Relevancy of PD-L1 as a Biomarker for Immunotherapies in NSCLC

“The field is changing so fast,” said Rizvi, director of Thoracic Oncology and Immunotherapeutics, Columbia University Medical Center, in an exclusive interview with Targeted Oncology. “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 [National Comprehensive Cancer Network] is going to be busy rewriting their guidelines every 6 months at this rate.”

One immunotherapy currently being investigated is the anti—PD-1 agent pembrolizumab (Keytruda), in the KEYNOTE-024 study. The study is looking at pembrolizumab in the first-line setting for patients with stage IV metastatic NSCLC whose tumors express PD-L1.

Another immunotherapy, the PD-L1 inhibitor atezolizumab, was investigated in the phase II POPLAR study. The study compared atezolizumab with docetaxel and 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). Rizvi says these data raise the question of how relevant PD-L1 is in the NSCLC treatment paradigm.

"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," he said.

"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."

Phase Ib data, published in The Lancet Oncology¹, showed 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, further raising the question of the biomarker's relevancy in NSCLC.

Rizvi said the relevancy of PD-L1 is tied to further research into making non-responders into responders.

"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," he said.

  

"That is the right direction; however, as we move forward, we need to determine exactly why these patients don’t respond and how we can convert those nonresponders to responders."

Rizvi adds that the combination of durvalumab and tremelimumab is also an attractive duplet for the treatment of NSCLC.

"It is a very active combination. The schedule is every 4 weeks for the durvalumab and tremelimumab regimen, which is attractive. Anytime a CTLA-4 antibody is used in combination with a PD-1/PD-L1 agent, you are going to have more toxicities than you would with an immunotherapy alone. You have to find the balance between better response rates versus more toxicities," he said.

A phase I, open-label, dose-escalation/expansion study enrolled 84 evaluable patients, 48 of which had more than two prior lines of therapy. The overall response rate was 25%, with 35% of PD-L1—positive patients experiencing a response and 22% of PD-L1&ndash;negative patients seeing a response (<25% tumor cell staining). Additionally, 33% of PD-L1&ndash;negative patients saw a response (0% tumor cell staining).

Immune agonists such as OX40 and 4-1BB are also an exciting possibility, says Rizvi.

"There is a lot of interest in looking at combinations with immune agonists such as OX40 and 4-1BB. There are different ways these agents could be used to remove the immune suppression within the tumor. There are hundreds of ongoing trials right now aiming to better understand this," he said.

"We don&rsquo;t know if anything is going to be better than CTLA-4 with PD-1/PD-L1. We need something we can give that has a more favorable toxicity profile or that is more active. Or, we need to figure out how to select patients for different combinations, based on what their profiles are."

References

1. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumor activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicenter, phase 1b study [published online February 5, 2016]. Lancet Oncol. doi:10.1016/S1470-2045(15)00544-6.