New Concepts: Multimodal Approaches to Advanced NSCLC - Episode 9
Marina Chiara Garassino, MD: The PACIFIC trial is a fundamental trial for the treatment of locally advanced non—small cell lung cancer. Because we have to think that for the past 20 years, we had nothing because we had to just get treatment strategies to go with chemotherapy and then radiotherapy to go with the concurrent chemoradiotherapy. But all the trials were not conclusive and there were just 30% of patients still alive after a certain period. So, the use of durvalumab after the chemoradiation is really important; it’s really practice changing—although we only have the results on the progression-free survival, which corresponds to an increase of about 11 months, which is quite a huge improvement. We still do not have the results on the overall survival, which is another important information to be achieved. But 11 months of progression-free survival is quite a large improvement. So, in my opinion, for all the patients who receive concurrent chemoradiation, durvalumab must be offered for the treatment of this kind of patient.
However, in the PACIFIC trial, there are still some questions that must be answered, because in the PACIFIC trial, only patients who received concurrent chemoradiation could receive durvalumab. And we know that sometimes you decide to go with the sequential treatment and not with a concurrent chemoradiation. So, there are still some areas that must be answered. For example, sequencing is one of them. And also, for example, another very important point is the toxicity, because the patients included in the PACIFIC trial were patients with a very-low-grade toxicity from the radiotherapy. And in fact, the number of patients with pneumonitis after chemoradiation and after durvalumab was very low. But the majority of patients after chemoradiation have grade 2 or grade 3 pneumonitis. So, we have no idea that if we treat these kinds of patients with durvalumab, we have increase of pneumonitis.
So, I think that it is a very important breakthrough, because from that point, the treatment of nonoperable non—small cell lung cancer has totally changed. And I think that also in the multidisciplinary teams, and sometimes if we are not sure if we need to go with the operation or to go with chemoradiation, now we have a new possibility of treating these kinds of patients. So, that sometimes can be important to decide to go with chemoradiation and not to go with the operation because you have more chances to have a progression-free survival that’s quite good. And what is also important is that the results of the PACIFIC show that there is not a very increased toxicity of chemoradiation if you are doing durvalumab. You have a quite safe regimen for this kind of patient after a treatment with curative intent. So, the goal is to try to cure a huge number of patients.
We could enroll patients within the PACIFIC trial, which was a double-blind trial. So, we were not aware if the patients were receiving durvalumab or the placebo. But this was also important because we’re not able to differentiate the patients receiving placebo or the drug, which means that there is not a huge difference between the placebo and the drug. Now, we started with the drug after the chemoradiotherapy. We have the possibility to have the drug in Italy after chemoradiation, and I can say that what we saw in the PACIFIC trial is true also in the clinical practice, because we did not observe an increase of toxicity in the treatment of these patients, so they are still on treatment. So, I can’t tell you if they will survive the cancer. But what I can tell you is that the toxicity profile is quite manageable.
Solange Peters, MD, PhD: Based on the PACIFIC data, we all imagine that immunotherapy will enter the game of surgical early disease, because if you have an impressive outcome after radiochemotherapy, it probably means that you can act on survival by adding immunotherapy to the current multimodality treatment and you can improve survival. That’s why there are many ongoing trials at the time being, also in resectable patients after or before surgery. What you were speaking about before, it’s neoadjuvant immunotherapy. We have a small trial from the United States giving only 2 cycles of nivolumab, which is already showing that by doing that, you observe an incredible number of patients with pathological response, so really faster than you will observe in late disease, in advanced disease. With 2 cycles, you already see a major effect on the tumor. We’re telling you that this early disease might be different from late-stage disease. It might be that the immune system is more, I would say, conserved or preserved, more active. Maybe the disease biology itself is here to present to the immune system and there’s something there that probably makes immunotherapy even more promising in this early disease setting.
Now, there are some trials, I would not say many, trying to give neoadjuvant immunotherapy or neoadjuvant immunotherapy and chemotherapy kind of intricated in this neoadjuvant phase. But, of course, you also have the—we know this from breast cancer—classical adjuvant trials where you randomized thousands of patients into standard-of-care chemotherapy versus chemotherapy plus immunotherapy in the adjuvant setting. Very often you first give the chemotherapy and then you give some immunotherapy for a longer period of time, 1 or 2 years, of course with an endpoint of progression-free survival. But what we would like to see is that you cure more patients. This trial will take a long time to read out. Adjuvant trials, of course, take a long time to read out. But this is a very important question, and I think we might achieve, for the first time, a real way of improving our survival rates in lung cancer, which is still not good even if you use surgery.
In the PACIFIC trial, as far as I understood—I was not an investigator in this trial, which is the reason why I could write the editorial—the aim of this trial was to try to start the durvalumab as soon as possible. So, it was to complete the radiochemotherapy and then in the 2 weeks after the radiochemotherapy, to start the durvalumab. However, in most of the centers, and also because the patients were suffering from some side effects from radiochemotherapy—fatigue, swallowing problems, cough, and so on—it was very often not feasible to immediately start durvalumab. So, some patients did follow the scheme, but the accrual was not very satisfactory because lots of patients were lost from this strategy because of this short timeframe of 2 weeks. The trial allowed up to 42 days afterwards in an amendment. Some patients had 2 weeks, but some had up to 6 weeks after the radiochemotherapy. So, basically, the evidence that it’s good to do is based on a 42 days’ timeframe at maximum.
But what is interesting—and there isn’t supplementary materials, if I’m right—is the comparison of the patients treated early with durvalumab or treated in the second step after the amendment with the 42 days. And it’s interesting to see, of course, it’s exploratory, but the benefit is higher in patients having the durvalumab as close as possible to the end of radiochemotherapy. This probably means that is the vaccination process, that you can mount an immune response that is stronger if you really have the cell deaths and the radiotherapy happening a short time before you give immunotherapy, some kind of multimodality treatment in a time as close as possible, one to the other one. So, to date, I would say for a patient, if you could start immediately, start immediately. If your patient has remaining side effects, toxicity grades 2 or grades 3, even grade 1 for pneumonitis, then you should wait until this toxicity resolves. But if it’s not the case, start as soon as possible. And theoretically, the window is 42 days. So, that’s where we are today. But this will be refined probably within the future through other clinical trials.
Marina Chiara Garassino, MD: Durvalumab is evaluated in several settings now, starting from the advanced lines with the ATLANTIC trial and the ARCTIC trial, where it is in combination with the anti-CTLA4. It is being investigated also in first-line setting with 2 important trials. One is the POSEIDON trial using the combination of chemotherapy plus durvalumab and plus or minus tremelimumab. There is also the MYSTIC trial, which is investigating the combination of tremelimumab with the anti-CTLA4 plus the durvalumab again. There is also a trial in the adjuvant setting. So, I think that durvalumab has been investigated everywhere.
Transcript Edited for Clarity