Patients with untreated mesothelioma may be able to avoid chemotherapy, say researchers reporting new survival data with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).
The two approaches were compared in more than 600 patients with treatment-naive mesothelioma in the phase 3 CheckMate 743 trial, which was supported by the manufacturer of both immunotherapies, Bristol-Myers Squibb.
The trial "met its primary endpoint of statistically improving overall survival for the experimental arm vs chemotherapy in a prespecified interim analysis," reported Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands,
The combined nivo+ipi immunotherapy regimen was associated with a 26% improvement in overall survival. At 2 years, 41% of patients in the immunotherapy arm were still alive, vs 27% in the chemotherapy group.
"This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma," he said. He suggested that it should therefore "be considered as a new standard of care."
The data were presented on August 8 in the presidential symposium of the World Congress on Lung Cancer 2020, which was held online because of the COVID-19 pandemic.
A key analysis for the study was by histologic subgroup. It is known that standard-of-care chemotherapy performs better in patients with epithelioid as opposed to nonepithelioid tumor subtypes.
Baas highlighted that the performance of nivo+ipi was "almost the same" in patients with epithelioid and nonepithelioid tumors, at a median overall survival of 18.7 months and 18.1 months, respectively.
In contrast, overall survival in the chemotherapy arm was markedly lower in patients with nonepithelioid tumors, at 8.8 months vs 16.5 months among those with epithelioid tumors.
This was reflected in the hazard ratios for overall survival vs nivo+ipi, at 0.46 and 0.86, respectively, the latter nonsignificantly different from combination immunotherapy.
For study discussant Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester, United Kingdom, the epithet of a "new standard of care" for nivo+ipi should be reserved for nonepithelioid disease.
In this setting, he described the overall survival improvement as "transformative," considering the "marked chemo resistance" of nonepithelioid tumors, which is "almost certainly" associated with epithelial-to-mesenchymal transition (EMT).
In the future, he suggested, combinations of chemotherapy and immunotherapy involving all histologies or selective targeting of nonepithelioid mesothelioma "could further extend the benefit for patients."
Improving Survival in Mesothelioma
"We have been trying to improve the overall survival of patients with mesothelioma now for many decades," Baas commented. Platinum-based chemotherapy plus pemetrexed is a standard of care, although the 5-year survival rate "is still below 10%," he noted.
Randomized trials of single-agent immune checkpoint inhibitor therapy in the second-line treatment of patients with mesothelioma have not shown any significant benefits.
However, nivolumab and ipilimumab have a "complementary mechanism of action," and two previous reports have indicated that together, they have clinical activity in the second-line setting.
The team conducted CheckMate 743 to determine the efficacy of the combination in the first-line setting.
The study involved 605 patients with pleural mesothelioma who had received no prior systemic therapy and had good performance status.
They were randomly assigned in a 1:1 ratio to receive nivo+ipi for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin until disease progression or unacceptable toxicity occurred.
"Patients could have a subsequent therapy," Baas noted; 44.0% of patients in the experimental arm received subsequent therapy, vs 44.1% of those in the chemotherapy arm.
Of the latter, 20% received an immune checkpoint inhibitor as subsequent therapy.
The minimum follow-up for overall survival was 22.1 months; the median follow-up was 29.7 months.
Nivo+ipi was associated with a significant improvement in overall survival vs standard-of-care chemotherapy, at a median overall survival of 18.1 months vs 14.1 months, with a hazard ratio of 0.74 (P = .0020).
The results indicated that overall survival was similar across key subgroups, which suggests that "no subgroup was harmed" by nivo+ipi, Baas said.
Stratification by PD-LI Expression
Stratifying the patients by the absence or presence of programmed cell death–ligand-1 (PD-L1) expression, the team found that the performance of nivo+ipi was "the same" as that of chemotherapy, Baas said.
"But in cases where there is any expression of PD-L1, the experimental arm performs better," at an overall survival 18.0 months vs 13.3 months for chemotherapy and a hazard ratio of 0.69, he said.
There was no difference between the two treatment arms in progression-free survival. Chemotherapy performed better in the first 6 months of treatment, after which the nivo+ipi arm had lower event rates.
Nivo+ipi was also associated with a greater duration of response, at a median of 11.0 months vs 6.7 months for standard-of-care chemotherapy.
Moreover, at 24 months, 32% of nivo+ipi patients were still experiencing a response, whereas 8% of those in the chemotherapy arm were.
Treatment-related adverse events rates were almost identical between the two treatment groups, although treatment with nivo+ipi was associated with more grade 3/4 serious treatment-related adverse events, at 15 vs six for chemotherapy.
Choosing Immunotherapy vs Chemotherapy
In his discussion of the new study, Fennell compared the current results with those from two studies, INITIATE and MAPS2. "What's very clear is the response rate is slightly higher," as is the disease control rate, he said.
This, he explained, "is perhaps not surprising, given that these two previous trials were in the relapse setting."
He pointed out, however, that the progression-free survival data from those previous trials were "not a million miles away" from results seen in CheckMate 743, "suggesting that this immunotherapy does have significant activity in the relapse setting."
For Fennell, the "pivotal data" are in patients with nonepithelioid tumors, particularly inasmuch as chemotherapy performed "poorly" in this setting, whereas it performs "as expected" in epithelioid mesothelioma.
He believes that the driver for this is the poor prognosis associated with sarcomatoid biphasic disease, a subtype characterized by increased expression of vimentin and ZEB1, proteins both associated with EMT.
"What does this mean?" Fennell asked.
"If you have have enrichment of EMT, what you see is increased drug resistance, increased invasiveness, something we know well with sarcomatoid mesotheliomas in particular, and this drug-resistance phenotype may account for the drug resistance that we see in CheckMate 743 with chemotherapy.
"This does not appear, however, to impact in any way the efficacy of the immunotherapy," he noted.
Fennell believes that, with regard to both efficacy and safety, the balance is "very much in favor" of nivo+ipi in epithelioid mesothelioma, although there is less to choose between immunotherapy and chemotherapy in the nonepithelioid setting.
Indeed, the choice is "possible tilting slightly towards chemotherapy" in patients with the nonepithelioid tumors, owing to the lower rates of grade 3/4 serious treatment-related adverse events in comparison with combination immunotherapy.
The study was supported by Bristol-Myers Squibb. Baas has served on the advisory boards of MSD, AstraZeneca, and Takeda. Fennell has received research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, MSD, and Roche; research funding from Astex Therapeutics, Bayer, and Boehringer Ingelheim; has served on the speaker bureau of AstraZeneca, Boehringer Ingelheim, and Roche; has acted as a consultant for Bayer and Lab 21; and has served on the advisory board of Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.
World Congress on Lung Cancer 2020: Presidential symposium, abstract 03, presented August 8, 2020.
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