Bria-IMT Combination Study with KEYTRUDA®: What to Know and Why

In a previous interview, BriaCell (TSX:BCT.V) (OTCQB:BCTXF) (or the Company)’s President and CEO, Dr. Bill Williams cited as a near-term catalyst data from the Company’s ongoing Phase IIa combination clinical trial of Bria-IMT™ with Merck’s (NYSE: MRK) KEYTRUDA® [(pembrolizumab) ], as listed in ClinicalTrials.gov as NCT03328026, in advanced breast cancer.
Initiated in October, the study is observing Bria-IMT in combination with KEYTRUDA, with safety data expected by the end of the year and an early look at efficacy in the first quarter of 2019. As with most next generation immuno-oncology approaches, the key of this study is to generate inflamed tumors and combine them with a first-generation, FDA-approved immuno-oncology drug to quickly and safely address breast cancer tumors.

Anti-Tumor Response
There are a couple of interesting points to make about this trial. First, the combination with a checkpoint inhibitor is a natural start. As has been seen in numerous cases, simply inflaming a tumor by an immune activating product does not lead to an anti-tumor response, as the tumor microenvironment can be very hostile. Immune checkpoint inhibitors such as KEYTRUDA are designed to alter the tumor microenvironment by making tumors more susceptible to the activated immune system.

Immune check point inhibitors have offered significant clinical benefits to some patients, but work only in certain cancers. Recently, the significance of immune checkpoint inhibitors was recognized by the Nobel committee by awarding Dr. Tasuku Honjo and Dr. James P. Allison the 2018 Nobel Prize in Physiology or Medicine.
Interestingly, an important pre-clinical study by Dr. Allison’s group indicated that combination treatment with anti-PD-1 antibodies improved the tumor-killing effect of irradiated melanoma cells engineered to produce immune-activating factors, i.e. inflaming tumors and dosing with checkpoints creates added efficacy.

Bria-IMT, essentially a breast cancer cell line engineered to produce an immune-activating factor (GM-CSF), has been shown to directly activate T cells (important cells of the immune system). BriaCell published these findings in a leading immunology journal earlier this year. Based on the published, proposed mechanism of action of Bria-IMT, the Company envisions that Bria-IMT and KEYTRUDA can exert additive or synergistic tumor-directed effects. It is important to note that KEYTRUDA has not been approved for breast cancer, but is approved for other cancers.
The trial also plans on testing for PD-L1 and/or PD-L2 status of the patients. Clearly, checkpoint inhibitors such as KEYTRUDA (anti PD-1) have generally done better in PD-L1/PD-L2 positive patients. Being able to understand how the combination of KEYTRUDA and Bria-IMT works in patients more or less likely to respond to checkpoint inhibition becomes critical information in future development plans. In other words, this information can be used to design future trials with an enriched population of patients most likely to benefit from the combination.

Previous Phase IIa studies with Bria-IMT monotherapy showed that the tumors appeared to have upregulated PD-L1 levels in response to Bria-IMT treatment. So even if the tumors are PD-L1 negative at the start of treatment, they might not remain negative during the treatment with the combination of Bria-IMT and KEYTRUDA, potentially offering clinical benefits to this subset of patients. As such, the Company will also test post treatment levels of PD-L1 to examine this dynamic. The treatment with a checkpoint inhibitor might help to avoid a negative impact on efficacy given the likely higher sensitivity to PD-L1 inhibitors including KEYTRUDA. This study will provide important information about how these tumors respond to help further refine the treatment schedule and timing.

Patient Enrollment
The trial plans on enrolling up to 40 patients and already has five clinical sites, some with multiple locations, recruiting patients. At times recruitment can be a slow process. Having multiple locations already in operation in a fairly large indication makes the timelines of the enrollment plausible. Of course, recruitment is not quite a straight forward process, so the exact number of patients that will be analyzed in the safety analysis in late 2018 remains to be seen. As such, I would expect the initial safety look to be a mid- to late-December event to maximize the number of treated patients.

One advantage of the trial is that despite only enrolling patients who failed previous systemic treatments, the Company has specified a series of inclusion criteria across the breast cancer spectrum. In other words, the trial can enroll triple negative patients, HER2 and ER or PR positive patients, HER2 negative and ER or PR positive, and HER2 positive and ER or PR negative patients. That is a large patient population from which to enroll, which will be an advantage to the rate of patient recruitment.

HLA Matching with Bria-IMT
While the ongoing trial will not be selecting patients based on their HLA matching with Bria-IMT, it will be collecting data on the patients’ HLA type. This will be very interesting as prior studies have demonstrated that matching of HLA type between patients and Bria-IMT seems to be predictive of a better clinical response. For the upcoming safety analysis, this is not important because there is no reason to expect that HLA matching with Bria-IMT would have a dramatic impact on the safety of the combination treatment; but, as we get into the efficacy data analysis in early 2019, HLA matching with Bria-IMT becomes very important.

In summary, the efficacy look in early 2019 is the big catalyst, clearing the safety bar in the combination therapy remains an important first step for later this year. Finally, the first look at the results could also provide some details about the patient characteristic of which HLA matching with Bria-IMT will be the key factor to follow. The more HLA matched (with Bria-IMT) patients will be enrolled, the more conclusive the efficacy analysis will become in early 2019, but as noted above, the safety remains the first hurdle.

 

Disclosure: BriaCell is a client of CRG