Samuel J. Klempner, MD

Samuel J. Klempner, MD, medical oncologist at Massachusetts General Hospital, discusses the preliminary results of a study of the investigational agent DKN-01 for patients with gastroesophageal adenocarcinoma.

The ongoing phase 2a DisTinGuish trial (NCT04363801) enrolled patients with advanced esophageal cancer to receive DKN-01 in combination with tislelizumab (BGB-A31) and capecitabine/oxaliplatin. Part A enrolled all patients with advanced disease for frontline therapy, while part B focused on second-line therapy following chemotherapy in those with high 

Klempner says the objective response rate in the part A frontline population was 68%, but in the 

-high second-line population in part B, it was 90%, including deep and durable responses. While the progression-free survival (PFS) and overall survival (OS) data were not yet mature, the median PFS was 10.7 months at a data cutoff of September 15, 2021, which he says is comparable with that of nivolumab (Opdivo) and ipilimumab (Yervoy) in CheckMate649 (NCT02872116).

In addition to the correlation between DKK1 expression and efficacy, the study found no clear correlation between high 

 and high PD-L1 expression, which supports the hypothesis that antitumor activity can be attributed to DKN-01’s targeting of 

 and not the anti–PD-1 activity of tislelizumab.

 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, as was shown in the spider plot on the poster. And the activity was higher in the 

-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.

 PFS and OS data [are] immature, but the median PFS is 10.7 months, which is encouraging in a phase 2 setting and compares favorably [with] the phase 3 trial data from CheckMate649, 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 message is in this population, 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 

 elevation correlates with PD-L1 expression, so it's not like the 

-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 DKN-01 agent added to the therapy.

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Samuel J. Klempner, MD, discusses the preliminary results of a study of the investigational agent DKN-01 for patients with gastroesophageal adenocarcinoma. 

DKK1-Targeted Agent Shows Efficacy in Gastroesophageal Cancer

Samuel J. Klempner, MD, a medical oncologist at Massachusetts General Hospital, discusses the mechanism of action of the investigational agent DKN-01 in patients with gastroesophageal adenocarcinoma.

DKN-01, an intravenous monoclonal antibody which binds to 

 and neutralizes it, can potentially reduce the expression of 

 is highly expressed in esophageal and gastric cancers, and it is associated with worse disease prognosis and poor response to chemotherapy.

 can cause tumor growth through stimulation of PI3 kinase pathways. It can also have immunosuppressive pro-angiogenic effects in tumors. The Wnt/β-catenin pathway, which influences immune cell infiltration of the tumor microenvironment, is also affected by high 

 expression, leading to inhibition of natural killer (NK) cells and reducing antitumor activity.

In the ongoing phase 2a DisTinGuish trial (NCT04363801), DKN-01 

showed promising efficacy and tolerability

 in patients with advanced esophageal cancer with 

 expression in combination with tislelizumab and capecitabine/oxaliplatin. 

 suppression can enable better treatment for a patient population known to have poorer overall survival.

-neutralizing antibody, and this is of interest based on several lines of evidence. First, 

 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.

 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 β–catenin-dependent Wnt signaling, elevated 

 expression enhances the suppressive function of some of the immune cells in the microenvironment such as myeloid-derived suppressor cells, as well as inhibiting NK cell function, which we know is an important part of the anti-tumor immune response.

Samuel J. Klempner, MD, discusses the mechanism of action of the investigational agent DKN-01 in patients with gastroesophageal adenocarcinoma. 

Mechanism of Action of DKN-01 in Gastroesophageal Adenocarcinoma

Samuel J. Klempner, MD, medical oncologist at Massachusetts General Hospital, discusses unmet needs in patients with gastroesophageal adenocarcinoma when it comes to biomarker-targeted agents.

Studies such as the CheckMate 649 trial (NCT02872116) of nivolumab (Opdivo) and ipilimumab (Yervoy) and the KEYNOTE-590 trial (NCT03189719) of pembrolizumab (Keytruda) have found benefit for many patients who receive an immune checkpoint inhibitor along with chemotherapy.

However, those with low combined positive score (CPS) and low PD-L1 expression do not benefit as much from checkpoint inhibitors. According to Klempner, a major unmet need in this setting is finding novel targeted agents that can provide benefit to these subgroups.

In addition to immunotherapy, HER2-positive disease can be targeted with the monoclonal antibody trastuzumab (Herceptin). Other targets that are currently being explored include the 

tight-junction protein which can be targeted by the monoclonal antibody zolbetuximab, and 

, which can be targeted with inhibitors such as pemigatinib (Pemazyre). Klempner says there is a pressing need for novel therapies in gastric cancers for patients who lack HER2 or other known targetable biomarkers.

 There are still a lot of unmet clinical needs for gastroesophageal adenocarcinoma. So, one thing that has been quite reproducible from the available datasets is that the patients with low CPS and low PD-L1 expression are certainly deriving a lesser magnitude, if any, benefit from the addition of checkpoint inhibitors in many patients. And so, how do we expand the benefit of novel therapies to this patient population? 

Then 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 

, for which there [are] 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.

Samuel J. Klempner, MD, discusses unmet needs in patients with gastroesophageal adenocarcinoma when it comes to biomarker-targeted agents. 

Samuel J. Klempner, MD | Authors

Articles

DKK1-Targeted Agent Shows Efficacy in Gastroesophageal Cancer

Mechanism of Action of DKN-01 in Gastroesophageal Adenocarcinoma

Unmet Needs For Targeted Therapies in Gastroesophageal Adenocarcinoma