthermore, it is important to remember that atezolizumab does not require tumor testing for PD-L1 expression prior to administration in contrast to pembrolizumab.

An added consideration in choosing a specific immune checkpoint inhibitor for NSCLC in the progressive disease setting is that pembrolizumab was recently approved as first-line therapy for patients with advanced NSCLC and ≥ 50% PD-L1 positivity based on the results of the phase III KEYNOTE‑024 trial. In KEYNOTE-024, pembrolizumab achieved a significantly improved both median PFS and OS rate in patients with newly diagnosed metastatic NSCLC and ≥ 50% PD-L1 positivity vs platinum-based chemotherapy. Therefore, for the approximately 30% of patients without actionable mutations and whose tumors stain ≥ 50% PD‑L1 positive, pembrolizumab will be the first-line therapy of choice, and at this time, it is unclear what should follow pembrolizumab. Until we figure out the best therapy for patients who progress on first-line pembrolizumab, I would recommend standard platinum-based doublet chemotherapy according to histology or a clinical trial as second-line therapy.

The Future of Checkpoint Inhibitor Therapy in Advanced NSCLC
For the time being, I anticipate that all 3 of these checkpoint inhibitors will continue to be used in the second‑line setting and beyond for advanced NSCLC, but this may change with increasing clinical experience and as we learn more about these agents. For example, the difference in mechanisms of action among PD-1 and PD-L1 inhibitors may prove to be important. Nivolumab and pembrolizumab block both PD-L1 and PD-L2 from interacting with PD-1, whereas atezolizumab blocks only PD-L1 binding to PD-1, leaving the PD-L2/PD-1 interaction intact, which may prove critical for peripheral immune homeostasis. We are also waiting for additional first-line trials of PD‑1 and PD‑L1 inhibitors as monotherapy vs chemotherapy and PD‑1 and PD‑L1 inhibitors in combination with chemotherapy to mature, the results of which may affect what drug we choose first in the future. For example, agent preference may change if combination regimens begin to demonstrate differences between these agents.

Please share your thoughts or questions on immune checkpoint therapy for patients with advanced NSCLC in the comment box below.

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Which immune checkpoint inhibitor do you prefer to use in the setting of progressive NSCLC?
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