Pembrolizumab/Chemo Earns Positive EU CHMP Opinion in Mesothelioma

In September 2024, the FDA approved first-line pembrolizumab/chemotherapy for patients with unresectable MPM based on findings from the KEYNOTE-483 trial.

The European Medicine Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion in support of approving frontline pembrolizumab (Keytruda) plus pemetrexed and platinum-based chemotherapy for patients in the European Union with unresectable non-epithelioid malignant pleural mesothelioma (MPM), according to a press release from the developer, Merck.¹

The European Commission will now review the CHMP’s recommendation for granting marketing authorization to the pembrolizumab combination for this patient population in the European Union. The organization is expected to issue a final decision on approving the regimen in the fourth quarter of 2024.

“The CHMP’s positive opinion marks an important milestone for patients in Europe with non-epithelioid mesothelioma, who experience worse survival outcomes than patients with epithelioid mesothelioma,” Gregory Lubiniecki, MD, vice president of Oncology Clinical Research at Merck Research Laboratories, stated in the press release.¹ “The positive CHMP opinion moves us closer to offering a new first-line treatment option with a proven overall survival [OS] benefit for certain patients in the European Union with this difficult-to-treat cancer.”

Supporting data for the CHMP’s recommendation came from the phase 2/3 IND.227/KEYNOTE-483 trial (NCT02784171). In September 2024, the FDA approved first-line pembrolizumab/chemotherapy for patients with unresectable MPM based on findings from the KEYNOTE-483 trial.²

Data showed a median OS of 17.3 months (95% CI, 14.4-21.3) with pembrolizumab/chemotherapy vs 16.1 months (95% CI, 13.1-18.2) with chemotherapy alone (HR, 0.79; 95% CI, 0.64-0.98; P = .0162). Additionally, the median progression-free survival (PFS) was 7.1 months (95% CI, 6.9-8.1) and 7.1 months (95% CI, 6.8-7.7) in each respective treatment arm (HR, 0.80; 95% CI, 0.65-0.99; P = .0194).

Pembrolizumab plus chemotherapy produced an objective response rate (ORR) of 52% (95% CI, 45.5%-59.0%) compared with 29% (95% CI, 23.0%-35.4%) among patients who received chemotherapy alone (P <.00001).

Safety data highlighted that toxicity occurring among those with MPM wereas comparable with prior reports of pembrolizumab/chemotherapy in other patients.

“We’re pleased to offer a new first-line treatment option for adult patients with unresectable advanced or metastatic [MPM], a disease where prognoses are generally poor. This milestone underscores our commitment to advancing research for patients with difficult-to-treat tumors,” Lubiniecki stated in a press release at the time of the FDA approval.²

In the phase 3 component of the open-label, multi-center KEYNOTE-483 trial, 440 patients with previously untreated unresectable advanced or metastatic MPM of any PD-L1 status were randomly assigned 1:1 to receive pembrolizumab or matched placebo in combination with chemotherapy. Specifically, study treatment included pembrolizumab at 200 mg or placebo plus pemetrexed at 500 mg/m² and cisplatin at 75 mg/m² or carboplatin area under the curve 5 or 6 on day 1 of each 21-day cycle for a maximum of 6 cycles.

Study treatment continued until progressive disease per investigator assessment using modified RECIST v1.1 criteria, unacceptable toxicity, or a maximum of 24 months.

The trial’s primary efficacy end point was OS. Secondary end points included PFS, ORR, and duration of response.

Patients 18 years and older with histologically confirmed MPM, no contraindications to standard chemotherapy, unresectable advanced and/or metastatic disease, and the presence of radiologically documented disease were eligible for enrollment on the trial.³ Other requirements for study entry included having the availability of a cellular tumor block from the primary or metastatic tumor and an ECOG performance status of 0 or 1.

Those with autoimmune disease who required systemic therapy within 3 years of treatment or a medical condition requiring immunosuppression were ineligible for enrollment on the trial.

References

1. Merck receives positive EU CHMP opinion for KEYTRUDA® (pembrolizumab) plus chemotherapy as first-line treatment for adult patients with unresectable non-epithelioid malignant pleural mesothelioma (MPM). News release. Merck. November 15, 2024. Accessed November 15, 2024. https://tinyurl.com/5dutvfbx
2. FDA approves Merck’s KEYTRUDA® (pembrolizumab) plus pemetrexed and platinum chemotherapy as first-line treatment for adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). News release. Merck. September 18, 2024. Accessed November 15, 2024. https://tinyurl.com/bp7sb9xt
3. Pembrolizumab in patients with advanced malignant pleural mesothelioma. ClinicalTrials.gov. Updated January 16, 2024. Accessed November 15, 2024. https://tinyurl.com/yknw223r