IMpower133: Exploratory analysis of maintenance therapy in patients with extensive-stage small-cell lung cancer

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Published: 1 Apr 2021
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Prof Martin Reck and Dr Antonio Passaro

Dr Antonio Passaro (European Institute of Oncology, Milan, Italy) and Prof Martin Reck (Lung Clinic Grosshansdorf, Grosshansdorf, Germany) discuss the IMpower133 study. This study is an exploratory analysis of maintenance therapy in patients with extensive-stage small-cell lung cancer, which was presented at WCLC 2020.

Prof Reck explains that in the Phase I/III IMpower133 study adding atezolizumab (anti–PD-L1) to carboplatin etoposide followed by atezolizumab maintenance for the first-line treatment of ES-SCLC led to significant overall survival (OS) and progression-free survival improvement vs placebo CP/ET.

In this analysis, he reports that they explored the benefit of atezolizumab vs placebo in the patients who reached the maintenance phase of IMpower133. They then talk about the updates from the IMpower133 study and what it means for patients with small cell lung cancer.

They further discuss the efficacy of atezolizumab and what treatment options are available for SCLC patients. Finally, the future of the IMpower133 study and other possible drug combinations are discussed.

This programme has been supported by an unrestricted educational grant from Roche.

IMpower133: Exploratory analysis of maintenance therapy in patients with extensive-stage small-cell lung cancer

Dr Antonio Passaro - European Institute of Oncology, Milan, Italy

Prof Martin Reck - Lung Clinic Grosshansdorf, Grosshansdorf, Germany

AP: Welcome to the ecancer expert discussion of IMpower133. I’m Antonio Passaro, I’m a thoracic oncologist in the European Institute of Oncology in Milan. Here with me today is Professor Martin Reck, Head of the Department of Thoracic Oncology at the Lung Clinic, Grosshansdorf in Germany. Dr Reck, welcome to the programme.

MR: Hi, nice to see you.

AP: So we know that standard of care in the first line treatment for small-cell lung cancer in extensive disease was platinum chemo plus etoposide in the last twenty years with no great survival control and disease response of 60-65%. But we know that small-cell has a high number mutation rate that suggests that these tumours are immunogenic and could respond to immune checkpoint inhibitors. The role of immune checkpoint inhibitors changed dramatically in this scenario in the non-small cell lung cancer, squamous and non-squamous. So, Dr Reck, let’s start with the IMpower133 – how do you consider this data and these results for patients with extensive disease of non-small cell lung cancer?

MR: Yes, thank you. I think it’s great to talk about new treatment opportunities that we do have for patients with advanced small cell lung cancer. As you mentioned, we haven’t seen any progress in recent decades, we have to say, so we had some modification of the chemotherapy schedules, we had some modification of the radiotherapy schedules but in the end we still are coming back to platinum etoposide with some described efficacy but we haven’t succeeded to overcome this plateau of efficacy. This has been the case with the implementation of checkpoint inhibitors in the management and, indeed, the IMpower133 trials was one of the milestones to implement the efficacy of immunotherapy in the management of patients with advanced small cell lung cancer. This was one of the first positive trials where we really have seen a significant improvement in survival, progression free survival. Besides that we also have seen some improvement in the long-term survival of patients with metastatic small-cell lung cancer and this is really a new opportunity that we do have for our patients.

AP: Yes, the key of long-term survival, of course, is more attractive for patients with small-cell lung cancer, as just seen for the long-term survival for non-squamous cell also in combination or immunotherapy alone. So recently during the World Lung Cancer Congress you presented the results of an exploratory analysis on the maintenance therapy in patients that were enrolled in the IMpower133. So can you explain to us these new findings and how this could be translated into daily clinical practice?

MR: The question that we did have was… actually we had two questions. So when we look on the schedule of the chemo-immunotherapy trials this treatment has two parts. Number one is the first line trial, the first line schedule – the combination of chemotherapy and the checkpoint inhibitor – and the second part in the patients responding to treatment is the maintenance therapy with an immunotherapy. The question is what is the contribution of each part – can we define this within our results? The second question was what are the patients that are really reaching this maintenance part? Do we see any patient characteristics associated with the probability to reach maintenance? So these were the two questions that we had for this exploratory analysis of the IMpower133.

Coming to the question of what are the factors that drive the opportunity to reach maintenance we could identify three factors. Number one was age, so older age was a poor prognostic factor to reach the maintenance part. Number two was the ADH level and number three was the performance status. So three typical prognostic factors were associated with the probability to reach maintenance.

The second question, we looked at the efficacy in this group of patients who reached the maintenance part of the schedule. We did observe a clear benefit favouring the immunotherapy. Overall it appeared that we have seen something like an enhanced efficacy favouring the immunotherapy or the combination with the first line treatment. So in our conclusion, and this was our interpretation, we do think that both parts of this schedule, the first line chemoimmunotherapy as well as the maintenance therapy, do contribute to the survival benefit that we have seen in the IMpower133 and therefore, coming back to the clinical practice, it is of great importance that patients do receive the first line therapy but that they also do receive the maintenance therapy afterwards.

AP: So this is a very interesting evaluation because you touched the base that the real need of clinical practice, daily clinical practice, when do we treat patients with small-cell lung cancer. Then we saw the Kaplan-Meier curves of the IMpower133 is that in the first part of the Kaplan-Meier curves we see that there is no difference among patients that receive the immuno combo or chemotherapy alone but the long tail of the Kaplan-Meier curves is very effective for patients that receive immunotherapy. In my opinion, this is the most attractive and dramatic picture for patients with small-cell lung cancer to date, jumping from the last twenty years of chemo to the long-term survival evaluation and potentiality. So, looking forward to the small-cell lung cancer setting, also in extensive disease and non-extensive disease, how do you consider scenarios, the new therapeutic options or the new treatment strategies that are upcoming in clinical practice?

MR: Now we have the standard of immunotherapy placing this treatment opportunity in the first line setting. Looking at all the trials that we have performed with immunotherapies in extensive disease small-cell lung cancers, it really appears to be very important to have a very early position of the immunotherapy. So when we look on the second line data, the CheckMate 331, we haven’t seen a survival benefit for nivolumab compared to topotecan in the second line scenario; when we look in the maintenance setting, the CheckMate 451, the same negative outcome. So it really appears to be very important to use the immunotherapy as early as possible.

The second question is what about patients with non-metastatic small-cell lung cancer? Can we also use checkpoint inhibitors as an opportunity of consolidation after chemo-radiotherapy like we have done in the PACIFIC trial in non-small cell lung cancer? There we have seen the results of a trial last year, the STIMULI trial, the ETOP STIMULI trial, which didn’t show any benefit for a consolidation with a checkpoint inhibitor after chemo-radiotherapy in this group of patients. So clearly we need more markers to identify those patients who might benefit and there are also additional trials currently on the way to explore potential usage of immunotherapy in patients with limited disease small-cell lung cancer.

AP: As a lead investigator of the IMpower133, what is the future of this trial? So you are planning subgroup analyses of biomarker evaluation?

MR: We have two strategies. Number one is the identification of the patients who benefit. We looked on the conventional markers like PD-L1 expression or TMB and we couldn’t find any clear correlation to the efficacy of the schedule. Now we dig a little bit deeper, we are looking at the genetic background. We will have this year also data coming from the RNA-Seq analysis. So stay tuned, we will have more data to tell you during this year.

The other avenue that we currently pursue is to increase the efficacy of the schedule. So we have seen a significant improvement. We have seen some improvement in also long-term survival but still the results are, I would say, a bit moderate. We would like to see more for our patients. One of the strategies is to add another promising target, to add another promising therapy there, and one of the potential new immunotherapies of interest is the usage of the anti-TIGIT antibodies. So currently there is a huge phase III trial on the way exploring the combination of platinum etoposide, atezolizumab and tiragolumab as a new immunotherapy opportunity with the primary endpoint of overall survival and hopefully we will see another improvement of the efficacy for this new treatment opportunity.

AP: Well, it’s very exciting to hear about so much on the horizon of small-cell lung cancer. I’d like to thank Professor Martin Reck for joining me to discuss the updated results of the IMpower133 and I would like to thank ecancer for their support. Thank you.

MR: Thank you.