Keytruda for Mesothelioma Flops in Phase III Clinical Trial

Results from a phase III clinical trial comparing Keytruda (pembrolizumab) to standard chemotherapy shows the immunotherapy drug still has a long way to go as a viable treatment option for malignant pleural mesothelioma.

Keytruda did not improve progression-free survival for mesothelioma patients who progressed after first-line chemotherapy.

The disappointing results from the PROMISE-meso study were presented at the European Society of Medical Oncology (ESMO) annual meeting last week.

It was the first randomized trial comparing progression-free survival between immunotherapy and first-line chemotherapy for mesothelioma patients.

Nearly four times more patients responded to the Keytruda over chemotherapy. However, these responses did not delay tumor progression or improve survival.

“Despite correcting for crossover, an overall survival benefit was not observed,” Dr. Sanjay Popat of Royal Marsden Hospital in London said at ESMO. “The pembrolizumab safety profile was consistent with that previously observed. Further exploratory translational work is ongoing to identify subgroups that could benefit from pembrolizumab.”

Chemotherapy Showed Longer Progression-Free Survival

The progression-free survival for patients treated with Keytruda was just 2.5 months, compared to 3.4 months with standard chemotherapy regimens.

Median overall survival did not change significantly between the two groups.

A combination of Alimta (pemetrexed) and platinum-based chemotherapy (cisplatin or carboplatin) has been the standard-of-care mesothelioma treatment since 2004. Researchers have since worked to find more effective and longer-lasting therapies.

Keytruda is FDA approved to treat advanced non-small cell lung cancer and several other cancers, but not mesothelioma.

Some mesothelioma patients have found success with Keytruda and other checkpoint inhibitors through clinical trials and compassionate use programs. However, these results are often short-lived, if the patient is eligible for the drug at all.

“It is important to remember that checkpoint inhibitors used to treat mesothelioma, like in the treatment of other tumors, can improve benefit in some people, but not all who take the drugs,” Alyson Haslam, Ph.D., told The Mesothelioma Center at Asbestos.com in June. “Tumor response seems to vary, depending on certain tumor molecular features.”

Haslam works at the Knight Cancer Institute at Oregon Health & Science University in Portland. He was the co-author of research that found less than 13% of cancer patients who receive Keytruda and other checkpoint inhibitors actually benefit from the treatment.

Keytruda works by blocking the PD-1 and PD-L1 pathway, allowing a patient’s immune system to better recognize and attack cancer cells. Malignant mesothelioma tumors often express high levels of PD-L1, which is typically a requirement for Keytruda eligibility.

Interestingly, Keytruda performed better in mesothelioma patients with a low total proportional score for PD-L1 expression in the PROMISE-meso trial, although the numbers were small.

Clinical Trial Still Brings Some Positives

While Keytruda did not prove better than chemotherapy, Popat and other researchers are encouraged that it could be an alternative for patients who don’t want to undergo platinum-based treatments.

“These findings are disappointing but, as in previous studies, some patients benefited from immunotherapy for long periods,” Popat said. “If we can find out how this happens, we will have a better idea of which patients should preferentially receive this treatment over chemotherapy.”

Emily Ward, a seven-year pleural mesothelioma survivor, began Keytruda in April after her second mesothelioma recurrence and a bad experience with her third round of chemotherapy. So far, her disease has remained stable.

“I made the decision to begin Keytruda because the chemotherapy was taking too much of a toll on my body,” Ward said. “I was bedridden for nearly a week after my last round of chemo. Scans showed the Alimta was preventing cancer growth, but the decrease in quality of life wasn’t worth it for me.”

There also may be hope in combining chemotherapy and immunotherapy as a first-line treatment for mesothelioma.

“In studies of lung cancer, we have already learned that we can improve results with immunotherapy by combining it with chemotherapy and the same may be true with mesothelioma,” Popat said. “I would advise clinicians to enroll their patients into one of the large ongoing trials of first-line combination treatment so we can get answers as soon as possible about how to improve mesothelioma treatment.”