BriaCell presented some data from the 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 at SABCS, as well as some additional monotherapy data. While the poster does not provide a lot of data on combination patients (as expected given such an early look), there are a couple of interesting points, but we can start the newer monotherapy findings.

Monotherapy
The monotherapy trial has enrolled a total of 23 patients and found that 15 have at least 1 HLA match with Bria-IMT. While the numbers are still relatively small, they are finding over 50% of patients have at least 1 HLA match with Bria-IMT. Given the role that the HLA matching with Bria-IMT may play in terms of expected efficacy, this relatively high rate of matches bodes well as it indicates a large patient population that could benefit from treatment. In addition, if future trials end up using HLA matching as an inclusion criteria, the high proportion of matching patients should mean the faster enrollment. So having such a high rate of matching is good for a couple of reasons.

Efficacy is always difficult to judge in monotherapy as the tumor microenvironment is so hostile that objective responses are unlikely. What is interesting, however, is that for all patients treated to date with monotherapy there were 4 patients who saw tumor shrinkage, and all had at least 1 HLA match with Bria-IMT which is exactly what one would expect. In addition, immune responses were seen in 60% of the patients including some patients who were anergic.

Why is this important? Anergic patients have immune systems that are basically exhausted making their immune system particularly difficult to activate. Getting an immune response in those patients indicates potent biologic activity, which becomes important for the combination trial. Patients need activated immune systems and a less hostile tumor microenvironment to respond to a tumor. In general, then, the monotherapy data indicates that Bria-IMT is able to trigger an immune response in patients who match with Bria-IMT at HLA , which is half of the equation. The next question is what happens in combination with an anti-PD1 agent that solves the other half of the equation?

The Combination Study of Bria-IMT with KEYTRUDA®: Safety
These data were always to be a safety look and there is nothing in the data to indicate that the combination generates any toxicity. The poster reported on 5 patients (2 are newly enrolled into the trial and 3 were enrolled into the trial from the monotherapy trial). We do not have a detailed list of reported adverse events but the poster notes that there were no serious adverse events. Perhaps more importantly, there have been no withdrawals from the trial due to adverse events. The lack of withdrawals is perhaps more telling as it is a clear objective look at the tolerability of a therapy.

The Combination Study of Bria-IMT with KEYTRUDA®: Efficacy
As noted above, these data were only an early safety look but we can get some tangential analysis of efficacy. Generally, patients stay on treatment as long as the disease is not progressing and remains tolerable. The poster shows that 4 of the 5 patients remain on treatment and that includes both patients who were directly enrolled in the combination trial.
To be clear the numbers are small and follow up short as none of these patients have completed treatment but it is encouraging that treatment continues. The next data look will still be relatively early but should have patients who have completed more cycles and have had time to respond to treatment.

Guideposts for the Efficacy Analysis
These data set the table for the early efficacy look in 2019. We know that there will at least be 5 patients available for efficacy analysis and likely more as enrollment continues. What are some of the guideposts that we should look for in 2019? There are no direct comparisons for this trial given the different type of breast cancer patients that are enrolled but there are some immuno-oncology breast cancer trials that can set rough estimates as to what is possible with immuno-oncology in this setting.

KEYNOTE Studies
Results have been recently presented on the use of KEYTRUDA® to treat women with advanced stage breast cancer, either as combination or monotherapy.
In the KEYNOTE-014 (PANACEA) trial, advanced HER2 positive breast cancer patients who have progressed on trastuzumab, more commonly known as Herceptin, were treated with a combination of KEYTRUDA® and Herceptin in a dose escalation fashion.

58 patients were treated, of whom 46 were PD-L1 tumor positive and with a median follow-up of 13.6 months, those in the PD-L1 positive cohort achieved a 15.2% overall response rate (ORR) and 24% disease control rate (DCR). There were no responses in the PD-L1 negative group.

KEYTRUDA® was used as monotherapy in a trial called KEYNOTE-028, which consisted of 25 women who were heavily pre-treated, most with at least 3 prior lines of therapy. They were PD-L1 positive, ER positive, HER2 negative, where 3 of 25 (12%) responded with durations ranging from 8.7 weeks to 44 weeks and 4 others had SD for a 28% DCR.

There are a lot of moving parts but some rough guidelines. In patients who are PD-L1 negative there do not appear to be any responses, so any objective responses in PD-L1 negative patients would be a nice sign of efficacy. In PD-L1 patients, it appears the mid-teens is the expectation and oddly both monotherapy and combination had basically the same results. The patient populations were clearly different in the two trials, which drives the similarity but in terms of rough guidelines a mid-teen response rate expectation for PD-L1 patients is fair. So the ORR for the combination needs to be above that rate for us to assign efficacy for the Bria-IMT combination.

To reiterate these remain approximated estimates based on the trials that do not directly compare but are the best comparable trials in our view. The cleanest scenario for Briacell would be an objective response in PD-L1 negative patients. These were the most difficult to treat patients with no responses even in the combination trial of KEYTRUDA® with Herceptin.

Conclusion
The early data confirm the safety of the treatment for the combination of KEYTRUDA® with Bria-IMT. BriaCell remains on pace to provide some efficacy updates for the combination trial in the first quarter of next year. Expectations should be tempered given the early nature but objective responses in PD-L1 negative patients would represent some of the strongest supportive evidence of the activity for the Bria-IMT combination with KEYTRUDA® as those patients remain exceptionally difficult to treat.

Disclosure: BriaCell is a client of CRG