Nick Mulcahy

April 24, 2015

PHILADELPHIA — Mesothelioma can be added to the list of cancers that respond to immunotherapy with programmed-death (PD) inhibitors, said one researcher in response to early results showing good disease control with pembrolizumab (Keytruda, Merck).

In fact, in the phase 1B clinical trial known as KEYNOTE-028, the rate of disease control in 25 participants with previously treated advanced pleural mesothelioma was 76%.

This rare form of lung cancer is largely related to asbestos exposure, and there are no treatments approved by the US Food and Drug Administration for second-line therapy.

The rate of disease control — which was comprised of partial responses in seven patients (28%) and stable disease in 48% 12 patients — is "unprecedented," said Evan Alley, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

Among the 10 patients who remained on treatment at data cutoff were all the partial responders, he told an audience here at the American Association for Cancer Research 2015 Annual Meeting.

Some of the treatment responses were for more than 24 weeks. The results need to be viewed in the context of mesothelioma, where median survival is only about 1 year, said Dr Alley.

"It's very exciting to see durable responses, including some over 24 weeks, because mesothelioma patients tend not to respond to second-line treatment," said Julie Brahmer, MD, from the Sidney Kimmel Comprehensive Cancer Center in Baltimore, who was not involved in the study.

With second-line chemotherapy, the response rate is less than 10%, Dr Alley reported.

The durable responses are "significant" and "give mesothelioma patients hope that immunotherapy will become a treatment reality in the near future," Dr Brahmer told Medscape Medical News. However, she cautioned, the population of mesothelioma patients in this study was small, and "a lot is left to be seen."

Another expert was a bit less cautious.

"Mesothelioma can now be added to the list of PD-1-sensitive diseases," said Ross Camidge, MD, PhD, from University of Colorado Cancer Center in Boulder, who acted as discussant at the oral presentation.

"The PD-1 pathway is implicated in evasion of the antitumor immune response," the investigators explain in their abstract. Pembrolizumab is designed to block interaction with PD-1 ligand 1 (PD-L1) and PD-L2, "thus removing inhibition of T-cell activation against cancer," they write.

PD-L1 is overexpressed in mesothelioma and associated with poor prognosis, said Dr Alley. In fact, only patients who had tumors that were positive for PD-L1 were eligible for enrollment in the trial.

The mesothelioma data are the first results to be presented from KEYNOTE-028, a "basket" trial designed to evaluate the efficacy and safety of pembrolizumab in 320 patients with 20 difficult-to-treat solid tumors with limited or no treatment options.

Dr Alley reported that the mesothelioma data are promising enough that a phase 2 trial evaluating pembrolizumab as a second-line therapy for advanced disease is underway.

In the phase 1B study, pembrolizumab was safe and tolerable. "None of our patients experienced any unexpected side effects and all adverse events could be managed without discontinuing treatment," Dr Alley said in a press statement.

Most of the mesothelioma patients in the trial were men (68%), and the average age was 65 years. Most participants (64%) had a performance status of 1, and many (88%) had received previous treatment (mainly pemetrexed and platinum-based chemotherapy).

The investigators used RECIST to assess response every 8 weeks for the first 6 months, and every 12 weeks thereafter.

Some of the treatment responses were seen as early as the first imaging session (at 8 weeks), Dr Alley highlighted during his presentation.

The study was funded by Merck. Dr Alley has disclosed no relevant financial relationships. Dr Brahmer reports ties to Merck and other pharmaceutical companies. Dr Camidge reports financial ties to Eli Lily and Pfizer.

American Association for Cancer Research (AACR) 2015 Annual Meeting: Abstract 8985. Presented April 20, 2015.


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