Expert Assesses Atezolizumab in NSCLC

Chandra P. Belani, MD

Atezolizumab (MPDL3280A) has shown great potential as a treatment for patients with advanced non—small cell lung cancer (NSCLC).

Based on early-stage studies, the PD-L1 inhibitor received a breakthrough therapy designation from the FDA as a potential treatment for patients with PD-L1—positive NSCLC following progression on prior therapy, including chemotherapy and targeted therapies.

In the phase II BIRCH trial, more than 61% of responses were ongoing after a minimum follow-up of 6 months in patients with stage IIIB/IV or recurrent NSCLC who received atezolizumab.

The phase II POPLAR study, which compared atezolizumab with docetaxel, found that patients with the highest level of PD-L1 expression experienced a median overall survival (OS) with atezolizumab of 15.5 months versus 11.1 months with docetaxel (HR, 0.49; 95% CI, 0.22-1.07; P = .068).

Atezolizumab has also demonstrated significant promise as part of a combination regimen.

In an ongoing clinical trial, 63.4% of evaluable patients who received atezolizumab with 1 of 4 chemotherapy regimens had an objective response.

Among the various chemotherapy regimen groups, the greatest response was seen in the arm that received the combination of atezolizumab, carboplatin, and pemetrexed, which showed a 77% response rate. Four patients who were treated with atezolizumab, carboplatin, and nab-paclitaxel also had complete responses.

OncLive: What is the mechanism of action for atezolizumab?

Can you discuss significant studies that have examined atezolizumab?

In an interview with OncLive, Chandra P. Belani, MD, Miriam Beckner Distinguished Professor of Medicine, Penn State Milton S. Hershey Medical Center, deputy director, Penn State Hershey Cancer Institute, discusses the impact of these atezolizumab trials and the role of PD-L1 as a predictive and prognostic biomarker for response to the agent. Belani: Atezolizumab targets PD-L1 and the ligand B7.1. Atezolizumab does not bind to PD-L2. It may actually result in less lung toxicity compared with PD-1 inhibitors, as there is some evidence that combining PD-1 and PD-L2 leads to increased toxicity. However, this has not yet been proven. Atezolizumab has been studied in various subsets of patients with NSCLC. The first study was the BIRCH trial, where it was investigated in patients in the frontline setting, the second-line setting, and beyond second-line in patients prior to metastatic disease.

There was activity seen across all subgroups of patients, but there seems to be increased activity in patients who have higher PD-L1 expression. Patients who have increased expression of PD-L1 by the specific antibody test that has been used—SP142—had an increased response rate. PD-L1 seems to be a predictor of response and efficacy for atezolizumab.

The second trial was the POPLAR study, which compared atezolizumab and docetaxel in the second-line setting in patients who had failed prior platinum-based chemotherapy.

Do you see potential for atezolizumab to be used in combination?

In this trial, there was an overall improvement in survival in all comers, with an approximate 3-month difference in OS with atezolizumab compared with docetaxel. In all comers, there was an overall benefit and the hazard ratio was 0.73. However, if you just look at those patients who don’t have expression of PD-L1, atezolizumab does not work in that subset of patients. The data is impressive in those who are high expressers of PD-L1. One study that I felt was impressive looked at atezolizumab with chemotherapy. It investigated the agent with 3 different regimens: carboplatin and paclitaxel, carboplatin and nab-paclitaxel, and carboplatin and pemetrexed. There was an almost 100% disease control rate in patients who had any expression of PD-L1.

That is impressive data. The numbers in the trial were small, but the results suggested that combining atezolizumab with chemotherapy might actually bring out those provocative responses in NSCLC.

Based on these trials, do you think PD-L1 expression is an accurate biomarker for atezolizumab response?

Phase III clinical trials are in progress where atezolizumab is being compared to chemotherapy as a single agent or combined with chemotherapy and then compared to chemotherapy alone. There are 4 large phase III studies in progress and they will be let out in 2017. I think that we are seeing a lot of interest in this. The activity seems to be based on PD-L1 expression. However, I think we will have to better study the tumors and patients to actually say this is a predictive and prognostic biomarker for treatment with these immunotherapeutic agents.

How does atezolizumab compare with other PD-1/PD-L1 agents being investigated in NSCLC?

There are dynamic changes that occur in PD-L1 expression if patients are treated with a driver drug that have a driver mutation, which might actually be disappearance of the PD-L1 expression. There may be appearance of PD-L1 expression after chemotherapy, because chemotherapy is known to increase that immune infiltrate and cause immunomodulation. There may be sequential administration of chemotherapy with PD-L1 targeted agents such as atezolizumab. There is no one winner amongst all of the PD-1/PD-L1 targeted drugs. All of their activity appears to be the same. Moving forward, if we are able to tease out a group of patients who will benefit preferentially from an agent that targets PD-1 or PD-L1 that will be the key.