Researchers at the forefront of cancer immunotherapy have unveiled a groundbreaking treatment avenue for patients battling inoperable pleural mesothelioma, a lethal lung cancer. A phase II clinical trial, spearheaded by experts from the Johns Hopkins Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy, showcased remarkable outcomes by combining the immunotherapy agent durvalumab with chemotherapy drugs pemetrexed and cisplatin or carboplatin.
The study, dubbed PrE0505 (NCT02899195), enrolled 55 mesothelioma patients who underwent a fixed dose of durvalumab intravenously every three weeks alongside chemotherapy, administered for up to six cycles.
Astonishingly, the median overall survival soared to 20.4 months, a stark improvement over the historical 12-month benchmark. For patients with epithelioid tumors, survival extended to a remarkable 24.3 months. Crucially, the addition of durvalumab to chemotherapy proved safe, and devoid of unexpected toxicities.
Published in the prestigious journal Nature Medicine, the study delved into the genomic and immunologic intricacies of responding mesothelioma tumors. Patients boasting a higher count of immunogenic mutations, coupled with a diverse T-cell repertoire, exhibited more favorable clinical outcomes.
Notably, genomic analyses unveiled heightened genomic instability among epithelioid tumors that responded to treatment. Moreover, alterations in cancer-predisposing genes, particularly those involved in DNA damage repair, correlated with prolonged survival.
Lead author Patrick Forde, M.B.B.Ch., emphasized the significance of the findings, hailing the concurrent durvalumab with platinum-based chemotherapy as a beacon of hope for mesothelioma patients. The PrE0505 study indicates promising clinical activity, propelled by the complex genomic landscape of malignant pleural mesothelioma,” remarked Forde. Notably, patients with epithelioid mesothelioma surpassed a two-year survival milestone, with some still free from tumor progression.
Mesothelioma, afflicting over 30,000 annually, is notorious for its grim prognosis. Predominantly triggered by asbestos exposure, this cancer presents a challenge due to its low mutation-driven immunogenicity. Yet, the study’s co-lead author Valsamo Anagnostou, M.D., Ph.D., expressed optimism, citing the unique genomic signatures that underpin treatment responses. “Our findings pave the way for personalized therapeutic strategies, unlocking new avenues for mesothelioma management,” Anagnostou noted.
With a median follow-up of 24.2 months, the study showcased encouraging survival rates, with 87% of patients alive at six months and 44% at 24 months. The objective response rate stood at a commendable 56.4%, indicating significant tumor shrinkage. Adverse events, predominantly low-grade, included fatigue, nausea, and anemia, with the majority of patients completing six treatment cycles.
Furthermore, the study underscored significant disparities in overall and progression-free survival based on histological tumor types. Patients with epithelioid mesothelioma exhibited superior outcomes compared to their non-epithelioid counterparts. Notably, tumors with a high immunogenic mutation load and distinct genomic alterations responded favorably to chemo-immunotherapy.
The findings have propelled the launch of the international phase III PrE0506/DREAM3R trial (NCT04334759), investigating the durvalumab-chemotherapy combination’s efficacy. With renowned experts at the helm, including study chairs Anna Nowak, Ph.D., M.B.B.S., and translational research lead Valsamo Anagnostou, M.D., Ph.D., this trial heralds a new era in mesothelioma treatment.
The study, supported by AstraZeneca Pharmaceuticals LP and other organizations, offers a ray of hope for mesothelioma patients worldwide. Conflict of interest disclosures were diligently addressed, ensuring transparency and integrity in research endeavors.
- Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial. Nature Medicine, 2021; DOI: 10.1038/s41591-021-01541-0
- https://www.hopkinsmedicine.org/profiles/details/patrick-forde
