Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies.

Abstract

4079 Background: Antitumor activity with pembro, an anti–PD-1 antibody, has been observed in patients (pts) with advanced/metastatic biliary tract cancers (BTC), who have limited treatment options. We present follow-up data from pts with advanced BTC treated with pembro in the KN158 (NCT02628067; phase 2) and KN028 (NCT02054806; phase 1) studies. Methods: Eligible pts ≥18 y in the KN158/KN028 BTC cohorts had histologically/cytologically confirmed incurable advanced BTC that progressed after/failed any number of prior standard treatment regimens, measurable disease per RECIST v1.1, ECOG PS of 0/1, and no prior immunotherapy. PD-L1–positivity (membranous PD-L1 expression in ≥1% of tumor and associated inflammatory cells or positive staining in stroma) was required for eligibility in KN028, but not KN158. Pts received pembro 200 mg Q3W (KN158) or 10 mg/kg Q2W (KN028) for up to 2 y. Radiographic imaging occurred Q9W for 12 mo (KN158) or Q8W for 6 mo (KN028) and Q12W thereafter. Primary efficacy endpoint in both studies was ORR by RECIST 1.1. Response assessed by independent central review is reported. Results: Median (range) follow-up was 7.5 (0.6–29.5) mo in the 104 pts from KN158 and 6.5 (0.6–33.1) mo in the 24 pts from KN028 with BTC. All pts in KN028 and 61 in KN158 had PD-L1–positive tumors. No pt had MSI-H tumors (not assessed in KN028). In KN158, ORR was 5.8% (6/104, all PR [including 1 pt with PD-L1–negative tumor]; 95% CI, 2.1%–12.1%) and median duration of response (DOR) was not reached (NR; range, 6.2 to 23.2+ mo). Median OS and PFS were 7.4 mo (95% CI, 5.5–9.6) and 2.0 mo (95% CI, 1.9–2.1). 12-mo OS rate was 32.7%. In KN028, ORR was 13.0% (3/23, all PR; 95% CI, 2.8%‒33.6%) and median DOR was NR (range, 21.5 to 29.4+ mo). Median OS and PFS were 6.2 mo (95% CI, 3.8‒10.3) and 1.8 mo (95% CI, 1.4‒3.7), respectively. 12-mo OS rate was 27.6%. Grade 3–5 treatment-related AEs occurred in 13.5% in KN158 (1 pt had grade 5 renal failure) and 16.7% of pts in KN028 (no grade 5). 18.3% in KN158 and 20.8% of pts in KN028 had an immune-mediated AE or infusion reaction. Conclusions: Pembro provides durable antitumor activity, regardless of PD-L1 expression, and manageable toxicity in a subset of pts with advanced BTC. Clinical trial information: NCT02054806 and NCT02628067.

Immune Therapy for Liver Cancers

“…In this same study, 34 patients with CPS < 1 received the same treatment, however, tumor control was lower: ORR was only 2.9% and median PFS was 1.9 months [93]. Of note, none of the patients across the two studies were MSI [92]. Interestingly, two cases of complete disease resolution were reported after pembrolizumab alone in second-line treatment [94].…”

“…Early studies of ICIs in BTCs, regardless of MSI status, showed the first signal of activity. Pembrolizumab monotherapy has been tested in a phase Ib study in pre-treated patients with PD-L1-positive (>1% positive cells) BTC [92]. Thirty-seven (42%) patients out of 89 screened had PD-L1-positive tumors, and 24 of them received pembrolizumab.…”

“…The ORR was 17%, including five long-lasting responses (>40 weeks). The safety profile was manageable, with low rates of immune-mediated toxicity [92]. In a phase II study in 61 patients with pre-treated BTCs with a PD-L1 combined positive score (CPS, number of PD-L1 staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of viable tumor cells, multiplied by 100) ≥1, pembrolizumab monotherapy yielded ORR of 6.6%, median PFS of 2.0 months, and a favorable toxicity profile.…”

Programmed death-ligand 1 expression and its correlation with clinicopathological parameters in gallbladder cancer

“…In patients with advanced cholangiocarcinoma or gallbladder adenocarcinoma, results from phase I KEYNOTE-028 and phase II KEYNOTE-158 research indicated that pembrolizumab, a humanized monoclonal antibody against PD-1, constitutes a possible treatment option regardless of PD-L1 expression [14]. The PD-L1 antibody (22C3) and a 1% cutoff level were used in these trials.…”

“…Existing research by Neyaz et al [11] and Lin et al [12] has reported inconsistent and contradictory results. Furthermore, although the possibility of immunotherapy has been studied, relevant information in this area is also very limited so far [13,14]. This study aimed to investigate the expression of PD-L1 and determine the potential association with prognostic impact in GBC.…”