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Immunotherapy Continues Rapid Advance in NSCLC

Laura Panjwani
Published: Tuesday, Feb 16, 2016

Naiyer Rizvi, MD

Naiyer Rizvi, MD

Immunotherapy in non–small cell lung cancer (NSCLC) is rapidly progressing—and it won’t be slowing down anytime soon, says Naiyer Rizvi, MD.

“The field is changing so fast,” says Rizvi, director of Thoracic Oncology and Immunotherapeutics at Columbia University Medical Center. “Soon, we will have a better understanding of the first-line use of PD-1 agents, Then, maybe a year later, the data on the combination of PD-1/PD-L1 and CTLA-4 will come out. It is going to be a busy year. The NCCN is going to be busy rewriting their guidelines every 6 months at this rate.”

Several immunotherapeutic agents are also being investigated in new combinations and earlier settings.

The ongoing KEYNOTE-024 study is currently investigating the anti–PD-1 agent pembrolizumab (Keytruda) in the first-line setting for patients with stage IV metastatic NSCLC whose tumors express PD-L1.

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

Despite these data, the significance of PD-L1 as a biomarker remains unclear. Phase Ib data recently published in The Lancet Oncology1 showed that the combination of the PD-L1 inhibitor durvalumab and the anti–CTLA-4 agent tremelimumab induced a response rate of 23% in patients with advanced NSCLC. Responses in the trial were observed regardless of PD-L1 status.

Immune agonists such as OX40 and 4-1BB are also an exciting possibility, says Rizvi. In an interview with OncLive, Rizvi discusses the role of PD-L1 testing, which PD-1/PD-L1 agents have the most potential, and what is on the horizon for the use of immunotherapies in NSCLC.

OncLive: What role do you predict for PD-L1 testing in NSCLC going forward?

Rizvi: The data with nivolumab in second-line lung cancer is pretty compelling due to the survival advantage that exists, so I think that is becoming the standard of care in all second-line NSCLC. If that is the case, the question then becomes, “How is the biomarker relevant?”

I think the biomarker is useful in understanding who will be more likely to respond in the context of clinical trials or at academic centers. If you have a patient who you are testing for PD-L1 upfront, and they come back as PD-L1 “zero”, they are more likely to benefit from a combination trial or something of that sort if they progress on chemotherapy.

The KEYNOTE-024 trial is looking at pembrolizumab in the first-line patient population versus chemotherapy. If that is positive, then I believe everyone will get PD-L1 testing upfront and then eventually receive first-line pembrolizumab.

What factors should be considered when choosing between nivolumab and pembrolizumab for NCSLC?

For newly diagnosed patients with known PD-L1 status, I think you could make the argument for either nivolumab or pembrolizumab in the first-line setting. I don’t think there is reason to pick one over the other.

I do think, however, giving pembrolizumab every 3 weeks is more favorable for patients than giving nivolumab.

Do you see a role for atezolizumab?

There is a similar trial to KEYNOTE-024 looking at atezolizumab versus chemotherapy in the first-line setting. Atezolizumab is a little bit late to the game to capture that space in lung cancer. I am not sure what the uptake is going to be, because the PD-L1 positivity requirement with that agent is less. Their biomarker requires 15% positivity, whereas for pembrolizumab, it is around 25%.

From a treatment standpoint, you will have a lower hit rate with the atezolizumab biomarker versus the pembrolizumab biomarker. They have multiple first-line chemotherapy combination trials, but they are not as far along as some of the immunotherapy combination trials with other PD-1/PD-L1 agents.

What are the biggest questions that remain regarding the use of immunotherapy?

I think the biggest question is, “How do we turn the 75% to 85% of patients who don’t respond to immunotherapy into responders?” We have made some process. We published preliminary data in The Lancet Oncology looking at the combination of durvalumab and tremelimumab that showed a response in patients who were PD-1–negative as well as positive.

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