DKN-01 Offers a Solution to Modest IO Benefit in Advanced Gastroesophageal Carcinoma

Samuel K. Klempner, MD

Beyond the immunotherapies that have become standard in the advanced gastroesophageal carcinoma space, new biomarkers have been identified and agents are in development that can treat these tumors. Among biomarkers like FGFR2 and Claudin 18.2, DKK1 expression is showing relevance for the treatment of this patient population.

In an ongoing phase 2a clinical trial (DisTinGuish; NCT04363801), the novel targeted anti-DKK1 monoclonal antibody, DKN-01 administered in combination with the anti-PD-1 antibody tislelizumab (BGB-A31) and capecitabine/oxaliplatin (CAPOX) has demonstrated encouraging clinical activity in the frontline setting and was well-tolerated in patients. Results showed that the objective response and response duration were both enhanced with the addition of DKN-01 at 300 mg.

Among patients with gastroesophageal carcinoma treated with the DNK-01 combination in the second-line setting, clinical responses were observed in patients with high DKK1 expression, and the combination was well-tolerated.

Following its positive results, the study will continue to treat the second-line population with DKN-01 at the escalated dose of 600 mg during part B of the trial.

In an interview with Targeted Oncology™, Samuel K. Klempner, MD, a medical oncologist at Massachusetts General Hospital, discussed the promise of DKN-01 and early results from the DisTinGuish trial.

TARGETED ONCOLOGY: Can you discuss the benefit derived from available treatment for gastroesophageal carcinoma?

KLEMPNER: The landscape for gastroesophageal adenocarcinoma continues to evolve. Up until 2021, the standard had been 5-fluorouracil and platinum in the frontline setting. And then there were several practice changing datasets and trials. Since then, perhaps most notably to the gastric and esophageal and gastroesophageal junction (GEJ) adenocarcinoma populations are the CheckMate-649 and Keynote 590 trials, both of which supported the addition of a checkpoint inhibitor on top of standard chemo for this patient population. There is, of course, some differential activity based on PD-L1 expression, and this does need to be considered [on] a case-by-case basis with our patients. But broadly, we now have a new tool and that has improved the survival of many of these patients.

What is needed from novel agents? What are the unmet clinical needs right now?

There are still a lot of unmet clinical needs for gastroesophageal adenocarcinoma. So, 1 thing that has been quite reproducible from the available datasets is that the patients with low combined positive score [CPS] and low PD-L1 expression are certainly deriving a lesser magnitude of any benefit, if any, from the addition of checkpoint inhibitors.

So, how do we expand the benefit of novel therapies to this patient population? Moving beyond immunotherapy, there are a lot of targets that are currently being explored and hopefully will come to the clinic in the relatively near future. These include things like Claudin 18.2 and FGFR2, for which there is a substantial amount of data and then certainly we need novel biomarkers and novel therapies for patients that don't express those biomarkers or biomarkers such as HER2.

Can you explain the mechanism of action of DKN-01 and what led to exploration in gastroesophageal adenocarcinoma?

DKN1 is a DKK1 neutralizing antibody, and this is of interest based on several lines of evidence. First DKK1 is highly expressed in esophageal and gastric cancers. It's been associated with a poor prognosis and a lesser benefit to frontline chemotherapy. So, this looks like a poor prognosis population that doesn't respond as well to standard therapies and then looking at what elevated DKK1 does, there are several effects. There are direct effects on tumor growth through PI3 kinase pathway stimulation. There are pro-angiogenic effects which we know are immunosuppressive and then via modulation of beta containing dependent WIN signaling, elevated DKK1 expression enhances the suppressive function of some of the tumor. [This impacts] some of the immune cells in the microenvironment such as myeloid derived suppressor cells, as well as inhibits NK cell function, which we know is an important part of the anti-tumor immune response.

What is important for oncologists to know about the design of the DisTinGuish trial?

The study design is relatively straightforward and it's essentially asking 2 questions. So, there's a part A and part B. Part A is intended for frontline [therapy] in newly-diagnosed, advanced patients and this is independent of PD-L1 status or DKK1 status, and it’s just looking at the addition of DKN-01 to standard chemotherapy and checkpoint inhibition to see if this enhances the response rate particularly in patients who may be DKK1-high.

The second part is asking a separate question and is addressing a second-line population biomarker enriched for DKK1-high, and this is essentially trying to validate a prior observation that pembrolizumab [Keytruda] and DKN-01 demonstrated significant activity in a subgroup of patients who were DKK1-high in a prior trial. In the DisTinGuish trial, a separate PD-1 agent tislelizumab was combined with DKN-01 in patients who were known to be DKK1-high in the second-line setting to try to validate the prior subgroup findings from the older trial.

What findings from DisTinGuish were recently presented at the 2022 Gastrointestinal Cancer Symposium?

There are a couple key findings. This is a relatively small trial, and ultimately, 1 of the take home messages is that we need more numbers to see if these things are as encouraging as what we see in the early data. But first of all, if we look at the trial population, we see that this does represent a US population of patients that we see in the clinic, primarily GEJ, and there is some gastric cancer. One thing to note when looking at the biomarker is just how prevalent is it?

So, these were previously untreated patients who had a tumor sample that was analyzed for DKK1 expression using an RNA in situ hybridization assay. What we saw is that encouragingly about 57% of patients had elevated DKK1 expression, so, that tells us this, this may be relevant to a substantial portion of the overall patient population. And then the rest of the patient demographics are relatively consistent with clinic. Specifically, if we look at the PD-L1 expression, because 1 of the obvious questions is, what if you just get a bunch of PD-L1-high patients, how do you know if the drug is adding anything? And important to note in this study, there was only about a third of patients who were PD-L1 negative, and 73% had a CPS score less than 5. So, these are patients who, based on prior data, are not deriving benefit from standardly adding a checkpoint inhibitor. So, it looks like we're not randomly selecting a patient population who is already predicted to have a significant benefit.

There were no microsatellite instability-high patients, and only 4 patients had a tumor mutation burden greater than 10. Again, this is just speaking to this is not an immune-responsive population based on what we know in terms of efficacy, that is one of the key findings of this presentation in part A. This is the frontline population, the response rate in the modified intention to treat population was 68%. But really what is of interest is in the biomarker high population where you would expect to see the greatest efficacy, the response rate was 90%. Again, the numbers are relatively small, but some of these responses are quite deep and durable. And the activity was higher in the DKK1-high patients which is what you would hope to see if the biomarker is identifying a population that is predicted to have a better response rate. [progression-free (PFS)] and [overall survival (OS)] data are immature, but the median PFS is 10.7 months, which is encouraging in a phase 2 setting and compares favorably to the phase 3 trial data from CheckMate 649 [NCT02872116], for example. But again, it's small numbers and we'll need larger numbers to confirm if this is a true observation. But I would say the take home messages in this population is that the biomarker does appear predictive of patients who are going to get the most benefit.

The final point that I would make is it does not appear that DKK1 elevation correlates with PD-L1 expression, so it's not like the DKK1-high patients are also the PD-L1-high patients who would have been more likely to benefit anyway. So those 2 things appear independent suggesting that the drug is not acting primarily via PD-L1, the efficacy is not mediated via the PD-1 inhibitor, we presume this reflects some activity of the decal on 1 agent added to the therapy.

How would you describe the safety profile of DKN-01 with checkpoint inhibition?

Overall, in this trial population, the tolerability was very good. It doesn't appear to potentiate or increase the rate of immune-related adverse events, for example. And so, it seems that this can be paired safely with standard chemotherapy and PD-1 agents.

What are the next steps of this study?

Anytime we see a high response rate, it's very encouraging. But that's only step 1. In terms of developing a hopeful advance for our patients, we need to confirm this with larger datasets, that is probably the most important next step. Ultimately in a randomized fashion, we need to confirm that 1), what we're seeing is true and holds up with larger sample sizes, and 2) that the performance of the biomarker and the biomarker enrichment for DKK1-high, is truly identifying patients who have this significantly higher response rate and more durable benefits.

So, I would say the next steps are really validation. And I hope that this goes in the direction of further development and subsequent validated randomized trials, so we can hopefully bring yet another agent to our patients and another tool for the toolbox. That's really the ultimate goal.