Progression Issues Surface With NSCLC Immunotherapy

Paul A. Bunn Jr, MD

Pseudoprogression, which has been observed in less than 10% of patients with lung cancer, occurs when an early scan shows tumor growth that may be due to a delayed benefit of the immunotherapy treatment or inflammation of the tumor as T cells become active. When a patient does respond to immunotherapy, the benefits can be long lasting.

In an interview with OncologyLive^® during the 18th Annual International Lung Cancer Congress hosted by Physicians’ Education Resource^®, LLC (PER^®) in July, Paul A. Bunn Jr, MD, said that it is important for physicians to be able to identify the difference between true progression and pseudoprogression. But until investigators learn more about this condition, it will take a bit of trial-and-error analysis, said Bunn.

Hyperprogression, which also occurs in a small subset of patients with lung cancer, is also a concern. It occurs when a patient experiences a significantly increased rate of tumor growth following immunotherapy treatment. A recent study published in Clinical Cancer Research defined this phenomenon as time-to-treatment failure (TTF) of less than 2 months, a greater than 50% increase in tumor burden compared with preimmunotherapy imaging, and a more than 2-fold increase in progression pace. Investigators found that MDM2/MDM4 and EGFR alterations correlated with TFF <2 months in a population of 155 patients with stage IV cancers who had been treated with anti—PD-1/PD-L1 immunotherapies.

“When it works, immunotherapy works for a long time, but when it doesn’t work, it doesn’t work,” Bunn said, adding that the ultimate goal is to identify biomarkers to help determine which patients will respond to immunotherapy, and which will not.

How do you define pseudoprogression?

During the interview, Bunn discussed strategies for analyzing and responding to signs of progression for patients receiving immunotherapy. Bunn is a professor and the James Dudley Chair in Cancer Research in the Division of Medical Oncology at the University of Colorado Denver School of Medicine. In 2014, he was named is a Giants of Cancer Care ^® award winner in the Lung Cancer category.Pseudoprogression is when it appears that the tumor is getting larger, but the patient is responding. If you have a tumor and the lymphocytes come in and kill the cancer, because of all the lymphocytes, the tumor might seem bigger in the scan, whereas the tumor may actually be smaller. That seems to happen more often in melanoma, but it clearly can happen in lung cancer.

Why is pseudoprogression a concern when you’re treating patients with immunotherapy?

How often does pseudoprogression occur in lung cancer?

What should community oncologists know about the difference between pseudoprogression and real progression?

An advantage of neoadjuvant care is you have the scan, but you also have the surgical specimen. If there are a bunch of lymphocytes in the surgical specimen and the tumor is gone or much smaller, you can actually see that. From preliminary data on less than 50 patients and 2 trials, there is no question that you can have major pathologic responses in the absence of a CT response because of all the infiltration of lymphocytes. For those people who benefit from immunotherapy, the responses frequently last a very long time. They occur in a minority of patients, so if they do occur, you don’t want to deprive the patient of the ability to have a long response.True pseudoprogression in lung cancer is not that common. It is true that patients with Response Evaluation Criteria in Solid Tumors [RECIST] stable disease may have a true pathologic response. We’ve seen that in the early neoadjuvant trials, but with stable disease and immunotherapy, if the patient is doing well, you could continue the treatment. The big issue is if the tumor is 20% larger or more, which is RECIST progression, if that patient is having pseudoprogression because of the lymphocytes, you don’t want to stop the treatment. Having it get 20% bigger and have a response is not that common, but it can occur. So, what do you do? When that happens, it occurs early. So if the patient is doing well, their symptoms go away, and they seem to be benefiting, you could continue for 1 or 2 more [cycles of] treatment and repeat the CT scan. If the patient is deteriorating and the scan is getting worse, you obviously stop the treatment.They should know that if the patient’s tumor got bigger and the patient has not gotten better, they should stop the treatment. But if early on the tumor got 25% bigger and the patient’s symptoms went away, they can consider continuing.

Why is hyperprogression a concern when treating patients with immunotherapy?

As we better understand immunotherapy, is there more that investigators are still learning about pseudoprogression and hyperprogression?

Another thing that isn’t standard of care yet, but that some of these studies have documented, is that if you have a molecular abnormality, that can be determined with circulating tumor DNA [ctDNA] in a liquid biopsy. In pseudoprogression, that has gone down. If the ctDNA is going down, but on scan the tumor got a little bigger and the patient is doing well, obviously you are going to continue. If the ctDNA goes up and the CT scan gets worse, time to stop the treatment. ctDNA may be helpful in the future as we get more data about this.In these patients, you don’t want to deprive them of the opportunity to get something else that might be effective. Again, you have the CT scan, and if that is getting worse and the patient is getting worse and/ or the ctDNA is getting worse, it’s time to stop. If the ctDNA is getting better and the patient is getting better, but the scan isn’t, it’s OK to continue for 2 more cycles and repeat. Yes. If you have high levels to begin with, ctDNA can be very helpful. It’s possible there will be other markers. For example, in the peripheral blood, we can look at subsets of T cells or we can look at cytokines in the blood and we might be able to tell from other biomarkers in the future which is true progression and which is pseudoprogression, and hopefully be more accurate than that.

Kato S, Goodman A M, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyper-progressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242-4250. doi:10.1158/1078-0432.CCR-16-3133.