JCO Article Insights: Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade

In this episode of JCO Article Insights, Rohit Singh interviews Dr. Ticiana Leal on the editorial, "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade."

TRANSCRIPT

The guests' disclosures can be found in the transcript.

Dr. Rohit Singh: Hello and welcome to JCO’s Article Insights. I am your host Rohit Singh and today we will be discussing the JCO article, “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade.” And we are joined by the senior author of the article, Dr. Ticiana Leal. Dr. Leal is an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and she serves as director of Thoracic Medical Thoracic Oncology Medical Program and Multidisciplinary Thoracic Oncology Leader at the Winship Cancer Institute. She also served as a member of the Board of Directors at the Georgia Society of Clinical Oncology.

Dr. Leal, welcome to our podcast and thank you for joining us.

Dr. Ticiana Leal: Thank you, Rohit. Thank you for this interesting opportunity to discuss our editorial. My co-authors and I are very glad to be here today. So, Dr. Jennifer Carlisle and Dr. Liu were co-authors with me on this editorial.

Dr. Rohit Singh: It's a really good article. And just for our audiences, the article again, titled “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade,” it discusses the challenges and the potential strategies for overcoming resistance to immune checkbox inhibitors in patients with non-small cell lung cancer. In this article, Dr. Leal and colleagues talk about the second line of drug when the patient developed disease progression while immunotherapy and they develop resistance and their definitions and what to do.

So, to Dr. Leal, can you please explain the mechanisms of primary and acquired resistance to immune check prohibitors in non-small cell lung cancer? I also saw in your article you proposed the definition of immunotherapy resistance in solid tumors, distinguishing between primary resistance and acquired resistance. So, if you can please share your thoughts and explain their mechanism.

Dr. Ticiana Leal: So primary resistance and acquired resistance are related to tumor intrinsic and tumor extrinsic factors. And this is mainly clinically defined as of now according to previous response patterns and timing of occurrence, and these definitions can be heterogeneous, and we certainly think that biologically they can be very different. And it can be different according to prior therapy, whether patients got immunotherapy as PD-1, PD-L1 inhibitor alone or combination strategy with CTLA-4, or the combination with chemotherapy. But the patterns of resistance can be very different and can be based on defects and antigen presentation. It can also be due to tumor microenvironment immunosuppressive effects, and there are also additional inhibitory checkpoints that can be involved.

The definition in terms of when to call it primary or acquired resistance at this point has really been based on consensus guidelines by SITC, by Esmo, as well as our group Lung-MAP has developed clinical trials in this space. Specifically, through Lung-MAP, we've defined and incorporated the definition of acquired resistance as patients who have had prior exposure of 84 days or greater and then have had progression of their disease.

Dr. Rohit Singh: I can see why it is so challenging to come up with a standard definition for immune checkpoint resistance and I think incorporating these definitions and predictive biomarkers for clinical trial design is going to be more important going forward. Your article talks about CONTACT-01 study, so can you please discuss the CONTACT-01 study and how the shifting treatment paradigm in the first-time study impacted it and at the same time also discuss the potential implication of the differential outcome observed between the men and women in the CONTACT-01 study.

Dr. Ticiana Leal: CONTACT-01 was a much-awaited study. The authors, Dr. Neal et al, looked at a very important question in the area of immunotherapy resistance. So, CONTACT-01 was a randomized phase three global study that investigated the combination of cabozantinib plus atezolizumab versus docetaxel in patients previously treated with chemotherapy and immunotherapy. And as background, cabozantinib is an inhibitor of multiple receptor tyrosine kinases including VEGFR-2, MET, RET and TAM family kinases. Preclinically, cabozantinib could lead to immuno permissive tumor microenvironment and so it was r...