Treatment Considerations for Unresectable Locally Advanced NSCLC - Episode 4
Heather Wakelee, MD:The checkpoint inhibitors for nonsmall cell lung cancer, the ones that are approved now, all target the PD-1 or PD-L1 pathway. PD-L1 is one of the important negative regulators of the immune system. It’s something that many tumors use as a way to escape immune detection. It’s also an important component of cell tolerance, so it is something that our normal cells use to evade immune detection and reaction.
What was discovered was that if we block either PD-1 or PD-L1, tumors that are using that as their mechanism of hiding from the immune system are better detected and better attacked by the immune system. The side effect profile of all these drugs relates to that as well. A normal cell is also using that as a primary mechanism of avoiding immune detection. You block it. Then you can get autoimmunity. That’s what we continually watch for with these drugsrates of autoimmunity and risks from that.
What was reassuring as these drugs were developed was that the rates of autoimmunity were much lower than we thought that they would be. The immune-related adverse events were lower than the initial fears, and that’s continued on. We found relative safety with these drugs.
There are 2 PD-1 drugs that are approved in lung cancerpembrolizumab and nivolumab. There are also 2 PD-L1 drugs that are approved—atezolizumab was the first, and, now, durvalumab. Theoretically, they might be a little bit different. The responses and the side effects that have been seen have been relatively similar. The initial indication was for patients who had already had chemotherapy. Then they were treated with a checkpoint inhibitor. There were head-to-head trials with most of those drugs looking at single-agent chemotherapy versus checkpoint drugs.
In the second-line setting, in unselected patients, the response rates aren’t that different. The progression-free survival was not always that much better, but the overall survival was markedly better. That’s what led to the initial approval. The expansions that have happened have looked at specific subgroups and then in different patient populations.
For the drugs that work in the second-line setting, we want to then see, “OK, can we bring them into the first-line setting?” In that setting, for patients who have high PD-L1 levels on their tumor, pembrolizumab alone was better than chemotherapy alone. Very recently, in April of 2018, there were data looking at the combination of nivolumab with a different checkpoint inhibitor, a CTLA-4 inhibitor, ipilimumab. That combination, versus chemotherapy, for patients with high tumor mutation burden, also showed that the combination was superior to chemotherapy.
In April of 2018, there were also data from the KEYNOTE-189 study, which looked at checkpoint inhibitor plus chemotherapy versus chemotherapy, alone, for all-comers, regardless of PD-L1 level. Results showed superiority in overall survival for the 3 drugs as opposed to just chemotherapy. That was just in adenocarcinoma patients. There are more trials that will be coming out.
So, the mechanism is to increase the immune detection of the tumor by taking away one of the negative regulators. The data looking at the combinations with chemotherapy hint at the fact that if you get a better antigen release because you’re getting cell kill for other reasons, that may allow the immune system to better detect the tumor. That was the rationale for the chemotherapy combination. It’s also been the rationale for some combinations with radiation that are in earlier trials, and it was the rationale for the PACIFIC trial. Patients were getting chemotherapy and radiation at the same time (better antigen release), and then, not concurrently, but right after, they started with durvalumab. That trial was also strikingly positive for progression-free survival. We don’t yet have the overall survival data.
That’s really how we think about how the drugs work. Of course, it’s much more complicated because it’s the immune system. It’s also helping us think about what the toxicities are and the rationale for bringing them in earlier. These drugs, by themselves, for patients who’ve already had a lot of treatmentsthe benefit’s probably only about 20%.
When you bring it into the first line, at least with pembrolizumab, in the patients who have tumors with a PD-L1 that is greater than 50%, it’s around a third of patients. In that third of patients, the response rates of benefit with pembrolizumab were over 50%. Now that we’re adding in chemotherapy plus pembrolizumab for patients who have never had any treatment before, the response rates of all 3 drugs are very, very high with high PD-L1. Even without the PD-L1, the survival benefit has been seen in all groups. And then, in PACIFIC, in the stage III patients, we’re also seeing benefit regardless of PD-L1 level. We don’t know about survival, but at least we see a progression-free survival benefit.
And then, even earlier, would be patients who essentially have resectable disease. There were data with nivolumab as a neoadjuvant option before surgery in a small cohort of 21 patients. They had significant benefit as far as what they call the major pathological response. Even though it didn’t shrink on imaging when the tumor was resected, a lot of the tumors were already dead. So far, the data on survival from that cohort look good. But, again, it’s small numbers. Now, we are exploring this more in the advanced stage, but also for early-staged patientslooking at other ways to give these drugs before or after surgery. There are a lot of adjuvant trials after surgical resection. We don’t have that data yet. There is some positive data in melanoma, but we don’t yet know for lung cancer.
Transcript edited for clarity.