Combining Immuno-Oncology and Standard Chemo in the Treatment of NSCLC
Solange Peters, MD, PhD, Chair Medical Oncology, Lausanne University Hospital, Switzerland, provides a summation of the Keynote-189, CheckMate 9LA, and CheckMate 227 clinical trials, and what the findings of these studies mean for the treatment of patients with non–small-cell lung cancer (NSCLC).
My name is Solange Peters. I'm working as medical oncologist in Lausanne in Switzerland. I am the head of medical oncology, as well as the thoracic unit, at the University Hospital in the city of the Lausanne.
I will cover some opinions and some data with you about, first of all, the ALEX study, which I presented at ASCO and the post‑discussion, and of course, also try to discuss with the essential of this ASCO 2020 meeting.
The other interesting presentation, so one was kind an update, and the other one was about a new strategy, are the 9LA and the (KEYNOTE-189)… I can even add to that the 227 trial.
The question of this trial is how to deliver immunotherapy front-line to NSCLC patients and how to optimally do it. We have been moving from late‑line IO to this medical need of delivering immunotherapy to all NSCLC advanced disease, because we know that it might be, I wouldn't say life‑saving, but at least providing a long‑term benefit to a small proportion of them.
So the aim of any treatment now is to make sure that NSCLC patients receive immunotherapy. The best way to achieve it is, of course, to give immunotherapy front-line.
The KEYNOTE‑189 is well‑known. We could see at meeting some longer follow‑up of the 189 also showing that a significant proportion of patients reached the 2 years of treatment with pembrolizumab.
I would say, always extremely interesting data, at longer follow‑up for this 189, which is focusing on nonsquamous NSCLC.
What I'm always extremely interested in beyond this presentation in long‑term data is to see the shape of the plateau a longer term at 3, 4, and 5 years, and considering long‑term benefit of the strategy as well as long‑term duration of response. And these data will be given probably later on, further in the KEYNOTE‑189.
It's also always interesting to understand what's happening beyond the 2 years of treatment. Do patients progress? How fast? And what the picture of the long‑term behavior of this patient with the dual therapy? 189 is absolutely one of the strategies which has proven efficacy across all patients with nonsquamous NSCLC.
To go back to the novel trial, the 9LA is more or less the same basis, as compared to the 227. It's about using low‑dose ipilimumab and nivolumab in patients with advanced NSCLC. The addition in 9LA is to give 2 cycles of chemotherapy in the initial treatment schedule in combination with nivolumab and ipilimumab in order to potentially biologically prime an immune response, and also, on the other hand, protect some patients from what we call an early progression or an early death that has been observed systematically in all the trials delivering only immunotherapy front‑line in NSCL patients.
When I'm speaking about this early progression or early death, it's about this crossing of the curves that we observed in the first 3 to 6 months in all the trials with immunotherapy only. This chemotherapy priming, trying to generate an immunogenic cell death, of course, it's also a way to make sure that easy immune response might take some time to mount and to be efficient. You try to aim at not observing any risk of losing the patient from this line of treatment or subsequent lines of treatment.
So basically, this can be fused to the presentation about long‑term result of 227; the long‑term results of 227 show a wonderful plateau and a wonderful duration of response at 3 years, really showing that this ipilimumab/nivolumab is able, like in melanoma, to maintain a subset of patients with long‑term benefit and now, we observe 3 years.
On the other hand, CHECKMATE‑9LA, which has a way shorter follow‑up, is able to show that this crossing of the curve doesn't happen. So one-on-one, 9LA might potentially fuse the benefit of the ipilimumab/nivolumab strategy for a T‑cell repertoire and a memory T-cell kind of constitution, as well as an initial satisfactory control of the disease, avoiding progression in the early stage.
Will the chemo add some more on plateau? We still don't know. And of course, we need to look at these data at 2, 3, 4, and 5 years again.
How can you choose? That's why maybe I evoked 189. I think at the time being, we have to keep in mind that all these trials perform quite similarly if you look at the landmark at 1 or 2 years, and the percentage of patients remaining alive. So I would guess, to learning from the melanoma colleagues, that if a difference has to be seen, this is a difference more on the long‑term benefit of the CTLA‑4 components.
And to my opinion, as well soon in melanoma in terms of long‑term survivorship, in terms of brain control, in terms of activity of the immune system long‑run, it might be that CTLA‑4 brings a little higher plateau and [becomes] potentially more flat.
This hypothesis comes mainly from the lab and mainly from the melanoma data. So I think at the time being, and to be extremely fair, you have several options front-line for your patients, 9LA, or the KEYNOTE‑189, so chemo/I or IO/IO, and you still have pembrolizumab or atezolizumab monotherapy for high PD‑L1.
I think these data deserve some discussion with the patients when you present the data.
The last important thing to me regarding looking at 9LA is to, like for 189, state that this is a regimen which does not identify one subgroup benefiting more - it's an all‑comer regimen. Maybe we should invest a bit more in trying to understand the truth among this variable destiny of patients. Maybe some do benefit better or more, but we haven't yet identified them.
More importantly, I think physicians in the lung cancer field need to address now the question of learning how to deliver ipilimumab.
I remember that at ESMO last year, it was the main remark of my discussion for 227, is the toxicity of ipilimumab. And I think that, if in melanoma, with way higher dose, this is very manageable now, all physicians need to learn about managing ipilimumab toxicity. Again, it's extremely manageable, but it's a learning process.
A bit like, at the time, we did learn to combine radio and chemotherapy for stage III. It was not so easy. Now, we need to learn how to combine ipilimumab and nivolumab. Maybe that's the effort that BMS has to do, is to give these educational tools in order to feel very safe in administrating it.
Remember, and you have seen that, maybe this combination will not only be renal, melanoma, and lung, but maybe some other disease entities to come in the future.
This is my summary. Thanks a lot.