Novel Targeted Agents for Lung Cancer: M7824, a Bifunctional Protein Targeting PD-L1 and TGB-β Receptor II

In conjunction with the 2018 American Society of Clinical Oncology Annual Meeting, Cancer Network had the opportunity to speak with Dr. Luis G. Paz-Ares, to discuss the results of a phase I trial with a novel, first-in-class fusion immunotherapy protein called M7824, in patients with advanced non–small-cell lung cancer (abstract 9017; ClinicalTrials.gov identifier: NCT02517398). Dr. Paz-Ares is an associate professor at the Universidad Complutense, and is head of the Lung Cancer Unit at the CNIO (National Oncology Research Center) both in Madrid, Spain. He specializes in the care of patients with lung cancer, including those participating in clinical trials.

-Interviewed by Anna Azvolinsky

Cancer Network: First, can you describe M7824, the agent that was tested in this phase I trial? What’s unique about this novel drug, and what does it target?

Dr. Paz-Ares: M7824 is a first-in-class, innovative bifunctional fusion protein

composed of an IgG1 monoclonal antibody against the PD-L1 [programmed death ligand 1] protein fused with the extracellular domain of human transforming growth factor–β (TGF-β) receptor II. It functions as a “trap” for all three TGF-β isoforms. In brief, the bifunctional protein works by inhibiting the PD-L1 protein ligand on the one hand; and [inhibiting] TGF-β signaling on the other hand. By these two functions, you are able to activate the immune system against the tumor. That is the idea behind this molecule.

Cancer Network: You presented results of an expansion cohort part of a phase I trial. Can you tell us the details? How many patients were involved, what kind of patient population was this, and what was the goal?

Dr. Paz-Ares: This cohort specifically enrolled non–small-cell lung cancer patients, and we had 80 patients on the trial. We previously treated patients with stage IV non–small-cell lung cancer with at least one platinum-based chemotherapy, and the design for this cohort was a randomized design. Half of the patients were treated at a 500-mg every 2 weeks dose, and the other 40 patients were treated at a higher dose of 1,200 mg every 2 weeks. The main endpoints were to see the activity at these two different doses in non–small-cell lung cancer, [and] to describe the toxicity profile of the drug in this patient setting.

Cancer Network: What were the most important efficacy results in this cohort?

Dr. Paz-Ares: In synthesis, the overall response rate was 23.8%. Actually, the response rate was higher at the higher, 1,200 mg dose, where [it] was 27.5% in the unselected population. In patients who had PD-L1–expressing tumors, the response rate at the higher dose was 40.7%. In the very high expressers [who had] more than 80% of [tumor] cells with PD-L1 expression, the response rate was 71% of those patients treated at 1,200 mg every 2 weeks.

Cancer Network: What was the notable safety profile for the treatment in this patient population?

Dr. Paz-Ares: The safety profile was pretty manageable, I would say. The number of safety events was reasonable; about 20% of patients had itching, 19% had some [degree of] rash, and 12.5% had loss of appetite. These were the most recent side effects. One peculiar effect was skin lesions. Four patients developed keratoacanthomas, and 3 patients developed squamous cell carcinomas of the skin. These lesions were fairly easily treated with excision of the skin. It has been described that when TGF-β signaling is inhibited, this is one of the side effects that can be produced.

Cancer Network: What’s next as far as the development of M7824 for cancer patients? Is this expansion cohort ongoing, and are additional trials ongoing or being planned?

Dr. Paz-Ares: There are many possibilities for M7824, particularly in settings where PD-L1 inhibitors are effective but also in other diseases. For example, the agent could be particularly good in [the treatment of] tumors that are typically immune deserts (when the immune system is not naturally activated as a result of the tumor). [Regarding] non–small-cell lung cancer, a few trials are being planned. One would be in PD-L1 high-expression tumors, particularly tumors that are treated with standard-of-care pembrolizumab, an anti-PD1 inhibiting antibody immunotherapy. The idea would be to do a trial in this setting, compared with pembrolizumab. There is another trial that is also reasonable to do, in patients with stage III lung cancer. It’s important to mention that TGF-β signaling is [essential] in the development of fibrosis of the lung. So by inhibiting TGF-β signaling, we may be able not only to improve the efficacy [of treatment of] tumor lesions of non–small-cell lung cancer, but also to decrease pneumonitis and fibrosis after platinum chemotherapy–radiation treatment. So, those could be the two settings where the priorities are for [patients with] non–small-cell lung cancer.