Frontline Nivolumab/Ipilimumab Maintains OS Benefit Across Subgroups in Unresectable Malignant Pleural Mesothelioma

Solange Peters, MD, PhD

The frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) continued to demonstrate improved overall survival (OS) across subgroups compared with standard chemotherapy at 3 years in patients with unresectable malignant pleural mesothelioma, according to findings from an updated analysis of the phase 3 CheckMate743 trial (NCT02899299) that were presented during the 2021 ESMO Congress.¹

At a median follow-up of 43.1 months (minimum, 35.5 months), the median OS was 18.1 months with nivolumab plus ipilimumab (n = 303) vs 14.1 months with chemotherapy (n = 302; HR, 0.73; 95% CI, 0.61-0.87). The 3-year OS rates were 23% vs 15%, respectively.

By histology, the median OS was 18.2 months with nivolumab/ipilimumab (n = 229) vs 16.7 months with chemotherapy (n = 226) in patients with epithelioid histology (HR, 0.85; 95% CI, 0.69-1.04). The median OS was 18.1 months with nivolumab/ipilimumab (n = 74) vs 8.8 months with chemotherapy (n = 76) in patients with non-epithelioid histology (HR, 0.48; 95% CI, 0.34-0.69).

Notably, treatment with nivolumab plus ipilimumab led to an OS benefit across all subgroups analyzed. Notably, the median OS was 17.3 months with nivolumab/ipilimumab vs 16.6 months with chemotherapy in the PD-L1–negative population (n = 135; HR, 0.99) and 18 months vs 13.3 months, respectively, in the PD-L1–positive population (n = 451; HR, 0.71).

“[These results from] CheckMate743 [provide] a unique dataset [that we can use] in order to try to identify new candidates for biomarkers, but also, to potentially better understand the role of immunotherapy, specifically in mesothelioma,” said lead study author Solange Peters, MD, PhD, a professor in the Department of Oncology at Lausanne University and head of the Medical Oncology Service and chair of Thoracic Oncology in the Oncology Department at Lausanne University Hospital in Lausanne, Switzerland, in a virtual presentation of the data. “With an additional 12 months of follow-up, these data from CheckMate743 confirm that nivolumab/ipilimumab is the standard of care for unresectable mesothelioma, regardless of histology.”

Nivolumab and ipilimumab have distinct but complementary mechanisms of action, targeting PD-1 and CTLA-4, respectively. The dual immunotherapy strategy was approved by the FDA on October 2, 2020, for the first-line treatment of patients with unresectable malignant pleural mesothelioma.² The regulatory decision was based on previously reported findings from CheckMate743, in which the combination elicited a 26% reduction in the risk of death compared with platinum-based chemotherapy (HR, 0.74; 95% CI, 0.61-0.89; P = .002).

Patients with unresectable malignant pleural mesothelioma who had not received prior systemic therapy and had an ECOG performance status (PS) of 0 or 1 were eligible for enrollment on the trial. Patients (n = 605) were randomized 1:1 to receive 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks for up to 2 years or cisplatin or carboplatin plus pemetrexed (Alimta) every 3 weeks for 6 cycles until disease progression or unacceptable toxicity.

The primary end point of the study was OS; secondary end points included overall response rate (ORR), disease control rate, and progression-free survival (PFS) by blinded independent central review, as well as efficacy by PD-L1 expression. Exploratory end points included safety and tolerability and biomarkers, including the 4-gene inflammatory signature score, tumor mutational burden (TMB), and lung immune prognostic index (LIPI).

Baseline characteristics were similar between arms among patients in the overall population, as well as the cohort of RNA-evaluable patients, Peters explained.

Overall, patients were a median age of 69 years, and the majority of patients were male. Most patients had an ECOG PS of at least 1, were current or former smokers, and had epithelioid histology. Most patients had a PD-L1 score of 1% or greater by immunohistochemistry with the 28-8 pharmDx assay.

Further results showed that the median PFS was 6.8 months with nivolumab plus ipilimumab compared with 7.2 months with chemotherapy (HR, 0.92; 95% CI, 0.76-1.11). The 3-year PFS rates were 14% vs 1%, respectively.

The ORR was 39.6% with the doublet vs 44% with chemotherapy. The median duration of response (DOR) was 11.6 months vs 6.7 months, respectively. At 3 years, 28% of patients who received nivolumab/ipilimumab vs 0% of patients who received chemotherapy remained in a response.

“As expected for immunotherapy, the DOR was significantly longer for nivolumab/ipilimumab vs chemotherapy…keeping in mind the fact that [patients] were off treatment for a year already at the time of analysis as they stopped at 2 years,” Peters said.

Exploratory biomarker analyses demonstrated that the median OS with nivolumab plus ipilimumab was 16.8 months vs 21.8 months in patients low (n = 82) vs high (n = 83) 4-gene inflammatory signature scores, respectively (HR, 0.57; 95% CI, 0.40-0.82). The 3-year OS rates were 35% vs 15%, respectively. With chemotherapy, the median OS was 15.2 months vs 11.6 months in patients low (n = 82) vs high (n = 80) 4-gene inflammatory signature scores, respectively (HR, 1.14; 95% CI, 0.82-1.59). The 3-year OS rates were 13% vs 11%, respectively.

In the nivolumab/ipilimumab arm, the median OS was 19.3 months in patients with low TMB (n = 103), 17.9 months in patients with intermediate TMB (n = 97), and 17.1 months in patients with high TMB (n = 95). In the chemotherapy arm, the median OS was 18.0 months (unstratified HR, 0.74), 9.9 months (unstratified HR, 0.48), and 14.1 months (unstratified HR, 0.70), respectively.

In the nivolumab/ipilimumab arm, the median OS was 21.6 months in patients with good LIPI scores (n = 293), 17.1 months in patients with intermediate LIPI scores (n = 233), and 6.1 months in patients with poor LIPI scores (n = 47). In the chemotherapy arm, the median OS was 16.3 months (unstratified HR, 0.78), 14.1 months (unstratified HR, 0.76), and 6.0 months (unstratified HR, 0.83), respectively.

“The 3 TMB tertiles did demonstrate a benefit with nivolumab/ipilimumab vs chemotherapy, but without any difference between the tertiles, showing us the lack of predictive ability of TMB in this specific disease entity when using this strategy,” Peters said, adding that an identical observation was made regarding LIPI score.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) were observed in 80% of patients who received nivolumab/ipilimumab (n = 300) vs 82% of patients who received chemotherapy (n = 284). Of these, 31% vs 32% were grade 3/4 TRAEs, respectively.

Any-grade TRAEs that led to discontinuation of any component of the regimen occurred in 23% of patients with nivolumab/ipilimumab vs 16% of patients with chemotherapy. Of these, 15% vs 7% were grade 3/4 TRAEs, respectively. Any-grade TRAEs that led to discontinuation of all regimen components were reported in 17% vs 8% of patients, respectively. Of these, 13% vs 5% were grade 3/4 TRAEs, respectively.

Any-grade serious TRAEs, including events reported between the first dose and 30 days after the last dose of study drug, were reported in 21% of patients with nivolumab/ipilimumab vs 8% of patients with chemotherapy. Grade 3/4 serious TRAEs occurred in 16% vs 6% of patients, respectively.

Treatment-related deaths occurred in 3 patients who received nivolumab plus ipilimumab and were caused by pneumonitis, encephalitis, and acute heart failure. One patient died from chemotherapy-related myelosuppression.

Additionally, the incidence of exposure-adjusted TRAEs per 100 person-years were 503.4 with nivolumab/ipilimumab vs 1354.1 with chemotherapy.

Furthermore, findings from a post-hoc analysis demonstrated that the median OS was 25.4 months with a 3-year OS rate of 37% from randomization in patients who discontinued all components of nivolumab/ipilimumab because of TRAEs. The ORR was 67%.

After treatment discontinuation, the median DOR was 20 months, and 34% of patients had ongoing responses for at least 3 years.

Among this population, a median of 9 doses (range, 1-47) of nivolumab were received and a median of 3 doses (range, 1-16) of ipilimumab. The median duration of treatment was 4.3 months (range, 0.0-22.5).

References

1. Peters S, Scherpereel A, Cornelissen R, et al. First-line nivolumab + ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year update from CheckMate 743. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA65.
2. FDA approves nivolumab and ipilimumab for unresectable malignant pleural mesothelioma. News release. FDA. October 2, 2020. Accessed September 17, 2021. https://bit.ly/2VS3E68