Lead Researcher Discusses Promising Antibody-Drug Conjugate for Ovarian Cancer

Jasgit Sachdev, MD

Results from an expansion cohort of a preliminary clinical trial have shown encouraging activity for a novel antibody-drug conjugate in patients with heavily pretreated advanced ovarian cancer.

The antibody-drug conjugate, PF-06647020, targets the protein tyrosine kinase 7 (PTK7) in these patients. PTK7 has several functions in developmental biology, including Wnt signaling and planar cell polarity. The enzyme is overexpressed in a variety of human cancers, including ovarian, breast, colon, lung, gastric, and esophageal, as well as in acute myeloid leukemia.

Six of 22 evaluable patients in the current expansion cohort responded to PF-06647020, including 1 complete response, and an additional 12 patients had stable disease. Some responses were durable, ranging from 6 to 10 months’ duration.

“We saw very encouraging activity in this very heavily pretreated group of patients,” lead study investigator Jasgit Sachdev, MD, said in an interview with OncLive at the 2016 ESMO Congress. “As we know, platinum resistance is a very significant problem in ovarian cancer. There’s not very robust activity seen for subsequent lines of therapy without traditional chemotherapy drugs. So a 27% response rate is very encouraging in this patient population with a very favorable tolerability profile.”

OncLive: Could you provide an overview of the data you presented at ESMO?

In an interview with OncLive, Sachdev, clinical associate professor at Translational Genomics Research Institute, discussed the major findings seen with this novel antibody-drug conjugate, its impressive efficacy in patients with ovarian cancer, and the next steps following these results.Sachdev: This is an initial phase I exploration of an antibody-drug conjugate molecule in the clinic. It started with the traditional dose escalation design which was for patients with advanced solid tumors. And then there were preplanned expansion groups for breast cancer, non—small cell lung cancer and ovarian cancer.

What were the most significant findings from that expansion arm?

The data we presented were from the expansion group for ovarian cancer, specifically, platinum-resistant ovarian cancer patients. The data from the dose escalation part were actually presented at last year’s ESMO in 2015. And once we reached our recommended phase II dose, then the planned expansions were undertaken. So today, we presented data for the 27 patients who were in the ovarian cancer expansion arm.The first point I want to highlight is that this is a very well-tolerated medicine. It’s a novel design, obviously, because it’s an antibody-drug conjugate. The antibody is targeting a tyrosine kinase called protein tyrosine kinase 7 (PTK7) on the surface of cancer cells. It delivers a very potent microtubule inhibitor called auristatin intracellularly. Auristatin is a very potent chemotherapy drug that is very hard to administer in its naked form, so to speak, but when bounded to the antibody, it makes it much more favorable in terms of its tolerability profile.

What are the next steps following these results?

Do you know what other agents it will be combined with yet?

Do you expect the findings to be very different in a population of patients that are not as heavily pretreated?

What would you like the community oncologist to take away from your presentation?

Are there any other trials in this space that you are excited about?

What do you hope to see in the next 5 to 10 years?

We saw very encouraging activity in this very heavily pretreated group of patients. As we know, platinum resistance is a very significant problem in ovarian cancer. There’s not very robust activity seen for subsequent lines of therapy without traditional chemotherapy drugs. So a 27% response rate is very encouraging in this patient population with a very favorable tolerability profile.We have already undertaken the next expansion group, which is going to be in less heavily pretreated patients. We’re restricting the number of allowed prior therapies just to get a better sense of the true therapeutic efficacy of this medicine. And we’re also looking at some novel combinations of the antibody-drug conjugate with other targeted therapies or chemotherapy drugs.Not yet. That’s still in the planning phase. But because of its advantages, and not having seen a lot of grade 3 or 4 side effects with this medicine—and even though it’s a microtubule-targeting drug, we don’t see a lot of neuropathy—there’s definitely potential with exploring it in combination with other chemotherapy drugs. But we also want to look at nonchemotherapy combinations as well.Yes, I think we might see actually better efficacy results, if I can speculate, because of better performance status for these patients and not as much treatment resistance. We also want to be able to study this in a more homogenous population, allowing for specific lines of therapy before they actually receive the study drug. So I think we will see differences in the reported efficacy in a more homogenous, less heavily treated population.I think the take-home message is that we’ve probably reached the ceiling of what we can do with our standard chemotherapy drugs, especially in the setting of platinum resistance. So the way forward is really to look at the more targeted delivery of chemotherapy, but also in combination with other agents that can maybe bypass some of the resistance that we see developing to chemotherapy and platinum resistance in ovarian cancer patients.There’s definitely other antibody-drug conjugate drugs out there in this space targeting some other receptors on the surface of cancer cells with different payloads. We’re also looking at novel combinations, especially with targeted drugs, whether it’s antiangiogenic drugs or immunotherapy combinations, those are something to keep an eye out for, for sure.Like we’ve seen for most other tumor types, being able to sub-stratify and sub-classify and figure out biomarkers which can help us predict which patients are going to benefit from which types of therapies, is very important. Whether it’s checkpoint inhibitors, or PARP inhibitors, or even some of these antibody-drug conjugate compounds, being able to have validated biomarkers to be able to preselect patients and understand what’s different at a biologic sublevel within even our category of high-grade ovarian cancer, but also being able to sub-stratify that and figure out which therapeutics match which patient populations best.

Sachdev JC, Maitland M, Sharma M, et al. A phase 1 study of PF-06647020, an antibody-drug conjugate (ADC) targeting protein tyrosine kinase 7 (PTK7), in patients with advanced solid tumors including platinum resistant ovarian cancer (OVCA). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA35.