Solange Peters, MD, PhD

Solange Peters, MD, PhD, the president of the European Society of Medical Oncology (ESMO), discusses the biomarkers for immunotherapy used in the phase 3 CheckMate 743 trial (NCT02899299).

CheckMate 743 evaluated the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in over 600 patients with untreated malignant pleural mesothelioma (MPM). Findings revealed that when used together, the combination significantly extended overall survival (OS) in patients with MPM and showed better results compared with patients who received platinum-based chemotherapy.

Peters explains the importance of the 3 biomarkers employed in the trial which included tumor mutational burden, lung immune prognostic index (LIPI), and an inflammatory signature. Each of these biomarkers showed promise in helping to predict which patients benefit from immunotherapy, if the combination was more effective than chemotherapy alone, if nivolumab and ipilimumab showed stronger benefits, and more.

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. 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.

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Solange Peters, MD, PhD, discusses the biomarkers for immunotherapy used in the phase 3 CheckMate 743 trial.


Biomarkers Employed in CheckMate 739 for Patients With MPM

Solange Peters, MD, PhD, the president of the European Society of Medical Oncology (ESMO), discusses the ways in which oncologists can manage toxicities in patients with unresectable malignant pleural mesothelioma (MPM).

The phase 3 CheckMate 743 trial (NCT02899299) examined nivolumab (Opdivo) in combination with ipilimumab (Yervoy) and found it to significantly extend overall survival (OS) in patients with MPM. The study was conducted on over 600 patients with untreated MPM and at the 3-year follow-up, even patients who stopped the treatment showed better results compared with those who received platinum-based chemotherapy.

Peters explains the importance of communication and how it is a main topic of importance within the trial. If patients and physicians are able to communicate well, more reassurance and comfort is provided and treatment outcomes will likely improve. 

 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.

 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.

Solange Peters, MD, PhD, discusses the ways in which oncologists can manage toxicities in patients with unresectable malignant pleural mesothelioma.

CheckMate 743 Underscores the Importance of Managing Toxicities in MPM

Solange Peters, MD, PhD, the president of the European Society of Medical Oncology (ESMO), discusses the design of the CheckMate743 study (NCT02899299) of doublet immunotherapy (IO) for patients with malignant pleural mesothelioma (MPM).

The phase 3 CheckMate743 study randomized 600 patients with untreated, unresectable MPM. Patients were stratified by epithelioid versus non-epithelioid histology and by gender.

Patients in the IO arm received 3 mg/kg of nivolumab (Opdivo) every 2 weeks and 1 mg/kg ipilimumab (Yervoy) every 6 weeks, while the control arm received chemotherapy consisting of pemetrexed plus cisplatin or carboplatin every 3 weeks for 6 total cycles.

The primary end point was overall survival (OS), and progression-free survival (PFS) was a secondary end point. Patients who received nivolumab/ipilimumab had a median OS of 18.1 months compared with 14.1 months with chemotherapy. As of the 3-year follow-up, the OS rate was 23.2% for the IO arm versus 15.4% for chemotherapy, while their rate of PFS was 13.6% compared with 0.8%. According to Peters, this is the longest-term data on IO in mesothelioma.

The study also gathered data on biomarkers including the 4-gene inflammatory signature score, tumor mutational burden, and lung immune prognostic index. Exploratory analyses suggested that the inflammatory gene signature was associated with better OS in the IO arm.

 CheckMate743 is a very straightforward study. It is a trial enrolling patients with unresectable pleural mesothelioma, naive from any treatment, with a good performance status. These patients [were] stratified by histology in mesothelioma—we speak about epithelioid versus non-epithelioid—and gender.

Knowing that, 600-plus 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 and pemetrexed for up to 6 cycles. The primary end point is OS. And at this meeting, we're able to update this OS with a minimum follow up of 3 years. So [this is] the longest ever presented data on IO in mesothelioma, as well as for the first time we're able to show some biomarker assessments. So [we’re] trying to identify new biomarkers and best better understand…the biology of mesothelioma.

Solange Peters, MD, PhD, discusses the design of the CheckMate743 study of doublet immunotherapy for patients with malignant pleural mesothelioma.

Solange Peters, MD, PhD | Authors

Articles

Biomarkers Employed in CheckMate 739 for Patients With MPM

CheckMate 743 Underscores the Importance of Managing Toxicities in MPM

CheckMate743 Study Provides Long-Term Data on IO in Mesothelioma