Nivolumab Proven Effective for Relapsed Mesothelioma

Dean Fennell, MD

Nivolumab (Opdivo) monotherapy is an effective treatment approach for patients with previously treated malignant mesothelioma, according to findings from the phase 3 CONFIRM trial.

Results showed that the trial met both its coprimary end points of overall survival (OS) and progression-free survival (PFS), expanding the treatment armamentarium for patients with relapsed/recurrent disease, according to Dean Fennell, MD, who presented the findings at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer.¹

In total, 332 adult patients with previously treated, unresectable, histologically confirmed metastatic mesothelioma were randomized to either nivolumab (n = 221) or placebo (n = 111). The median OS was 9.2 months (95% CI, 7.5-10.8) with nivolumab compared with 6.6 months (95% CI, 5.0-7.5) with placebo (HR, 0.72; 95% CI, 0.55-0.94; P = .02). Investigator-assessed PFS was 3.0 months with nivolumab versus 1.8 months with placebo (HR, 0.61; 95% CI, 0.48-0.77; P <.001).

“[Effective therapy] for relapsed mesothelioma is an unmet need and there have been no randomized phase 3 trials that have demonstrated overall survival [benefit] in the relapsed setting,” said Fennell, a professor and chair of thoracic medical oncology at the Leicester Cancer Research Centre at the University of Leicester in the United Kingdom. “Nivolumab is deemed a safe and effective treatment and should be considered the new treatment option for patients with relapsed mesothelioma.”

Patients with mesothelioma who had received at least 1 prior line of therapy and had an ECOG performance status of 0 or 1 were eligible to enroll in the CONFIRM trial (NCT03063450). The target sample size was 336 patients; however, enrollment was halted at 332 patients because of the coronavirus disease 2019 pandemic. Fennell noted that sufficient event and follow-up was feasible with the recruited participants. Patients were randomized 2:1 to receive 240 mg in 30-minute intravenous infusions of either nivolumab or placebo on day 1 of a 14-day cycle. The secondary outcomes were RECIST-determined PFS, response rate, and safety.

Patients were heavily pretreated with 124 patients (56%) in the nivolumab arm and 66 patients (59%) in the placebo arm having received 2 prior lines of therapy.

Further primary end point data showed that the 12-month OS rates were 39.5% (95% CI, 32.5%-46.3%) with nivolumab versus 26.9% (95% CI, 18.2%-36.4%) with placebo. The 12-month PFS rates were 14.5% (95% CI, 10.2%-19.7%) and 4.9% (1.8%-10.6%), respectively. Fennel noted that the OS data were immature, with only 232 events having occurred by the analysis out of the target of 291 events. PFS data were mature with 310 events over the target 284.

“The large majority of immunotherapy studies in relapsed mesothelioma were small phase 1b and 2 studies and the only phase 3 study (PROMISE-meso; NCT02991482) in relapsed mesothelioma unfortunately showed no difference in PFS and OS when comparing pembrolizumab (Keytruda) with single-agent chemotherapy,” Rina Hui, MBBS, PhD, said in a discussion of the CONFIRM data.²

Patients were stratified by PD-L1 status; however, there was no statistically significant evidence to support the utility of PD-L1 tumor proportion score (TPS) as a predictive marker for patient selection. Fifty-six patients who received nivolumab and 24 who received placebo were classified as PD-L1 positive (TPS ≥1%), and 94 patients who received nivolumab were PD-L1 negative (TPS <1%) compared with 60 who received placebo.¹

The median OS for patients with PD-L1–positive disease was 8.0 months with nivolumab versus 8.7 months with placebo (HR, 0.95; 95% CI, 0.51-1.76; P = .864). For patients with PD-L1–negative disease, the median OS was 9.0 months versus 6.4 months, respectively (HR, 0.74; 95% CI, 0.51-1.08; P = .115).

In terms of safety, the outcomes were balanced between the 2 arms. Grade 3/4 adverse events (AEs) were reported in 45% of patients treated with nivolumab compared with 42% of patients who received placebo. Serious AEs were reported in 36% and 39%, respectively. Further, 5 (3.6%) deaths were reported in relation to a serious AE in the nivolumab arm versus 4 (5.3%) in the placebo arm.

Outcomes in CONFIRM Stratified by Histology

Participants in the CONFIRM trial were also stratified by epithelioid versus nonepithelioid histology.2 Eighty-eight percent of patients in each arm were identified as having epithelioid disease at baseline.

The median OS for epithelioid patients in the nivolumab arm (n = 195) was 9.4 months compared with 6.6 months for patients in the placebo arm (n = 98; HR, 0.71; 95% CI, 0.53-0.95; P = .021). The 12-month OS rates were 40.0% (95% CI, 32.6%-47.3%) and 26.7% (95% CI, 17.5%-36.8%), respectively.

For those with nonepithelioid disease, the median OS for patients in the nivolumab arm (n = 26) was 5.9 months compared with 6.7 months for patients in the placebo arm (n = 13; HR, 0.79; 95% CI, 0.35-1.79; P = .572). The 12-month OS rates were 34.6% (95% CI, 15.8%-54.3%) and 30.8% (95% CI, 9.5%-55.4%), respectively.¹

Hui noted that the sample size for those with nonepithelioid histology may be too small to draw a conclusion of benefit, however she added that she would consider nivolumab for these patients in the salvage setting.

“The authors concluded that significant clinical benefit was observed in the epithelioid subtype with a hazard ratio of 0.71 and a P value of .021,” Hui said.2 “We know that nonepithelioid [disease] is a more-aggressive, chemo-resistant subtype as indicated with a steep decline in the survival curve of the chemotherapy arm of the first-line study, CheckMate-743. Therefore a lot of patients would not have made it to a subsequent line clinical trial, explaining why only 12% [of patients had this subtype] in the CONFIRM study.”

Investigators of the CheckMate-743 trial (NCT02899299) evaluated the first-line combination of nivolumab plus ipilimumab (Yervoy) versus chemotherapy in patients with malignant pleural mesothelioma. The combination was approved by the FDA as first-line treatment for adult patients with unresectable malignant pleural mesothelioma in October 2020.³

Updated findings presented at the 2020 International Association for the Study of Lung Cancer showed an observed OS benefit with nivolumab plus ipilimumab over chemotherapy in those with epithelioid disease (n = 456), at 18.7 months (95% CI, 16.9-22.0) versus 16.5 months (95% CI, 14.9-20.5), respectively (HR, 0.86; 95% CI, 0.69-1.08). For those with nonepithelioid disease (n = 149) the median OS was 18.1 months (95% CI, 12.2-22.8) versus 8.8 months (95% CI, 7.4-10.2), respectively (HR, 0.46; 95% CI, 0.31-0.68).⁴

The combination was approved by the FDA as first-line treatment for adult patients with unresectable malignant pleural mesothelioma in October 2020.

Hui concluded that there is still much to be learned about sequencing of nivolumab in the second-line setting and beyond based on results of ongoing first-line immunotherapy combination studies. “For patients who had received platinum-pemetrexed chemotherapy as first-line treatment, monotherapy nivolumab now can be considered as a treatment option in the second-line setting or third-line setting after second-line chemotherapy,” Hui said.

“As [CONFIRM] was placebo-controlled, the question is whether nivolumab provides better outcomes than second line single-agent chemotherapy or second-line gemcitabine with the VEGFR inhibitor ramucirumab [Cyramza]….What could be considered as salvage treatment if nivolumab and ipilimumab has been used in the first line setting?”

In addition to these questions, Hui stressed the importance of identifying predictive biomarkers to determine and develop other salvage treatments.

_References

1. _{Fennel D, Ottensmeier, Califano R, et al. Nivolumab versus placebo in relapsed malignant mesothelioma: preliminary results from the CONFIRM phase 3 trial. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract PS01.11.}
2. _{Hui R. Immune checkpoint inhibition for relapsed mesothelioma: a long time coming. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual.}
3. _{FDA approves nivolumab and ipilimumab for unresectable malignant pleural mesothelioma. FDA. October 2, 2020. Accessed January 30, 2021. https://bit.ly/3rckLcZ.}
4. _{Baas P, Scherpereel A, Nowak A, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: International Association for the Study of Lung Cancer 2020 Presidential Symposium; August 8, 2020; Virtual. Abstract 3.}