One phase 3 trial to watch is IND277, which is comparing pembrolizumab plus cisplatin/pemetrexed chemotherapy to cisplatin/pemetrexed alone; that trial has enrolled 520 participants and has an estimated primary completion date in July 2022, according to the ClinicalTrials.gov website. Another is BEAT-Meso, a comparison of atezolizumab plus bevacizumab and chemotherapy against bevacizumab and chemotherapy, which has an estimated enrollment of 400 participants and primary completion date of January 2024. A third trial of interest is DREAM3R, which compares durvalumab plus chemotherapy followed by durvalumab maintenance to standard chemotherapy followed by observation. That study should enroll 480 participants and has an estimated primary completion date of April 2025.
CAR T-cell therapy, while best known for its emerging role in the treatment of hematologic malignancies, may also have a place in mesothelioma therapy one day. In a recently published report, investigators described a first-in-human phase I study of a mesothelin-targeted CAR T-cell therapy given in combination with pembrolizumab. Among 18 MPM patients who received pembrolizumab safely, median OS from time of CAR T-cell infusion was 23.9 months and 1-year OS was 83%, according to investigators.6An OS of nearly 24 months is “very encouraging” and compares favorably with historical results with systemic therapy in this difficult-to-treat disease, said Jacques P. Fontaine, MD, a thoracic surgeon and section head of mesothelioma research and treatment center at Moffitt Cancer Center in Tampa, Fla.
“It’s huge, but you have to take into account that this [OS] is still less than 2 years,” Dr. Fontaine said in an interview. “There’s still a lot of work to be done.”
Radiotherapy making an IMPRINT
Meanwhile, new developments in the multimodality treatment of resectable MPM are progressing and have the potential to extend survival among patients who undergo lung-sparing surgery.
Less aggressive intervention is increasingly the preferred approach to surgery in this patient population. That shift is supported by studies showing that lung-sparing pleurectomy-decortication (P/D) resulted in less morbidity and potentially better survival outcomes than extrapleural pneumonectomy (EPP), according to Andreas Rimner, MD, associate attending physician and director of thoracic radiation oncology research at Memorial Sloan Kettering Cancer Center in New York.
However, it is more challenging to deliver radiotherapy safely in patients who have undergone P/D as compared with patients who have undergone EPP, according to Dr. Rimner.
“When there’s no lung in place [as in EPP], it’s pretty simple – you just treat the entire empty chest to kill any microscopic cells that may still be left behind,” he said in an interview. “But now we have a situation where both lungs are still in place, and they are very radiation sensitive, so that’s not an easy feat.”
Driven by the limitations of conventional radiation, Dr. Rimner and colleagues developed a novel technique known as hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) that allows more precise application of radiotherapy.
In a phase 2 study published in 2016, IMPRINT was found to be safe, with an acceptable rate of radiation pneumonitis (30% grade 2 or 3), according to investigators.7
Subsequent studies have demonstrated encouraging clinical outcomes, including a 20.2-month median OS for IMPRINT versus 12.3 months for conventional adjuvant radiotherapy in a retrospective study of 209 patients who underwent P/D between 1975 and 2015.8 Those findings led to the development of a phase 3 trial known as NRG-LU006 that is evaluating P/D plus chemotherapy with or without adjuvant IMPRINT in an estimated 150 patients. The study has a primary endpoint of OS, and an estimated primary completion date in July 2025, according to ClinicalTrials.gov.
Dr. Rimner said he’s optimistic about the prospects of this study, particularly with recently published results of a phase 3 study in which Italian investigators demonstrated an OS benefit of IMPRINT over palliative radiation in patients with nonmetastatic MPM.9
“That’s more data and rationale that shows there is good reason to believe that we are adding something here with this radiation technique,” said Dr. Rimner.
Dr. Fontaine, the thoracic surgeon and mesothelioma research head at Moffitt Cancer Center, said he’s hoping to see a substantial impact of IMPRINT on disease-free survival (DFS) once results of NRG-LU006 are available.
“I think DFS plays a role that we’ve underestimated over the last few years for sure,” he said.
For a patient with MPM, a short DFS can be anxiety provoking and may have negative impacts on quality of life, even despite a long OS, he explained.
“In terms of your outlook on life, how many times you have to go see a doctor, and how you enjoy life, there’s a big difference between the two,” he said.
Dr. Tsao provided disclosures related to Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, Epizyme, Genentech, Huron, Merck, Millennium, Novartis, Polaris, Roche, Seattle Genetics, SELLAS Life Sciences Group, and Takeda. Dr. Fontaine reported no relevant disclosures. Dr. Rimner reported disclosures related to Bristol-Myers Squibb, GE Healthcare, Varian Medical Systems, and Boehringer Ingelheim.