Immunotherapy-chemotherapy treatment coupled with in-depth genomic analyses leads to improved survival for patients with mesothelioma

In the multicenter study PrE0505 (NCT02899195), 55 patients with mesothelioma received a fixed dose of durvalumab intravenously once every three weeks, in combination with pemetrexed and cisplatin or carboplatin for up to six cycles. The median overall survival for all patients was 20.4 months -- significantly longer than the 12 months seen historically for similar patients. For patients with epithelioid tumors, the most common subtype of mesothelioma, survival was 24.3 months. The addition of durvalumab to chemotherapy did not lead to any unexpected toxicities.

These results were published in the Nov. 8 issue of Nature Medicine.

Investigators also explored the genomic and immunologic features of responding mesothelioma tumors. They found that patients whose cancers harbored a higher number of immunogenic mutations (changes in the genetic material of cancer cells that may provoke an immune response against the tumor), and a more diverse repertoire of T-cells that recognize and destroy abnormal cells, were more likely to have a favorable clinical outcome. Genome-wide analyses demonstrated a higher degree of genomic instability among epithelioid tumors that responded. Additionally, patients with alterations in genes that predispose people to cancer especially those involved in DNA damage repair -- were more likely to have long-term survival.

"Mesothelioma is a rare and fatal cancer with limited therapeutic options," says study lead author Patrick Forde, M.B.B.Ch., director of the thoracic cancer clinical research program at the Johns Hopkins Kimmel Cancer Center and an associate professor of oncology at the Johns Hopkins University School of Medicine. "The PrE0505 study indicates that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma [MPM]," says Forde. "The survival for patients with epithelioid MPM exceeded two years, and some patients with epithelioid MPM who enrolled in the clinical trial continue to be free from tumor progression today."

MPM affects more than 30,000 people each year and is nearly always fatal. The majority of mesotheliomas are caused by exposure to asbestos and consequent chronic inflammation in the pleural cavity -- the space between the lining of the lungs. More than half of MPMs carry mutations in the genes involved in DNA damage repair, and the inactivation of tumor suppressor genes such as BAP1, NF2, CDKN2A, TP53 and SETD2 is thought to play a role in the development of MPM. Mesotheliomas have a relatively low number of mutations and thus historically have been considered a tumor type with low mutation-driven immunogenicity.

"Our findings not only point toward a potential new effective therapy for patients with mesothelioma but also explain at a molecular level why patients respond," says study co-lead author Valsamo Anagnostou, M.D., Ph.D., director of the thoracic oncology biorepository at the Johns Hopkins Kimmel Cancer Center and an associate professor of oncology at the Johns Hopkins University School of Medicine. "We discovered some very unique features related to the genomic footprints of both the patient and the tumor that seem to determine clinical responses. These have to do with genomic scarring signatures and a higher degree of genome-wide copy number changes in mesothelioma tumors that respond to chemo-immunotherapy. Additionally, patients with germline mutations in genes that predispose people to cancer are the ones who do well on chemo-immunotherapy. All of these findings have the potential to be translated into new strategies to treat patients with mesothelioma."

The median follow-up for the study was 24.2 months, and the estimated percentages of patients alive were 87% at six months, 70% at 12 months and 44% at 24 months. The objective response rate (ORR) -- the percentage of patients for whom a therapy causes significant tumor shrinkage -- was 56.4%.

The most commonly reported adverse events were predeominantly low grade, and included fatigue, nausea and anemia. All patients who enrolled in the study received at least one cycle of durvalumab with chemotherapy; 48 patients (87%) completed six cycles.

Investigators found a significant difference in overall and progression-free survival (time to cancer progression or death) and ORR looking at the histological type of the mesothelioma tumors. Patients with tumors of the epithelioid subtype had a higher ORR (66%) than those with nonepithelioid tumors (29%). Similarly, patients with epithelioid MPM had significantly longer overall survival than those with non-epithelioid MPM (24.3 months versus 9.2 months), as well as significantly longer progression-free survival (8.2 months versus 4.9 months).

Mesothelioma tumors with a high immunogenic mutation load responded favorably to chemo-immunotherapy, especially in the epithelioid group. In addition to changes in the sequence of the genetic material of cancer cells, genome-wide structural changes and a signature of homologous recombination deficiency (indicating defects in repair mechanisms of damaged DNA in cancer cells) were more pronounced in responding tumors. Patients with deleterious germline mutations in cancer predisposing genes, including but not limited to genes involved in DNA damage repair, had significantly longer progression-free and overall survival with chemo-immunotherapy. In looking at the tumor microenvironment (which comprises of normal cells and blood vessels that surround the tumor, contains immune cells and can affect how cancer cells grow and spread), the investigators found that tumors that responded to therapy were surrounded by a greater variety of a specific population of immune cells, called T cells.

The combination of durvalumab with chemotherapy, versus chemotherapy alone, in conjunction with in-depth genomic characterization of biospecimens from patients with mesothelioma, is being further investigated in the international phase III PrE0506/DREAM3R study (NCT04334759). This clinical trial is sponsored by PrECOG in the United States, with Forde and Anna Nowak, Ph.D., M.B.B.S. from the University of Western Australia as study chairs and Anagnostou as translational research lead.

Study coauthors were Noushin Niknafs, Mara Lanis, Zineb Belcaid, Kellie Smith, Archana Balan, James White, Christopher Cherry, I.K. Ashok Sivakumar, Xiaoshan Shao, Hok Yee Chan, Dipika Singh, Sampriti Thapa, Peter Illei, Drew Pardoll, Victor Velculescu, Rachel Karchin and Julie Brahmer of Johns Hopkins. Other investigators contributing to the study were from the ECOG-ACRIN Cancer Research Group's Biostatistics Center in Boston; the Frontier Science Foundation in Boston; Boston Children's Hospital; University of Chicago Medicine; the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center in Seattle; the Metro-Minnesota Community Oncology Research Consortium in St. Louis Park; the Fox Chase Cancer Center in Philadelphia and the Winship Cancer Institute of Emory University in Atlanta.

This research was conducted with support from AstraZeneca Pharmaceuticals LP. The PrE0505 clinical trial was sponsored by PrECOG, LLC. PrECOG is a not-for-profit limited liability company whose central focus is to support the scientific mission of the ECOG-ACRIN Cancer Research Group. This work was supported in part by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins support grant NCI CCSG P30 CA006973, the Department of Defense Congressionally Directed Medical Research Programs grant CA190755, National Institutes of Health grants CA121113, CA006973 and R37CA251447, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant UG1CA233259, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, the V Foundation, the International Association for the Study of Lung Cancer's International Lung Cancer Foundation, the Lung Cancer Foundation of America, Swim Across America, the Florence Lomax Eley Fund and the LUNGevity Foundation.

Anagnostou receives research funding from Bristol Myers Squibb and AstraZeneca. Forde has received research funding from AstraZeneca, Bristol Myers Squibb, Novartis, Corvus Pharmaceuticals and Kyowa. He also has served as a consultant for Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, iTeos Therapeutics, Janssen, Mirati, and Novartis and as a DSMB member for Polaris and Flame Therapeutics. The terms of these arrangements are managed by The Johns Hopkins University in accordance with its conflict of interest policies.