Combination PARP/PD-1 Inhibition Shows Promise in Phase I Trial of Advanced Solid Tumors

Combination PARP/PD-1 Inhibition Shows Promise in Phase I Trial of Advanced Solid Tumors

Dr. Linda R. Mileshkin presents Abstract 48.
The combination of a selective PARP inhibitor known as pamiparib (BGB-290) and an agent targeting the PD-1 receptor known as tislelizumab (BGB-A317) was well tolerated with activity that supports continued investigation, according to a phase I trial in patients with advanced malignancies (Abstract 48).

“The rationale for using this combination was the hope that we could see some upregulation of tumor-associated antigens with PARP inhibitors,” which may improve the antitumor activity of checkpoint inhibitors, Linda R. Mileshkin, MD, of the Peter MacCallum Cancer Centre, in Australia, said during an Oral Abstract Session on clinical trials on January 25.

The phase I study included malignancies that are likely to harbor DNA damage repair deficiencies, or that are potentially responsive to PD-1 blockade. Patients were treated with a combination of the PARP inhibitor pamiparib and tislelizumab; the latter is a humanized IgG4 monoclonal antibody that targets the PD-1 receptor, and is in development for solid and hematologic malignancies.

In total, the dose-escalation portion of the trial included 49 patients with a median age of 63, with the most common tumor site being the ovary/fallopian tube/peritoneum in 34 patients. Other malignancies included pancreas (three patients), prostate (three patients), breast (three patients), and one patient each with cancer of the bile duct, bladder, lung, peripheral nerve sheath, uterus, and cervix.

The dose-escalation trial included five dose levels, beginning at tislelizumab 2 mg/kg infusion every 3 weeks plus pamiparib 20 mg twice daily. “These patients were heavily pretreated, with a median of four prior lines of therapy,” Dr. Mileshkin said.

All patients reported at least one treatment-emergent adverse event (TEAE), and 21 reported a serious TEAE. Four patients experienced a dose-limiting toxicity, including one case each of grade 2 nausea and grade 3 rash at dose level 4 (200 mg of tislelizumab and 40 mg of pamiparib), and one case each of grade 2 nausea/vomiting and grade 4 autoimmune hepatitis at dose level 5 (200 mg of tislelizumab and 60 mg of pamiparib). The investigators concluded that dose level 4 should be used as the recommended phase II dose, which includes tislelizumab 200 mg infusion every 3 weeks plus pamiparib 40 mg twice daily.

Dr. Deborah J.L. Wong discusses Abstract 48.
The most common TEAEs related to pamiparib included nausea (grades 1/2, 55.1%; grades 3/4, 4.1%), fatigue (38.8% and 4.1%, respectively), diarrhea (20.4% and 0%, respectively), vomiting (12.2% and 2.0%, respectively), and anemia (12.2% and 12.2%, respectively). Most of the TEAEs related to tislelizumab were grade 1/2, with fatigue (36.7%), nausea (20.4%), and diarrhea (14.3%) as the most common. There was one grade 3/4 case of fatigue (2.0%), and one of pruritus (2.0%).

A total of 23 patients (46.9%) experienced at least one immune-related TEAE. These included six patients with increased ALT (grade 3 or higher, two patients), five with increased AST (one patient grade 3 or higher), five with hypothyroidism (none grade 3 or higher), four with diarrhea (none grade 3 or higher), and several others in fewer patients.

Dr. Mileshkin noted that there were 13 hepatic TEAEs reported in the trial, nine of which were grade 3/4. This included six instances of hepatitis/autoimmune hepatitis and seven instances of ALT and/or AST elevations. The median time to onset of these hepatic TEAEs was 55 days; 10 patients with grade 2 or higher transaminitis recovered after treatment with corticosteroids. The study’s protocol was amended to increase hepatic safety monitoring, consistent with new guidelines from the European Society for Medical Oncology regarding the management of immunotherapy toxicities.1

“We recognize that we did see a significant number of liver-related adverse events, but these were all manageable and reversible,” Dr. Mileshkin said. “We need to monitor it moving forward to understand it better.” She noted that since the study protocol was amended to improve hepatic monitoring, the number of such events observed has been falling.

There were two complete responses seen in the trial (4%), and eight confirmed partial responses (16%), for an objective response rate of 20%. The clinical benefit rate, which included complete and partial responses as well as durable stable disease of at least 24 weeks, was 39%. The median duration of response was 168.5 days.

Ten patients had a duration of treatment with the combination therapy of more than 200 days. As of the time of data cutoff, 11 patients remained on treatment. Of the 25 patients who had BRCA status assessed, there were 11 patients with wild-type BRCA, 13 germline mutations, and 1 somatic mutation. Most of the responses seen were in the patients with germline BRCA mutations, but some responses did occur in patients with wild-type status.

Dr. Mileshkin said the results support ongoing investigation of this combination, and the enrollment of disease-specific cohorts in a second part of this trial is now ongoing. The dose expansion cohort is designed to include 20 patients in each of several malignancies, including ovarian cancer, triple-negative breast cancer, urothelial cancer, and several others.

“There is a preclinical rationale, as well as in vitro and in vivo data, demonstrating potential benefit of PARP inhibitors in combination with immunotherapy,” Deborah J.L. Wong, MD, PhD, of the David Geffen School of Medicine at the University of California, and discussant for the abstract, said.

She said the study offers an “interesting signal of activity,” particularly in patients with BRCA mutations. “It’s interesting to note that among the patients with BRCA mutations, all of them experienced at least stable disease as their best response,” Dr. Wong said. “Careful understanding of the mechanisms of toxicity […] will be key.”

 

–Dave Levitan