麻豆传媒

NEW ORLEANS -- Clinical evaluation of immune checkpoint inhibitors made some headway toward defining a role for anti-PD-1 drugs in gynecologic cancers, according to studies reported here.

The combination of pembrolizumab (Keytruda) and pegylated liposomal doxorubicin (PLD) produced a response rate of 19% and a clinical benefit rate (CBR) of 43% in patients with relapsed platinum-resistant ovarian cancer. The activity met prespecified criteria for continued evaluation of the combination in that subgroup of patients, Ursula Matulonis, MD, of Dana-Farber Cancer Institute in Boston, said at the Society of Gynecologic Oncology meeting here.

"The combination of pegylated liposomal doxorubicin and pembrolizumab was well tolerated, with no grade 5 events and very few grade 4 events. This combination is deserving of further study. Translational objective studies are ongoing."

In another study, a trial of avelumab (Bavencio) monotherapy for endometrial cancer showed activity in the setting of microsatellite instability (MSI) and polymerase epsilon (POLE)-mutated disease but not microsatellite stable (MSS) tumors, reported Panagiotis A. Konstantinopoulos, MD, PhD, also of Dana-Farber, who was also a co-author of the Matulonis et al study. "The results are consistent with previously reported data for pembrolizumab in MSI endometrial cancer."

Patients with platinum-resistant ovarian cancer have limited therapeutic options, including chemotherapy with or without bevacizumab (Avastin), PARP inhibitors for BRCA-mutated cancers, and miscellaneous chemotherapy drugs, such as gemcitabine, said Matulonis (also a co-author of the avelumab study). Prior of PLD in platinum-resistant ovarian cancer yielded a response rate of <10%, increasing modestly but still <15% with the addition of bevacizumab.

Single-agent immune checkpoint inhibition has led to objective response rates of 10-15%.

"Clearly, better options are needed," said Matulonis.

Toward that end, an investigator-initiated phase II trial evaluated combination therapy with pembrolizumab and PLD in patients with platinum-resistant ovarian cancer. The rationale for the combination included the potential for a chemotherapy-induced to stimulate an immune response and evidence that anthracyclines have .

The primary objective of the study was to assess the combination's CBR, defined as an objective response plus stable disease for more than 24 weeks. Secondary objectives included toxicity, response rate, and progression-free survival (PFS).

The investigators defined the null hypothesis as a CBR <25%. A CBR ≥50% would of interest for continued evaluation, and clinical benefit in 10 of 26 patients would be sufficient to reject the null hypothesis, the team explained.

Eligible patients could have received as many as two prior regimens for recurrent ovarian cancer but no more than one prior nonplatinum regimen. Patients with prior exposure to anthracyclines or immuno-oncology agents were excluded.

The combination led to objective responses in five of the 26 patients (19.2%), and six others (23.1%) had stable disease exceeding 24 weeks, resulting in a CBR of 42.3% (11 of 26 patients). Seven additional patients had stable disease for less than 24 weeks, on or off treatment.

Responses had a median duration of 16.3 weeks and a range of 9 to 32 weeks. The median PFS had yet to be reached, but the cohort had a 6-month PFS rate of 63%.

The most frequently reported adverse events (30-50%, all grades) were fatigue, rash, abdominal pain, anemia, nausea, vomiting, and constipation. The most common grade 3/4 adverse events were rash and anemia (11.5% each). Grade 3/4 adverse events of special interest included liver enzyme elevation (AST 7.6%; ALT, 11.5%) and intestinal obstruction (7.7%).

The evaluation of avelumab in endometrial cancer examined the effects of PD-L1 blockade in genomics-defined subgroups. The endometrial cancer dataset of The Cancer Genome Atlas includes ultramutated (POLE) and hypermutated (MSI) classifications.

The POLE and MSI cancers have more tumor-specific neoantigens, more tumor-infiltrating lymphocytes, and exhibit compensatory upregulation of immune checkpoints, including the PD-1/PD-L1 pathway. Those tumors would be predicted to respond to PD-1/PD-L1 blockade, said Konstantinopoulos.

He and his colleagues conducted a multicenter phase II trial of avelumab in patients with POLE/MSI and MSS endometrial cancers (which included tumors with unknown POLE mutation status). All patients received avelumab every 2 weeks until disease progression. The trial had co-primary endpoints of PFS for at least 6 months (PFS6) and objective response rate.

Eligibility criteria placed no limit on the number of prior therapies but excluded patients with prior anti-PD-1/PD-L1 immunotherapy.

The trial was conducted in two stages. If two of the first 16 patients enrolled had objective responses or PFS6, the trial would continue with enrollment of an additional 19 patients. If four of the 35 had objective responses or eight achieved PFS6, avelumab would be considered for additional evaluation in the corresponding cohort (POLE/MSI, MSS, or both).

Data analysis included 32 patients -- 16 each with POLE/MSI or MSS tumors. In the MSS cohort, one patient had a partial response, for an objective response rate of 6.3%. The same patient attained PFS6. As a result, avelumab did not meet the performance criteria for further evaluation.

Of the 16 patients with MSI tumors (none with POLE mutations), one never received avelumab. Among the remaining 15 patients, three (21.4%) had partial responses and five patients (33.3%) attained PFS6, meaning that avelumab did meet performance criteria for further evaluation. All partial responses and PFS6 responses occurred in patients who had three or more prior lines of therapy, said Konstantinopoulos.

Analysis of toxicity in 31 patients showed that grade 3 treatment-related adverse events consisted of two cases of diarrhea and one each of anemia, infection, and myositis. No grade 4 toxicities were reported.

Comment