Pembrolizumab Leads to Promising Outcomes in Advanced ASCC

Pembrolizumab (Keytruda) demonstrated positive activity in patients with previously treated advanced anal squamous cell carcinoma (ASCC), regardless of PD-L1 expression, according to the results of the KEYNOTE-158 trial presented at the 2020 Gastrointestinal Cancers Symposium.¹

“Pembrolizumab demonstrated antitumor activity, durable response, and encouraging overall survival with manageable safety in patients with previously treated anal squamous cell  carcinoma,” Aurélien Marabelle,  MD, PhD,  a senior medical oncologist at Gustave Roussy in France,  said when presenting the results of the phase II trial.

In the prior phase Ib multicohort KEYNOTE-028 trial, pembrolizumab monotherapy demonstrated modest antitumor activity and acceptable safety in patients with advanced anal carcinoma and positive PD-L1 expression. The objective response rate (ORR) was 17% among 24 patients with squamous cell carcinoma histology, and an additional 42% had stable disease. The median duration of response (DOR) was not reached.²

KEYNOTE-158 is an ongoing multicohort phase II trial exploring the efficacy and safety of the anti—PD-1 antibody in patients with advanced solid tumors (NCT02628067). The ASCC cohort enrolled patients who had progressed on or had developed an intolerance to ≥1 prior line of therapy in the unresectable and/or metastatic disease setting.¹

Patients underwent PD-L1 testing using the PD-L1 IHC 22C3 pharmDx assay, and their expression levels were defined by combined positive score (CPS). PD-L1 expression level was not a criterion of enrollment in the trial.

A total of 112 patients received 200 mg of intravenous pembrolizumab every 3 weeks for up to 35 cycles, or approximately 2 years.

The primary end point was ORR,  as assessed by central review using RECIST v1.1 criteria, and secondary end points included DOR, progression-free survival (PFS), OS, and safety.

The median age of all patients was 61 (range, 32-79). A majority of patients had an ECOG performance status of 1 (59.8%), M1 stage disease (92.9%), and positive PD-L1 expression (CPS, ≥1; 67.0%). About three-quarters of the patients in the cohort (74.1%) were being treated beyond the second line, and most had previously received radiation therapy (92.9%). Marabelle noted that human papillomavirus status was not reported for the patients in  the study.

A total of 112 patients received 200 mg of intravenous pembrolizumab every 3 weeks for up to 35 cycles, or approximately 2 years. The primary end point was ORR,  as assessed by central review using RECIST v1.1 criteria, and secondary end points included DOR, progression-free survival (PFS), OS, and safety. The median age of all patients was 61 (range, 32-79). A majority of patients had an ECOG performance status of 1 (59.8%), M1 stage disease (92.9%), and positive PD-L1 expression (CPS, ≥1; 67.0%). About three-quarters of the patients in the cohort (74.1%) were being treated beyond the second line, and most had previously received radiation therapy (92.9%). Marabelle noted that human papillomavirus status was not reported for the patients in  the study.

The ORR was 10.7% (95% CI, 5.7%-18.0%) in the overall cohort,  with  6 complete responses and 6 partial responses. Seventeen patients (15.2%) also achieved stable disease. However, 9 patients were not included in the evaluation. Among the 75 patients with positive PD-L1 expression, the ORR was 14.7% (95% CI, 7.6%24.7%); the ORR was 3.3% (95% CI, 0.1%-17.2%) in patients with negative expression (TABLE).

The median DOR was not yet reached at the time  of data cutoff (range, 6.0+  to  33.9+ months). At both 12 and 24 months, the DOR rate was 90%.

The median PFS was 2.0 months (95% CI, 2.0-2.1), and at 1 year, the PFS rate was 15%. Median OS was 11.9 months (95% CI, 9.1-14.9). At 1 and 2 years, the OS rates were 49.1% and 25.8%, respectively.

Treatment-related adverse events  (AEs)  were reported in 60.7% of patients, with grade 3/4 events occurring in 17.9%. The most frequent treatment-related AEs included fatigue (15.2%), diarrhea (11.6%), hypothyroidism (11.6%), nausea (11.6%), asthenia (8.9%), and pruritus (7.1%).

Investigators observed immune-mediated AEs and infusion reactions of any grade and grade 3/4 in 23.2% and 4.5% of patients, respectively. The most common immune-mediated AE was hypothyroidism, in 11.6% of patients, followed by hyperthyroidism, in 6.3%. Only 1 patient had a mild infusion reaction.  

“These are typical adverse events that are seen with pembrolizumab and anti—PD-1 treatments,” Marabelle commented, adding that no differences were observed in the type of incidence of the AEs.”

References

1. Marabelle A, Cassier PA, Fakih M, et al. Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): results from the multicohort, phase II KEYNOTE-158 study.J Clin Oncol. 2020;38(suppl 4; abstr 1). doi: 10.1200/JCO.2020.38.4_suppl.1.
2. Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal.Ann Oncol. 2017;28(5):1036-1041. doi: 10.1093/ annonc/mdx029.