Antibody-Drug Conjugate Active in Pretreated Ovarian Cancer

Jasgit Sachdev, MD

A fourth of patients with heavily pretreated advanced ovarian cancer achieved objective responses with novel antibody-drug conjugate targeting protein tyrosine kinase 7 (PTK7), results of a preliminary clinical trial showed.

The encouraging single-agent activity will be examined in additional studies of patients with ovarian cancer and other advanced malignancies, Jasgit Sachdev, MD, clinical associate professor at Translational Genomics Research Institute in Scottsdale, AZ, reported at the 2016 ESMO Congress in Copenhagen.

“PF-06647020 has an acceptable and manageable safety profile,” Sachdev and colleagues concluded in a poster presentation. “Most adverse events were grade 1-2, and the majority of adverse events were self-limited and did not require intervention.”

An invited discussant found the results “very interesting” but offered several caveats about interpretation.

“The patients were unselected for PTK7 expression,” said Ignace Vergote, MD, president of the Leuven Cancer Institute in Belgium. “The response data involved an expansion cohort treated with the recommended phase II dose. The objective response rate is interesting but no information was provided about the number of prior lines of therapy, histologic type, BRCA status, and prior therapy.”

PTK7 has a number of 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.

Expression of PTK7 has been associated with poor prognosis in patients with triple-negative breast cancer and non-small cell lung cancer (NSCLC), Sachdev and colleagues noted. PTK7 is enriched on cancer stem cells, which might contribute to treatment resistance and relapse.

PF-06647020 consists of a humanized monoclonal antibody against PTK7, linked to the microtubule inhibitor auristatin. Sachdev and colleagues reported findings from a phase I trial to investigate the safety and tolerability of PF-06747020 and, in a cohort-expansion phase, determined the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), and continued the evaluation of PF-06647020 safety and tolerability at the MTD and RP2D.

The trial included a total of 76 patients. The study included patients with triple-negative breast cancer preselected by PTK7 expression, patients with NSCLC selected for PTK7 expression, and patients with pretreated ovarian cancer unselected for PTK7 expression.

Patients were excluded from the trial if they had symptomatic brain metastases, active and clinically significant bacterial, fungal, or viral infection, the presence of grade ≥2 peripheral neuropathy, or previously underwent high-dose chemotherapy that required stem-cell rescue.

The patients had a median age of 58, and women accounted for 85% of the study population. The most common adverse events (all grades) were nausea (46%), alopecia (34%), headache (32%), fatigue (30%), neutropenia (26%), and vomiting (22%). The most common grade 3/4 adverse event was neutropenia, occurring in 12% of patients.

Aside from 7 cases of neutropenia, no other grade 4 adverse events were reported. The remaining grade 3 adverse events consisted of headache (5%), fatigue (4%), vomiting (3%), myalgia (3%), arthralgia (1%), and diarrhea (1%). Evaluation of dose-limiting toxicity showed no clinically concerning patterns of safety issues, the authors reported.

The trial included 27 patients with heavily pretreated ovarian cancer, 22 of whom were evaluable for clinical response. The overall response rate was 27.3%, which encompassed one complete response, 4 definite partial responses, and 1 unconfirmed partial response.

The confirmed partial responses had durations of 12 to 24 weeks, and the 1 complete response persisted beyond 40 weeks. One patient had stable disease that persisted for about 24 weeks.

The confirmed response occurred in a patient treated with the 2.1 mg/kg dose of PF-06647020. The remaining ovarian cancer patients who had objective responses or stable disease were treated with the RP2D of 2.8 mg/kg.

A total of 13 patients discontinued treatment, most often because of disease progression. One patient discontinued because of an adverse event, and 0 deaths were reported.

Retrospective assessment of PTK7 expression in archived ovarian cancer tissue from 12 patients showed digital H scores ranging from 1 to 198, an average of 105, and a median of 116. Patients who attained partial response had H-scores that ranged from 110 to 166 and an average of 133. H-scores for 6 patients with stable disease ranged from 43 to 154, with an average of 88. Two patients with progressive disease had H-scores of 1 and 198.

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