Updates in Systemic Therapy for Non-Metastatic Lung Cancer - Episode 11

Considering PD-L1 and EGFR Status With I/O in Stage 3 NSCLC

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Benjamin P. Levy, MD: Dr Zhang, trials are fine and dandy, but real-world data can also be important to look at. There were recent updates from ESMO [the European Society for Clinical Oncology annual meeting] looking at some real-world data with durvalumab. Do you want to go over that data and tell us your impressions? Any take-home points?

Jun Zhang, MD, PhD: Yes. They actually had 3 studies related to real-world use. One abstract that was presented was on a retrospective review of practice in British Columbia. About 196 patients were identified, and they found that 50% of patients did not receive durvalumab. This was partly due to physician’s choice as well as patient preference. They argued that the benefits need to be better communicated so that more patients can benefit from the treatment. Now, their median time to start was about 43 days after chemoradiation therapy, which is a little bit different from the PACIFIC trial. But their 1-year overall survival [OS] is pretty good—91% in the durvalumab arm versus 72% in those who received surveillance. This is more impactful then what was reported in the PACIFIC study.

There’s another study that presented data from a German expanded access program. This study looked at 126 patients, and 43% of them finished 1 year of treatment. The 12/18-month overall survival rate was 79%/75%. This is equivalent to what we saw in the PACIFIC study.

I think the more interesting thing is Nicolas Girard, MD, in fact, also had this study called PACIFIC-R. “R” stands for real world. They actually described patients’ clinical characteristics, but more data regarding the PFS and OS, as well as the duration of durvalumab are still pending, probably for the next meeting.

Benjamin P. Levy, MD: Nice summary. I’m encouraged to see that the real-world data presented in some ways mirrors, at least in outcomes, what we’ve seen from phase 3 data. Hopefully, there will be more uptake of durvalumab across the world as the drug gets approved across countries for unresectable stage III disease. This is the standard in the US and is one that should be considered, I think, for all patients.

Let’s talk about all patients. I used the phrase considered. There are subsets of patients in the PACIFIC trial who maybe didn’t derive a benefit. There were the PD-L1 0% patients, the confidence interval for cross unity…. And then, the EGFR-positive patients. I get a lot of, and I’m sure we all do, questions from community oncologists. “What are you doing with the patient who is unresectable, who is EGFR-mutated, who has gotten concurrent chemoradiation?”

We’ve got this great ADAURA data, but the drug is not approved in the unresectable stage setting. Are you giving immunotherapy? Dr Naidoo, you are the unfortunate analyst who has to talk to us about what you do for these patients.

Jarushka Naidoo, MBBCh: Yes, I think it’s tricky. When PACIFIC was first presented and published, there was also the controversial European Medicines Agency approval of durvalumab only in patients who were PD-L1–positive. That caused a stir in the beginning, but I think highlighted some of these issues and the fact that there are subsets of patients who may or may not derive benefit from this approach. I think as Dr Leal said before, it requires a careful discussion with the patient. They biologically probably have a different cancer. Also, particularly for the EGFR-mutated patients, what are we going to do next? Or, what does this imply for their whole cancer journey?

From there, I think the Adam Schoenfeld, MD, data published in the Annals of Oncology about sequential EGFR-TKI [tyrosine kinase inhibitor] therapy after PD-1/PD-L1 therapy is really important. As a recap, that was a retrospective analysis from Memorial Sloan Kettering Cancer Center that looked at patients with EGFR-mutated lung cancer who got PD-1 or PD-L1 therapy followed by osimertinib, versus the other way around. That sort of sequence was associated with severe immune-related toxicities, whereas the opposite sequence was not associated with immune-related toxicity. And similarly, other EGFR TKIs were not associated with that toxicity. So, sequencing really matters. For those patients, I often will have a frank discussion of whether we think durvalumab may make sense. In terms of the PD-L1 subsets, again, I think it’s a tricky situation. I would probably offer durvalumab regardless of the PD-L1 status, but recognizing and saying to the patient that, “These are the factors that we take into consideration.” How do they feel about it?

Benjamin P. Levy, MD: What are other people’s thoughts on delivering immunotherapy for the EGFR subset and the PD-L1 0% groups? Are people extrapolating from ADAURA and giving osimertinib as consolidation therapy even though it’s not approved, or are people sticking by the data? Dr Zhang?

Jun Zhang, MD, PhD: I would probably not consider PD-L1 as the factor to make a decision as to whether to give durvalumab. I’m aware that this post-hoc analysis is basically suggesting that if the patient’s PD-L1 is negative, there is not much value or benefit from durvalumab. But we have to remember this is only a post-hoc analysis, number 1. And number 2 is, this is a pretreatment biopsy. The reason we are giving chemoradiation therapy right before durvalumab is we hope that chemoradiation therapy can change the immune profiling of the cancer. I don’t think completely relying on the pretreatment PD-L1 is the way to go. And number 3 is, in the PACIFIC study about half of the patients did not have the biopsy. So based on that, I think our decision purely based on PD-L1 expression is probably not ideal.

Now, regarding an EGFR mutation, I think it’s very tempting for me to consider osimertinib in this setting. However, I would not go to this after immunotherapy, as Dr Naidoo mentioned. That study reports about 15% incidence of immune-mediated toxicities, and some of them are pretty severe. I would not take that risk. But having said this, it seems like this is only relevant to osimertinib. When they look at the patients who are receiving immunotherapy followed by erlotinib, they do not see the same incidence. It could be something just relevant to osimertinib, but not necessarily the EGFR TKI, the whole category.

Now, whether there’s any value, let’s say a patient has not received immunotherapy and has finished chemoradiation therapy. Is there any value or reason to consider osimertinib? I think there is a study, LAURA, that is ongoing. I very much anticipate the results. I think the chance of success will be high.

Benjamin P. Levy, MD: Yes.

Jun Zhang, MD, PhD: Look at the ADAURA study. In earlier-stage disease, we already see a good response. For this LAURA study, the patient population, regarding stage of disease, is much higher. My educational guess is there is a high chance that this study will be successful, but we’re waiting for that.

Ticiana Leal, MD: The LAURA trial randomizes osimertinib to no osimertinib. There is no durvalumab arm in that trial.

Benjamin P. Levy, MD: It’s osimertinib indefinitely.

Ticiana Leal, MD: Right, it’s osimertinib indefinitely. It’s a global trial, and I think one important point is that if you do have a patient in that setting, they’re enrolling in the trial. This is a difficult trial to complete accrual to get meaningful end points. So I think it would be important to consider the trial if you have a patient in that setting, instead of trying it off trial because otherwise we won’t learn and we won’t know if that’s really the way to go.

Ravi Salgia, MD, PhD: I think you can extrapolate that a little bit more. In our clinical practice, we don’t tend to give durvalumab to the EGFR-positive patient population. But then we have to think about the ALK translocated population as well, and the MET exon 14 and the RS1 patients. We’re seeing a large number of those patients. Since they don’t respond as well to the immune checkpoint inhibitors, it requires a discussion with the patient. It is important to think about clinical trials, if you have them. If not, you have to individualize the therapy.

Benjamin P. Levy, MD: Yes, I think it requires shared decision-making. I’m not convinced that consolidation durvalumab is best for EGFR-mutated patients, but I think the jury is still out and we’ll learn from LAURA.

Transcript Edited for Clarity