Phase 2 CHIMERA Trial Tests Neoadjuvant Pembrolizumab in Mesothelioma

A new phase 2 trial is testing whether adding an immune checkpoint inhibitor to standard chemotherapy before and after surgery can improve outcomes in resectable pleural mesothelioma, a rare cancer for which pathological complete response to induction chemotherapy alone has remained near 5% for more than a decade.

The trial, CHIMERA (NCT06155279), enrolls treatment-naive adults with stage I to IIIa epithelioid or biphasic pleural mesothelioma who are considered surgical candidates.^1,2 Patients receive 3 cycles of neoadjuvant pembrolizumab (Keytruda) 200 mg combined with cisplatin or carboplatin and pemetrexed every 3 weeks, followed by pleurectomy/decortication or extended pleurectomy/decortication at 1 of 2 high-volume Italian surgical centers, then 14 cycles of adjuvant pembrolizumab.¹ The open-label, multicenter study is sponsored by the Veneto Institute of Oncology IRCCS with support from an investigator-initiated grant. Enrollment began in November 2024, with completion of accrual of approximately 40 patients.

The primary end point is pathological complete response, defined as no residual viable tumor in the resected primary tumor or sampled lymph nodes. Investigators designed the study to detect an increase in that rate from a historical baseline of about 5% with platinum-pemetrexed chemotherapy alone to 18%, a threshold informed by pathological response data from earlier-phase immunotherapy trials in mesothelioma and from neoadjuvant chemo-immunotherapy trials in resectable non–small cell lung cancer. Secondary end points include major pathological response, objective response rate, event-free survival, overall survival, and treatment feasibility; the study also incorporates serial blood and tissue sampling to explore predictive biomarkers and radiomic features on imaging.

Study Rationale

Pleural mesothelioma remains uncommon but consequential. Italian registry data cited by the investigators put 2024 incidence at 3.78 per 100,000 men and 1.15 per 100,000 women, with epithelioid histology accounting for nearly 70% of cases. Outcomes vary widely by histologic subtype and by eligibility for multimodality treatment, which remains available to only a highly selected subset of patients.

The rationale for adding immunotherapy builds on recent shifts in first-line treatment of unresectable disease. In the phase 3 CheckMate 743 trial (NCT02899299), nivolumab (Opdivo) plus ipilimumab (Yervoy) improved overall survival compared with chemotherapy alone, with the largest benefit in nonepithelioid tumors.³ Separately, the phase 3 IND227/KEYNOTE-483 trial (NCT02784171) found that adding pembrolizumab to platinum-pemetrexed chemotherapy extended median overall survival to 17.3 months vs 16.1 months with chemotherapy alone and nearly doubled response rates; that combination is now approved by the European Medicines Agency for unresectable, non-epithelioid disease.⁴

Whether that benefit extends to the perioperative setting is unresolved. Several early-phase studies have tested checkpoint inhibitors before or after surgery, but most were designed to establish feasibility and safety rather than pathological efficacy, and few have reported pathological complete response rates.¹

The role of surgery itself is also under scrutiny. The phase 3 MARS 2 trial (NCT02040272) found no survival advantage when extended pleurectomy/decortication was added to chemotherapy and reported more perioperative complications in the surgery group, a result that has fueled debate over patient selection and surgical standardization even as guidelines from the American Society of Clinical Oncology and the European Society for Medical Oncology continue to favor multimodality treatment in carefully chosen candidates.⁵

REFERENCES

1. Passello Gi, Scattolin D, Faccioli E, et al. CHIMERA: A Phase II Study of Neoadjuvant Pembrolizumab in Combination With Cisplatin or Carboplatin and Pemetrexed Followed by Surgery and Adjuvant Pembrolizumab in Resectable Pleural Mesothelioma. Clin Lung Canc. 2026; 27, 31-35. doi: 10.1016/j.cllc.2026.05.004

2. Induction Chemo+Immunotherapy in Resectable Epithelioid and Biphasic Pleural Mesothelioma (CHIMERA Study) (CHIMERA). ClinicalTrials.gov. Updated January 13, 2026. Accessed July 27 2026. https://clinicaltrials.gov/study/NCT06155279

3. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397(10272):375-386. doi:10.1016/S0140-6736(20)32714-8

4. Chu Q, Perrone F, Greillier L, et al. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10419):2295-2306. doi:10.1016/S0140-6736(23)01613-6

5. Lim E, Waller D, Lau K, et al. Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial. Lancet Respir Med. 2024;12(6):457-466. doi:10.1016/S2213-2600(24)00119-X