Nivolumab/Ipilimumab Improves OS in Unresectable Malignant Pleural Mesothelioma

August 10, 2020
Nichole Tucker

Nichole Tucker, MA, is the Web Editor for Targeted Oncology. Tucker received her Bachelor of Arts in Mass Communications from Virginia State University and her Master of Arts in Media & International Conflict from University College Dublin.

Nivolumab in combination with ipilimumab significantly improved overall survival (OS) in treatment-naïve patients with unresectable malignant pleural mesothelioma (MPM) who were treated in the phase 3 CheckMate 743 clinical trial.

Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) significantly improved overall survival (OS) in treatment-naïve patients with unresectable malignant pleural mesothelioma (MPM) who were treated in the phase 3 CheckMate-743 clinical trial (NCT02899299), Bristol Myers Squibb announced in a press release.1

Results were presented on August 8, during the 2020 World Conference on Lung Cancer Virtual Presidential Symposium by Paul Bass, MD, PhD, professor of oncology at the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital.2

“An aggressive cancer with a 5-year survival rate of less than 10%, malignant pleural mesothelioma has shown resistance to many clinical treatments,” said Baas, in a statement. “Now, for the first time, we have evidence that a dual immunotherapy combination showed a superior, sustained overall survival benefit compared to chemotherapy in the first-line treatment of all types of malignant pleural mesothelioma. The CheckMate-743 data support the potential for nivolumab plus ipilimumab to become a new standard of care.”

CheckMate-743 is a phase 3, randomized, open-label trial investigating nivolumab plus ipilimumab versus standard-of-care chemotherapy (cisplatin or carboplatin plus pemetrexed) in the frontline setting of unresectable MPM. The trial was designed to offer a solution for the low 5-year survival rate historically observed with MPM, which is below 10%.1,2

A total of 605 patients were enrolled, 303 of whom were included in the nivolumab/ipilimumab arm, and 302 in the chemotherapy arm. Nivolumab was administered at a dose level of 3 mg/kg every 2 weeks, and ipilimumab 1 mg/kg was administered every 6 weeks. Treatment in the experimental arm lasted for up to 2 years. In the chemotherapy arm, patients received 6 cycles of cisplatin 75 mg/m2 or carboplatin AUC 5 plus pemetrexed 500 mg/m2 every 3 weeks. All study treatment was continued until disease progression or unacceptable toxicity.

The primary end point assessed in CheckMate-743 was OS, and the secondary end points were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) by blinded independent committee review (BICR). In addition, PD-L1 was explored as a predictive biomarker. CheckMate-743 was 90% powered to detect a hazard ratio (HR) of 0.72 with a 5% type-I error.

Patients with unresectable MPM, no prior systemic therapy, and an ECOG performance status of 0 or 1 were enrolled and stratified by histology and gender. At baseline, both arms were 77% male. In terms of histology, the majority of the patient population had epithelioid tumors including 76% of the nivolumab/ipilimumab arm and 75% of the chemotherapy arm. The remaining patients had non-epithelioid tumors.

Other baseline characteristics showed a median age in the nivolumab plus ipilimumab arm and the chemotherapy arm that matched at 69 years (range, 65-75). In terms of ECOG performance status, 38% of the patients in the experimental arm had a score of 0, and 62% had a score of 1. In the chemotherapy arm, 42% of patients had a score of 0, and 57% had a score of 1. Forty-two percent of patients in the nivolumab plus ipilimumab arm never smoke while 57% were current or former smokers. The numbers were similar in the chemotherapy arm where 40% of patients never smoked and 57% were current or former smokers. In the experimental versus the control arm, 10% compared with 9% of patients received prior radiotherapy.

PD-L1 was quantified at baseline in 289 patients from the nivolumab/ipilimumab arm and 297 from the chemotherapy arm. In the nivolumab/ipilimumab arm group, 20% of patients had PD-L1 expression of less than 1%, while 80% had PD-L1 expression of 1% or greater. In the chemotherapy group, 26% of patients had PD-L1 expression <1%, and 74% had PD-L1 expression of ≥1%.

At a median follow up of 29.7 months, the median OS observed with nivolumab plus ipilimumab was 18.1 months (95% CI, 16.8-21.4), compared with 14.1 months (95% CI, 12.4-16.2) in the chemotherapy arm (HR, 0.74; 96.6% CI, 0.60-0.91; P = .0020). At 2 years, the OS rate was 41% in the immunotherapy arm versus 27% in the chemotherapy arm.

Across the subgroup populations in the study, OS trended better in the nivolumab-plus-ipilimumab arm. In male patients who received the immunotherapy regimen, the median OS was 17.5 months versus 13.7 months with chemotherapy (unstratified HR, 0.74). Females had a median OS of 21.4 months with nivolumab plus ipilimumab compared with 18.0 months with chemotherapy (unstratified HR, 0.76).

In patients with epithelioid tumors treated with the immunotherapy combination, the median OS was 18.7 months (95% CI, 16.9-22.0) versus 16.5 months (95% CI, 14.9-20.5) with chemotherapy (HR, 0.86; 95% CI, 0.69-1.08). For subjects with non-epithelioid tumors, the median OS was 18.1 months (95% CI, 12.2-22.8) in the nivolumab-plus-ipilimumab arm compared with only 8.8 months (95% CI, 7.4-10.2) in the chemotherapy arm (HR, 0.46; 95% CI, 0.31-0.68).

Among the 167 patients aged 65 years or younger, the median OS with nivolumab plus ipilimumab was 17.2 months versus 13.3 months with chemotherapy (unstratified HR, 0.76). Patients 65 years of age or older (n = 281) had a median OS of 20.3 months with the immunotherapy combination versus 14.9 months with chemotherapy (unstratified HR, 0.63). The oldest group of patients (75 years and above), had a median OS of 16.9 months compared with 15.4 months with chemotherapy (unstratified HR, 1.02).

When patients were assessed according to ECOG status, patients with a score of 0 who received the immunotherapy combination regimen showed a median OS of 20.7 months versus 19.5 months in the chemotherapy arm (unstratified HR, 0.87). Patients with a score of 1 or higher who were treated with nivolumab/ipilimumab had a median OS of 17.0 months versus those in the chemotherapy arm who had a median OS of just 11.6 months (unstratified HR, 0.66).

The group of patients with PD-L1 expression <1% achieved a median OS of 17.3 months (95% CI, 10.1-24.3) with nivolumab plus ipilimumab compared with 16.5 months (95% CI, 13.4-20.5) with chemotherapy (HR, 0.94; 95% CI, 0.62-1.40). Those with PD-L1 expression of 1% or higher had a median OS of 18.0 months (95% CI, 16.8-21.5) in the nivolumab-plus-ipilimumab arm compared with 13.3 months (95% CI, 11.6-15.4) in the chemotherapy arm (HR, 0.69; 95% CI, 0.55-0.87).

The median PFS by BICR was 6.8 months (95% CI, 5.6-7.4) with the nivolumab/ipilimumab combination versus 7.2 months (95% CI, 6.9-8.0) with chemotherapy (HR, 1.00; 95% CI, 0.82-1.21). At 2 years, the PFS rate was 16% with nivolumab and ipilimumab versus 7% with chemotherapy. The median DOR was 11.0 months (95% CI, 8.1-16.5) in the immunotherapy combination arm versus 6.7 months (95% CI, 5.3-7.1) in the chemotherapy arm. At 2 years, the DOR rate was 32% with the immunotherapy regimen versus 8% with the chemotherapy regimen.

The ORR in the immunotherapy combination arm was 40%, with complete responses in 2%, compared with an ORR of 43% in the chemotherapy arm, consisting of all partial responses. The DCR was 76.6% and 85.1% for the immunotherapy and chemotherapy arms, respectively.

Treatment lasted for a median duration of 5.6 months (range, 2.0-11.4) in the immunotherapy arm and 3.5 months (range, 2.7-3.6) in the chemotherapy arm.

Treatment-related adverse events (TRAEs) of any grade were reported in 80% of patients in the nivolumab-plus-ipilimumab arm compared with 82% in the chemotherapy arm. Events occurring in ≥15% of patients included diarrhea and pruritis in the immunotherapy arm and nausea, anemia, neutropenia, fatigue, decreased appetite, and asthenia in the chemotherapy arm.

TRAEs led to treatment discontinuation in 23 patients in the nivolumab/ipilimumab arm and 16 in the chemotherapy arms. Grade 3/4 TRAEs led to therapy discontinuation in 15 patients who received nivolumab/ipilimumab and 7 who were receiving chemotherapy.

Serious TRAEs were observed and were more abundant in the nivolumab/ipilimumab arm with 21 any-grade serious TRAEs and 15 grade 3/4 events. In the chemotherapy arm, there were 8 serious TRAEs of any grade and 6 grade 3/4 events.

One treatment-related death occurred in the study, in the nivolumab/ipilimumab arm.

The safety profile of nivolumab/ipilimumab observed in CheckMate-743 was consisted with that previously observed at the dose level and schedule pursued in this study. No new safety signals were observed.

“These data in malignant pleural mesothelioma follow on the established long-term efficacy of Opdivo plus Yervoy in patients with non-small cell lung cancer and further demonstrate the combination’s potential to change survival expectations in thoracic cancers,” said Sabine Maier, vice president, Oncology Clinical Development, Bristol Myers Squibb, in a statement. “For more than 15 years, no new systemic treatment options that can extend survival have been approved for patients with malignant pleural mesothelioma. We look forward to discussions with global health authorities over the coming months about the positive results from CheckMate-743.”


1. Opdivo® (nivolumab) plus Yervoy® (ipilimumab) demonstrates durable survival benefit vs. chemotherapy in patients with previously untreated malignant pleural mesothelioma. News release. Bristol Myers Squibb. August 8, 2020. Accessed August 8, 2020.

2. Baas P, Scherpereel A, Nowal AK, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: 2020 World Conference on Lung Cancer Virtual Presidential Symposium. August 8, 2020.