Nivolumab Plus Ipilimumab Prolongs Survival in Mesothelioma

Solange Peters, MD

Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) was found to significantly extend overall survival (OS) in patients with unresectable malignant pleural mesothelioma (MPM). At the 3-year follow-up, even patients who stopped the treatment showed better results compared with those who received platinum-based chemotherapy.¹

The phase 3 CheckMate 743 study (NCT02899299) was conducted on over 600 patients with untreated MPM.² Patients were stratified by histology and gender and then received 3 mg/kg of nivolumab every 2 weeks and 1 mg/kg ipilimumab every 6 weeks, while the control arm received chemotherapy every 3 weeks for 6 total cycles. Investigators followed biomarkers associated with OS: 4-gene inflammatory gene expression signature (CD8A, PD-L1, STAT-1, LAG-3) and lung immune prognostic index (LIPI) score.¹

Patients who received nivolumab/ipilimumab had a median OS of 18.1 months compared with 14.1 months with chemotherapy. The 3-year OS rate was 23.2% versus 15.4%, while their progression-free survival rate was 13.6% compared with 0.8%.

Solange Peters, MD, head of the medical oncology service and chair of thoracic oncology in the Oncology Department at the Centre Hospitalier Universitaire Vaudois and president of the European Society for Medical Oncology (ESMO), presented the findings of the 3-year update at the ESMO Congress 2021 and discussed the significance of the follow-up analysis of nivolumab/ipilimumab in mesothelioma in an interview with Targeted Oncology^TM.

TARGETED ONCOLOGY: Can you discuss the standard frontline treatment for this patient population and why are new strategies are needed?

PETERS: [Mesothelioma] is a rare disease entity where we have not been making any significant advances in recent years. We've been seeing some signals that immunotherapy might work in a small proportion of patients and the signal came from late line, second or third line [treatments].

However, we are still unable to identify which patients, meaning that a trial [such as] PROMISE-meso, a randomized trial of chemotherapy versus pembrolizumab [Keytruda] in second-line, couldn't reach statistical significance in favor of immuno-oncology agents [IO], because only a small proportion of mesothelioma patients benefited from anti-PD-1 or anti-PD-L1 only.³ What is interesting with these data I presented is that, first of all, the first data set shows that IO gives rise to a significant durable survival benefit. And it is a frontline strategy before any chemotherapy. It's really a new paradigm. First of all, [we have] established IO in mesothelioma, [not] as a late line but as a frontline therapy.

I think the difference here is the dual immunotherapy. You have nivolumab and low-dose ipilimumab for up to 2 years versus the usual platinum-based chemotherapy up to 6 cycles.

But by having seen this immunotherapy, and with a minimum of 3 years of follow-up, you can show this durable benefit in OS with a hazard ratio of 0.73 for nivolumab/ipilimumab versus chemotherapy. This is also proceeding in a wonderful duration of response. I would say, to give some numbers in terms of duration of response, almost 1 patient out of 3 is still in response at 3 years despite stopping the drugs at 2 years—so when you're off treatment. It's very interesting data. It's the first time we have randomized data in mesothelioma for immunotherapy. It’s also the first time we have long-term follow-up data on immunotherapy for mesothelioma, [including] about toxicity.

What was the design of the study and the methods used?

CheckMate 743 is a very straightforward study. It is a trial that enrolled patients with unresectable MPM, naive from any treatment, with a good performance status. These patients were stratified by histology in mesothelioma [epithelioid vs non-epithelioid], and gender. Over 600 patients were randomized 1:1 to nivolumab and low-dose ipilimumab for up to 2 years, versus the usual platinum-based chemotherapy with cisplatin or carboplatin pemetrexed for up to 6 cycles. The primary end point was OS. At this meeting, we were able to update the OS with a minimum follow-up of 3 years, [which is] the longest ever presented data on IO and mesothelioma. As well, for the first time, we were able to show some biomarker assessments.

Could you describe the biomarkers employed in this study?

We tried to look at 3 important biomarkers for immunotherapy. The first one, which was not predictive, is TMB, or tumor mutational burden. We took the patients in this trial and evaluated the number of mutations, counting somatic missense mutations, and classified a patient into 3 subgroups: low, intermediate, or high [TMB]. Looking at TMB, what was interesting is to see that nivolumab/ipilimumab was better than chemotherapy across [both arms], and equivalently. TMB was not at all predictive of the added value of nivolumab/ipilimumab versus chemo in that trial. [TMB] is not a biomarker in mesothelioma. Let's keep in mind that in mesothelioma, the number of mutations in the disease is quite low, as compared, for example, to non–small cell lung cancer where it's up to 10 times higher.

The second biomarker we looked at is the LIPI. This is an important index because it has been shown to be strongly prognostic in non–small cell lung cancer. The LIPI score assesses lactate dehydrogenase as well as the derived neutrophil-to-lymphocyte ratio from peripheral blood samples. In the trial, the LIPI was prognostic, but not at all predictive. So again, [it did not help] to predict who benefits from IO.

The most promising is a third one. We look at what we call an inflammatory signature. Here we used a signature which was also shown to correlate with other larger inflammatory signatures. It's looking at the RNA level by RNA sequencing at 4 genes: CD8A, STAT-1, LAG-3, and PD-L1. You can create a Z-score and classify patients by a high or low relative to the median across the whole data set, so you're above or under the median. By doing that, we are able to show that when gene inflammatory signature score was high, it was predicting a way stronger benefit of nivolumab/ipilimumab as compared with the low inflammatory signature score subgroup at 2 years, with 35% of living patients in the high inflammatory score level versus 15% in the low inflammatory score level.

Interestingly, this was not seen at all in the chemotherapy arm, where no difference was seen according to the inflammatory score. So maybe there's something about immune inflammatory gene expression which might in the future help us across diseases, but particularly mesothelioma. Of course, this is exploratory, and it will need a prospective validation, but it's a very nice signal that maybe we will move [forward] with new biomarkers.

Based on this research, is there any advice that you can give to oncologists on how to move forward with managing toxicities?

Management of toxicities is now the topic of many guidelines, and the main thing to say to colleagues is to create your circle of expertise around you and follow the guidelines, because no intervention should be delayed and nothing should be derived from the guidance, because you can manage toxicities without any high-grade AE and without any death if you do it well. But management is something which is well-established by guidelines and has to be locally established within a small circle of specialists. But it should prevent any severe toxicity or any deaths related to toxicity nowadays, because we know how to manage toxicity.

But the message of this trial is more about communication to the patient. If a patient has to stop because of toxicity, the message and the tone you use might not [need to] be very negative because you can tell them that despite having to stop in all of these trials with nivolumab/ipilimumab, the long-term outcome remains particularly good, meaning that the toxicity also reflects some overdue immune reaction. I think it's more about reassuring or comforting our patient that it doesn't mean that the outcome will be worse than expected because of toxicity. The outcome is pretty good when people have to stop due to toxicity.

_References:

_{1. Peters S, Scherpereel A, Cornelissen R, et al. LBA65 - First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (MPM): 3-year update from CheckMate 743. Ann Oncol. 2021;32:(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc7412}

_{2. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021; 397(10272), 375-386. doi:10.1016/s0140-6736(20)32714-8}

_{3. Popat S, Curioni-Fontecedro A, Polydoropoulou V, Shah R, O’Brien M, Pope A. A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM): results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol. 2019;30:v931.}