For the vast majority of mesothelioma patients — the 85 to 90 percent ineligible for potentially curative surgery at diagnosis — chemotherapy is the best option for improving survival and quality of life.
Most doctors recommend chemotherapy with cisplatin and pemetrexed as the standard first line regimen for most of those patients. No single drug or drug combination has surpassed them in terms of response rates or survival.
Still, many experts are convinced there’s a better way.
Dr. Jordi Remón, an oncologist at Mataró Hospital in Barcelona and lead author of a 2014 study, Malignant Pleural Mesothelioma: New Hope in the Horizon with Novel Therapeutic Strategies, explains that target therapies, such as NGR-hTNF, Ganetespib and fresolimumab, will lead to more effective, personalized treatments and better tools for early diagnosis.
“Probably cytotoxic therapies have reached a plateau,” oncologist Dr. Jordi Remón said. “New approaches based on deregulated pathways and targeted therapies are necessary to improve survival.”
According to Remón, targeted cancer therapies can help doctors avoid some major drawbacks of chemotherapy that hinder progress toward improved survival.
These novel treatments are designed to interfere with specific molecular pathways, or targets, that drive cancer growth. Instead of killing cancer cells with toxic drugs, like traditional chemotherapy, targeted therapies manage cancer by blocking its ability to grow and spread throughout the body.
A major benefit of this approach is that it prevents chemoresistance, a common problem where cancer develops immunity to chemotherapy drugs. In many cases, it is chemoresistance that causes treatments to fail.
If the survival benefit of traditional chemotherapy for mesothelioma has in fact plateaued, focused research on targeted therapy and other novel treatments could bring hope for improved survival rates and more effective approaches to therapy.
Anti-tumor Drug NGR-hTNF
Researchers are now testing a targeted therapy called NGR-hTNF in clinical trials. The treatment works by preventing the growth of new blood vessels, starving tumors of fresh oxygen and vital nutrients. Without these resources, tumors stop growing or begin to shrink.
In a phase II clinical trial involving 57 pleural mesothelioma patients previously treated with chemotherapy, NGR-hTNF showed promising early results. Researchers reported a median overall survival of 12.1 months, with 46 percent of patients experiencing a decrease in tumor size or stable disease.
This prompted researchers to launch a larger phase III trial, which has already enrolled 390 pleural mesothelioma patients who previously completed therapy with pemetrexed.
Remón says this trial is powered to detect a survival benefit of NGR-hTNF over placebo. It will test the effectiveness of the treatment on its own and in combination with chemotherapy.
Protein Inhibitor Ganetespib
Another hopeful targeted therapy called ganetespib works by blocking HSP90, a protein that plays an important role in the growth and survival of mesothelioma and other tumors.
By stopping HSP90 signals that tell cancer cells to multiply and spread, researchers believe ganetespib can slow down or halt the growth of cancer.
Ganetespib has already demonstrated success as a second line treatment for non-small cell lung cancer when combined with the chemotherapy drug docetaxel.
In a phase I and II trial now recruiting patients in the U.K., researchers will determine the effectiveness of ganetespib as a maintenance therapy for pleural mesothelioma. The trial will explore the ability of ganetespib to prevent relapse after initial treatment with a combination of cisplatin, pemetrexed and ganetespib.
Long-term disease control and improved survival may also come from treatments that modify the patient’s immune system. This approach, known as immunotherapy, empowers the immune system to destroy cancer cells, or prevents the cancer from evading anti-cancer immune cells.
The way cancer interacts with a patient’s immune system is highly complex, but researchers are making great strides to understand this relationship and develop immune-based treatments that can help improve outcomes.
Human Antibody Tremelimumab
Studies have shown an experimental therapy called tremelimumab can trigger a response from the immune system, improving the body’s ability to hunt down cancer cells and prevent the formation of tumors. It works by blocking CTLA4, a protein receptor that acts as an off switch for anti-cancer immune cells.
In 2008, a phase II clinical trial evaluated the treatment’s effectiveness on 29 patients with advanced mesothelioma who had become resistant to chemotherapy. Although only two patients experienced a decrease in tumor size, nine patients showed no sign of cancer progression.
“These preliminary results suggested that anti-CTLA4 immunotherapy, although generally not effective at reducing [the size of mesothelioma tumors], could have an encouraging long-lasting clinical activity and a good safety profile in pre-treated [pleural mesothelioma] patients, possibly resulting in extended survival,” Remón said.
A follow-up study involving 564 patients, now underway, will give researchers a clearer idea of how tremelimumab benefits overall survival for pleural or peritoneal mesothelioma patients who do not qualify for surgery.
In a 2013 study involving 13 previously treated mesothelioma patients, fresolimumab helped 23 percent of patients achieve stable disease, with an overall median survival of 12 months.
This immunotherapy works by neutralizing TGF-?, a protein that normally keeps tumor growth in check. However, advanced tumors often grow immune to this effect and produce large amounts of the protein. As a result, TGF-? limits the immune system’s ability to fight the cancer and encourages the growth and spread of tumors.
The Future for Novel Therapies
While the incidence of mesothelioma continues to increase worldwide, standard chemotherapy is failing to make noteworthy improvements to survival.
As researchers unlock more information about the biology of mesothelioma, this knowledge will pave the way for better treatment options.
Early results from clinical trials hint that several targeted therapies and immunotherapies show great promise, but much work lies ahead.